text:
... Liver Function Liver Fast Facts: Pregnancy and Liver Function | Pregnancy and Liver Function How does pregnancy affect the liver? Pregnancy has ... liver. There are no significant changes in liver function during pregnancy, but some markers of liver function ...
... the liver is working. This is called liver function. Tests include: Albumin Alpha-1 antitrypsin ALP ALT ... M, Bowne WB, Bluth MH. Evaluation of liver function. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...
Rapid mapping of protein functional epitopes by combinatorial alanine scanning
A combinatorial alanine-scanning strategy was used to determine simultaneously the functional contributions of 19 side chains buried at the interface between human growth hormone and the extracellular domain of its receptor. A phage-displayed protein library was constructed in which the 19 side chains were preferentially allowed to vary only as the wild type or alanine. The library pool was subjected to binding selections to isolate functional clones, and DNA sequencing was used to determine the alanine/wild-type ratio at each varied position. This ratio was used to calculate the effect of each alanine substitution as a change in free energy relative to that of wild type. Only seven side chains contribute significantly to the binding interaction, and these conserved residues form a compact cluster in the human growth hormone tertiary structure. The results were in excellent agreement with free energy data previously determined by conventional alanine-scanning mutagenesis and suggest that this technology should be useful for analyzing functional epitopes in proteins. PMID:10908667
Weiss, Gregory A.; Watanabe, Colin K.; Zhong, Alan; Goddard, Audrey; Sidhu, Sachdev S.
OBJECTIVE:The ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is often greater than 2:1 in alcoholic hepatitis. The purpose of this study was to determine whether this ratio may be used to distinguish nonalcoholic steatohepatitis (NASH) from alcoholic liver disease.METHODS:Patients with NASH were matched with controls with alcoholic liver disease based on age, gender, and date of diagnosis. The
Darius Sorbi; Jessica Boynton; Keith D Lindor
Rat liver glutamine synthetase (s20,w 15.0 S; MW about 352,000) resembles ovine brain glutamine synthetase in that it (a) has 8 subunits, (b) acts on both L- and D-glutamate and certain glutamate analogs (e.g., ?-glutamate, cis-cycloglutamate, and ?-methyl-L-glutamate), and (c) is irreversibly inhibited by L-methionine-S-sulfoximine. The liver enzyme (but not the brain enzyme) is (a) markedly activated by ?-ketoglutarate and less so by citrate, and (b) inhibited noncumulatively by glycine and alanine, in the presence of Mn++ but not Mg++; inhibition increases with increasing concentrations of glutamate. These regulatory phenomena seem to be correlated with metabolically related enzymes, e.g., glutamine transaminase. Both liver and brain glutamine synthetases are inhibited by carbamyl phosphate (with Mn++ but not with Mg++), which provides a means for controlling glutamine for pyrimidine biosynthesis. Addition of Mn++ to the Mg++-synthetase system, even at Mg++: Mn++ ratios of 1000, markedly inhibits synthesis by both brain and liver enzymes. This finding, and the fact that Mn++ promotes sensitivity to the negative effectors, indicates that Mn++ plays a central role in the regulation of glutamine synthetase. Properties of the glutamine synthetases that have been isolated from mammalian, plant, and bacterial cells are compared. They are similar with respect to subunit size, substrate specificity, inhibition by methionine sulfoximine, and Mn++-sensitive inhibition by glycine, alanine, and carbamyl phosphate, but differ in certain other regulatory phenomena and in subunit structure. PMID:5279520
Tate, Suresh S.; Meister, Alton
Drug-induced liver injury in hospitalized patients with notably elevated alanine aminotransferase
AIM: To identify the proportion, causes and the nature of drug-induced liver injury (DILI) in patients with notably elevated alanine aminotransferase (ALT). METHODS: All the inpatients with ALT levels above 10 times upper limit of normal range (ULN) were retrospectively identified from a computerized clinical laboratory database at our hospital covering a 12-mo period. Relevant clinical information was obtained from medical records. Alternative causes of ALT elevations were examined for each patient, including biliary abnormality, viral hepatitis, hemodynamic injury, malignancy, DILI or undetermined and other causes. All suspected DILI cases were causality assessed using the Council for International Organizations of Medical Sciences scale, and only the cases classified as highly probable, probable, or possible were diagnosed as DILI. Comments related to the diagnosis of DILI in the medical record and in the discharge letter for each case were also examined to evaluate DILI detection by the treating doctors. RESULTS: A total of 129 cases with ALT > 10 ULN were identified. Hemodynamic injury (n = 46, 35.7%), DILI (n = 25, 19.4%) and malignancy (n = 21, 16.3%) were the top three causes of liver injury. Peak ALT values were lower in DILI patients than in patients with hemodynamic injury (14.5 � 5.6 ULN vs 32.5 � 30.7 ULN, P = 0.001). Among DILI patients, one (4%) case was classified as definite, 19 (76%) cases were classified as probable and 5 (20%) as possible according to the CIOMS scale. A hepatocellular pattern was observed in 23 (92%) cases and mixed in 2 (8%). The extent of severity of liver injury was mild in 21 (84%) patients and moderate in 4 (16%). Before discharge, 10 (40%) patients were recovered and the other 15 (60%) were improved. The improved patients tended to have a higher peak ALT (808 � 348 U/L vs 623 � 118 U/L, P = 0.016) and shorter treatment duration before discharge (8 � 6 d vs 28 � 12 d, P = 0.008) compared with the recovered patients. Twenty-two drugs and 6 herbs were found associated with DILI. Antibacterials were the most common agents causing DILI in 8 (32%) cases, followed by glucocorticoids in 6 (24%) cases. Twenty-four (96%) cases received treatment of DILI with at least one adjunctive drug. Agents for treatment of DILI included anti-inflammatory drugs (e.g., glycyrrhizinate), antioxidants (e.g., glutathione, ademetionine 1,4-butanedisulfonate and tiopronin), polyene phosphatidyl choline and herbal extracts (e.g., protoporphyrin disodium and silymarin). Diagnosis of DILI was not mentioned in the discharge letter in 60% of the cases. Relative to prevalent cases and cases from wards of internal medicine, incident cases and cases from surgical wards had a higher risk of missed diagnosis in discharge letter [odds ratio (OR) 32.7, 95%CI (2.8-374.1), and OR 58.5, 95%CI (4.6-746.6), respectively]. CONCLUSION: DILI is mostly caused by use of antibacterials and glucocorticoids, and constitutes about one fifth of hospitalized patients with ALT > 10 ULN. DILI is underdiagnosed frequently. PMID:23139615
Xu, Hui-Min; Chen, Yan; Xu, Jie; Zhou, Quan
The effects of L-ascorbic acid and its stable analogue L-ascorbic acid 2-glucoside on the restoration of liver mass and recovery of liver function after 70% partial hepatectomy (PH), were compared with other natural vitamin C analogues in rats in vivo. L-Ascorbic acid (100 mg/kg/d, intraperitoneally (i.p.))- and L-ascorbic acid 2-glucoside (50 mg/kg/d, i.p.)-treated rats showed an approximately 1.3-fold increase in the ratio of liver weight (LW) to body weight (BW), when compared to saline (as control)-, L-dehydroascorbic acid (150 mg/kg/d, i.p.)- and D-isoascorbic acid (150 mg/kg/d, i.p.)-administrated rats on day 3 after PH. Accordingly, 5-bromo-2-deoxyuridine-labeling index in the regenerating liver was significantly higher in L-ascorbic acid- and L-ascorbic acid 2-glucoside-treated rats compared with saline-, L-dehydroascorbic acid and D-isoascorbic acid-treated rats on day 1. In control rats, liver-related serum alanine aminotransferase (ALT) activity was rapidly elevated on day 1, and then decreased to near pre-operative levels on day 5 following PH. L-Ascorbic acid and L-ascorbic acid 2-glucoside significantly lowered the serum ALT on day 1 after PH compared with saline-, L-dehydroascorbic acid- and D-isoascorbic acid-administered rats. These results demonstrate that L-ascorbic acid and L-ascorbic acid 2-glucoside significantly promote the regeneration of liver mass and function with full recovery after liver injury. PMID:24818255
Kimura, Mitsutoshi; Moteki, Hajime; Uchida, Masaki; Natsume, Hideshi; Ogihara, Masahiko
Rat liver glutamine synthetase (s(20,w) 15.0 S; MW about 352,000) resembles ovine brain glutamine synthetase in that it (a) has 8 subunits, (b) acts on both L- and D-glutamate and certain glutamate analogs (e.g., beta-glutamate, cis-cycloglutamate, and alpha-methyl-L-glutamate), and (c) is irreversibly inhibited by L-methionine-S-sulfoximine. The liver enzyme (but not the brain enzyme) is (a) markedly activated by alpha-ketoglutarate and less so by citrate, and (b) inhibited noncumulatively by glycine and alanine, in the presence of Mn(++) but not Mg(++); inhibition increases with increasing concentrations of glutamate. These regulatory phenomena seem to be correlated with metabolically related enzymes, e.g., glutamine transaminase. Both liver and brain glutamine synthetases are inhibited by carbamyl phosphate (with Mn(++) but not with Mg(++)), which provides a means for controlling glutamine for pyrimidine biosynthesis. Addition of Mn(++) to the Mg(++)-synthetase system, even at Mg(++): Mn(++) ratios of 1000, markedly inhibits synthesis by both brain and liver enzymes. This finding, and the fact that Mn(++) promotes sensitivity to the negative effectors, indicates that Mn(++) plays a central role in the regulation of glutamine synthetase. Properties of the glutamine synthetases that have been isolated from mammalian, plant, and bacterial cells are compared. They are similar with respect to subunit size, substrate specificity, inhibition by methionine sulfoximine, and Mn(++)-sensitive inhibition by glycine, alanine, and carbamyl phosphate, but differ in certain other regulatory phenomena and in subunit structure. PMID:5279520
Tate, S S; Meister, A
Propylthiouracyl (PTU)-related liver toxicity is likely to oc- cur in about 1% of treated patients. In case of acute or subacute hepatitis, liver failure may occur in about one third. We report two further cases of PTU-induced sub- acute hepatitis, in whom the delay between occurrence of liver damage after the initiation of treatment, the un- derestimation of its severity
M Benyounes; C Sempoux; C Daumerie; J Rahier; AP Geubel
Abnormality on Liver Function Test
Children with abnormal liver function can often be seen in outpatient clinics or inpatients wards. Most of them have respiratory disease, or gastroenteritis by virus infection, accompanying fever. Occasionally, hepatitis by the viruses causing systemic infection may occur, and screening tests are required. In patients with jaundice, the tests for differential diagnosis and appropriate treatment are important. In the case of a child with hepatitis B virus infection vertically from a hepatitis B surface antigen positive mother, the importance of the recognition of immune clearance can't be overstressed, for the decision of time to begin treatment. Early diagnosis changes the fate of a child with Wilson disease. So, screening test for the disease should not be omitted. Non-alcoholic fatty liver disease, which is mainly discovered in obese children, is a new strong candidate triggering abnormal liver function. Muscular dystrophy is a representative disease mimicking liver dysfunction. Although muscular dystrophy is a progressive disorder, and early diagnosis can't change the fate of patients, it will be better to avoid parent's blame for delayed diagnosis. PMID:24511518
A novel alanine:glyoxylate aminotransferase (AGT) mutation involved in primary hyperoxaluria type 1 (PH1) was studied in Japanese patients. Two mutations in exon 7, c.751T>A and c.752G>A, lead to a W251K amino acid substitution. Proband 1 (patient 1) was homozygous for the W251K mutation allele (DDBJ Accession No. AB292648), and AGT-specific activity in the patient's liver was very low. To reveal the cause of the low enzymatic activity, the intracellular localization of AGT (W251K) was studied using immunohistochemistry and immunoelectron microscopy. The latter analysis showed that patient 2 had only one-fifth of the normal AGT expression per catalase, suggesting impairment of AGT (W251K) dependent transport into peroxisomes. Peroxisomal transport of human AGT is believed to be dependent on the presence of the type 1 peroxisomal targeting sequence. The C-terminal tripeptide of AGT, KKL is necessary for peroxisomal targeting. In cultured cells, EGFP-AGT (W251K) localized both in the peroxisome and cytosol. These results were consistent with the data obtained from liver analysis of patient 2. The subcellular distribution of AGT (W251K) and the results from a random mutagenesis study suggest that KKL is necessary for peroxisomal targeting of human AGT, but additional signal other than KKL may be necessary. PMID:22685354
Kawai, Chikage; Minatogawa, Yohsuke; Akiyoshi, Hidetaka; Hirose, Shinichi; Suehiro, Tsunatoshi; Tone, Shigenobu
Rats were stressed by intravenous injection, tail-warming or moderate restraint for 30s, i.e. by stresses imposed by normal handling during experiment. Liver glutamate concentrations were greatly affected. The results were substantially the same in two varieties of rat (Wistar and Sprague�Dawley), in two laboratories, in experiments carried out by two sets of workers, and after all three stresses. The following detailed results refer to Wistar rats. 1. In starved rats at 20�C and 30�C and in post-absorptive rats at 20�C stress by injection raised liver glutamate concentrations from 1.54, 1.57 and 1.88?mol/g wet wt. 30s after injection to 3.4, 2.7 and 3.6?mol/g wet wt. respectively a few minutes later. In starved rats at 20�C the concentration then fell slowly to 2.3?mol/g wet wt., in starved rats at 30�C it remained steady, and in post-absorptive rats at 20�C it rose slowly to about 4.3?mol/g wet wt. The final values seemed fairly steady and corresponded to an `alert' state. 2. In starved rats at 20�C anaesthesia, with or without injection or cannulation during it, raised glutamate concentrations to the `alert' values, which were maintained for 2�3h. 3. Liver alanine concentration in post-absorptive rats initially fell from 1.5 to 0.8?mol/g, and then stayed fairly constant. 4. Aspartate and glutamine concentrations altered only in starved rats, and proportionately much less than those of glutamate. 5. The necessity for knowing the time-dependence of glutamate concentrations after experimental handling is emphasized. 6. There is no wholly satisfactory explanation of the observations. PMID:5145894
Heath, D. F.; George, D. R.; Rose, J. G.
Background There are no known studies that have examined ?-alanine supplementation in military personnel. Considering the physiological and potential neurological effects that have been reported during sustained military operations, it appears that ?-alanine supplementation may have a potential benefit in maintaining physical and cognitive performance during high-intensity military activity under stressful conditions. The purpose of this study was to examine the effect of 28�days of ?-alanine ingestion in military personnel while fatigued on physical and cognitive performance. Methods Twenty soldiers (20.1?�?0.9�years) from an elite combat unit were randomly assigned to either a ?-alanine (BA) or placebo (PL) group. Soldiers were involved in advanced military training, including combat skill development, navigational training, self-defense/hand-to-hand combat and conditioning. All participants performed a 4-km run, 5-countermovement jumps using a linear position transducer, 120-m sprint, a 10-shot shooting protocol with assault rifle, including overcoming a misfire, and a 2-min serial subtraction test to assess cognitive function before (Pre) and after (Post) 28�days of supplementation. Results The training routine resulted in significant increases in 4-km run time for both groups, but no between group differences were seen (p?=?0.597). Peak jump power at Post was greater for BA than PL (p?=?0.034), while mean jump power for BA at Post was 10.2% greater (p?=?0.139) than PL. BA had a significantly greater (p?=?0.012) number of shots on target at Post (8.2?�?1.0) than PL (6.5?�?2.1), and their target engagement speed at Post was also significantly faster (p?=?0.039). No difference in serial subtraction performance was seen between the groups (p?=?0.844). Conclusion Results of this study indicate that 4-weeks of ?-alanine ingestion in young, healthy soldiers did not impact cognitive performance, but did enhance power performance, marksmanship and target engagement speed from pre-ingestion levels. PMID:24716994
Alanine scan of core positions in ubiquitin reveals links between dynamics, stability, and function.
Mutations at solvent-inaccessible core positions in proteins can impact function through many biophysical mechanisms including alterations to thermodynamic stability and protein dynamics. As these properties of proteins are difficult to investigate, the impacts of core mutations on protein function are poorly understood for most systems. Here, we determined the effects of alanine mutations at all 15 core positions in ubiquitin on function in yeast. The majority (13 of 15) of alanine substitutions supported yeast growth as the sole ubiquitin. Both the two null mutants (I30A and L43A) were less stable to temperature-induced unfolding in vitro than wild type (WT) but were well folded at physiological temperatures. Heteronuclear NMR studies indicated that the L43A mutation reduces temperature stability while retaining a ground-state structure similar to WT. This structure enables L43A to bind to common ubiquitin receptors in vitro. Many of the core alanine ubiquitin mutants, including one of the null variants (I30A), exhibited an increased accumulation of high-molecular-weight species, suggesting that these mutants caused a defect in the processing of ubiquitin-substrate conjugates. In contrast, L43A exhibited a unique accumulation pattern with reduced levels of high-molecular-weight species and undetectable levels of free ubiquitin. When conjugation to other proteins was blocked, L43A ubiquitin accumulated as free ubiquitin in yeast. Based on these findings, we speculate that ubiquitin's stability to unfolding may be required for efficient recycling during proteasome-mediated substrate degradation. PMID:24361330
Lee, Shirley Y; Pullen, Lester; Virgil, Daniel J; Casta�eda, Carlos A; Abeykoon, Dulith; Bolon, Daniel N A; Fushman, David
Background Oxygen-base (O-base) oxidation in protein backbone is important in the protein backbone fragmentation due to the attack from reactive oxygen species (ROS). In this study, an alanine peptide was used model system to investigate this O-base oxidation by employing density functional theory (DFT) calculations combining with continuum solvent model. Detailed reaction steps were analyzed along with their reaction rate constants. Results Most of the O-base oxidation reactions for this alanine peptide are exothermic except for the bond-breakage of the C?-N bond to form hydroperoxy alanine radical. Among the reactions investigated in this study, the activated energy of OH ?-H abstraction is the lowest one, while the generation of alkylperoxy peptide radical must overcome the highest energy barrier. The aqueous situation facilitates the oxidation reactions to generate hydroxyl alanine peptide derivatives except for the fragmentations of alkoxyl alanine peptide radical. The C?-C? bond of the alkoxyl alanine peptide radical is more labile than the peptide bond. Conclusion the rate-determining step of oxidation in protein backbone is the generation of hydroperoxy peptide radical via the reaction of alkylperoxy peptide radical with HO2. The stabilities of alkylperoxy peptide radical and complex of alkylperoxy peptide radical with HO2 are crucial in this O-base oxidation reaction. PMID:22524792
Background��Human obesity is associated with increased serum phenylalanine concentration, which is probably caused by liver dysfunction\\u000a related to liver steatosis. This study examines whether improvements of liver function after bariatric surgery is associated\\u000a with a decrease of serum phenylalanine concentration caused by an increase of phenylalanine metabolism.\\u000a \\u000a \\u000a \\u000a Method��Serum phenylalanine and alanine aminotransferase (an independent predictor of liver steatosis) concentrations as
Julian Swierczynski; Tomasz Sledzinski; Ewa Slominska; Ryszard Smolenski; Zbigniew Sledzinski
beta-Alanine synthase (EC 188.8.131.52), which catalyzes the final step of pyrimidine catabolism, has only been characterized in mammals. A Saccharomyces kluyveri pyd3 mutant that is unable to grow on N-carbamyl-beta-alanine as the sole nitrogen source and exhibits diminished beta-alanine synthase activity was used to clone analogous genes from different eukaryotes. Putative PYD3 sequences from the yeast S. kluyveri, the slime mold Dictyostelium discoideum, and the fruit fly Drosophila melanogaster complemented the pyd3 defect. When the S. kluyveri PYD3 gene was expressed in S. cerevisiae, which has no pyrimidine catabolic pathway, it enabled growth on N-carbamyl-beta-alanine as the sole nitrogen source. The D. discoideum and D. melanogaster PYD3 gene products are similar to mammalian beta-alanine synthases. In contrast, the S. kluyveri protein is quite different from these and more similar to bacterial N-carbamyl amidohydrolases. All three beta-alanine synthases are to some degree related to various aspartate transcarbamylases, which catalyze the second step of the de novo pyrimidine biosynthetic pathway. PYD3 expression in yeast seems to be inducible by dihydrouracil and N-carbamyl-beta-alanine, but not by uracil. This work establishes S. kluyveri as a model organism for studying pyrimidine degradation and beta-alanine production in eukaryotes. PMID:11454750
Gojkovic, Z; Sandrini, M P; Piskur, J
Metabolism of 7-ethyoxycoumarin by Isolated Perfused Rainbow Trout Livers
Isolated trout livers were perfused using methods designed to preserve tissue viability and function. Liver performance was evaluated by measuring O2 consumption, vascular resistance, K+ leakage, glucose flux, lactate flux, alanine aminotransferase leakage, and metabolic clearanc...
National Technical Information Service (NTIS)
23 patients where liver cirrhosis was established were subjected to an epigastric sonogram, a liver-spleen scintigram, a liver-function scintigram, and to various relevant laboratory tests. The liver-spleen scintigram was evaluated for size of the liver, ...
R. Geiger
Detoxification Functions of the Liver
\\u000a The body is exposed to a variety of chemicals everyday in the form of pharmaceutical agents, household chemicals, dietary\\u000a supplements, and environmental contaminants, many of which are extremely toxic. The primary defense mechanisms against xenobiotics\\u000a in the body are the drug metabolizing enzymes (DMEs) involved in metabolism and excretion of xenobiotics [1]. Liver is the\\u000a primary organ involved in the
Udayan Apte; Partha Krishnamurthy
Increasing risk of diabetes mellitus according to liver function alterations in electronic workers
Aims/Introduction We sought to determine the association between change in fasting plasma glucose (FPG) and levels of liver enzymes, such as aspartate transaminase, alanine transaminase and gamma-glutamyltransferase, from health examinations. Materials and Methods A total of 9,393 health screen examinees with no evidence of viral hepatitis, liver diseases, abnormal liver function and diabetes in their past disease history were enrolled in the present study. All the participants underwent three health examinations. Group�1 and 4 were stationary groups of those with normal liver enzyme levels in the first and second health examinations (G1), and abnormal liver enzyme levels in the first and second health check-up (G4). Groups�2 and 3 were altered groups of those with abnormal liver enzyme levels in the first health examination, which became normal in the second health examination (G2), and from a normal liver enzymes level to an abnormal liver enzymes level (G3). Results FPG levels were elevated in male participants (P�<�0.01), and were related to old age (P�<�0.01), drinking (P�<�0.01), smoking (P�<�0.01) and so on. There was a strong relationship between FPG levels in the last health examination and altered liver function enzyme levels from the first health examination to the second check-up. In other words, group�4 had the highest level of FPG compared with the other groups (G1�<�G2�<�G3). Conclusions An association was observed between FPG levels and abnormal liver function in manufacturing workers. Abnormal liver function can be closely associated with the development of diabetes.
Lee, Kyoungho; Han, Joohee; Kim, Soo-Geun
In order to assess the functional state of the liver in 45 repair service workers of a chemical plant producing pesticides the serum concentration and electrophoretic pattern of proteins, the concentration of bilirubin and the activity of alkaline phosphatase, gamma-glutamyl- transpeptidase, alanine and aspartate aminotransferase, and lactic and malic dehydrogenase were determined. As compared to 35 healthy controls, not exposed to noxious chemicals, a significantly lower serum protein concentration with higher percentage of gamma-globulins and lower albumins and alpha 2-globulins were observed, the serum alanine and aspartate aminotransferase activities were significantly elevated. Ultrasound examination of the hepatic structure revealed liver steatosis in 11 (24.4%) workers. The results of our study point to a discrete lesion of the liver. PMID:1284252
Kossmann, S; Magner-Krezel, Z
We investigated the antiischemic properties of a new compound, S-15176, in an experimental model of rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of S-15176 (1.25, 2.5, 5 and 10 mg\\/kg\\/day by intramuscular injection) or solvent alone, and subjected to the ischemia-reperfusion process. Another group served as the
Aziz Elimadi; Rosa Sapena; Abdellatif Settaf; Herve Le Louet; Jean-Paul Tillement; Didier Morin
Isolated trout livers were perfused using methods designed to preserve tissue viability and function. Liver performance was evaluated by measuring O2 consumption (VO2), vascular resistance, K+ leakage, glucose flux, lactate flux, alanine aminotransferase (ALT) leakage, and meta...
Moesin functionality in hypothermic liver preservation injury.
The objective of this study was to determine how expression and functionality of the cytoskeletal linker protein moesin is involved in hepatic hypothermic preservation injury. Mouse livers were cold stored in University of Wisconsin (UW) solution and reperfused on an isolated perfused liver (IPL) device for one hour. Human hepatocytes (HepG2) and human or murine sinusoidal endothelial cells (SECs) were cold stored and rewarmed to induce hypothermic preservation injury. The cells were transfected with: wild type moesin, an siRNA duplex specific for moesin, and the moesin mutants T558D and T558A. Tissue and cell moesin expression and its binding to actin were determined by Western blot. Liver IPL functional outcomes deteriorated proportional to the length of cold storage, which correlated with moesin disassociation from the actin cytoskeleton. Cell viability (LDH and WST-8) in the cell models progressively declined with increasing preservation time, which also correlated with moesin disassociation. Transfection of a moesin containing plasmid or an siRNA duplex specific for moesin into HepG2 cells resulted in increased and decreased moesin expression, respectively. Overexpression of moesin protected while moesin knock-down potentiated preservation injury in the HepG2 cell model. Hepatocytes expressing the T558A (inactive) and T558D (active) moesin binding mutants demonstrated significantly more and less preservation injury, respectively. Cold storage time dependently caused hepatocyte detachment from the matrix and cell death, which was prevented by the T558D active moesin mutation. In conclusion, moesin is causally involved in hypothermic liver cell preservation injury through control of its active binding molecular functionality. PMID:24836372
Tian, Tao; Lindell, Susanne L; Kowalski, Chris; Mangino, Martin J
The most significant modulators of the cyanotoxins microcystin and ?-N-methylamino-L-alanine in laboratory cyanobacterial cultures are the concentration of growth-medium combined nitrogen and nitrogen uptake rate. The lack of field studies that support these observations led us to investigate the cellular content of these cyanotoxins in cyanobacterial bloom material isolated from a freshwater impoundment and to compare these to the combined nitrogen availability. We established that these toxins typically occur in an inverse relationship in nature and that their presence is mainly dependent on the environmental combined nitrogen concentration, with cellular microcystin present at exogenous combined nitrogen concentrations of 29 ?M and higher and cellular BMAA correlating negatively with exogenous nitrogen at concentrations below 40 ?M. Furthermore, opposing nutrient and light gradients that form in dense cyanobacterial blooms may result in both microcystin and BMAA being present at a single sampling site. PMID:24878376
Scott, L L; Downing, S; Phelan, R R; Downing, T G
A Clinical Perspective on the Criteria for Liver Resection and the Use of Liver Function Tests
� The Author(s) 2009. This article is published with open access at Springerlink.com To the Editor, In a recently published survey of 100 liver centers, Breitenstein et al. [1] reported that on a global scale, (1) the average minimal remnant liver volume for resection is 25% (range = 15-40%) for normal liver parenchyma and 50% (range = 25�90%) for cirrhotic livers, (2) portal vein occlusion is employed in 89 % of the centers for purposes of augmenting liver volume before surgery, and that (3) 38 % of the centers employed liver function tests as part of their clinical routine, of which 76 % used the ICG clearance test. The interesting survey provoked a few issues that we feel obliged to address. The authors contend that ��below a certain volume, a remnant liver cannot sustain metabolic, synthetic, and detoxifying functions� � [1]�a statement that is unequivocal and uncontested. However, it should be born in mind that liver volume is not a directly proportional measure of liver function. We have demonstrated a few fundamental aspects of the volume-function relationship that support this notion: (i) Whereas liver function correlates with volume in uncompromised livers [2], there is significantly less correlation between liver volume and
Michal Heger; Wilmar Graaf; Roelof J. Bennink; Ulrich Beuers; Thomas M. Gulik; M. Heger; R. J. Bennink; U. Beuers
Combined effects of fluoride and cadmium on liver and kidney function in male rats.
It has been shown that cadmium and fluoride may both have adverse effects on liver and kidney functions, but most studies focus on a single agent. In this study, we observed the effects of cadmium and fluoride on liver and kidney functions using a rat model. Total of 24 Sprague-Dawley male rats were divided into four groups, one control group and three exposure groups that were given cadmium (50�mg/L) and fluoride (100�mg/L) alone or in combination via drinking water. At the 12th week, urine, blood, and kidney tissues were collected. Aspartate transaminase, alanine transaminase (ALT), urinary ?2-microglobulin, and albumin were determined. Contents of malondialdehyde (MDA) and superoxide dismutase (SOD) in liver and kidney homogenates were measured to evaluate oxidative stress. There was a significant increase in serum ALT and urinary ?2-microglobulin of rats in exposure groups compared with control. Serum ALT and urinary ?2-microglobulin of rats exposed to cadmium and fluoride in combination was significantly higher than those treated with cadmium alone and fluoride alone. SOD declined significantly and MDA increased in combination group compared with control and those treated with cadmium and fluoride alone. Cadmium and fluoride co-exposure increase the liver and kidney damage compared with that exposed to cadmium or fluoride alone. PMID:24006106
Zhang, Junmin; Song, Jingjuan; Zhang, Jun; Chen, Xiao; Zhou, Meixia; Cheng, Guang; Xie, Xinyou
Liver function assessment in workers exposed to vinyl chloride
Objective: To investigate liver function in vinyl chloride workers and assess its relation with current\\/past occupational exposure\\u000a to vinyl chloride monomer (VCM). Methods: A medical examination including the execution of liver function tests (LFTs) and liver ultrasonography was executed in a\\u000a group of 757 workers with a long-standing service in the production of VCM\\/polyvinylchloride (PVC). Cumulative and maximum\\u000a VCM exposures
Marco Maroni; Anna Clara Fanetti
Objective To determine whether abnormal results for liver function tests are investigated in primary care and findings on full investigation. Design Retrospective audit and prospective clinical investigation. Setting University hospital and surrounding general practices serving around 330?000 people. Subjects Adults with abnormal results for liver function based on tests requested by their doctor between 1 January and 30 June 1995. Interventions All patients with ?-glutamyltransferase, alanine aminotransferase, or alkaline phosphatase concentrations at least twice the upper limit of the reference range were studied. A median of 15 months later (range 12-21) records of hospital attendances and further investigations were examined. Where investigations were incomplete the records from the general practice were examined, and suitable patients were invited to attend the liver clinic. Main outcome measures Investigations requested by the doctor and final diagnoses reached. Results 933 patients with abnormal liver function tests were identified; follow up data were obtained in 873 (94%). 531 patients were already under hospital review. Of the remaining 342 patients, 157 were suitable for investigation; the others had died, moved away, were elderly, or had repeat liver function tests with normal results. No further tests were requested for 91 (58%) of these patients. 66 had been partially investigated by their doctor, and in seven patients results suggesting a treatable chronic liver disease had not been followed up. On investigation, 97 (62%) had an identifiable diagnosis requiring hospital intervention or follow up, or both. Conclusions Abnormal results for liver function are often not adequately investigated, missing an important chance of identifying treatable chronic liver disease. PMID:11157530
Sherwood, Paul; Lyburn, Iain; Brown, Sandy; Ryder, Stephen
Myristoylated Alanine-Rich C Kinase Substrate (MARCKS), a substrate of protein kinase C, is a key regulatory molecule controlling mucus granule secretion by airway epithelial cells as well as directed migration of leukocytes, stem cells and fibroblasts. Phosphorylation of MARKCS may be involved in these responses. However, the functionality of MARCKS and its related phosphorylation in lung cancer malignancy have not been characterized. This study demonstrated elevated levels of MARCKS and phospho-MARCKS in highly invasive lung cancer cell lines and lung cancer specimens from non-small-cell lung cancer patients. siRNA knockdown of MARCKS expression in these highly invasive lung cancer cell lines reduced cell migration and suppressed PI3K (phosphatidylinositol 3'-kinase)/Akt phosphorylation and Slug level. Interestingly, treatment with a peptide identical to the MARCKS N-terminus sequence (the MANS peptide) impaired cell migration in vitro and also the metastatic potential of invasive lung cancer cells in vivo. Mechanistically, MANS peptide treatment resulted in a coordination of increase of E-cadherin expression, suppression of MARCKS phosphorylation and AKT/Slug signalling pathway but not the expression of total MARCKS. These results indicate a crucial role for MARCKS, specifically its phosphorylated form, in potentiating lung cancer cell migration/metastasis and suggest a potential use of MARCKS-related peptides in the treatment of lung cancer metastasis. PMID:23955080
Chen, C-H; Thai, P; Yoneda, K; Adler, K B; Yang, P-C; Wu, R
Magnetic resonance imaging for the assessment of liver function.
??This thesis presents dynamic hepatocyte-specific contrast-enhanced magnetic resonance imaging (DHCE-MRI) as a new method for total and segmental liver function assessment. The method is based� (more)
Nilsson, Henrik
Function of GATA Factors in the Adult Mouse Liver
GATA transcription factors and their Friend of Gata (FOG) cofactors control the development of diverse tissues. GATA4 and GATA6 are essential for the expansion of the embryonic liver bud, but their expression patterns and functions in the adult liver are unclear. We characterized the expression of GATA and FOG factors in whole mouse liver and purified hepatocytes. GATA4, GATA6, and FOG1 are the most prominently expressed family members in whole liver and hepatocytes. GATA4 chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) identified 4409 occupied sites, associated with genes enriched in ontologies related to liver function, including lipid and glucose metabolism. However, hepatocyte-specific excision of Gata4 had little impact on gross liver architecture and function, even under conditions of regenerative stress, and, despite the large number of GATA4 occupied genes, resulted in relatively few changes in gene expression. To address possible redundancy between GATA4 and GATA6, both factors were conditionally excised. Surprisingly, combined Gata4,6 loss did not exacerbate the phenotype resulting from Gata4 loss alone. This points to the presence of an unusually robust transcriptional network in adult hepatocytes that ensures the maintenance of liver function. PMID:24367609
Zheng, Rena; Rebolledo-Jaramillo, Boris; Zong, Yiwei; Wang, Liqing; Russo, Pierre; Hancock, Wayne; Stanger, Ben Z.; Hardison, Ross C.; Blobel, Gerd A.
Polysialic acid (PSA) is a homopolymeric glycan that plays crucial roles in the developing and adult nervous system. So far only a few PSA-binding proteins have been identified. Here, we identify myristoylated alanine-rich C kinase substrate (MARCKS) as novel PSA binding partner. Binding assays showed a direct interaction between PSA and a peptide comprising the effector domain of MARCKS (MARCKS-ED). Co-immunoprecipitation of PSA-carrying neural cell adhesion molecule (PSA-NCAM) with MARCKS and co-immunostaining of MARCKS and PSA at the cell membrane of hippocampal neurons confirm the interaction between PSA and MARCKS. Co-localization and an intimate interaction of PSA and MARCKS at the cell surface was seen by confocal microscopy and fluorescence resonance energy transfer (FRET) analysis after the addition of fluorescently labeled PSA or PSA-NCAM to live CHO cells or hippocampal neurons expressing MARCKS as a fusion protein with green fluorescent protein (GFP). Cross-linking experiments showed that extracellularly applied PSA or PSA-NCAM and intracellularly expressed MARCKS-GFP are in close contact, suggesting that PSA and MARCKS interact with each other at the plasma membrane from opposite sides. Insertion of PSA and MARCKS-ED peptide into lipid bilayers from opposite sides alters the electric properties of the bilayer confirming the notion that PSA and the effector domain of MARCKS interact at and/or within the plane of the membrane. The MARCKS-ED peptide abolished PSA-induced enhancement of neurite outgrowth from cultured hippocampal neurons indicating an important functional role for the interaction between MARCKS and PSA in the developing and adult nervous system. PMID:23329829
Theis, Thomas; Mishra, Bibhudatta; von der Ohe, Maren; Loers, Gabriele; Prondzynski, Maksymilian; Pless, Ole; Blackshear, Perry J.; Schachner, Melitta; Kleene, Ralf
Effect of Anoceptin on Detoxifying Function of the Liver
The absence of negative effects of anoceptin on the liver tissue and detoxifying function was proven experimentally in vitro and in vivo. It was proven for the fi rst time that comenic acid (anoceptin active substance) in concentrations of 10�4-10�12 does not\\u000a modulate the growth of liver explants from 10-12-day chicken embryos. The effect of anoceptin on the detoxifying function
A. V. Kipenko; V. A. Penniyaynen; E. V. Lopatina; V. A. Tsyrlin; G. I. Lobov; B. V. Krylov
Drug metabolism and liver function after methyldopa withdrawal.
1 The effects of methyldopa withdrawal on liver function and drug metabolism were investigated in ten elderly females suffering from the drug-induced orthostatic reaction and resistant hypertension. 2 There was a significant increase in serum albumin level, antipyrine metabolism and urinary excretion of D-glucaric acid 6 months after the methyldopa withdrawal. 3 The results suggest that patients treated with methyldopa might show a reduced metabolizing ability in spite of normal liver function tests. PMID:7426273
Ylikallio, A; Sotaniemi, E A
By performing regular blood transfusion and iron chelation therapy, most patients with beta thalassemia major (BTM) now survive beyond the third decade of life. Liver disease is becoming an important cause of morbidity and mortality in these patients. Chronic hepatitis and/or severe iron overload are both important causes of liver pathology. Iron chelation with desferrioxamine (DFO) reduces excessive body iron, but its efficacy is limited by poor compliance and dose related toxicity. The recent use of Deferasirox ( DFX ), an oral single dose therapy, has improved the compliance to chelation. Aims To study the long-term liver functions in BMT patients, seronegative for liver infections before versus after DFX treatment in relation to ferritin level. Methods Only BTM patients with hepatitis negative screening (checked every year) and on treatment with DFO for at least five years and with DFX for four years were enrolled. Liver function tests including serum bilirubin, alanine transferase (ALT), aspartate transferase (AST), albumin, insulin-like growth factor � I (IGF-I) and serum ferritin concentrations were followed every six months in 40 patients with BTM. Results DFX treatment (20 mg/kg/day) significantly decreased serum ferritin level in patients with BTM; this was associated with a significant decrease in serum ALT, AST, ALP and increase in IGF-I concentrations. Albumin concentrations did not change after DFX treatment. ALT and AST levels were correlated significantly with serum ferritin concentrations ( r = 0.45 and 0.33 respectively, p < 0.05). IGF-I concentrations were correlated significantly with serum ALT (r= 0.26, p = 0.05) but not with AST, ALP, bilirubin or albumin levels. The negative correlation between serum ferritin concentrations and ALT suggests that the impairment of hepatic function negatively affect IGF-I synthesis in these patients due to iron toxicity, even in the absence of hepatitis. Conclusions Some impairment of liver function can occur in hepatitis negative thalassemic patients with iron overload. The use of DFX was associated with mild but significant reduction of ALT, AST and ALP and increase in IGF-I levels. The negative correlation between IGF-I and ALT concentrations suggest that preventing hepatic dysfunction may improve the growth potential in these patients. PMID:24803998
Soliman, Ashraf; Yassin, Mohamed; Al Yafei, Fawzia; Al-Naimi, Lolwa; Almarri, Noora; Sabt, Aml; De Sanctis, Vincenzo
Context: Nonalcoholic fatty liver disease is common to insulin-resistant states such as polycystic ovary syndrome (PCOS). Metformin (MET) is often used to treat PCOS but information is limited as to its effects on liver function. Objective: We sought to determine the effects of MET on serum hepatic parameters in PCOS patients. Design: This was a secondary analysis of a randomized, doubled-blind trial from 2002�2004. Setting: This multi-center clinical trial was conducted in academic centers. Patients: Six hundred twenty-six infertile women with PCOS with serum liver function parameters less than twice the upper limit of normal were included. Interventions: Clomiphene citrate (n = 209), MET (n = 208), or combined (n = 209) were given for up to 6 months. Main Outcome Measure: The percent change from baseline in renal and liver function between- and within-treatment arms was assessed. Results: Renal function improved in all treatment arms with significant decreases in serum blood urea nitrogen levels (range, ?14.7 to ?21.3%) as well as creatinine (?4.2 to ?6.9%). There were similar decreases in liver transaminase levels in the clomiphene citrate and combined arms (?10% in bilirubin, ?9 to ?11% in transaminases) without significant changes in the MET arm. When categorizing baseline bilirubin, aspartate aminotransferase, and alanine aminotransferase into tertiles, there were significant within-treatment arm differences between the tertiles with the highest tertile having the largest decrease from baseline regardless of treatment arm. Conclusion: Women with PCOS can safely use metformin and clomiphene even in the setting of mildly abnormal liver function parameters, and both result in improved renal function. PMID:21832111
Aubuchon, Mira; Kunselman, Allen R.; Schlaff, William D.; Diamond, Michael P.; Coutifaris, Christos; Carson, Sandra A.; Steinkampf, Michael P.; Carr, Bruce R.; McGovern, Peter G.; Cataldo, Nicholas A.; Gosman, Gabriella G.; Nestler, John E.; Myers, Evan R.
?-alanine biosynthesis in Methanocaldococcus jannaschii.
One efficient approach to assigning function to unannotated genes is to establish the enzymes that are missing in known biosynthetic pathways. One group of such pathways is those involved in coenzyme biosynthesis. In the case of the methanogenic archaeon Methanocaldococcus jannaschii as well as most methanogens, none of the expected enzymes for the biosynthesis of the ?-alanine and pantoic acid moieties required for coenzyme A are annotated. To identify the gene(s) for ?-alanine biosynthesis, we have established the pathway for the formation of ?-alanine in this organism after experimentally eliminating other known and proposed pathways to ?-alanine from malonate semialdehyde, l-alanine, spermine, dihydrouracil, and acryloyl-coenzyme A (CoA). Our data showed that the decarboxylation of aspartate was the only source of ?-alanine in cell extracts of M. jannaschii. Unlike other prokaryotes where the enzyme producing ?-alanine from l-aspartate is a pyruvoyl-containing l-aspartate decarboxylase (PanD), the enzyme in M. jannaschii is a pyridoxal phosphate (PLP)-dependent l-aspartate decarboxylase encoded by MJ0050, the same enzyme that was found to decarboxylate tyrosine for methanofuran biosynthesis. A Km of ?0.80 mM for l-aspartate with a specific activity of 0.09 ?mol min(-1) mg(-1) at 70�C for the decarboxylation of l-aspartate was measured for the recombinant enzyme. The MJ0050 gene was also demonstrated to complement the Escherichia coli panD deletion mutant cells, in which panD encoding aspartate decarboxylase in E. coli had been knocked out, thus confirming the function of this gene in vivo. PMID:24891443
Wang, Yu; Xu, Huimin; White, Robert H
To investigate the effects of icaritin, an active ingredient extracted from Epimedium Sagittatum (Sieb. et Zucc.), on CCl4-induced liver injury and its possible mechanisms. Hepatocytes isolated from Sprague-Dawley male rats were treated with 3�mmol/L CCl4 for 24�h to induce acute liver cell injury, then icaritin (0.1, 1, 10, 100�?mol/L, respectively) was administrated to the cells, and estrogen receptor antagonist ICI182,780 (1�?mol/L) was co-treated with 10�?mol/L icaritin. Biochemical parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), and superoxide dismutase (SOD)) and cell apoptosis were detected to evaluate the injury degree. Protein expressions of Bax, Bcl-2, liver fatty acid-binding protein (L-FABP), and peroxisome proliferator-activated receptor-? (PPAR-?) as well as reactive oxygen species (ROS) generation were determined by western blot. Icaritin alleviated CCl4-induced liver cell injury in a concentration-dependent manner and 10�?mol/L was the optimal concentration. Icaritin (10�?mol/L) significantly reduced activities of ALT, AST in cell culture medium and MDA level of the impaired liver cells, but increased the intercellular SOD activity. The apoptotic rate of the impaired liver cells was also decreased by icaritin (10�?mol/L) treatment. Icaritin might exert antioxidative and anti-apoptotic functions via estrogen-like effect, as the ratio of Bcl-2/Bax was significantly increased, while protein expressions of L-FABP and PPAR-? were markedly increased, and this function was blocked by the estrogen receptor antagonist ICI182,780 efficiently. Icaritin may be a promising drug candidate for acute liver injury benefiting from the antioxidative and anti-apoptotic functions via estrogen-like effect. PMID:25148823
Liu, Peng; Jin, Xiang; Lv, Hao; Li, Jing; Xu, Wen; Qian, Hai-Hua; Yin, Zhengfeng
Erosive esophagitis associated with metabolic syndrome, impaired liver function, and dyslipidemia
AIM: To investigate whether erosive esophagitis is correlated with metabolic syndrome and its components, abnormal liver function, and lipoprotein profiles. METHODS: We conducted a cross-sectional, case control study of subjects who underwent upper endoscopy during a health examination at the Health Management and Evaluation Center of a tertiary medical care facility located in Southern Taiwan. Metabolic syndrome components, body mass index (BMI), liver function, dyslipidemia, and cardiovascular risk factors, as defined by the ratio of total cholesterol to high-density lipoprotein cholesterol (HDL-C), and the ratio of low-density lipoprotein cholesterol to HDL-C were compared between individuals with and without erosive esophagitis. Risk factors for erosive esophagitis were evaluated by multivariate logistic regression. RESULTS: Erosive esophagitis was diagnosed in 507 of 5015 subjects who were individually age and sex matched to 507 esophagitis-free control subjects. In patients with erosive esophagitis, BMI, waist circumference, blood pressure, fasting plasma glucose, triglyceride levels, aspartate aminotransferase, alanine aminotransferase, the ratio of total cholesterol to HDL-C, and the ratio of low-density lipoprotein cholesterol to HDL-C were significantly higher and HDL-C was significantly lower compared to patients without erosive esophagitis (all P < 0.05). In a multivariate analysis, central obesity (OR = 1.38; 95%CI: 1.0-1.86), hypertension (OR = 1.35; 95%CI: 1.04-1.76), hypertriglyceridemia (OR = 1.34; 95%CI: 1.02-1.76), cardiovascular risk factors as defined by a ratio of total cholesterol to HDL-C > 5 (OR = 1.45; 95%CI: 1.06-1.97), and aspartate aminotransferase (OR = 1.59; 95%CI: 1.08-2.34) were significantly associated with erosive esophagitis. CONCLUSION: Metabolic syndrome, impaired liver function, and a higher ratio of total cholesterol to HDL-C were associated with erosive esophagitis. PMID:24124334
Loke, Song-Seng; Yang, Kuender D; Chen, Kuang-Den; Chen, Jung-Fu
Evaluation of liver function tests in scleroderma patients.
Systemic sclerosis is a clinically heterogeneous, systemic disorder which affects the connective tissue of the skin, internal organs, and the walls of blood vessels. It is characterized by alterations of the microvasculature, disturbances of the immune system and by massive deposition of collagen and other matrix substances in the connective tissue. This study was done to evaluate the frequency of liver disease in patients with scleroderma and, secondarily, to study the frequency of infection of hepatitis B and C virus in these patients and determine frequency of serum auto-antibodies in this disease. We studied patients with scleroderma, localized or systemic, in the outpatient clinic of rheumatology and dermatology departments, at King Khalid University Hospital. As for a comparison, healthy persons coming to the clinic with the same mean age were considered as control group. Forty patients with the diagnosis of scleroderma included in this work, 35% had elevated gamma-glutamyl-transferase (?-GT), 30% had elevated alkaline phosphatase (AP) and in 17.5%, the alanine-amino-transferase (ALT) was above the reference values. The ALT had changed to be more in scleroderma patients than in controls. Twenty percent (20%) of the patients tested positive for anti-smooth muscle antibodies (anti-SMA) and only one patient had anti-mitochondrial antibodies (AMA). There was no statistical difference between the two groups regarding antibody testing. Anti-HCV antibodies were observed in one patient, and HBsAg was detected in another scleroderma patient. There was no patient with clinically significant hepatic disease. In this study, although changes in liver enzymes in patients with scleroderma were not uncommon, there was no scleroderma patient with clinical manifestations of liver disease. PMID:21644046
Salem, Gehan Ibrahim Abdelrazek; Abdulrahman, Awni Ali
Expression and Function of TRP Channels in Liver Cells
\\u000a The liver plays a central role in whole body homeostasis by mediating the metabolism of carbohydrates, fats, proteins, drugs\\u000a and xenobiotic compounds, and bile acid and protein secretion. Hepatocytes together with endothelial cells, Kupffer cells,\\u000a smooth muscle cells, stellate and oval cells comprise the functioning liver. Many members of the TRP family of proteins are\\u000a expressed in hepatocytes. However, knowledge
Grigori Y. Rychkov; Gregory J. Barritt
The purpose of this study was to determine the effects of beta-alanine supplementation and high-intensity interval training\\u000a (HIIT) on electromyographic fatigue threshold (EMGFT) and efficiency of electrical activity (EEA). A total of 46 men completed four, 2-min work bouts on a cycle ergometer. Using\\u000a bipolar surface electrodes, the EMG amplitude was averaged and plotted over the 2-min. The resulting slopes
Abbie E. Smith; Jordan R. Moon; Kristina L. Kendall; Jennifer L. Graef; Christopher M. Lockwood; Ashley A. Walter; Travis W. Beck; Joel T. Cramer; Jeffrey R. Stout
Asialoglycoprotein receptor-targeted radiopharmaceuticals for measurement of liver function.
The number of Asialoglycoprotein (ASGP) receptors on the hepatocytes of patients with liver disease is reduced and is thus considered a good indicator for the evaluation of liver function. ASGP receptor-targeted radiopharmaceuticals permit a non-invasive way to evaluate total and regional hepatic function and hepatic functional reserve visually and quantitatively. Over the past three decades, a variety of ASGP receptor-targeted probes have been developed with different molecular backbones (albumin, polymer, small-molecular-weight ligand), different glycol-residues (galactose, lactose, N-acetyl-galactosamine) and different chelating systems suitable for radiolabeling with SPECT isotopes ((99m)Tc, (111)In, (67)Ga, (131/125)I, (153)Sm) and PET isotopes ((68)Ga, (18)F). In this review, we present an overview of ASGP receptor-targeted radiopharmaceuticals, discuss their chemistry, biodistribution, catabolism and challenge as well as application for measurement of liver function. PMID:23992344
Yang, W; Zhang, X; Liu, Y
Objectives: Sarcopenia may negatively affect short-term outcomes after liver resection. The present study aimed to explore whether total functional liver volume (TFLV) is related to sarcopenia in patients undergoing partial liver resection. Methods: Analysis of total liver volume and tumour volume and measurements of muscle surface were performed in patients undergoing liver resection using OsiriX� and preoperative computed tomography. The ratio of TFLV to bodyweight was calculated as: [TFLV (ml)/bodyweight (g)]*100%. The L3 muscle index (cm2/m2) was then calculated by normalizing muscle areas (at the third lumbar vertebral level) for height. Results: Of 40 patients, 27 (67.5%) were classified as sarcopenic. There was a significant correlation between the L3 skeletal muscle index and TFLV (r= 0.64, P < 0.001). Median TFLV was significantly lower in the sarcopenia group than in the non-sarcopenia group [1396 ml (range: 1129�2625 ml) and 1840 ml (range: 867�2404 ml), respectively; P < 0.05]. Median TFLV : bodyweight ratio was significantly lower in the sarcopenia group than in the non-sarcopenia group [2.0% (range: 1.4�2.5%) and 2.3% (range: 1.5�2.5%), respectively; P < 0.05]. Conclusions: Sarcopenic patients had a disproportionally small preoperative TFLV compared with non-sarcopenic patients undergoing liver resection. The preoperative hepatic physiologic reserve may therefore be smaller in sarcopenic patients. PMID:23020663
Dello, Simon A. W. G.; Lodewick, Toine M.; van Dam, Ronald M.; Reisinger, Kostan W.; van den Broek, Maartje A. J.; von Meyenfeldt, Maarten F.; Bemelmans, Marc H. A.; Olde Damink, Steven W. M.; Dejong, Cornelis H. C.
Limitation of liver function tests in metastatic carcinoid tumors
To evaluate the utility of liver function tests (LFT) as indicators of metastatic carcinoid tumors, a retrospective study was performed. The LFT results of 17 patients with carcinoid tumors metastatic to the liver were compared with 17 patients with other malignant tumors. In the noncarcinoid group, 82.4% of the patients had elevated alkaline phosphatase (AP) or gamma glutamyl transpeptidase (GGTP), whereas only 28.6% of carcinoid patients had abnormal enzymes. The medians of all LFT values were significantly higher in noncarcinoid patients than in the carcinoid group, except for glutamic pyruvic transaminase (SGPT). Our data indicate that LFT are helpful in screening for liver metastases in patients with noncarcinoid tumors, but are unreliable in carcinoid tumors. Imaging tests should be used to rule out liver metastases in carcinoid tumors, irrespective of LFT results.
Moinuddin, M.; Dean, P.; Vander Zwaag, R.; Dragutsky, M.
HNP1 is a human alpha defensin that forms dimers and multimers governed by hydrophobic residues, including Tyr16, Ile20, Leu25, and Phe28. Previously, alanine scanning mutagenesis identified each of these residues and other hydrophobic residues as important for function. Here we report further structural and functional studies of residues shown to interact with one another across oligomeric interfaces: I20A-HNP1 and L25A-HNP1, plus the double alanine mutants I20A/L25A-HNP1 and Y16A/F28A-HNP1, and the quadruple alanine mutant Y16A/I20A/L25A/F28A-HNP1. We tested binding to HIV-1 gp120 and HNP1 by surface plasmon resonance, binding to HIV-1 gp41 and HNP1 by fluorescence polarization, inhibition of anthrax lethal factor, and antibacterial activity using the virtual colony count assay. Similar to the previously described single mutant W26A-HNP1, the quadruple mutant displayed the least activity in all functional assays, followed by the double mutant Y16A/F28A-HNP1. The effects of the L25A and I20A single mutations were milder than the double mutant I20A/L25A-HNP1. Crystallographic studies confirmed the correct folding and disulfide pairing, and depicted an array of dimeric and tetrameric structures. These results indicate that side chain hydrophobicity is the critical factor that determines activity at these positions. PMID:24236072
Zhan, Changyou; Wu, Xueji; Yuan, Weirong; Li, Xu; Pazgier, Marzena; Lu, Wuyuan
Two complexes of alanine with water, alanine-(H2O)n (n = 1,2), have been generated by laser ablation of the amino acid in a supersonic jet containing water vapor and characterized using Fourier transform microwave spectroscopy. In the observed complexes, water molecules bind to the carboxylic group of alanine acting as both proton donors and acceptors. In alanine-H2O, the water molecule establishes two intermolecular hydrogen bonds forming a six-membered cycle, while in alanine-(H2O)2 the two water molecules establish three hydrogen bonds forming an eight-membered ring. In both complexes, the amino acid moiety is in its neutral form and shows the conformation observed to be the most stable for the bare molecule. The microsolvation study of alanine-(H2O)n (n = 1,2) can be taken as a first step toward understanding bulk properties at a microscopic level. PMID:24617287
Vaquero, Vanesa; Sanz, M Eugenia; Pe�a, Isabel; Mata, Santiago; Cabezas, Carlos; L�pez, Juan C; Alonso, Jos� L
Mesenchymal stem cells support hepatocyte function in engineered liver grafts
Recent studies suggest that organ decellularization is a promising approach to facilitate the clinical application of regenerative therapy by providing a platform for organ engineering. This unique strategy uses native matrices to act as a reservoir for the functional cells which may show therapeutic potential when implanted into the body. Appropriate cell sources for artificial livers have been debated for some time. The desired cell type in artificial livers is primary hepatocytes, but in addition, other supportive cells may facilitate this stem cell technology. In this context, the use of mesenchymal stem cells (MSC) is an option meeting the criteria for therapeutic organ engineering. Ideally, supportive cells are required to (1) reduce the hepatic cell mass needed in an engineered liver by enhancing hepatocyte function, (2) modulate hepatic regeneration in a paracrine fashion or by direct contact, and (3) enhance the preservability of parenchymal cells during storage. Here, we describe enhanced hepatic function achieved using a strategy of sequential infusion of cells and illustrate the advantages of co-cultivating bone marrow-derived MSCs with primary hepatocytes in the engineered whole-liver scaffold. These co-recellularized liver scaffolds colonized by MSCs and hepatocytes were transplanted into live animals. After blood flow was established, we show that expression of adhesion molecules and proangiogenic factors was upregulated in the graft. PMID:24488046
Kadota, Yoshie; Yagi, Hiroshi; Inomata, Kenta; Matsubara, Kentaro; Hibi, Taizo; Abe, Yuta; Kitago, Minoru; Shinoda, Masahiro; Obara, Hideaki; Itano, Osamu; Kitagawa, Yuko
Expression and Function of Methylthioadenosine Phosphorylase in Chronic Liver Disease
To study expression and function of methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme in the methionine and adenine salvage pathway, in chronic liver disease. Design MTAP expression was analyzed by qRT-PCR, Western blot and immunohistochemical analysis. Levels of MTA were determined by liquid chromatography-tandem mass spectrometry. Results MTAP was downregulated in hepatocytes in murine fibrosis models and in patients with chronic liver disease, leading to a concomitant increase in MTA levels. In contrast, activated hepatic stellate cells (HSCs) showed strong MTAP expression in cirrhotic livers. However, also MTA levels in activated HSCs were significantly higher than in hepatocytes, and there was a significant correlation between MTA levels and collagen expression in diseased human liver tissue indicating that activated HSCs significantly contribute to elevated MTA in diseased livers. MTAP suppression by siRNA resulted in increased MTA levels, NF?B activation and apoptosis resistance, while overexpression of MTAP caused the opposite effects in HSCs. The anti-apoptotic effect of low MTAP expression and high MTA levels, respectively, was mediated by induced expression of survivin, while inhibition of survivin abolished the anti-apoptotic effect of MTA on HSCs. Treatment with a DNA demethylating agent induced MTAP and reduced survivin expression, while oxidative stress reduced MTAP levels but enhanced survivin expression in HSCs. Conclusion MTAP mediated regulation of MTA links polyamine metabolism with NF?B activation and apoptosis in HSCs. MTAP and MTAP modulating mechanisms appear as promising prognostic markers and therapeutic targets for hepatic fibrosis. PMID:24324622
Czech, Barbara; Dettmer, Katja; Valletta, Daniela; Saugspier, Michael; Koch, Andreas; Stevens, Axel P.; Thasler, Wolfgang E.; Muller, Martina; Oefner, Peter J.; Bosserhoff, Anja-Katrin; Hellerbrand, Claus
Effect of ulinastatin on liver function of patients after bilateral total knee arthroplasty.
Objective To investigate the effect of ulinastatin,a urinary trypsin inhibitor,on the postoperative liver function in patients who have received bilateral total knee arthroplasty(TKA)under pneumatic tourniquet. Methods Totally 40 patients who were scheduled to receive bilateral TKA under thigh tourniquet were randomly assigned into trial group(U group,receiving intravenous ulinastatin)and control group(C group,receiving natural saline). All patients received the same general anesthesia and postoperative analgesia. The plasma concentrations of alanine transaminase(ALT),total bilirubin(TBil),and direct bilirubin(DBil)were recorded and compared preoperatively and 4,24,48,and 72 hours after the surgery. Results The demographic data were not significantly different between these two groups(P>0.05). The ALT was not significantly changed after the surgery in the C group(P>0.05)but was significantly decreased 48 hours(P=0.002)and 72 hours(P=0.001)after the surgery in the U group. TBil and DBil were significantly increased 48 hours(P=0.012,P=0.000)and 72 hours(P=0.000,P=0.000)after the surgery in C group,while only that at 48 hours(P=0.010,P=0.038)was significantly increased in the U group. ALT 4 hours(P=0.026),48 hours(P=0.013),72 hours(P=0.004)after the surgery were significantly lower in the U group than those in C group. TBil at the 72 hours postoperatively in U group was significantly lower than that in C group(P=0.036). DBil was not significantly different between C group and U group at all time points(all P>0.05). Conclusion The application of ulinastatin in bilateral TKA can protect postoperative liver function. PMID:25360652
Tang, Shuai; Xu, Zhong-Huang; Liu, Shuo; Yang, Hong; Ren, Li-Ying; Qian, Wen-Wei; Huang, Yu-Guang
Bilirubin binding with liver cystatin induced structural and functional changes.
Cysteine proteinases and their inhibitors play a significant role in the proteolytic environment of the cells. Inhibitors of cysteine proteinases regulate the activity of these enzymes helping in checking the degdration activity of cathepsins. The bilirubin secreated by liver cells can bind to cystatin present in the liver resulting in its functional inactivation, which may further lead to the increase in cathepsins level causing liver cirrhosis. In case of some pathophysiological conditions excess bilirubin gets accumulated e.g. in presence of Fasciola hepatica (liver fluke) in mammals and humans, leading to liver cirrhosis and possibly jaundice or normal blockade of bile duct causing increased level of bilirubin in blood. Protease-cystatin imbalance causes disease progression. In the present study, Bilirubin (BR) and liver cystatin interaction was studied to explore the cystatin inactivation and structural alteration. The binding interaction was studied by UV-absorption, FT-IR and fluorescence spectroscopy. The quenching of protein fluorescence confirmed the binding of BR with buffalo liver cystatin (BLC). Stern-Volmer analysis of BR-BLC system indicates the presence of static component in the quenching mechanism and the number of binding sites to be close to 1. The fluorescence data proved that the fluorescence quenching of liver cystatin by BR was the result of BR-cystatin complex formation. FTIR analysis of BR-Cystatin complex revealed change in the secondary structure due to perturbation in the microenvironment further confirmed by the decreased caseinolytic activity of BLC against papain. Fluorescence measurements also revealed quenching of fluorescence and shift in peak at different time intervals and at varying pH values. Photo-illumination of BR-cystatin complex causes change in the surrounding environment of liver cystatin as indicated by red-shift. The binding constant for BR-BLC complex was found to be 9.279 � 10(4) M(-1). The cystatin binding with bilirubin has a significant biophysical and pathophysiological significance, hence our effort to study the same. PMID:24711081
Mustafa, Mir Faisal; Bano, Bilqees
Effect of D-amino acids on some mitochondrial functions in rat liver
Summary.��?We studied the role of the D-amino acids (D-aa) D-serine, D-alanine, D-methionine, D-aspartate, D-tyrosine and D-arginine\\u000a on rat liver mitochondria. The stability of D-amino acids, mitochondrial swelling, transmembrane potential and oxygen consumption\\u000a were studied under oxidative stress conditions in rat liver mitochondria. In the presence of glutamate-malate all D-aas salts\\u000a increased mitochondrial swelling, while in the presence of succinate plus
J. C. Gonz�lez-Hern�ndez; L. Aguilera-Aguirre; V. P�rez-V�zquez; J. Ram�rez; M. Clemente-Guerrero; C. Cort�s-Rojo; A. Saavedra-Molina
The sensitivity to denaturant stress of the major (AGT-Ma) and the minor (AGT-Mi) allele of alanine:glyoxylate aminotransferase and P11L mutant has been examined by studying their urea-induced equilibrium unfolding processes with various spectroscopic and analytical techniques. AGT-Ma loses pyridoxal 5'-phosphate (PLP) and unfolds completely without exposing significant hydrophobic clusters through a two-state model (C(m)�?�6.9�M urea). Instead, the unfolding of AGT-Mi and P11L variant proceeds in two steps. The first transition (C(m)�?�4.6�M urea) involves PLP release, dimer dissociation and exposure of hydrophobic patches leading to a self-associated intermediate which is converted to an unfolded monomer in the second step. The unfolding pathways of apoAGT-Mi and apoP11L are similar to each other, but different from that of apoAGT-Ma. Notably, the monomerization step in apoAGT-Mi and apoP11L occurs with a C(m) value (?1.6�M urea) lower than in apoAGT-Ma (?2.4�M urea). These data indicate that Pro11 is relevant for the stability of both the dimeric structure and the PLP binding site of AGT. Moreover, to understand the pathogenic consequences of G170R mutation on AGT-Mi at the protein level, G170R-Mi has been characterized. HoloG170R-Mi exhibits spectroscopic and catalytic features and urea unfolding profiles comparable to those of AGT-Mi, while the apo form monomerizes with a C(m) of ?1.1�M urea. These biochemical results are discussed in the light of the characteristics of the enzymatic phenotype of PH1 patients bearing G170R mutation in AGT-Mi and the positive response of these patients to pyridoxine treatment. PMID:20713123
Cellini, Barbara; Lorenzetto, Antonio; Montioli, Riccardo; Oppici, Elisa; Voltattorni, Carla Borri
Lipids in liver wet and dry matter, liver moist and dry matter and their relationships were investigated based on species, sex and age in cows, buffaloes, sheep and goats. Mean percentage of lipids in liver wet and dry matter and liver dry matter in cows were 3.60%, 1.10%, 29.70%, and for buffaloes were 5.30%, 1.55%, 29.20%, sheep 3.00%, 0.83%, 27.90%, and goats 2.910%, 1.55 % and 28.40%, respectively. The highest and lowest percentage of lipids in liver wet and dry matter was observed in buffaloes and sheep, and for the liver dry matter was recorded in cows and sheep, respectively. Analyses showed significant differences in liver parameters among ruminants (p liver parameters. In overall 15.00 % of buffaloes and 3.50 % of cows showed over 10.00 % lipids in liver, while none of small ruminants appeared to have over 6.00 % lipids in liver. There was no correlation between liver lipid and liver dry matter. In conclusion mean percentage of lipid in liver dry matter in small ruminants was less than large ruminants. Liver dry matter was high in cows and low in sheep. Mean differences in liver parameters was significant, while the age and sex of the
Aligholi Ramin; Shahram Nozad; Babak Jelodari; Ghazaleh Ashtab; Zohreh Eftekhari; Sina Ramin; Key Words
Additives in petroleum solvents have been reported to have adverse health implications. An evaluation study on some toxicological effects of occupational exposure to petroleum products (especially petrol which contains tetraethyl lead) amongst twenty five occupationally exposed artisans and twenty five graduate students of College of Health Sciences, Nnamdi Azikiwe University, Nnewi, Nigeria as controls, was carried out using the following biochemical markers: electrolytes, urea, uric acid, inorganic phosphorus, creatinine, zinc and blood lead, as well as the activities of alanine and aspartate aminotransferases, and alkaline phosphatase. The results showed that occupational exposure of human subjects to lead in petrol increases the concentrations of uric acid (357 +/- 123micro mol/L) and phosphate (1.5 +/- 0.5m mol/L) in exposed subjects compared with unexposed subjects (uric acid 228 +/- 105micro mol/L, phosphate 1.2 +/- 0.41m mol/L; p < 0.01 in both cases). Significantly lower activities were observed for alkaline phosphatase (66 +/- 18.9 iu/L). The activities of alanine aminotransferase (11.4 +/- 4.0 iu/L) and aspartate aminotransferase (15.8 +/- 4.4 iu/L) in occupationally exposed artisans were higher compared with unexposed subjects (alkaline phosphatase = 78 +/- 22.4 iu/L alanine aminotranferase = 6.8 +/- 2.7 iu/L, aspartate aminotranferase = 9.6 +/- 3.5i u+/-L; p < 0.01 in all cases). Occupational exposure of human subjects to lead significantly increased blood lead (59.6 +/- 15.9 microg/dL) and decreased plasma zinc (71.3 +/- 14.4 microg/L) in exposed compared with unexposed subjects (blood lead = 35 +/- 7 microg/dL, zinc = 108.4 +/- 16.9 microg/dL; p < 0.01). The results indicate that occupational exposure to lead in petrol may compromise liver and renal function. PMID:16696177
Dioka, C E; Orisakwe, O E; Adeniyi, F A A; Meludu, S C
Eosinophilia-myalgia syndrome (EMS) was an intoxication episode that occurred in the US in 1989 and affected 1,500 people. EMS was associated with the ingestion of manufactured L-tryptophan, and 3-(N-phenylamino)alanine (PAA) was identified as one of the contaminants present in the L-tryptophan batches responsible for intoxication. In previous studies (Mart�nez-Cabot et al., Chem Res. Toxicol., in press), we have shown that the incubation of 3-(N-phenylamino)propane-1,2-diol (PAP), a toxic biomarker of the oil batches that caused Toxic Oil Syndrome in Spain, with human liver microsomes generates a reactive quinoneimine intermediate. The structural similarity between PAA and PAP led Mayeno and co-workers (Mayeno et al. (1995) Chem. Res. Toxicol. 8, 911-916) to hypothesize that both xenobiotics could be linked to a common etiologic agent. We thus set about to study the bioactivation of PAA by human liver microsomes. Under these conditions, PAA is converted to its 4'-hydroxy derivative, an unstable intermediate that is rapidly transformed into the final metabolites 4-aminophenol and formylglycine, which were identified in the incubations by GC/MS using the H2(18)O-labeled medium. We also provide evidence that 4-aminophenol and formylglycine are formed from a quinoneimine intermediate via a pathway similar to that demonstrated for PAP bioactivation. This quinoneimine, in the absence of nucleophiles in the incubation medium, could isomerize to give the corresponding imine, which could undergo hydrolysis to yield the aforementioned final products. These findings establish that EMS and TOS are linked by a common toxic metabolite (4-aminophenol) and that they may be further linked by the concomitant release of potentially hazardous carbonyl species. PMID:17892268
Mart�nez-Cabot, Anna; Messeguer, Angel
The paradigm gerA operon is required for endospore germination in response to l-alanine as the sole germinant, and the three protein products, GerAA, GerAB, and GerAC are predicted to form a receptor complex in the spore inner membrane. GerAB shows homology to the amino acid-polyamine-organocation (APC) family of single-component transporters and is predicted to be an integral membrane protein with 10 membrane-spanning helices. Site-directed mutations were introduced into the gerAB gene at its natural location on the chromosome. Alterations to some charged or potential helix-breaking residues within membrane spans affected receptor function dramatically. In some cases, this is likely to reflect the complete loss of the GerA receptor complex, as judged by the absence of the germinant receptor protein GerAC, which suggests that the altered GerAB protein itself may be unstable or that the altered structure destabilizes the complex. Mutants that have a null phenotype for l-alanine germination but retain GerAC protein at near-normal levels are more likely to define amino acid residues of functional, rather than structural, importance. Single-amino-acid substitutions in each of the GerAB and GerAA proteins can prevent incorporation of GerAC protein into the spore; this provides strong evidence that the proteins within a specific receptor interact and that these interactions are required for receptor assembly. The lipoprotein nature of the GerAC receptor subunit is also important; an amino acid change in the prelipoprotein signal sequence in the gerAC1 mutant results in the absence of GerAC protein from the spore. PMID:21378181
Cooper, Gareth R.; Moir, Anne
Dissociative electron attachment to ?-alanine.
A detailed study on dissociative electron attachment (DEA) to ?-alanine (?A) in the gas phase is presented. Ion yields as a function of the incident electron energy from about 0 to 15 eV have been measured for most of the fragments. As for all ?-amino acids, the main reaction corresponds to the loss of a hydrogen atom, although many other fragments have been observed that involved more complex bond cleavages. Threshold energies have been calculated by using the G4(MP2) method for various decomposition reactions. Fragmentation pathways were also investigated to measure metastable decays of the intermediate fragment anion (?A-H)(-) by using the mass-analyzed ion kinetic energy (MIKE) scan technique. Comparisons with ?-alanine and other amino acids are made when relevant. PMID:21509925
Vizcaino, Violaine; Bartl, Peter; Gschliesser, David; Huber, Stefan E; Probst, Michael; M�rk, Tilmann D; Scheier, Paul; Denifl, Stephan
Redox Control of Liver Function in Health and Disease
Abstract Reactive oxygen species (ROS), a heterogeneous population of biologically active intermediates, are generated as by-products of the aerobic metabolism and exhibit a dual role in biology. When produced in controlled conditions and in limited quantities, ROS may function as signaling intermediates, contributing to critical cellular functions such as proliferation, differentiation, and cell survival. However, ROS overgeneration and, particularly, the formation of specific reactive species, inflicts cell death and tissue damage by targeting vital cellular components such as DNA, lipids, and proteins, thus arising as key players in disease pathogenesis. Given the predominant role of hepatocytes in biotransformation and metabolism of xenobiotics, ROS production constitutes an important burden in liver physiology and pathophysiology and hence in the progression of liver diseases. Despite the recognized role of ROS in disease pathogenesis, the efficacy of antioxidants as therapeutics has been limited. A better understanding of the mechanisms, nature, and location of ROS generation, as well as the optimization of cellular defense strategies, may pave the way for a brighter future for antioxidants and ROS scavengers in the therapy of liver diseases. Antioxid. Redox Signal. 12, 1295�1331. PMID:19803748
Mar�, Montserrat; Colell, Anna; Morales, Albert; von Montfort, Claudia; Garcia-Ruiz, Carmen
The Relationship of Liver Function Tests to Mixed Exposure to Lead and Organic Solvents
Objective This study aims to compare liver function indices (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma glutamyl transferase [GGT]) among males who work with lead, organic solvents, or both lead and organic solvents, under the permissible exposure limit (PEL). Methods A total of 593 (out of 2,218) male workers who agreed to share their personal health information for medical research were selected for this study. Those excluded were hepatitis B carriers, individuals exposed to occupational risk factors other than lead and organic solvents, and individuals without liver function results. The 593 were divided into five groups: a lead-exposed group, an organic solvent-exposed group exposed to trichloroethylene (TCE co-exposed solvent group), an organic solvent-exposed group not exposed to trichloroethylene (TCE non-exposed solvent group), a lead and organic solvent-exposed group (mixed exposure group), and a non-exposed group (control group). We performed a one way-analysis of variance (one way-ANOVA) test to compare the geometric means of liver function indices among the groups, using a general linear model (GLM) to adjust for age, work duration, body mass index (BMI), smoking, and alcohol intake. In addition, we performed a binary logistic regression analysis to compare the odds ratios among groups with an abnormal liver function index, according to a cut-off value. Results The ALT and AST of the mixed exposure group were higher than those of the other groups. The GGT of the mixed exposure group was higher than the TCE co-exposed solvent group, but there was no difference among the control group, TCE non-exposed solvent group, lead-exposed group, and mixed exposure group. The same result was evident after adjusting by GLM for age, work duration, BMI, smoking, and alcohol intake, except that ALT from the mixed exposure group showed no difference from the TCE co-exposed solvent group. When the cut-off values of the AST, ALT, and GGT were 40 IU/L, 42 IU/L, and 63 IU/L, respectively, a logistic regression analysis showed no differences in the odds ratios of those who had an abnormal liver function index among the groups. However, if the cut-off values of the AST, ALT, and GGT were 30 IU/L, 30 IU/L, and 40 IU/L, respectively, the odds ratio of the AST in the mixed exposure group was 4.39 (95% CI 1.86-10.40) times higher than the control. Conclusion This study indicates that a mixed exposure to lead and organic solvents is dangerous, even if each single exposure is safe under the permissible exposure limit. Therefore, to ensure occupational health and safety in industry, a continuous efforts to study the effects from exposure to mixed chemicals is needed. PMID:24472152
Ostensibly ineffectual doses of cadmium and lipopolysaccharide causes liver damage in rats
Various hepatotoxicants co-treated with lipopolysaccharide (LPS) have the potential to cause severe hepatic damage. Whether co-treatment with ostensibly ineffectual (without effect on customary clinical liver function tests, such as aspartate aminotransferase and alanine aminotransferase) doses of cadmium (Cd) and LPS cause liver damage is still unknown. We examined the effects of treating ostensibly ineffectual doses of Cd and LPS on
Periasamy Srinivasan; Ya-Hui Li; Dur-Zong Hsu; Shih-Bin Su; Ming-Yie Liu
Herein, we discuss the role of the native cysteines present in a major multidrug ABC transporter of Candida albicans, Cdr1p, and describe the construction of this transporter's functional cysteine-less (cysless) protein version for cross-linking studies. In the experiments in which all 23 cysteines were replaced individually, we observed that most of the cysteine replacements were tolerated by the protein, but the replacement of C1056, C1091, C1106, C1294 or C1336 resulted in an enhanced drug susceptibility together with an abrogated drug efflux. Notably, the ATPase activity was uncoupled, which largely remained unaffected in these variants. The substitution of the critical cysteines with serines restored the normal expression and functionality of Cdr1p because serine can effectively mimic the hydrogen bonding properties of cysteine. Finally, we constructed a functional cysless His-tagged Cdr1p in which all the cysteines of the native protein were replaced with alanines and the critical cysteines were replaced with serines. Notably, cysless GFP-tagged variant of Cdr1p was non-functional. The cysless His-tagged variant of Cdr1p is the first example of a cysless ABC transporter in yeast, and it will lead to a greater understanding of the architecture of this important protein and provide insight into the nature of drug binding and interdomain communication. PMID:22166216
Prasad, Rajendra; Shah, Abdul Haseeb; Sanwal, Hina; Kapoor, Khyati
While obstructive jaundice has been associated with a predisposition toward infections, the effects of bile duct ligation (BDL) on bulk intrahepatic T cells have not been clearly defined. The aim of this study was to determine the consequences of BDL on liver T cell phenotype and function. Following BDL in mice, we found that bulk liver T cells were less responsive to allogeneic or syngeneic antigen-loaded DC. Spleen T cell function was not affected and the viability of liver T cells was preserved. BDL expanded the number of CD4+CD25+FoxP3+ regulatory T cells (Treg), which were anergic to direct CD3 stimulation and mediated T cell suppression in vitro. Adoptively transferred CD4+CD25- T cells were converted into Treg within the liver following BDL. In vivo depletion of Treg following BDL restored bulk liver T cell function, but exacerbated the degrees of inflammatory cytokine production, cholestasis, and hepatic fibrosis. Thus, BDL expands liver Treg which reduce the function of bulk intrahepatic T cells yet limit liver injury. PMID:21697460
Katz, Steven C.; Ryan, Kristin; Ahmed, Naseem; Plitas, George; Chaudhry, Umer I.; Kingham, T. Peter; Naheed, Seema; Nguyen, Cang; Somasundar, Ponnandai; Espat, N. Joseph; Junghans, Richard P.; DeMatteo, Ronald P.
The effects of two vasodilators, papaverine and pentoxifylline (a methylxanthine derivative), on liver function after 19 hr hypothermic preservation were investigated. Hypothermic preservation was performed according to the standard technique, and liver hemodynamics and function were studied during 70 min immediately after reperfusion in an isolated perfused rat liver system. No significant changes occurred after hypothermic storage for 5 hr. However, when the storage was prolonged to 19 hr, bile flow and taurocholate intrinsic clearance were significantly reduced; transaminase release was markedly increased and histological studies demonstrated centrilobular necrosis. Concomitantly, liver blood flow was significantly reduced and intrahepatic vascular resistance was increased. Papaverine and pentoxifylline administered during preservation and at the time of reperfusion significantly improved all parameters. The improvement was more pronounced after pentoxifylline, and this group showed no significant difference in any of the studied parameters from the control livers. The results show that two vasodilators significantly protect the liver during long hypothermic preservation. The data suggest that abnormalities of liver microcirculation are of major importance in the pathogenesis of liver injury after hypothermic storage. PMID:2653994
Chazouill�res, O; Ballet, F; Chr�tien, Y; Marteau, P; Rey, C; Maillard, D; Poupon, R
Pheochromocytoma with Markedly Abnormal Liver Function Tests and Severe Leukocytosis
Pheochromocytoma is a rare neuroendocrine tumor arising from the medulla of the adrenal glands, which causes an overproduction of catecholamines. The common symptoms are headache, palpitations, and sweating; however, various other clinical manifestations might also be present. Accurate diagnosis of pheochromocytoma is important because surgical treatment is usually successful, and associated clinical problems are reversible if treated early. A 49-year-old man with a history of uncontrolled hypertension and diabetes mellitus presented with chest pain, fever, and sweating. His liver function tests and white blood cell counts were markedly increased and his echocardiography results suggested stress-induced cardiomyopathy. His abdominal computed tomography showed a 5�5-cm-sized tumor in the left adrenal gland, and laboratory tests confirmed catecholamine overproduction. After surgical resection of the left adrenal gland, his liver function tests and white blood cell counts normalized, and echocardiography showed normal cardiac function. Moreover, his previous antihypertensive regimen was deescalated, and his previously uncontrolled blood glucose levels normalized without medication. PMID:24741459
Eun, Chai Ryoung; Ahn, Jae Hee; Seo, Ji A
The liver is a unique organ with a remarkably high potential to regenerate upon injuries. In severely damaged livers where hepatocyte proliferation is impaired, facultative liver progenitor cells (LPCs) proliferate and are assumed to contribute to regeneration. An expansion of LPCs is often observed in patients with various types of liver diseases. However, the underlying mechanism of LPC activation still remains largely unknown. Here we show that a member of the fibroblast growth factor (FGF) family, FGF7, is a critical regulator of LPCs. Its expression was induced concomitantly with LPC response in the liver of mouse models as well as in the serum of patients with acute liver failure. Fgf7-deficient mice exhibited markedly depressed LPC expansion and higher mortality upon toxin-induced hepatic injury. Transgenic expression of FGF7 in vivo led to the induction of cells with characteristics of LPCs and ameliorated hepatic dysfunction. We revealed that Thy1(+) mesenchymal cells produced FGF7 and appeared in close proximity to LPCs, implicating a role for those cells as the functional LPC niche in the regenerating liver. These findings provide new insights into the cellular and molecular basis for LPC regulation and identify FGF7 as a potential therapeutic target for liver diseases. PMID:23322300
Takase, Hinako M; Itoh, Tohru; Ino, Seitaro; Wang, Ting; Koji, Takehiko; Akira, Shizuo; Takikawa, Yasuhiro; Miyajima, Atsushi
Crystallization of the zebrafish P2X4 receptor in both open and closed states revealed conformational differences in the ectodomain structures, including the dorsal fin and left flipper domains. Here, we focused on the role of these domains in receptor activation, responsiveness to orthosteric ATP analogue agonists, and desensitization. Alanine scanning mutagenesis of the R203-L214 (dorsal fin) and the D280-N293 (left flipper) sequences of the rat P2X4 receptor showed that ATP potency/efficacy was reduced in 15 out of 26 alanine mutants. The R203A, N204A, and N293A mutants were essentially non-functional, but receptor function was restored by ivermectin, an allosteric modulator. The I205A, T210A, L214A, P290A, G291A, and Y292A mutants exhibited significant changes in the responsiveness to orthosteric analog agonists 2-(methylthio)adenosine 5?-triphosphate, adenosine 5?-(?-thio)triphosphate, 2?(3?-O-(4-benzoylbenzoyl)adenosine 5?-triphosphate, and ?,?-methyleneadenosine 5?-triphosphate. In contrast, the responsiveness of L206A, N208A, D280A, T281A, R282A, and H286A mutants to analog agonists was comparable to that of the wild type receptor. Among these mutants, D280A, T281A, R282A, H286A, G291A, and Y292A also exhibited increased time-constant of the desensitizing current response. These experiments, together with homology modeling, indicate that residues located in the upper part of the dorsal fin and left flipper domains, relative to distance from the channel pore, contribute to the organization of the ATP binding pocket and to the initiation of signal transmission towards residues in the lower part of both domains. The R203 and N204 residues, deeply buried in the protein, may integrate the output signal from these two domains towards the gate. In addition, the left flipper residues predominantly account for the control of transition of channels from an open to a desensitized state. PMID:25398027
Tvrdonova, Vendula; Rokic, Milos B.; Stojilkovic, Stanko S.; Zemkova, Hana
Liver and kidney function tests amongst paint factory workers in Nkpor, Nigeria.
Lead, cadmium, nickel and other industrial metals used as part of paint varnishes have been reported to have adverse health implications. An evaluation study on some toxicological effects of occupational exposure to paint, among 25 occupationally exposed artisans and 25 students (control) of Ichi Technical College, Ichi Ekwusigo Local Government Area, Anambra State, Nigeria was carried out. Heavy metals were analysed by atomic absorption spectrophotometry and standard assay procedures were employed for biochemical parameters. The biochemical indices used include serum electrolytes urea, creatinine, alanine (ALT) and aspartate aminotransferases (AST), alkaline phosphatase (ALP), conjugated and total bilirubin. Others include blood lead, serum cadmium and nickel. Our results showed that occupational exposure of humans to paints increased the blood lead (39 +/- 4 microg/dL), serum cadmium (13 +/- 1 microg/dL) and nickel (63 +/- 1 microg/dL), when compared with non-paint factory workers (PFW) lead (17 +/- 4 microg/dL), serum cadmium (9 +/- microg/dL) and nickel (25 +/- 44 microg/dL), significantly at P < 0.05 lower values were observed for serum sodium (138.96 +/- 0.58 mmol/L), bicarbonate (26.88 +/- 0.39 mmol/L), urea (3.15 +/- 0.13 mmol/L) and creatinine (80.48 +/- 1.04 micromol/L) for paints factory workers when compared with non-paint factory workers, sodium (139.84 +/- 0.62 mmol/L), bicarbonate (26.20 +/- 0.22 mmol/L), urea (3.44 +/- 0.11 mmol/L) and creatinine (80.40 +/- 1.55 micromol/L); at P > 0.05. The activities of AST (10.36 +/- 0.58 micro/L), ALT(8.76 +/- 0.47 micro/L) and ALP (47.12 +/- 3.33 micro/L) in PFW were slightly elevated compared with non-PFW. Our result indicates that occupational exposure of humans to heavy metals in paints may have long term deleterious effects on liver and renal functions. In conclusion, it should be noted that occupational exposure to cadmium or lead among PFW, may compromise the liver and renal functions in man. PMID:18220158
Orisakwe, O E; Nwachukwu, E; Osadolor, H B; Afonne, O J; Okocha, C E
A portable centrifugal analyser for liver function screening.
Mortality rates of up to 50% have been reported after liver failure due to drug-induced hepatotoxicity and certain viral infections (Gao et al., 2008). These adverse conditions frequently affect HIV and tuberculosis patients on regular medication in resource-poor settings. Here, we report full integration of sample preparation with the read-out of a 5-parameter liver assay panel (LAP) on a portable, easy-to-use, fast and cost-efficient centrifugal microfluidic analysis system (CMAS). Our unique, dissolvable-film based centrifugo-pneumatic valving was employed to provide sample-to-answer fashion automation for plasma extraction (from finger-prick of blood), metering and aliquoting into separate reaction chambers for parallelized colorimetric quantification during rotation. The entire LAP completes in less than 20 min while using only a tenth the reagent volumes when compared with standard hospital laboratory tests. Accuracy of in-situ liver function screening was validated by 96 separate tests with an average coefficient of variance (CV) of 7.9% compared to benchtop and hospital lab tests. Unpaired two sample statistical t-tests were used to compare the means of CMAS and benchtop reader, on one hand; and CMAS and hospital tests on the other. The results demonstrate no statistical difference between the respective means with 94% and 92% certainty of equivalence, respectively. The portable platform thus saves significant time, labour and costs compared to established technologies, and therefore complies with typical restrictions on lab infrastructure, maintenance, operator skill and costs prevalent in many field clinics of the developing world. It has been successfully deployed to a centralised lab in Nigeria. PMID:24534553
Nwankire, Charles E; Czugala, Monika; Burger, Robert; Fraser, Kevin J; O'Connell, Tr�ona M; Glennon, Thomas; Onwuliri, Blessing E; Nduaguibe, Isikaku E; Diamond, Dermot; Ducr�e, Jens
Obesity-related metabolic abnormalities, including adipokine imbalance and chronic inflammation, are involved in liver carcinogenesis. Chemerin, a novel adipokine, plays a critical role in adipogenesis, energy metabolism, and inflammation. We evaluated the impact of serum chemerin levels on liver functional reserves in hepatocellular carcinoma (HCC) patients and on the recurrence and prognosis of HCC. This study included 44 patients with any stage of HCC who underwent curative treatment at Gifu Municipal Hospital (Gifu, Japan) between 2006 and 2007. Recurrence-free survival and overall survival were estimated using the Kaplan-Meier method. Serum albumin levels (Pearson�s correlation coefficient; r = 0.3110, p = 0.0399), platelet counts (r = 0.4159, p = 0.0050), and prothrombin times (r = 0.3775, p = 0.0115) were significantly correlated with serum chemerin levels in patients with HCC, and they were inversely correlated with Child-Pugh scores (r = ?0.3732, p = 0.0126), serum alanine aminotransferase levels (r = ?0.3864, p = 0.0105), and total bilirubin levels (r = ?0.4023, p = 0.0068). Among these variables, a multiple comparison test identified that platelet counts and total bilirubin levels were associated with serum chemerin levels (p < 0.0083). No significant correlation was found between serum chemerin levels and recurrence-free survival (p = 0.3691) or overall survival (p = 0.7916). In HCC patients, serum chemerin concentrations were correlated with liver functional reserves and platelet counts, but not with recurrence or prognosis. PMID:24968270
Imai, Kenji; Takai, Koji; Hanai, Tatsunori; Shiraki, Makoto; Suzuki, Yusuke; Hayashi, Hideki; Naiki, Takafumi; Nishigaki, Youichi; Tomita, Eiichi; Shimizu, Masahito; Moriwaki, Hisataka
# 2009 The Author(s). This article is published with open access at Springerlink.com Introduction Portal vein embolization is an accepted method to increase the future remnant liver preoperatively. The aim of this study was to assess the effect of preoperative portal vein embolization on liver volume and function 3 months after major liver resection. Materials and methods This is a retrospective case-control study. Data were collected of patients who underwent portal vein embolization prior to (extended) right hemihepatectomy and of control patients who underwent the same type of resection
Jacomina W. Van Den Esschert; Wilmar De Graaf; Krijn P. Van Lienden; Roelof J. Bennink
The aims of this study were to evaluate left ventricular (LV) systolic and diastolic function in obese adolescents with nonalcoholic fatty liver disease (NAFLD) using conventional echocardiography and pulsed-wave tissue Doppler imaging and to investigate the relations between LV function and carotid intima-media thickness (CIMT). LV remodeling, tissue Doppler-derived LV velocities, and cardiovascular risk profiles in obese adolescents with NAFLD were also studied. One hundred eighty obese adolescents and 68 healthy controls were enrolled in the study. LV end-diastolic and end-systolic and left atrial diameters and LV mass were higher in the 2 obese groups compared with controls. By pulsed-wave Doppler echocardiography and pulsed-wave tissue Doppler imaging, the NAFLD group had normal LV systolic function, impaired diastolic function, and altered global systolic and diastolic myocardial performance. In patients with NAFLD, LV mass was positively correlated with homeostasis model assessment of insulin resistance and serum alanine aminotransferase. CIMT was positively correlated with homeostasis model assessment of insulin resistance, alanine aminotransferase, and LV mass. By multiple stepwise regression analysis, alanine aminotransferase (? = 0.124, p = 0.026), homeostasis model assessment of insulin resistance (? = 0.243, p = 0.0001), LV mass (? = 0.874, p = 0.0001) were independent parameters associated with increased CIMT. In conclusion, insulin resistance has a significant independent impact on CIMT and LV remodeling in the absence of diabetes in patients with NAFLD. Pulsed-wave tissue Doppler imaging is suggested to detect LV dysfunction at an earlier stage in obese adolescents with NAFLD for careful monitoring of cardiovascular risk. PMID:23642511
Sert, Ahmet; Aypar, Ebru; Pirgon, Ozgur; Yilmaz, Hakan; Odabas, Dursun; Tolu, Ismet
Bilirubin: an autofluorescence bile biomarker for liver functionality monitoring.
Excitation at 366-465 nm of bilirubin in aqueous solution with solubilizing agents results in emission spectra composed by two main bands. The variation of their relative contributions as shown by changes in the spectral shape are consistent with the bilirubin bichromophore nature. This latter accounts for an exciton-coupling phenomenon, intramolecular interchromophore energy transfer efficiency being affected by microenvironment. Excitation at 366 nm, despite the poor absorption of bilirubin, gives rise to appreciable emission signals from both pure compounds and bile - collected from functionally altered rat livers - favouring the spectral shape response to environment and molecular conformation changes. As compared to the merely bile flow estimation, real-time detection of fluorescence, revealing composition variations, improves near-UV optical-biopsy diagnostic potential in hepatology. (� 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim). PMID:23616471
Croce, Anna C; Ferrigno, Andrea; Santin, Giada; Vairetti, Mariapia; Bottiroli, Giovanni
Lysosomal acid lipase (LAL) plays a critical role in the intracellular handling of lipids by hydrolyzing cholesteryl esters (CE) and triacylglycerols (TAG) contained in newly internalized lipoproteins. In humans, mutations in the LAL gene result in cholesteryl ester storage disease (CESD), or in Wolman disease (WD) when the mutations cause complete loss of LAL activity. A rat model for WD and a mouse model for CESD have been described. In these studies we used LAL-deficient mice to investigate how modulating the amount of intestinally-derived cholesterol reaching the liver might impact its mass, cholesterol content, and function in this model. The main experiment tested if ezetimibe, a potent cholesterol absorption inhibitor, had any effect on CE accumulation in mice lacking LAL. In male Lal(-/-) mice given ezetimibe in their diet (20 mg/day/kg bw) for 4 weeks starting at 21 days of age, both liver mass and hepatic cholesterol concentration (mg/g) were reduced to the extent that whole-liver cholesterol content (mg/organ) in the treated mice (74.3�3.4) was only 56% of that in those not given ezetimibe (133.5�6.7). There was also a marked improvement in plasma alanine aminotransferase (ALT) activity. Thus, minimizing cholesterol absorption has a favorable impact on the liver in CESD. PMID:24370824
Chuang, Jen-Chieh; Lopez, Adam M; Posey, Kenneth S; Turley, Stephen D
Effects of Synthetic Androgens on Liver Function Using the Rabbit as a Model*�
The objective of this study was to determine if the rabbit was a suitable model to test new synthetic androgens for potential liver toxicity within a short dosing interval. Adult male rabbits were dosed orally daily on days 0�13 with 17?-methyltestosterone (MT), as a positive control, and testosterone (T), as a negative control, to validate this model. Synthetic androgens tested were: 7?-methyl-19-nortestosterone (MENT), dimethandrolone-undecanoate (DMAU), and 11?-methyl-19-nortestosterone-17?-dodecylcarbonate (11?-MNTDC). Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and sorbitol dehydrogenase (SDH), as well as clearance of intravenous injected bromsulfonphthalein (BSP) from serum on days 0, 7 and 14, were determined. As expected, T (10 mg/kg/day) did not adversely affect BSP retention or serum liver enzymes. MT (10 mg/kg/day) increased BSP retention, and AST, ALT, GGT, and SDH levels indicating that this model could detect androgens known to be hepatotoxic. DMAU and MENT (10 mg/kg/day), increased BSP retention, and all 4 serum liver enzymes as well, but the effects were less than those observed with MT at the same dose. All parameters returned to baseline 2 weeks after cessation of dosing. 11?-MNTDC at 10 mg/kg/day did not have an effect on BSP retention or liver enzymes, but a slight increase in serum GGT levels was observed in rabbits treated with 25 mg/kg/day. For the androgens that exhibited liver toxicity at 10 mg/kg/day (MT, DMAU, and MENT), a no observed effect level (NOEL) of 1 mg/kg/day was established. Overall ranking of the synthetic androgens from most to least hepatotoxic based on %BSP retention was: MT ? DMAU > MENT > 11?-MNTDC. Hence, the rabbit appears to be a promising model for detection of potential liver toxicity by synthetic androgens using BSP clearance and serum liver enzyme levels as early indicators of injury. PMID:20378929
Hild, Sheri Ann; Attardi, Barbara J.; Koduri, Sailaja; Till, Bruce A.; Reel, Jerry R.
As part of a wider study on the molecular evolution of alanine:glyoxylate aminotransferase 1 (AGT1) intracellular compartmentalization, we have determined the subcellular distribution of immunoreactive AGT1, using postembedding protein A-gold immunoelectron microscopy, in the livers of various members of the classes Mammalia, Aves, and Amphibia. As far as organellar distribution is concerned, three categories could be distinguished. In members of the first category (type I), all, or nearly all, of the immunoreactive AGT1 was concentrated within the peroxisomes. In the second category (type II), AGT1 was found more evenly distributed in both peroxisomes and mitochondria. In the third category (type III), AGT1 was localized mainly within the mitochondria with much lower, but widely variable, amounts in the peroxisomes. Type I animals include the human, two great apes (gorilla, orangutan), two Old World monkeys (anubis baboon, Japanese macaque), a New World monkey (white-faced Saki monkey), a lago, morph (European rabbit), a bat (Seba's short-tailed fruit bat), two caviomorph rodents (guinea pig, orange-rumped agouti), and two Australian marsupials (koala, Bennett's wallaby). Type II animals include two New World monkeys (common marmoset, cotton-top tamarin), three prosimians (brown lemur, fat-tailed dwarf lemur, pygmy slow loris), five rodents (a hybrid crested porcupine, Colombian ground squirrel, laboratory rat, laboratory mouse, golden hamster), an American marsupial (grey short-tailed opossum), and a bird (raven). Type III animals include the large tree shrew, three insectivores (common Eurasian mole, European hedgehog, house shrew), four carnivores (domestic cat, ocelot, domestic dog, polecat ferret), and an amphibian (common frog). In addition to these categories, some animals (e.g. guinea pig, common frog) possessed significant amounts of cytosolic AGT1. Whereas the subcellular distribution of AGT1 in some orders (e.g. Insectivora and Carnivora) did not appear to vary markedly between the different members, in other orders (e.g. Primates, Rodentia and Marsupialia) it fluctuated widely between the different species. Phylogenetic analysis indicates that the subcellular distribution of AGT1 has changed radically on numerous occasions during the evolution of mammals. The new observations presented in this paper are compatible with our previous demonstration of a relationship between AGT1 subcellular distribution and either present or putative ancestral dietary habit, and our previous suggestion that the molecular evolution of the AGT gene has been markedly influenced by dietary selection pressure. PMID:7813517
Danpure, C J; Fryer, P; Jennings, P R; Allsop, J; Griffiths, S; Cunningham, A
Effect of Benzene on liver functions in rats ( Rattus norvegicus )
Rats (Rattus norvegicus) were intraperitoneally injected with a 100�mg kg???1 dosage of benzene, a toxic and carcinogenic agent widely used for industrial purposes. Changes in lactate dehydrogenase (LDH),\\u000a alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST) activities in serum of rats\\u000a were investigated at 2, 4, 8, 16, 32, and 64�h following injection. Serum physiological was administered
Egemen Dere; Ferda Ari
Advances in solid alanine radiolysis understanding
NASA Astrophysics Data System (ADS)
To better understand the composite character of irradiated alanine ESR spectra, a comparative study of few simple amino acids is performed in order to identify the different radio-induced radicals and their proportions. A dedicated spin-trapping method coupled with High Performance Liquid Chromatography (HPLC) is developed and carried out on irradiated alanine, glycine and valine; labeled or not. This study leads us to obtain different isolated trapped radical spectra where hyperfine coupling constants could be evaluated. For alanine, only two species are identified with relative proportions around 97 and 3% in contradiction with recent published articles. The main species has a particularity on its hyperfine coupling constants when labeled carbons are used. Very high hyperfine coupling constants are observed with the carboxylic acid function carbon for the three studied amino acid.
Raffi, J.; Talbi, S.; Dolo, J.-M.; Garcia, T.; Kister, J.
The influence of Enteral Nutrition in postoperative patients with poor liver function
AIM: To investigate the safety, rationality and the practicality of enteral nutritional (EN) support in the postoperative patients with damaged liver function and the protective effect of EN on the gut barrier. METHODS: 135 patients with liver function of Child B or C grade were randomly allocated to enteral nutrition group (EN, 65 cases), total parenteral nutrition group (TPN, 40
Qing-Gang Hu; Qi-Chang Zheng
The role of CUGBP1 in age-dependent changes of liver functions
Aging liver is characterized by alterations of liver biology and by a reduction of many functions which are important for the maintenance of body homeostasis. The main dysfunctions include appearance of enlarged hepatocytes, impaired liver regeneration after partial hepatectomy (PH), development of hepatic steatosis, reduction of secretion of proteins and alterations in the hepatic sinusoid. RNA binding proteins are involved in the regulation of gene expression in all tissues including regulation of biological processes in the liver. This review is focused on the role of a conserved, multi-functional RNA-binding protein, CUGBP1, in the development of aging phenotype in the liver. CUGBP1 has been identified as a protein which binds to RNA CUG repeats expanded in Myotonic Dystrophy type 1 (DM1). CUGBP1 is highly expressed in the liver and regulates translation of proteins which are critical for maintenance of liver functions. In livers of young mice, CUGBP1 forms complexes with eukaryotic translation initiation factor eIF2 and supports translation of C/EBP? and HDAC1 proteins, which are involved in liver growth, differentiation and liver cancer. Aging changes several signaling pathways which lead to the elevation of the CUGBP1-eIF2? complex and to an increase of translation of C/EBP? and HDAC1. These proteins form multi-protein complexes with additional transcription factors and with chromatin remodeling proteins causing epigenetic alterations of gene expression in livers of old mice. It appears that CUGBP1-mediated translational elevation of HDAC1 is one of the key events in the epigenetic changes in livers of old mice, leading to the development of age- associated dysfunctions of the liver. This review will also discuss a possible role of CUGBP1 in liver dysfunction in patients affected with DM1. PMID:22446383
Jones, Karlie; Timchenko, Lubov; Timchenko, Nikolai A.
The intracellular concentration of chloride ([Cl-]i) determines the strength and polarity of GABA neurotransmission. STE20/SPS1-related proline/alanine-rich kinase (SPAK) is known as an indirect regulator of [Cl-]i for its activation of Na-K-2 Cl-co-transporters (NKCC) and inhibition of K-Cl-co-transporters (KCC) in many organs. NKCC1 or KCC2 expression changes have been demonstrated previously in the hippocampal neurons of mice with pilocarpine-induced status epilepticus (PISE). However, it remains unclear whether SPAK modulates [Cl-]i via NKCC1 or KCC2 in the brain. Also, there are no data clearly characterizing SPAK expression in cortical or hippocampal neurons or confirming an association between SPAK and epilepsy. In the present study, we examined SPAK expression and co-expression with NKCC1 and KCC2 in the hippocampal neurons of mice with PISE, and we investigated alterations in SPAK expression in the hippocampus of such mice. Significant increases in SPAK mRNA and protein levels were detected during various stages of PISE in the PISE mice in comparison to levels in age-matched sham (control) and blank treatment (control) mice. SPAK and NKCC1 expression increased in vitro, while KCC2 was down-regulated in hippocampal neurons following hypoxic conditioning. However, SPAK overexpression did not influence the expression levels of NKCC1 or KCC2. Using co-immunoprecipitation, we determined that the intensity of interaction between SPAK and NKCC1 and between SPAK and KCC2 increased markedly after oxygen-deprivation, whereas SPAK overexpression strengthened the relationships. The [Cl-]i of hippocampal neurons changed in a corresponding manner under the different conditions. Our data suggests that SPAK is involved in the plasticity of GABA signaling function in acquired epilepsy via adjustment of [Cl-]i in hippocampal neurons. PMID:24058604
Zhou, Jueqian; Chen, Shuda; Chen, Yishu; Chen, Ziyi; Wang, Qian; Fang, Ziyan; Zhou, Liemin
Intrahepatic T helper (Th)17 cytokine and serum interleukin (IL)?17 levels in patients with hepatitis�B are positively correlated with the progression of liver cirrhosis (LC). IL?35 can significantly inhibit the differentiation of Th17 cells and the synthesis of IL?17. The present study aimed to investigate the function and expression of IL?17 and IL?35 in the blood of patients with hepatitis�B?related LC. The levels of IL?17 and IL?35 in the peripheral blood of 30�patients with chronic hepatitis�B (CHB), 79 with LC, 14 with chronic severe hepatitis B (CSHB), and 20 normal controls were detected by ELISA. Quantitative polymerase chain reaction was used to evaluate Epstein?Barr virus?induced gene 3 (EBI3), forkhead box (FOX)P3 and IL?17 mRNA expression levels in peripheral blood mononuclear cells (PBMCs). Western blotting was used to determine protein expression. The liver function of patients and normal controls was measured. EBI3, IL?17 and FOXP3 mRNA expression levels in PBMCs from patients with LC, CHB and CSHB were higher than those in cells from the controls. IL?17 mRNA levels differed significantly according to the Child?Pugh classification and exhibited an upward trend over time in contrast to a downward trend for EBI3 and FOXP3 mRNA. The changes in protein expression in the peripheral blood were consistent with the changes in mRNA expression. Serum IL?17 levels were positively correlated with total bilirubin (TBIL), alanine aminotransferase (ALT) and Child?Pugh grade, and were negatively correlated with albumin. These observed differences were significant. Serum IL?35 levels were negatively correlated with albumin, but not with Child?Pugh grade, ALT and TBIL. IL?17 and IL?35 may be critically involved in the pathogenesis of hepatitis�B?related LC. PMID:25323532
Shi, Min; Wei, Jue; Dong, Jinbin; Meng, Wenying; Ma, Jiali; Wang, Ting; Wang, Na; Wang, Yugang
Function of interleukin-17 and ?35 in the blood of patients with hepatitis B-related liver cirrhosis
Intrahepatic T helper (Th)17 cytokine and serum interleukin (IL)-17 levels in patients with hepatitis B are positively correlated with the progression of liver cirrhosis (LC). IL-35 can significantly inhibit the differentiation of Th17 cells and the synthesis of IL-17. The present study aimed to investigate the function and expression of IL-17 and IL-35 in the blood of patients with hepatitis B-related LC. The levels of IL-17 and IL-35 in the peripheral blood of 30 patients with chronic hepatitis B (CHB), 79 with LC, 14 with chronic severe hepatitis B (CSHB), and 20 normal controls were detected by ELISA. Quantitative polymerase chain reaction was used to evaluate Epstein-Barr virus-induced gene 3 (EBI3), forkhead box (FOX)P3 and IL-17 mRNA expression levels in peripheral blood mononuclear cells (PBMCs). Western blotting was used to determine protein expression. The liver function of patients and normal controls was measured. EBI3, IL-17 and FOXP3 mRNA expression levels in PBMCs from patients with LC, CHB and CSHB were higher than those in cells from the controls. IL-17 mRNA levels differed significantly according to the Child-Pugh classification and exhibited an upward trend over time in contrast to a downward trend for EBI3 and FOXP3 mRNA. The changes in protein expression in the peripheral blood were consistent with the changes in mRNA expression. Serum IL-17 levels were positively correlated with total bilirubin (TBIL), alanine aminotransferase (ALT) and Child-Pugh grade, and were negatively correlated with albumin. These observed differences were significant. Serum IL-35 levels were negatively correlated with albumin, but not with Child-Pugh grade, ALT and TBIL. IL-17 and IL-35 may be critically involved in the pathogenesis of hepatitis B-related LC. PMID:25323532
Thymus influences liver functions through hypothalamus-pituitary-gonad axis in rats
The aim of the review is to summarize our recent studies on the influence of the thymus on liver functions and its intermediary pathway in rats. Young adult thymectomized rats were used as a model in the experiments, and either thymic peptides or sex hormones were supplemented to these animals. Liver microsomal cytochrome P-450 and aminopyrine-N-demethylase (ADM) activities were decreased
Lin Li; Jin-huang Zhou; Shan-tian Xing
Alterations in Enzymatic Functions in Hepatocytes and Hepatocellular Carcinomas From Ras malignant and nonmalignant liver dis-adult rat hepatocytes in vivo. Hepatocytes from Ras-gal eases in acute pro- on liver sections. Ras-galtransduced hepatocytes failed myelocytic leukemia, where retinoic
Ponder, Katherine P.
Liver dysfunction in alcoholics in Western Nepal.
To estimate liver function tests in patients with alcoholic fatty liver disease, alcoholic hepatitis and alcoholic cirrhosis and to compare the levels of enzymes between the groups. A hospital based case control study was carried out at Nepalgunj Medical College, Nepal from January 2013 to June 2013. A total of 150 alcoholic associated liver disorders patients aged between 20-70 years and 50 sex age matched normal healthy controls were taken to assess liver function tests (LFTs) by measuring Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Gamma glutamyltranspeptidase (GGT) & Albumin. The mean�SD of liver function tests (LFTs) of patients of alcoholic fatty liver disease is highest followed by alcoholic hepatitis patients. All the 3 groups of alcoholic associated liver disorders patients when compared to normal healthy control subjects showed statistically significant increase in the levels of AST (p<0.000), ALT (p<0.000), ALP (p<0.006), GGT (p<0.000), & Albumin (p<0.000). Liver function tests values for alcoholic associated liver disorders patients when compared to the healthy control subjects was significantly altered. PMID:24858167
Thanpari, C; Shrewastwa, M K; Takhelmayum, R; Yadav, N K; Thapa, P; Mittal, R K
The aim of this study was to examine the accumulation of cadmium (Cd) incorporated in radish bulb and its effects on liver and kidney functions in male rats. Control animals were given diet containing ordinary radish bulb for 4, 8 and 12 weeks, while contaminated animals were given diet containing Cd-polluted radish bulb (1.1 microg Cd/g of diet) for the same periods as in controls. At each time point, rats were killed and plasma was collected, and the liver and the kidneys were removed. Results indicated that body weight gain of contaminated rats was identical to that of control rats. Cd concentration in the liver and the kidney increased significantly and gradually from the 4th to the 12th week of treatment. Plasma alanine aminotrasfase (ALT) and lactate dehydrogenase (LDH) activities increased significantly after 8 and 12 weeks of treatment, while plasma alkaline phosphatase (ALP) activity was increased significantly only after 12 weeks. Plasma urea concentration was comparable in the two groups during the experimental period, while plasma creatinine concentration increased significantly after 12 weeks of treatment. PMID:17576059
Haouem, Samir; Hmad, Najla; Najjar, Mohamed Fathel; El Hani, Abdelhamid; Sakly, Rachid
Developing a Causal Model from Liver Function Test Data
NASA Astrophysics Data System (ADS)
As Active Mining is a new concept among data mining and/or knowledge discovery in databases communities, in order to validate the effectiveness, it is important to carry out empirical studies using practical data. Based on the concept of Active User Reaction, this paper develops a causal model from liver function test data in a medical domain. To develop the model, we have set a problem to predict the values of ICG (indocyanine green) test from given observation data and experts' background knowledge. We therefore employ a framework of meta-learning and structural equation modeling. In this paper meta-learning means learning about mined results from multiple data-mining techniques. Structural equation modeling enables us to describe flexible models from background knowledge. The construction of the causal model contains two phases: meta-learning and the model building. The meta-learning phase utilizes both the linear regression and the neural network as data mining techniques, then examines the predictability on the given data set. Mining models are n-folded learned from the training data set. Each of the prediction accuracy of the mining models is compared using with the testing data. On the model building phase, we use structural equation modeling to develop a causal model based on results of meta-learning and background knowledge. We again compare the accuracy of the causal model with each of the mining models. Consequently we have developed the causal model, which is comprehensible and have good predictive performance, via the meta-learning phase. Through the empirical study, we have got the conclusion that the framework of meta-learning is effective in data mining in a difficult medical domain.
Inada, Masanori; Terano, Takao
... Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Liver Facts How the Liver Works The liver is one of the largest and most complex ... a spongy mass of wedge-shaped lobes. The liver has numerous functions that are necessary for life. ...
Evaluation of liver function using gadoxetate disodium (Gd-EOB-DTPA) enhanced MR imaging
NASA Astrophysics Data System (ADS)
Indocyanine green (ICG) is widely used for its clearance test in the evaluation of liver function. Gadoxetate disodium (Gd-EOB-DTPA) is a targeted MR contrast agent partially taken up by hepatocytes. The objective of this study was to evaluate the feasibility of an estimation of the liver function corresponding to plasma disappearance rate of indocyanine green (ICG-PDR) by use of the signal intensity of the liver alone in Gd-EOB-DTPA enhanced MR imaging (EOB-MRI). We evaluated fourteen patients who had EOB-MRI and ICG clearance test within 1 month. 2D-GRE T1 weighted images were obtained at pre contrast, 3 min (equilibrium phase) and 20 min (hepatobiliary phase) after the intravenous administration of Gd-EOB-DTPA, and the mean signal intensity of the liver was measured. The correlation between ICG-PDR and many parameters derived from the signal intensity of the liver in EOB-MRI was evaluated. The correlation coefficient between ICG-PDR and many parameters derived from the signal intensity of the liver in EOBMRI was low and not significant. The estimation of the liver function corresponding to ICG-PDR by use of the signal intensity of the liver alone in EOB-MRI would not be reliable.
Yamada, Akira; Hara, Takeshi; Li, Feng; Doi, Kunio
Pharmacological Effects of Ginseng on Liver Functions and Diseases: A Minireview
Ginseng, an ancient and famous medicinal herb in the Orient, has been used as a valuable tonic and for the treatment of various diseases including hepatic disorders. Ginseng saponins, commonly known as ginsenosides, are principal constituents and have believed to be responsible for multiple ginseng health benefits. There are more 40 ginsenosides isolated from ginseng. To date, treatment options for common liver diseases such as cirrhosis, fatty liver, and chronic hepatitis remain problematic. In this regard, ginseng extracts and individual ginsenosides have shown a wide array of beneficial role in the regulation of regular liver functions and the treatment of liver disorders of acute/chronic hepatotoxicity, hepatitis, hepatic fibrosis/cirrhosis, hepatocellular carcinoma, and so on in various pathways and mechanisms. In this paper, we first outline the pharmacological effects of ginseng and ginsenosides on the liver functions. PMID:22997528
Huu Tung, Nguyen; Uto, Takuhiro; Morinaga, Osamu; Kim, Young Ho; Shoyama, Yukihiro
To evaluate residual liver functional reserve before major hepatectomy, volumetry of the residual liver was measured by computed tomography (CT) and the uptake of l-[methyl-11C] methionine of the residual liver was expressed by differential absorption ratio (DAR) with positron emission tomography (PET). Residual liver functional volume was quantified as the functional volume index (FVI). FVI of 11 normal whole liver
Kazunori Otsuki; Takehide Asano; Shinichi Okazumi; Kazuo Enomoto; Wataru Takayama; Yasushi Shinohara; Fumihiko Miura; Kaichi Isono
Rat experiments have shown preliminary administration of phenobarbital and zixoryn (before ischemia) fails to prevent the hepatic monoxygenase system from ischemic lesion, followed by profound destructive changes in the liver, though the functional activity of the microsomal system remained high. Phenobarbital and zixoryn induction of monooxygenases in the postischemic period contributed to the complete restoration of the levels of microsomal cytochromes and the metabolic activity of xenobiotics in the liver just in its early periods. It is concluded that it is advisable to use the inductors in the postischemic restorative period to correct the detoxifying function of the liver. PMID:8312805
Grek, O R; Rybakova, T A; Sharapov, V I; Zakharova, M V; Shkurupi?, V A
[Antitoxic function of the liver and the effect of zixorin in patients with diabetes mellitus].
A study of 79 patients with insulin dependent and insulin independent types of diabetes mellitus showed a significant decrease in antitoxic liver function according to the criteria of the antipyrine test. A 10-day course with zixorin (an inductor of the oxidase enzymatic system of the hepatocytic microsomal fraction improved considerably antitoxic liver function indices in the patients with both types of diabetes mellitus. PMID:3658956
Geller, L I; Griaznova, M V
Oxidative stress and low-grade systemic inflammation may contribute to the pathogenesis of obesity-induced comorbidities, including nonalcoholic fatty liver disease. Increasing intake of dietary antioxidants might be beneficial, but there are few data in obese children. To examine the effect of antioxidant supplementation on biomarkers of oxidative stress, inflammation, and liver function, we randomly assigned overweight or obese children and adolescents (n = 44; mean � SD age: 12.7 � 1.5 y) participating in a lifestyle modification program to a 4-mo intervention with daily antioxidants (vitamin E, 400 IU; vitamin C, 500 mg; selenium, 50 ?g) or placebo. We measured anthropometrics, antioxidant status, oxidative stress (F(2)-isoprostanes, F(2)-isoprostane metabolites), inflammation, liver enzymes, fasting insulin and glucose, and lipid profile at baseline and endpoint. There was a significant treatment effect of antioxidant supplementation on antioxidant status [?-tocopherol, ? = 23.2 (95% CI: 18.0, 28.4); ascorbic acid, ? = 70.6 (95% CI: 51.7, 89.4); selenium, ? = 0.07 (95% CI: 0.01, 0.12)] and oxidative stress [8-iso-prostaglandin F2?, ? = -0.11 (95% CI: -0.19, -0.02)] but not on any of the inflammatory markers measured. There was a significant treatment effect on alanine aminotransferase [? = -0.13 (95% CI: -0.23, -0.03)], a trend toward a significant effect on aspartate aminotransferase [? = -0.04 (95% CI: -0.09, 0.01)], and no significant effect on ?-glutamyltransferase [? = -0.03 (95% CI: -0.11, 0.06)]. In summary, antioxidant supplementation for 4 mo improved antioxidant-oxidant balance and modestly improved liver function tests; however, it did not reduce markers of systemic inflammation despite significant baseline correlations between oxidative stress and inflammation. The study was registered at clinicaltrials.gov as NCT01316081. PMID:24353344
Murer, Stefanie B; Aeberli, Isabelle; Braegger, Christian P; Gittermann, Matthias; Hersberger, Martin; Leonard, Scott W; Taylor, Alan W; Traber, Maret G; Zimmermann, Michael B
Membrane fusion by human immunodeficiency virus type 1 (HIV-1) is promoted by the refolding of the viral envelope glycoprotein into a fusion-active conformation. The structure of the gp41 ectodomain core in its fusion-active state is a trimer of hairpins in which three antiparallel carboxyl-terminal helices pack into hydrophobic grooves on the surface of an amino-terminal trimeric coiled coil. In an effort to identify amino acid residues in these grooves that are critical for gp41 activation, we have used alanine-scanning mutagenesis to investigate the importance of individual side chains in determining the biophysical properties of the gp41 core and the membrane fusion activity of the gp120-gp41 complex. Alanine substitutions at Leu-556, Leu-565, Val-570, Gly-572, and Arg-579 positions severely impaired membrane fusion activity in envelope glycoproteins that were for the most part normally expressed. Whereas alanine mutations at Leu-565 and Val-570 destabilized the trimer-of-hairpins structure, mutations at Gly-572 and Arg-579 led to the formation of a stable gp41 core. Our results suggest that the Leu-565 and Val-570 residues are important determinants of conserved packing interactions between the amino- and carboxyl-terminal helices of gp41. We propose that the high degree of sequence conservation at Gly-572 and Arg-579 may result from selective pressures imposed by prefusogenic conformations of the HIV-1 envelope glycoprotein. Further analysis of the gp41 activation process may elucidate targets for antiviral intervention. PMID:11602754
Lu, Min; Stoller, Marisa O.; Wang, Shilong; Liu, Jie; Fagan, Melinda B.; Nunberg, Jack H.
[The effect of chronic internal irradiation from incorporated radionuclides on liver function].
On chronic supply to the body of a mixture of nuclear division products lanthanum-140, barium-140, tellurium-132, neodymium-147, neptunium-239, zirconium-95, niobium-95, iodine-131, cerium-141, -144, cesium-134, -137, and ruthenium-103 are detectable in liver tissue within the first months. In the 2 to 4 years following the disaster, liver tissue primarily accumulates cerium-144, radium-226, thorium-228, -232, ruthenium-106, antimony-125, and europium-154. Within the first periods the liver radionuclide content was 19 to 31% higher than that in the blood, and in the following years it was 24 to 38% higher. The radionuclides indicated were actively excreted with the bile into the gastrointestinal lumen. Within the first months after the chronic internal radiation the functional liver disorders were detectable in 30 to 40% of the patients. Later on diverse acute and chronic diseases of the liver, gallbladder and pancreas were detectable in 20 to 30% of the patients. The radionuclide content in the body was found to be in parallel with functional liver disorders. Acceleration of radionuclide excretion from the body results in liver function improvement. PMID:2084889
Dedenko, I K; Zakharash, M P; Ganich, O N; Siksa?, L T; Shnitser, R I; Sofienko, G I; Bytsa?, N N; Zemskov, V S; Trunov, V I; Bukanov, V N
Prediction of Liver Function by Using Magnetic Resonance-based Portal Venous Perfusion Imaging
Purpose: To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning. Methods and Materials: Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation between mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model. Results: There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P<.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P<.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT. Conclusions: This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which could aid in individualizing therapy, particularly for patients at risk for liver injury after RT.
Cao Yue, E-mail: firstname.lastname@example.com [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Wang Hesheng [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)] [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Johnson, Timothy D. [Department of Biostatistics, University of Michigan, Ann Arbor, Michigan (United States)] [Department of Biostatistics, University of Michigan, Ann Arbor, Michigan (United States); Pan, Charlie [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)] [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Hussain, Hero [Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States)] [Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Balter, James M.; Normolle, Daniel; Ben-Josef, Edgar; Ten Haken, Randall K.; Lawrence, Theodore S.; Feng, Mary [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)] [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)
Choline's role in maintaining liver function: new evidence for epigenetic mechanisms
Purpose of review Humans eating diets low in choline develop fatty liver and liver damage. Rodents fed choline�methionine-deficient diets not only develop fatty liver, but also progress to develop fibrosis and hepatocarcinoma. This review focuses on the role of choline in liver function, with special emphasis on the epigenetic mechanisms of action. Recent findings Dietary intake of methyl donors like choline influences the methylation of DNA and histones, thereby altering the epigenetic regulation of gene expression. The liver is the major organ within which methylation reactions occur, and many of the hepatic genes involved in pathways for the development of fatty liver, hepatic fibrosis, and hepatocarcinomas are epigenetically regulated. Summary Dietary intake of choline varies over a three-fold range and many humans have genetic polymorphisms that increase their demand for choline. Choline is an important methyl donor needed for the generation of S-adenosylmethionine. Dietary choline intake is an important modifier of epigenetic marks on DNA and histones, and thereby modulates the gene expression in many of the pathways involved in liver function and dysfunction. PMID:23493015
Mehedint, Mihai G.; Zeisel, Steven H.
Functional and DNA binding analyses were used to investigate transcriptional regulation of liver arginase, a mammalian urea cycle enzyme with marked tissue specificity. Reporter constructs containing the proximal 111 bp of the gene from man andMacaca fascicularis showed over sixfold background activity in HepG2 hepatoma cells, which express significant levels of liver arginase, and 12-fold background activity in minimally expressing
Barbara K. Goodman; Deborah Klein; David E. Tabor; Joseph G. Vockley; Stephen D. Cederbaum; Wayne W. Grody
Hepatic function testing can assist in treatment planning for liver cancer patients
Monitoring the hepatic function of unresectable liver cancer patients, measured by 99mTc-labeled iminodiacetic acid (HIDA) via single-photon emission computed tomography (SPECT) prior to and during radiation therapy, provides vital information that could guide more customized treatment plans and reduce risks of liver injury, according to University of Michigan research being presented at the 2013 Cancer Imaging and Radiation Therapy Symposium. The University of Michigan is home to the University of Michigan Comprehensive Cancer Center.
Aim: To evaluate the effect of genistein on the fibrosis and matrix degradation caused by experimentally induced fibrosis in rats. Methods: Hepatic fibrosis was brought about by chronic administration of carbon tetrachloride to rats. To evaluate the effect of genistein on liver fibrosis and function, total collagen content and proteolytic activity in the liver were quantified. Urokinase-type plasminogen activator (uPA)
Alfonso Leija Salas; Tania D�az Montezuma; German Garrido Fari�a; Jorge Reyes-Esparza; Lourdes Rodr�guez-Fragoso
NASA Astrophysics Data System (ADS)
Traumatic injury or surgery may trigger extensive bleeding. However, conventional hemostatic methods have limited efficacy and may cause surrounding tissue damage. In this study, we use self-assembling peptides (SAPs) and specifically extend fragments of functional motifs derived from fibronectin and laminin to evaluate the capability of these functionalized SAPs in the effect of hemostasis and liver tissue regeneration. From the results, these peptides can self-assemble into nanofibrous network structure and gelate into hydrogel with pH adjustment. In animal studies, the efficacy of hemostasis is achieved immediately within seconds in a rat liver model. The histological analyses by hematoxylin-eosin stain and immunohistochemistry reveal that SAPs with these functionalized motifs significantly enhance liver tissue regeneration. In brief, these SAPs may have potential as pharmacological tools to extensively advance clinical therapeutic applications in hemostasis and tissue regeneration in the field of regenerative medicine.Traumatic injury or surgery may trigger extensive bleeding. However, conventional hemostatic methods have limited efficacy and may cause surrounding tissue damage. In this study, we use self-assembling peptides (SAPs) and specifically extend fragments of functional motifs derived from fibronectin and laminin to evaluate the capability of these functionalized SAPs in the effect of hemostasis and liver tissue regeneration. From the results, these peptides can self-assemble into nanofibrous network structure and gelate into hydrogel with pH adjustment. In animal studies, the efficacy of hemostasis is achieved immediately within seconds in a rat liver model. The histological analyses by hematoxylin-eosin stain and immunohistochemistry reveal that SAPs with these functionalized motifs significantly enhance liver tissue regeneration. In brief, these SAPs may have potential as pharmacological tools to extensively advance clinical therapeutic applications in hemostasis and tissue regeneration in the field of regenerative medicine. Electronic supplementary information (ESI) available: Fig. S1. Experimental models of rat liver injury. See DOI: 10.1039/c3nr33710c
Cheng, Tzu-Yun; Wu, Hsi-Chin; Huang, Ming-Yuan; Chang, Wen-Han; Lee, Chao-Hsiung; Wang, Tzu-Wei
Eating a healthy lunch improves serum alanine aminotransferase activity
Background Nutritional guidance and diet control play important roles in the treatment of obesity and non-alcoholic fatty liver. However, in Japan, nutritional guidance is difficult to provide in practice. Therefore, we evaluated the effects of providing the �once-a-day� intervention of a healthy lunch on various metabolic parameters. Methods For a 1-month preparatory period, 10 subjects generally consumed the lunches that were provided by the worksite cafeteria. This was followed by a 1-week washout period, after which, the subjects consumed healthy, low-calorie, well-balanced lunches for a 1-month test period. After the preparatory and test periods, blood samples were obtained from all subjects. The serum levels of indices relevant to metabolic syndrome and fatty liver were measured. Results Serum alanine aminotransferase activity significantly decreased by 20.3% after the healthy intervention. However, the indices of metabolic syndrome did not significantly change. Analysis of the relationship between serum alanine aminotransferase activity and nutrient content indicated that the improvement of serum alanine aminotransferase status was due to the higher vegetable content and lower animal-source protein of the meals provided. Conclusions In summary, the �once-a-day� intervention of providing a healthy lunch improved serum alanine aminotransferase status. A diet high in vegetables and low in animal-based protein is important in maintaining a healthy condition. PMID:24034595
Objective To derive and validate a clinical prediction model to estimate the risk of liver disease diagnosis following liver function tests (LFTs) and to convert the model to a simplified scoring tool for use in primary care. Design Population-based observational cohort study of patients in Tayside Scotland identified as having their LFTs performed in primary care and followed for 2?years. Biochemistry data were linked to secondary care, prescriptions and mortality data to ascertain baseline characteristics of the derivation cohort. A separate validation cohort was obtained from 19 general practices across the rest of Scotland to externally validate the final model. Setting Primary care, Tayside, Scotland. Participants Derivation cohort: LFT results from 310?511 patients. After exclusions (including: patients under 16?years, patients having initial LFTs measured in secondary care, bilirubin >35??mol/L, liver complications within 6?weeks and history of a liver condition), the derivation cohort contained 95?977 patients with no clinically apparent liver condition. Validation cohort: after exclusions, this cohort contained 11?653 patients. Primary and secondary outcome measures Diagnosis of a liver condition within 2?years. Results From the derivation cohort (n=95?977), 481 (0.5%) were diagnosed with a liver disease. The model showed good discrimination (C-statistic=0.78). Given the low prevalence of liver disease, the negative predictive values were high. Positive predictive values were low but rose to 20�30% for high-risk patients. Conclusions This study successfully developed and validated a clinical prediction model and subsequent scoring tool, the Algorithm for Liver Function Investigations (ALFI), which can predict liver disease risk in patients with no clinically obvious liver disease who had their initial LFTs taken in primary care. ALFI can help general practitioners focus referral on a small subset of patients with higher predicted risk while continuing to address modifiable liver disease risk factors in those at lower risk. PMID:24889852
McLernon, David J; Donnan, Peter T; Sullivan, Frank M; Roderick, Paul; Rosenberg, William M; Ryder, Steve D; Dillon, John F
OBJECTIVE. The purpose of this article is to characterize the temporal evolution and clinical impact of laboratory liver function parameters after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS. In this single-institution retrospective study, 157 patients (98 men and 59 women; median age, 55 years) underwent TIPS between 2000 and 2012 and had 1-month hepatobiliary laboratory follow-up. Medical record review was used to compare baseline, peak, and low bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and international normalized ratio (INR) levels within 30 days after TIPS in surviving and dying patients to assess laboratory responses to shunt creation. RESULTS. TIPSs were created with a hemodynamic success rate of 98%, with median pressure gradient reduction of 13 mm Hg. Ninety-day mortality was 21%. Hepatobiliary laboratory values showed significant increases in the days after TIPS compared with baseline levels (bilirubin, 1.6 vs 3.5 mg/dL; AST, 49 vs 149 U/L; ALT, 26 vs 90 U/L; alkaline phosphatase, 97 vs 177 U/L; and INR, 1.5 vs 2.0; p < 0.05 in all cases). Patients surviving to 90 days experienced statistically significant but transient laboratory value elevations-up to twofold over baseline-within days of TIPS, whereas patients dying within 90 days experienced three-to fourfold increases over a longer period that did not return to baseline. Differences in laboratory evolution were statistically significant in surviving versus dying patients. CONCLUSION. TIPS results in acute transient elevation of hepatobiliary enzymes, which may be more pronounced in patients with early mortality. An exaggerated laboratory elevation in excess of threefold greater than baseline or a prolonged increase exceeding 1 week may herald poorer clinical outcome. PMID:25415716
Casadaban, Leigh C; Parvinian, Ahmad; Couture, Patrick M; Minocha, Jeet; Knuttinen, M Grace; Bui, James T; Gaba, Ron C
During chronic hepatitis C virus (HCV) infection, the role of intra-hepatic (IH) natural killer (NK) cells is still controversial. To clarify their functions, we investigated anti-viral and cytotoxic activity of NK cells in human fresh liver biopsies. We compared the functions of IH-NK cells in HCV-infected and NASH patients in physiological conditions as well as after stimulation using flow cytometric and immunohistochemical analyses. Interestingly, few IH-NK cells produced anti-viral cytokine IFN-? in HCV-infected patients similarly as in non-infected individuals. Spontaneous degranulation activity was extremely low in peripheral NK cells compared to IH-NK cells, and was significantly higher in IH-NK cells from HCV-infected patients compared to non-infected individuals. Immunohistochemical analysis revealed that perforin granules were polarized at the apical pole of IH-NK cells. The presence of CD107a and perforin in IH-NK cells demonstrated that NK cells exerted a cytolytic activity at the site of infection. Importantly, IH-NK cell functions from HCV-infected patients were inducible by specific exogenous stimulations. Upon ex vivo K562 target cell stimulations, the number of degranulating NK cells was significantly increased in the pool of IH-NK cells compared to circulating NK cells. Interestingly, after stimulation, the frequency of IFN-?-producing IH-NK cells in HCV-infected patients was significantly higher at early stage of inflammation whereas the spontaneous IH-NK cell degranulation activity was significantly impaired in patients with highest inflammation and fibrosis Metavir scores. Our study highlights that some IH-NK cells in HCV-infected patients are able to produce INF-? and degranulate and that those two activities depend on liver environment including the severity of liver injury. Thus, we conclude that critical roles of IH-NK cells have to be taken into account in the course of the liver pathogenesis associated to chronic HCV infection. PMID:24759660
Macek Jilkova, Zuzana; Van Campenhout, Nicolas; Dufeu-Duchesne, Tania; Leroy, Vincent; Zarski, Jean-Pierre; Sturm, Nathalie; Marche, Patrice N.; Jouvin-Marche, Evelyne
Aims��Relationships of renal function and liver disease are described in acute and chronic liver failure. The aim of the study is\\u000a to investigate which relationship, if any, is present between severity of non-alcoholic fatty liver disease (NAFLD), assessed\\u000a by bright liver score (BLS) versus mild-moderate renal insufficiency assessed by glomerular filtration rate (GFR) and by ultrasound\\u000a intra-renal arterial resistive index
Daniela Catalano; Guglielmo M. Trovato; Giuseppe Fabio Martines; Clara Pirri; Francesca M. Trovato
[Liver cell function test based on selective laboratory studies].
Laboratory tests have been carried out in 517 workers of a Chemical Fibres Plant. This was aimed at the detection of the changes resulting from cumulative exposure to caprolactam, dowtherm and physical factors. There have been performed hematological investigations, uninalyses and biochemical tests: total protein level, activity of enzymes: ASPAT, ALAT, PA, ChE, thymol test. The results have been analysed as the mean values for particular divisions and workstands; then they have been compared with standards. In order to evaluate the degree of occupational exposure of particular groups of workers, an index of the liver cell damage has been calculated. It was expressed in % of the results exceeding the standards in relation to all results in a given group of workers. The highest values of the index were those in the group employed at the polymerization division. The authoresses promote the advisability of special care for this group of workers. PMID:7289867
Sliwi?ska-Przyjemska, H; Pilawska, H
The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo 2H/13C tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial ?-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis. PMID:22493093
Satapati, Santhosh; Sunny, Nishanth E.; Kucejova, Blanka; Fu, Xiaorong; He, Tian Teng; Mendez-Lucas, Andres; Shelton, John M.; Perales, Jose C.; Browning, Jeffrey D.; Burgess, Shawn C.
[The function of the monooxygenase system of the liver in patients with psoriasis].
Liver monoxygenase system function has been examined in psoriasis patients and possible modifications of current methods of therapy analyzed with due consideration for the detected disorders. A total of 139 patients with various clinical forms of psoriasis have been examined. The function of the liver monoxygenase system has been examined with the use of antipyrine test. The studies have revealed that this system's disorders are most marked in the patients with psoriatic eruptions involving a significant area, in whom the disease runs a protracted severe course. Twenty patients with normal and impaired functions of the monoxygenase system have been administered combined treatment including zixorin (600 mg orally once a week). The results evidence that zixorin improves the therapy efficacy, particularly in the patients with depressed activity of the liver microsomal enzymes. PUVA therapy has been administered to some patients. Zixorin has alleviated the side effects of phototherapy. PMID:2816028
Chichenina, I V
an animal's body. Many naturally occuring chemicals, synthetic drugs, pesticides and environmental contaminants are known to be hepatotoxic or to have an affect on hepatic function. (1, 2, 3, 4, 5, 6). The list of agents known to be hepatotoxic continues... an animal's body. Many naturally occuring chemicals, synthetic drugs, pesticides and environmental contaminants are known to be hepatotoxic or to have an affect on hepatic function. (1, 2, 3, 4, 5, 6). The list of agents known to be hepatotoxic continues...
Hansson, Lucille Ann
Liver function and morphology of the mountain vole, Microtus montanus, were examined after i.p. injections of phenobarbital, beta-naphthoflavone, or Aroclor 1254 at three dose levels. The results of the liver function tests showed serum glutamic pyruvic transaminase and serum malathion carboxylesterase activities were normal in all the treatment groups. The histological results showed no necrotic tissue but did reveal two different morphological stages related to the level of monooxygenase activity; a low induction state was represented by foamy vacuolated hepatocytes while high induction states were related to enlarged, swollen, hypertrophied cells. PMID:2882929
Hincks, J R; Brindley, W A
[Changes in the liver function of workers exposed to petroleum products].
The function of the liver is examined in 120 workers (at 52 controls) in biological purification of the waters in a petrochemical plant, exposed to above the norm concentrations of strong hepatotropic chemical substances: benzene, toluene, styrene, aldehydes, ketones, mercaptans, acrylonitrile, octanole, butanol. etc. The established hyperenzymia, hyperlipaemia and significant reduction of glutathione in certain per cent of the workers (from 7 to 31% at different indices) points out an effect of the above mentioned toxic substances on the enzymic, lipidic and detoxic function of the liver. This proves the presence of certain potential risk for those working in this production and especially workers engaged in repair and technology process. PMID:2635316
Nosko, M; Mikha?lova, A
Monocyte Subsets in Human Liver Disease Show Distinct Phenotypic and Functional Characteristics
Liver fibrosis is a wound healing response to chronic liver injury and inflammation in which macrophages and infiltrating monocytes participate in both the development and resolution phase. In humans, three monocyte subsets have been identified: the classical CD14++CD16?, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes. We studied the phenotype and function of these monocyte subsets in peripheral blood and liver tissue from patients with chronic inflammatory and fibrotic liver diseases. The frequency of intrahepatic monocytes increased in disease compared with control liver tissue, and in both nondiseased and diseased livers there was a higher frequency of CD14++CD16+ cells with blood. Our data suggest two nonexclusive mechanisms of CD14++CD16+ accumulation in the inflamed liver: (1) recruitment from blood, because more than twice as many CD14++CD16+ monocytes underwent transendothelial migration through hepatic endothelial cells compared with CD14++CD16? cells; and (2) local differentiation from CD14++CD16? classical monocytes in response to transforming growth factor ? and interleukin (IL)-10. Intrahepatic CD14++CD16+ cells expressed both macrophage and dendritic cell markers but showed high levels of phagocytic activity, antigen presentation, and T cell proliferation and secreted proinflammatory (tumor necrosis factor ?, IL-6, IL-8, IL-1?) and profibrogenic cytokines (IL-13), chemokines (CCL1, CCL2, CCL3, CCL5), and growth factors (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor), consistent with a role in the wound healing response. Conclusion Intermediate CD14++CD16+ monocytes preferentially accumulate in chronically inflamed human liver as a consequence of enhanced recruitment from blood and local differentiation from classical CD14++CD16? monocytes. Their phagocytic potential and ability to secrete inflammatory and profibrogenic cytokines suggests they play an important role in hepatic fibrogenesis. PMID:22911542
Liaskou, Evaggelia; Zimmermann, Henning W.; Li, Ka-Kit; Oo, Ye H.; Suresh, Shankar; Stamataki, Zania; Qureshi, Omar; Lalor, Patricia F.; Shaw, Jean; Syn, Wing-kin; Curbishley, Stuart M.; Adams, David H.
Functional Role of Monocytes and Macrophages for the Inflammatory Response in Acute Liver Injury
Different etiologies such as drug toxicity, acute viral hepatitis B, or acetaminophen poisoning can cause acute liver injury or even acute liver failure (ALF). Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1beta, or monocyte-chemoattractant protein-1 (MCP-1, CCL2) as well as activating other non-parenchymal liver cells, e.g., endothelial or hepatic stellate cells. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g., via caspase activation, but also activate protective signaling pathways, e.g., via nuclear factor kappa B (NF-?B). Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+) monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation, and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF. PMID:23091461
Zimmermann, Henning W.; Trautwein, Christian; Tacke, Frank
Diabetes is a serious health problem and a source of risk for numerous severe complications such as obesity and hypertension. Treatment of diabetes and its related diseases can be achieved by inhibiting key digestive enzymes related to starch and lipid digestion. The findings revealed that the administration of trigonelline to surviving diabetic rats helped to protect the pancreas ?-cells from death and damage. Additionally, the supplement of trigonelline to surviving diabetic rats significantly decreased intestinal ?-amylase and maltase by 36 and 52%, respectively, which led to a significant decrease in the blood glucose rate by 46%. Moreover, the administration of trigonelline to surviving diabetic rats potentially inhibited key enzymes of lipid metabolism and absorption such as lipase activity in the small intestine by 56%, which led to a notable decrease in serum triglyceride (TG) and total cholesterol (TC) rates and an increase in the HDL cholesterol level. This treatment also improved glucose, maltase, starch, and lipid oral tolerance. Trigonelline was also observed to protect the liver-kidney functions efficiently, which was evidenced by the significant decrease in the serum aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), and lactate dehydrogenase (LDH) activities and creatinine, albumin, and urea rates. The histological analysis of the pancreas, liver, and kidney tissues further established the positive effect of trigonelline. Overall, the findings presented in this study demonstrate that the administration of trigonelline to diabetic rats can make it a potentially strong candidate for industrial application as a pharmacological agent for the treatment of hyperglycemia, hyperlipidemia, and liver-kidney dysfunctions. PMID:23641341
Hamden, Khaled; Mnafgui, Kais; Amri, Zahra; Aloulou, Ahmed; Elfeki, Abdelfattah
The pathogenesis of biliary atresia (BA), which leads to end-stage cirrhosis in most patients, has been thought to inflame and obstruct the intrahepatic and extrahepatic bile ducts. BA is not believed to be caused by abnormalities in parenchymal hepatocytes. However, there has been no report of a detailed analysis of hepatocytes buried in the cirrhotic livers of patients with BA. Therefore, we evaluated the proliferative potential of these hepatocytes in immunodeficient, liver-injured mice [the urokinase-type plasminogen activator (uPA) transgenic NOD/Shi-scid IL2r?null (NOG); uPA-NOG strain]. We succeeded in isolating viable hepatocytes from the livers of patients with BA who had various degrees of fibrosis. The isolated hepatocytes were intrasplenically transplanted into the livers of uPA-NOG mice. The hepatocytes of only 3 of the 9 BA patients secreted detectable amounts of human albumin in sera when they were transplanted into mice. However, human leukocyte antigen-positive hepatocyte colonies were detected in 7 of the 9 mice with hepatocyte transplants from patients with BA. We demonstrated that hepatocytes buried in the cirrhotic livers of patients with BA retained their proliferative potential. A liver that was reconstituted with hepatocytes from patients with BA was shown to be a functioning human liver with a drug-metabolizing enzyme gene expression pattern that was representative of mature human liver and biliary function, as ascertained by fluorescent dye excretion into the bile canaliculi. These results imply that removing the primary etiology via an earlier portoenterostomy may increase the quantity of functionally intact hepatocytes remaining in a cirrhotic liver and may contribute to improved outcomes. PMID:24838399
Suemizu, Hiroshi; Nakamura, Kazuaki; Kawai, Kenji; Higuchi, Yuichiro; Kasahara, Mureo; Fujimoto, Junichiro; Tanoue, Akito; Nakamura, Masato
Liver morphology and function tests in obesity and during total starvation
Five markedly obese patients were subjected to complete starvation of several weeks, for the purpose of weight reduction, for periods of 10�28 days. Studies of liver function and structure were conducted prior to, during, and after the period of starvation.
Paul Rozental; Claude Biava; Herta Spencer; Hyman J. Zimmerman
Enhanced external counterpulsation: a new technique to augment renal function in liver cirrhosis
Background. Advanced liver cirrhosis is characterized by cardiovascular changes, such as low arterial blood pressure, peripheral vasodilation and renal vasocon- striction. As a consequence, renal hypoperfusion, impaired diuresis and natriuresis and eventual hepato- renal syndrome may ensue. Previous studies using head-out water immersion to increase central blood volume have demonstrated the functional nature of the renal abnormalities. Enhanced external counter-
Dierk Werner; Peter Tragner; Andrea Wawer; Heiner Porst; Werner G. Daniel; Peter Gross
Summary We hereby describe a patient with amyloidosis complicated by reversible functional asplenia and spontaneous rupture of the liver with subcapsular hematoma which resolved completely with conservative therapy. These two rare findings may result from extensive vascular amyloid in this patient.
E. Levy-Lahad; D. Steiner-Salz; N. Berkman; R. Chisin; P. Levensart; E. Leitersdorf
Introduction: The prevalence of deranged liver function tests (LFT) in patients on long-term home parenteral nutrition (HPN) is poorly documented. The aim of our study was to document the prevalence of this complication and possible associated factors.Method: Retrospective analysis of case notes of 107 patients on HPN was performed. Deranged LFT was defined as any biochemical parameter of LFT that
Biochemical Indicators and Cardiac Function Tests in Chronic Alcohol Abusers
To determine the effect of chronic alcohol abuse on cardiac function, antioxidant system, trace ele- ments, and liver function tests. Methods Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), superoxide dismutase (SOD), malondialdehyde (MDA), as well as zinc, magnesium, and copper were assayed in 25 chronic alcoholic patients and their
Tamer C. Inal; Mesut Demir; G�len Attila; Yunus Emre Evlice; Levent Kayrin
Liver transplant - series (image)
The liver is in the right upper abdomen. The liver serves many functions, including the detoxification of substances delivered ... A liver transplant may be recommended for: liver damage due to alcoholism (Alcoholic cirrhosis) primary biliary cirrhosis long-term ( ...
Functional Roles of Protein Nitration in Acute and Chronic Liver Diseases
Nitric oxide, when combined with superoxide, produces peroxynitrite, which is known to be an important mediator for a number of diseases including various liver diseases. Peroxynitrite can modify tyrosine residue(s) of many proteins resulting in protein nitration, which may alter structure and function of each target protein. Various proteomics and immunological methods including mass spectrometry combined with both high pressure liquid chromatography and 2D PAGE have been employed to identify and characterize nitrated proteins from pathological tissue samples to determine their roles. However, these methods contain a few technical problems such as low efficiencies with the detection of a limited number of nitrated proteins and labor intensiveness. Therefore, a systematic approach to efficiently identify nitrated proteins and characterize their functional roles is likely to shed new insights into understanding of the mechanisms of hepatic disease pathophysiology and subsequent development of new therapeutics. The aims of this review are to briefly describe the mechanisms of hepatic diseases. In addition, we specifically describe a systematic approach to efficiently identify nitrated proteins to study their causal roles or functional consequences in promoting acute and chronic liver diseases including alcoholic and nonalcoholic fatty liver diseases. We finally discuss translational research applications by analyzing nitrated proteins in evaluating the efficacies of potentially beneficial agents to prevent or treat various diseases in the liver and other tissues. PMID:24876909
Abdelmegeed, Mohamed A.; Song, Byoung-Joon
The present study reports on the effects of horminone on serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, on hepatic cytochrome P450 (P450) and cytochrome b5 (cyt b5) contents and on the activities of NADPH-cytochrome P450 reductase (NR), mixed function mono-oxygenases (MFO), glutathione-S-transferase (GST) and glutathione reductase (GR) of Wistar male rat. Horminone is a diterpenoid quinone (7,12-dihydroxyabiet-8,12-diene-11,14-dione) present
Rui Ferreira; F�tima Candeias; F�tima Sim�es; Jos� Nascimento; J. Cruz Morais
Molecular Functions of Thyroid Hormones and Their Clinical Significance in Liver-Related Diseases
Thyroid hormones (THs) are potent mediators of several physiological processes, including embryonic development, cellular differentiation, metabolism, and cell growth. Triiodothyronine (T3) is the most biologically active TH form. Thyroid hormone receptors (TRs) belong to the nuclear receptor superfamily and mediate the biological functions of T3 via transcriptional regulation. TRs generally form heterodimers with the retinoid X receptor (RXR) and regulate target genes upon T3 stimulation. Research over the past few decades has revealed that disruption of cellular TH signaling triggers chronic liver diseases, including alcoholic or nonalcoholic fatty liver disease and hepatocellular carcinoma (HCC). Animal model experiments and epidemiologic studies to date imply close associations between high TH levels and prevention of liver disease. Moreover, several investigations spanning four decades have reported the therapeutic potential of T3 analogs in lowering lipids, preventing chronic liver disease, and as anticancer agents. Thus, elucidating downstream genes/signaling pathways and molecular mechanisms of TH actions is critical for the treatment of significant public health issues. Here, we have reviewed recent studies focusing on the roles of THs and TRs in several disorders, in particular, liver diseases. We also discuss the potential therapeutic applications of THs and underlying molecular mechanisms. PMID:23878812
Chi, Hsiang Cheng; Chen, Cheng-Yi; Tsai, Ming-Ming; Tsai, Chung-Ying; Lin, Kwang-Huei
Coffee consumption is worldwide spread with few side effects. Interestingly, coffee intake has been inversely related to the serum enzyme activities gamma-glutamyltransferase, and alanine aminotransferase in studies performed in various countries. In addition, epidemiological results, taken together, indicate that coffee consumption is inversely related with hepatic cirrhosis; however, they cannot demonstrate a causative role of coffee with prevention of liver injury. Animal models and cell culture studies indicate that kahweol, diterpenes and cafestol (some coffee compounds) can function as blocking agents by modulating multiple enzymes involved in carcinogenic detoxification; these molecules also alter the xenotoxic metabolism by inducing the enzymes glutathione-S-transferase and inhibiting N-acetyltransferase. Drinking coffee has been associated with reduced risk of hepatic injury and cirrhosis, a major pathogenic step in the process of hepatocarcinogenesis, thus, the benefit that produces coffee consumption on hepatic cancer may be attributed to its inverse relation with cirrhosis, although allowance for clinical history of cirrhosis did not completely account for the inverse association. Therefore, it seems to be a continuum of the beneficial effect of coffee consumption on liver enzymes, cirrhosis and hepatocellular carcinoma. At present, it seems reasonable to propose experiments with animal models of liver damage and to test the effect of coffee, and/or isolated compounds of this beverage, not only to evaluate the possible causative role of coffee but also its action mechanism. Clinical prospective double blind studies are also needed. PMID:19825397
Muriel, Pablo; Arauz, Jonathan
Mitochondrial abnormalities are suggested to be associated with the development of nonalcoholic fatty liver. Liver mitochondrial content and function have been shown to improve in oral feeding of acetyl-L-carnitine (ALC) to rodents. Carnitine is involved in the transport of acyl-coenzyme A across the mitochondrial membrane to be used in mitochondrial ?-oxidation. We hypothesized that oral administration ALC with the antioxidant lipoic acid (ALC + LA) would benefit nonalcoholic fatty liver. To test our hypothesis, we fed Balb/C mice a standard diet (SF) or SF with ALC + LA or high-fat diet (HF) or HF with ALC + LA for 6 months. Acetyl-L-carnitine and LA were dissolved at 0.2:0.1% (wt/vol) in drinking water, and mice were allowed free access to food and water. Along with physical parameters, insulin resistance (blood glucose, insulin, glucose tolerance), liver function (alanine transaminase [ALT], aspartate transaminase [AST]), liver histology (hematoxylin and eosin), oxidative stress (malondialdehyde), and mitochondrial abnormalities (carbamoyl phosphate synthase 1 and electron microscopy) were done. Compared with SF, HF had higher body, liver, liver-to-body weight ratio, white adipose tissue, ALT, AST, liver fat, oxidative stress, and insulin resistance. Coadministration of ALC + LA to HF animals significantly improved the mitochondrial marker carbamoyl phosphate synthase 1 and the size of the mitochondria in liver. Alanine transaminase and AST levels were decreased. In a nonalcoholic fatty liver mice model, ALC + LA combination improved liver mitochondrial content, size, serum ALT, and AST without significant changes in oxidative stress, insulin resistance, and liver fat accumulation. PMID:24176233
Kathirvel, Elango; Morgan, Kengathevy; French, Samuel W; Morgan, Timothy R
Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma
Purpose: Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials: The subjects were 259 patients treated with PBT at University of Tsukuba between January 2001 and December 2007. We evaluated the Child-Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the Child-Pugh score of 1 or more was defined as an adverse event. Results: Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child-Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child-Pugh score, 15 had a 1-point increase, and 10 had an increase of {>=}2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion: Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.
Mizumoto, Masashi; Okumura, Toshiyuki; Hashimoto, Takayuki [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Fukuda, Kuniaki [Department of Gastroenterology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Oshiro, Yoshiko; Fukumitsu, Nobuyoshi [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Abei, Masato [Department of Gastroenterology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Kawaguchi, Atsushi [Biostatistics Center, Kurume University, Kurume-shi, Fukuoka (Japan); Hayashi, Yasutaka; Ohkawa, Ayako; Hashii, Haruko; Kanemoto, Ayae [Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Moritake, Takashi [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Tohno, Eriko [Department of Diagnostic Radiology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Tsuboi, Koji [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan); Sakae, Takeji [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Sakurai, Hideyuki, E-mail: email@example.com [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, University of Tsukuba, Tsukuba, Ibaraki (Japan)
Liver metabolism and glucogenesis in trauma and sepsis.
The relationship of glucogenesis and other energy-requiring functions of the liver to the proteolysis which is characteristic of trauma and sepsis was studied in conscious pigs following laporotomy and after the induction of intraperitoneal sepsis. By means of appropriately placed thermal dilution catheters, portal and hepatic arterial blood flows, hepatic oxygen consumption, glucogenesis, and uptake of the fuel, substrates were measured. No animal was in shock. Despite significant increases of lactate and aminoacids delivered to the liver, the blood concentrations were maintained in the normal range. The rate of glucogenesis was proportional (r equals 0.71) to the sum of the glucogenic precursors (lactate, pyruvate, glycerol, and alanine) taken up by the liver. Higher rates of glucose production were accompanied by elevated blood insulin values. Hepatic oxygen consumption and the uptake of free fatty acids also were related directly to the glucogenic rate, the correlation coefficients being 0.69 and 0.74, respectively. In the absence of shock, the liver function and hepatic energy production remained normal in post-traumatic and septic states. Under the conditions insulin-resistant muscle in the presence of reduced free fatty acid availability mobilize protein to satisfy local energy requirements. Skeletal muscle can oxidize only branch chain aminoacids; other aminoacids, including alanine, are transported to the liver for glucogenesis or other purposed. This concept accounted for failure of glucose infusion to eliminate post-traumatic and septic proteolysis, since alanine is cleared only from blood by conversion in the liver to glucose. Thus it is concluded that in sepsis the release of glucogenic substrates because of altered metabolism in peripheral tissues determines the rate of hepatic glucogenesis. This relationship constitutes an important metabolic homeostatic mechanism. PMID:1145447
Imamura, M; Clowes, G H; Blackburn, G L; O'Donnell, T F; Trerice, M; Bhimjee, Y; Ryan, N T
Genome-Wide Association Study of Liver Enzymes in Korean Children
Liver enzyme elevations, as an indicator of liver function, are widely associated with metabolic diseases. Genome-wide population-based association studies have identified a genetic susceptibility to liver enzyme elevations and their related traits; however, the genetic architecture in childhood remains largely unknown. We performed a genome-wide association study to identify new genetic loci for liver enzyme levels in a Korean childhood cohort (n = 484). We observed three novel loci (rs4949718, rs80311637, and rs596406) that were multiply associated with elevated levels of alanine transaminase and aspartate transaminase. Although there are some limitations, including genetic power, additional replication and functional characterization will support the clarity on the genetic contribution that the ST6GALNAC3, ADAMTS9, and CELF2 genes have in childhood liver function. PMID:24124411
Park, Tae-Joon; Hwang, Joo-Yeon; Go, Min Jin; Lee, Hye-Ja; Jang, Han Byul; Choi, Youngshim; Kang, Jae Heon; Park, Kyung Hee; Choi, Min-Gyu; Song, Jihyun; Kim, Bong-Jo; Lee, Jong-Young
Outcomes following liver trauma in equestrian accidents
Background Equestrian sports are common outdoor activities that may carry a risk of liver injury. Due to the relative infrequency of equestrian accidents the injury patterns and outcomes associated with liver trauma in these patients have not been well characterized. Methods We examined our experience of the management of equestrian liver trauma in our regional hepatopancreaticobiliary unit at a tertiary referral center. The medical records of patients who sustained liver trauma secondary to equestrian activities were analysed for parameters such as demographic data, liver function tests, patterns of injury, radiological findings, the need for intervention and outcomes. Results 20 patients sustained liver trauma after falling from or being kicked by a horse. The majority of patients were haemodynamically stable on admission. Alanine transaminase (ALT) levels were elevated in all patients and right-sided rib fractures were a frequently associated finding. CT demonstrated laceration of the liver in 12 patients, contusion in 3 and subcapsular haematoma in 2. The right lobe of the liver was most commonly affected. Only two patients required laparotomy and liver resection; the remaining 18 were successfully managed conservatively. Conclusions The risk of liver injury following a horse kick or falling off a horse should not be overlooked. Early CT imaging is advised in these patients, particularly in the presence of high ALT levels and concomitant chest injuries such as rib fractures. Despite significant liver trauma, conservative management in the form of close observation, ideally in a high-dependency setting, is often sufficient. Laparotomy is only rarely warranted and associated with a significantly higher risk of post-operative bile leaks. PMID:25177363
Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated whether 1) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo and 2) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content. Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo positron emission tomography with [(11)C]acetate and [(11)C]palmitate to quantify liver FFA metabolism (n = 8), or magnetic resonance spectroscopy (MRS) to measure hepatic fat content (n = 8), before and after the acute lowering of circulating FFAs by using the antilipolytic agent acipimox. MRS was again repeated after a 1-wk treatment period. Acipimox suppressed FFA levels while stimulating hepatic fractional extraction of FFAs (P < 0.05). As a result, fasting liver FFA uptake was decreased by 79% (P = 0.0002) in tight association with lipolysis (r = 0.996, P < 0.0001). The 1-wk treatment induced a significant improvement in systemic (+30%) and liver (+70%) insulin sensitivity (P < 0.05) and decreased circulating triglycerides (-20%, P = 0.06) and liver enzymes (ALT -20%, P = 0.03). No change in liver fat content was observed after either acute or sustained FFA suppression. We conclude that acute and sustained inhibitions of lipolysis and liver FFA uptake fail to deplete liver fat in healthy human subjects. Liver FFA uptake was decreased in proportion to FFA delivery. As a consequence, liver and systemic insulin sensitivity were improved, together with liver function, independently of changes in hepatic triglyceride accumulation. PMID:18505832
Rigazio, Sara; Lehto, Hanna-Riikka; Tuunanen, Helena; N�gren, Kjell; Kankaanpaa, Mikko; Simi, Claudia; Borra, Ronald; Naum, Alexandru G; Parkkola, Riitta; Knuuti, Juhani; Nuutila, Pirjo; Iozzo, Patricia
Liver injury in hypervitaminosis A: Evidence for activation of Kupffer cell function
The most important and novel finding of this work was enhanced liver Kupffer cell phagocytic and metabolic function by hypervitaminosis A. An animal model of hypervitaminosis A was developed in male Sprague-Dawley rats gavaged with 250,000 I.U. retinol/kg body weight/day for 3 weeks. Presence of hypervitaminosis A was indicated by characteristic changes in the fur coat, presence of brittle bones and spontaneous fractures and a significant increase in plasma and liver concentrations of retinyl palmitate while retinol levels remained the same as in controls. Hypervitaminosis A did not cause severe liver abnormalities as reflected by normal plasma glutamate pyruvate transaminase activity and bilirubin. The main change was a marked increase in size of the fat or Vitamin A storing cells. Measurement of clearance from blood of indocyanine green and {sup 99m}Tc-disofenin indicated this hepatocyte function was normal. Kupffer cell phagocytic function was enhanced in hypervitaminosis A as determined by clearance from blood of {sup 99m}Tc-sulfur colloid. In vitro, there was also evidence that treatment with high doses of Vitamin A activated or enhanced Kupffer cell function. Kupffer cells from control and Vitamin A treated rats were isolated by enzymatic dispersion, purified by centrifugal elutriation, and placed in culture. Activation was indicated by (1) increased phagocytosis of {sup 51}Cr-labeled opsonized sheep red blood cells (2) enhanced release of superoxide anion and (3) enhanced production of tumor cytolytic factor by Kupffer cells from Vitamin A treated rats.
Sim, W.L.W.
Except for increased serum alkaline phosphatase (AP) levels, the changes in liver function test (LFT) values during normal pregnancy have not been clearly established, mainly because most studies do not include matched controls. We therefore measured the serum values of routine liver tests including 5'-nucleotidase and total bile acids in 103 healthy pregnant women (first trimester, n = 34; second
Y Bacq; O Zarka; J Brechot; N Mariotte; S Vol; J Tichet; J Weill
OBJECTIVES:Liver involvement is common in patients with inflammatory bowel disease (IBD). However, the frequency and the significance of liver function test (LFT) abnormalities in patients with ileal pouch�anal anastomosis (IPAA) for underlying IBD have not been studied. The aim of this study was to evaluate the prevalence and to identify risk factors for abnormal LFTs in patients with IPAA and
Udayakumar Navaneethan; Feza H Remzi; Benjamin Nutter; Victor W Fazio; Bo Shen
Glycyl-L-alanine: a multi-temperature neutron study.
Neutron diffraction data have been collected at 12, 50, 150 and 295?K for the dipeptide glycyl-L-alanine, C5H10N2O3, in order to obtain accurate positional and anisotropic displacement parameters for the H atoms. The values of these parameters serve as a benchmark for assessing the equivalent parameters obtained from a so-called Hirshfeld-atom refinement of X-ray diffraction data described elsewhere [Capelli et al. (2014). IUCrJ, 1, 361-379]. The flexibility of the glycyl-L-alanine molecule in the solid and the hydrogen-bonding interactions as a function of temperature are also considered. PMID:25279594
Capelli, Silvia C; B�rgi, Hans Beat; Mason, Sax A; Jayatilaka, Dylan
Background: Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), appears to be increasingly common worldwide. Its histopathology and the effects of nutrition on liver function have not been fully determined. Aim: To elucidate the cellular mechanisms of NAFLD induced by a methionine-choline-deficient (MCD) diet in mice. Particular focus was placed on the role of phagocytic cells. Methods: Male C57BL/6 mice were fed an MCD diet for 30 weeks. A recovery model was also established wherein a normal control diet was provided for 2 weeks after a period of 8, 16, or 30 weeks. Results: Mice fed the MCD diet for ?2 weeks exhibited severe steatohepatitis with elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Steatohepatitis was accompanied by the infiltration of CD68-positive macrophages (Kupffer cells). The severity of steatohepatitis increased in the first 16 weeks but was seen to lessen by week 30. Fibrosis began to develop at 10 weeks and continued thereafter. Steatohepatitis and elevated serum hepatic enzyme concentrations returned to normal levels after switching the diet back to the control within the first 16 weeks, but fibrosis and CD68-positive macrophages remained. Conclusions: The histopathological changes and irreversible fibrosis seen in this model were caused by prolonged feeding of an MCD diet. These results were accompanied by changes in the activity of CD68-positive cells with temporary elevation of CCL-2, MMP-13, and MMP-9 levels, all of which may trigger early steatohepatitis and late fibrosis through phagocytosis-associated MMP induction. PMID:24294355
Itagaki, Hiroko; Shimizu, Kazuhiko; Morikawa, Shunichi; Ogawa, Kenji; Ezaki, Taichi
To examine the role of keratin intermediate filament proteins in cell structure and function, trans- genie mice were isolated that express a modified form of the human K14 keratin protein in liver hepatoeytes. A modified K14 eDNA (K14.P) sequence was linked downstream of the mouse transthyretin (TTR) gene promoter and enhancer elements to achieve targeted expression in hepatocytes. Hepatoeytes expressing
Kathryn M. Albers; Frankie E. Davis; Teresa N. Perrone; Eun Y. Lee; Yong Liu; Mary Vore
To investigate the relationship between elevated serum alanine-transaminase (e-ALT) and persistent rotating shift work (p-RSW) among employees with sonographic fatty liver (SFL), the authors performed a retrospective analysis on a cohort of electronics manufacturing workers. The records of 758 workers (507 men, 251 women) with initially normal ALT and a mean age of 32.9 years were analyzed. A total of 109 workers (14.4%) developed e-ALT after 5 years. Compared with those having neither initial SFL nor p-RSW exposure, multivariate analysis indicated that employees who had initial SFL but without p-RSW finally had a higher risk (odds ratio = 2.9; 95% confidence interval [CI] = 1.7-5.1) for developing e-ALT; workers with baseline SFL plus p-RSW had a 3.7-fold increased risk (95% CI = 1.8-7.5). SFL poses a conspicuous risk for the development of e-ALT, and persistent p-RSW exposure significantly aggravates the development of e-ALT among on-site workers with preexisting SFL. PMID:23239752
Lin, Yu-Cheng; Chen, Pau-Chung
The Benefits of vitamin E on liver function and the hemopoietic System in thalassemia Patients
Background ??Thalassemic children have oxidative stress and antioxidant deficiency even without iron overload status. In these patients, tissue damage due to oxidative stress may be occurred. Also, it seems that thalassemic patients have higher levels of ALT, AST therefore, the main aim of the present study was to determine the benefits of vitamin E as an antioxidant supplements in ?-Thalassemia children. Materials and Methods This clinical trial was carried out on 45 beta-thalassemic patients undergoing occasional transfusions (24 males, 21 females), mean age 16� 8 years, admitted to Yazd and Shahid Sadoughi hospital in 2011. Fallowing three months treatment of vitaminE (vitamin E 400-600 unit/day),liver function test and hemopoitic system parameters were measured. Results Fourty five patients with laboratory confirmation of ?-Thalassemia were recruited following three months vitamin E supplementation, liver function test had higher improvement compared to hemopoitic system parameters , and also serum SGOT was significantly reduced (P-value<0.004 ). Conclusion It seems clear that treatments of ?-thalassemic patients with vitamins E have benefits in promoting antioxidant status and may improve liver function test, as AST and ALT to decrease but this supplement is not effective for hemopoietic system variables. PMID:24575256
Hashemian, Z; Hashemi, A; Fateminasab, M
Bioartificial liver (BAL) system is promising as an alternative treatment for liver failure. We have developed a bioreactor with stacked sandwich culture plates for the application of BAL. This bioreactor design addresses some of the persistent problems in flat-bed bioreactors through increasing cell packing capacity, eliminating dead flow, regulating shear stress, and facilitating the scalability of the bioreactor unit. The bioreactor contained a stack of twelve double-sandwich-culture plates, allowing 100 million hepatocytes to be housed in a single cylindrical bioreactor unit (7�cm of height and 5.5�cm of inner diameter). The serial flow perfusion through the bioreactor increased cell-fluid contact area for effective mass exchange. With the optimal perfusion flow rate, shear stress was minimized to achieve high and uniform cell viabilities across different plates in the bioreactor. Our results demonstrated that hepatocytes cultured in the bioreactor could re-establish cell polarity and maintain liver-specific functions (e.g. albumin and urea synthesis, phase I&II metabolism functions) for seven days. The single bioreactor unit can be readily scaled up to house adequate number of functional hepatocytes for BAL development. PMID:22889484
Xia, Lei; Arooz, Talha; Zhang, Shufang; Tuo, Xiaoye; Xiao, Guangfa; Susanto, Thomas Adi Kurnia; Sundararajan, Janani; Cheng, Tianming; Kang, Yuzhan; Poh, Hee Joo; Leo, Hwa Liang; Yu, Hanry
Frostbite of the liver: an unrecognized cause of primary non-function?
Appropriate hypothermic packaging techniques are an essential part of organ procurement. We present a case in which deviation from standard packaging practice may have caused sub-zero storage temperatures during transport, resulting in a clinical picture resembling PNF. An 18-month-old male with alpha-1-antitrypsin deficiency underwent liver transplant from a size-matched pediatric donor. Upon arrival at the recipient hospital, ice crystals were noted in the UW solution. The transplant proceeded uneventfully with short ischemia times. Surprisingly, transaminases, INR, and total bilirubin were markedly elevated in the postoperative period but returned to near normal by discharge. Follow-up of over five yr has demonstrated normal liver function. Upon review, it was discovered that organ packaging during recovery included storage in the first bag with only 400 mL of UW solution, and pure ice in the second bag instead of slush. This suggests that the postoperative delayed graft function was related to sub-zero storage of the graft during transport. This is the first report of sub-zero cold injury, or frostbite, following inappropriate packaging of an otherwise healthy donor liver. The clinical picture closely resembled PNF, perhaps implicating this mechanism in other unexpected cases of graft non-function. PMID:24384052
Potanos, Kristina; Kim, Heung Bae
The effect of Lactobacillus plantarum NCU116 on liver function, oxidative stress and lipid metabolism in rats with high fat diet induced non-alcoholic fatty liver disease (NAFLD) was studied. The rats were divided into four groups: the normal diet (ND) group; the high fat diet (HFD) group; and HFD plus L. plantarum NCU116 as two doses (NCU116-L, 10(8) CFU mL(-1); NCU116-H, 10(9) CFU mL(-1)) groups. Treatment of L. plantarum NCU116 for 5 weeks was found to restore liver function and oxidative stress in rats with NAFLD, and decrease the levels of fat accumulation in the liver. In addition, the bacterium significantly reduced endotoxin and proinflammatory cytokines, and regulated bacterial flora in the colon and the expression of lipid metabolism in the liver. These results suggest that possible underlying mechanisms for the beneficial effect of L. plantarum NCU116 on NAFLD may include two pathways of downregulating lipogenesis and upregulating lipolysis and fatty acid oxidation related gene expression. PMID:25317840
Li, Chuan; Nie, Shao-Ping; Zhu, Ke-Xue; Ding, Qiao; Li, Chang; Xiong, Tao; Xie, Ming-Yong
The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity. PMID:23720323
Bogdanos, Dimitrios P.; Gao, Bin; Gershwin, M. Eric
Aim: Activator protein 2? (AP-2?) belongs to the AP-2 family of transcription factors that are involved in the regulation of cell proliferation, differentiation, apoptosis and carcinogenesis and has been suggested to function as a tumor suppressor in many cancers. However, the physiological role of AP-2? in hepatocytes is unknown. The present study is to characterize the expression and function of AP-2? in the liver of conscience mouse. Methods: Exogenous AP-2? was overexpressed in the mouse liver by in vivo gene delivery and changes in transcription factor expression were identified by using protein-DNA arrays and immunoblotting. Results: Western blotting and protein/DNA arrays showed that AP-2? is expressed in the nuclei of mouse hepatocytes. Overexpression of AP-2? in vivo significantly suppressed transcription factors AP-1, CREB and c-Myc, and markedly increased CBF, c-Myb, NF-1, Pax-5, RXR, Smad3/4, TR(DR-4), USF-1 and GATA. Among all GATA proteins, only GATA-4 level was dramatically elevated and there was a concomitant loss of phospho-GATA-4. Corresponding changes were detected in upstream kinases Akt, GSK-3? and PKA, which regulates the phosphorylation status and stability of GATA-4 protein. Conclusions: AP-2? is expressed in mouse hepatocytes and it acts as a master regulator of numerous transcription factors in the liver. PMID:21682828
Li, Qingjie; Luo, Cunhui; Lohr, Christiane V.; Dashwood, Roderick H.
The dye indocyanine green is familiar to anaesthetists, and has been studied for more than half a century for cardiovascular and hepatic function monitoring. It is still, however, not yet in routine clinical use in anaesthesia and critical care, at least in Europe. This review is intended to provide a critical analysis of the available evidence concerning the indications for clinical measurement of indocyanine green elimination as a diagnostic and prognostic tool in two areas: its role in peri-operative liver function monitoring during major hepatic resection and liver transplantation; and its role in critically ill patients on the intensive care unit, where it is used for prediction of mortality, and for assessment of the severity of acute liver failure or that of intra-abdominal hypertension. Although numerous studies have demonstrated that indocyanine green elimination measurements in these patient populations can provide diagnostic or prognostic information to the clinician, 'hard' evidence - i.e. high-quality prospective randomised controlled trials - is lacking, and therefore it is not yet time to give a green light for use of indocyanine green in routine clinical practice. PMID:24894115
Vos, J J; Wietasch, J K G; Absalom, A R; Hendriks, H G D; Scheeren, T W L
Function of the liver and bile ducts in humans exposed to lead.
Lead is very common in the environment, and it is therefore important to characterize its possible adverse health effects. The aim of this study was to evaluate the impact of lead exposure on selected functions of the liver and bile ducts in people who are chronically exposed to the metal because of their occupations. To provide this information, the activity of specific enzymes and the bilirubin concentration were determined in blood serum, and morphological parameters of the liver and bile ducts were evaluated using the ultrasonic imaging method. Healthy male employees of a lead-zinc processing facility (n�=�145) who were occupationally exposed to lead were divided into two subgroups as a function of the lead concentrations in blood (PbB): low lead exposure (PbB�=�20-35�?g/dl; n�=�57) and high lead exposure (PbB�=�35-60�?g/dl; n = 88). Human exposure to lead compounds was found to cause liver enlargement and to activate inflammatory reactions with the characteristics of moderate cholestasis within the bile ducts, while no characteristics of necrotic damage of hepatic cells were noted. It seems that lipid peroxidation can be one of the toxic mechanisms of lead which induce moderate cholestasis. The effects depend on the extent of the lead exposure and were greater in subjects with higher exposure levels, particularly subjects with PbB values greater than 35�?g/dl. PMID:23529799
Kasperczyk, A; Dziwisz, M; Osta?owska, A; Swietochowska, E; Birkner, E
Background\\/Aims: Intermittent ischemia (INT) can improve liver function following inflow occlusion. The aim was to test whether the number of cycles of INT can be increased without impairing liver function. Methods:Liver function in the acute phase of ischemia reperfusion injury was assessed by measuring bile flow in rat livers. Phospholipid and bile salts in bile, liver marker enzymes in blood,
J. Peters; V. B. Nieuwenhuijs; A. Morphett; R. J. Porte; R. T. A. Padbury; G. J. Barritt
Burkholderia pseudomallei and Burkholderia mallei are category B select agents and must be studied under BSL3 containment in the United States. They are typically resistant to multiple antibiotics, and the antibiotics used to treat B. pseudomallei or B. mallei infections may not be used as selective agents with the corresponding Burkholderia species. Here, we investigated alanine racemase deficient mutants of B. pseudomallei and B. mallei for development of non-antibiotic-based genetic selection methods and for attenuation of virulence. The genome of B. pseudomallei K96243 has two annotated alanine racemase genes (bpsl2179 and bpss0711), and B. mallei ATCC 23344 has one (bma1575). Each of these genes encodes a functional enzyme that can complement the alanine racemase deficiency of Escherichia coli strain ALA1. Herein, we show that B. pseudomallei with in-frame deletions in both bpsl2179 and bpss0711, or B. mallei with an in-frame deletion in bma1575, requires exogenous d-alanine for growth. Introduction of bpsl2179 on a multicopy plasmid into alanine racemase deficient variants of either Burkholderia species eliminated the requirement for d-alanine. During log phase growth without d-alanine, the viable counts of alanine racemase deficient mutants of B. pseudomallei and B. mallei decreased within 2 hours by about 1000-fold and 10-fold, respectively, and no viable bacteria were present at 24 hours. We constructed several genetic tools with bpsl2179 as a selectable genetic marker, and we used them without any antibiotic selection to construct an in-frame ?flgK mutant in the alanine racemase deficient variant of B. pseudomallei K96243. In murine peritoneal macrophages, wild type B. mallei ATCC 23344 was killed much more rapidly than wild type B. pseudomallei K96243. In addition, the alanine racemase deficient mutant of B. pseudomallei K96243 exhibited attenuation versus its isogenic parental strain with respect to growth and survival in murine peritoneal macrophages. PMID:21720554
Zajdowicz, Sheryl L. W.; Jones-Carson, Jessica; Vazquez-Torres, Andres; Jobling, Michael G.; Gill, Ronald E.; Holmes, Randall K.
17?-estradiol (E2) may interfere with endocrine, metabolic, and gender-differentiated functions in liver in both females and males. Indirect mechanisms play a crucial role because of the E2 influence on the pituitary GH secretion and the GHR-JAK2-STAT5 signaling pathway in the target tissues. E2, through its interaction with the estrogen receptor, exerts direct effects on liver. Hypothyroidism also affects endocrine and metabolic functions of the liver, rendering a metabolic phenotype with features that mimic deficiencies in E2 or GH. In this work, we combined the lipid and transcriptomic analysis to obtain comprehensive information on the molecular mechanisms of E2 effects, alone and in combination with GH, to regulate liver functions in males. We used the adult hypothyroid-orchidectomized rat model to minimize the influence of internal hormones on E2 treatment and to explore its role in male-differentiated functions. E2 influenced genes involved in metabolism of lipids and endo-xenobiotics, and the GH-regulated endocrine, metabolic, immune, and male-specific responses. E2 induced a female-pattern of gene expression and inhibited GH-regulated STAT5b targeted genes. E2 did not prevent the inhibitory effects of GH on urea and amino acid metabolism-related genes. The combination of E2 and GH decreased transcriptional immune responses. E2 decreased the hepatic content of saturated fatty acids and induced a transcriptional program that seems to be mediated by the activation of PPAR?. In contrast, GH inhibited fatty acid oxidation. Both E2 and GH replacements reduced hepatic CHO levels and increased the formation of cholesterol esters and triacylglycerols. Notably, the hepatic lipid profiles were endowed with singular fingerprints that may be used to segregate the effects of different hormonal replacements. In summary, we provide in vivo evidence that E2 has a significant impact on lipid content and transcriptome in male liver and that E2 exerts a marked influence on GH physiology, with implications in human therapy. PMID:24816529
Fernandez-Perez, Leandro; Santana-Farre, Ruyman; de Mirecki-Garrido, Mercedes; Garcia, Irma; Guerra, Borja; Mateo-Diaz, Carlos; Iglesias-Gato, Diego; Diaz-Chico, Juan Carlos; Flores-Morales, Amilcar; Diaz, Mario
Liver Test Results Do Not Identify Liver Disease in Adults with ?-1 Antitrypsin Deficiency
BACKGROUND & AIMS Liver disease is a significant cause of mortality among adults with ?-1 antitrypsin (AAT) deficiency. Age and male sex are reported risk factors for liver disease. In the absence of adequate risk stratification, current recommendations are to intermittently test AAT-deficient adults for liver function. We evaluated this recommendation in a large group of adults with AAT deficiency, to determine the prevalence of increased levels of alanine aminotransferase (ALT) and identify risk factors for liver disease. METHODS We used the Alpha-1 Foundation DNA and Tissue Bank to identify a cross-section of AAT-deficient adults (n=647) with and without liver disease; individuals without AAT-deficiency were used as controls (n=152). Results from ALT tests were compared between groups. RESULTS The prevalence of liver disease among individuals with ATT-deficiency was 7.9%; an increased level of ALT was observed in 7.8% of ATT-deficient individuals, which did not differ significantly from controls. Mean levels of ALT fell within normal range for all groups. An increased level of ALT identified patients with liver disease with 11.9% sensitivity. The level of only ?- glutamyl transpeptidase was significantly higher in the AAT-deficient group than in controls (43 vs 30 IU/ml; P<.003). A childhood history of liver disease and male sex were risk factors for adult liver disease in the multivariate analysis. CONCLUSIONS An increased level of ALT does not identify adults with AAT deficiency who have liver disease. Male sex and liver disease during childhood might help identify those at risk. PMID:22835581
Clark, Virginia C.; Dhanasekaran, Renumathy; Brantly, Mark; Rouhani, Farshid; Schreck, Pamela; Nelson, David R.
Circulating alanine disposal in diabetes mellitus.
Alanine was selected for study as a representative circulating glucose precursor in relation to the question of the source of the excess circulating glucose in diabetes mellitus. U-14C alanine and U-14C glucose infusions were given to healthy subjects and to subjects with untreated mild maturity, severe maturity, and juvenile diabetes. Comparative studies after a 24-hour fast were made in healthy and in mildly diabetic subjects. The alanine production rate was unaltered by fasting or diabetes. The glucose production rate was unaltered by fasting but increased in diabetes in relation to the severity of the disease. The fractions of alanine-to-glucose and of glucose-from-alanine were increased by fasting. The effect of diabetes was different. The fraction of alanine-to-glucose was much less in mild maturity diabetes than in health, and it was increased only in juvenile diabetes. In all the diabetic groups the glucose-from-alanine fraction was much less than in health. In every group the change in the alanine oxidation rate was reciprocal to that in the alanine-derived glucogenesis rate. The results are consistent with the possibility that the principal source of the excess circulating glucose in diabetes is glycogen. PMID:640247
Chochinov, R H; Bowen, H F; Moorhouse, J A
Vitamin D deficiency is common among patients with liver diseases. Both cholestatic and non-cholestatic liver diseases can cause vitamin D deficiency. Whether vitamin D status can also affect liver function is poorly understood. To investigate the association between vitamin D status, liver enzymes, and incident liver disease, we included a total of 2,649 individuals from the Monica10 study conducted in 1993-1994. Vitamin D status as assessed by serum 25-hydroxyvitamin, serum alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transferase (GGT) were measured at baseline. Information on fatal and non-fatal liver disease was obtained from the Danish National Patient Register and The Danish Registry of Causes of Death, respectively. Median follow-up time was 16.5 years, and there were 62 incident cases of fatal and non-fatal liver disease. Multivariable Cox regression analyses with age as underlying time axis and delayed entry showed a statistically significant inverse association between vitamin D status and incident liver disease with a hazard ratio = 0.88 (95 % confidence interval 0.79-0.99) per 10 nmol/l higher vitamin D status at baseline (adjusted for gender, season, alcohol consumption, smoking, physical activity, dietary habits, education, body mass index, and ALT). The risk of having a high level of ALT, AST, or GGT tended to be higher for lower vitamin D levels, although not statistically significant. In this general population study, vitamin D status was inversely associated with incident liver disease. Further studies are needed to determine whether patients in risk of developing impaired liver function should be screened for vitamin D deficiency for preventive purposes. PMID:24272594
Skaaby, Tea; Husemoen, Lise Lotte Nystrup; Borglykke, Anders; J�rgensen, Torben; Thuesen, Betina Heinsb�k; Pisinger, Charlotta; Schmidt, Lars Ebbe; Linneberg, Allan
Probing alanine transaminase catalysis with hyperpolarized 13CD3-pyruvate
NASA Astrophysics Data System (ADS)
Hyperpolarized metabolites offer a tremendous sensitivity advantage (>104 fold) when measuring flux and enzyme activity in living tissues by magnetic resonance methods. These sensitivity gains can also be applied to mechanistic studies that impose time and metabolite concentration limitations. Here we explore the use of hyperpolarization by dissolution dynamic nuclear polarization (DNP) in mechanistic studies of alanine transaminase (ALT), a well-established biomarker of liver disease and cancer that converts pyruvate to alanine using glutamate as a nitrogen donor. A specific deuterated, 13C-enriched analog of pyruvic acid, 13C3D3-pyruvic acid, is demonstrated to have advantages in terms of detection by both direct 13C observation and indirect observation through methyl protons introduced by ALT-catalyzed H-D exchange. Exchange on injecting hyperpolarized 13C3D3-pyruvate into ALT dissolved in buffered 1H2O, combined with an experimental approach to measure proton incorporation, provided information on mechanistic details of transaminase action on a 1.5 s timescale. ALT introduced, on average, 0.8 new protons into the methyl group of the alanine produced, indicating the presence of an off-pathway enamine intermediate. The opportunities for exploiting mechanism-dependent molecular signatures as well as indirect detection of hyperpolarized 13C3-pyruvate and products in imaging applications are discussed.
Barb, A. W.; Hekmatyar, S. K.; Glushka, J. N.; Prestegard, J. H.
Phenotypic and in vivo functional characterization of immortalized human fetal liver cells
We report the establishment and characterization of immortalized human fetal liver progenitor cells by expression of the Simian virus 40 large T (SV40 LT) antigen. Well-characterized cells at various passages were transplanted into nude mice with acute liver injury and tested for functional capacity. The SV40LT antigen-immortalized fetal liver cells showed a morphology similar to primary cells. Cultured cells demonstrated stable phenotypic expression in various passages, of hepatic markers such as albumin, CK 8, CK18, transcription factors HNF-4? and HNF-1? and CYP3A/7. The cells did not stain for any of the tested cancer-associated markers. Albumin, HNF-4? and CYP3A7 expression was confirmed by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry showed expression of some progenitor cell markers. In vivo study showed that the cells expressed both fetal and differentiated hepatocytes markers. Our study suggests new approaches to expand hepatic progenitor cells, analyze their fate in animal models aiming at cell therapy of hepatic diseases. PMID:24730442
Patil, Pradeep B.; Begum, Setara; Joshi, Meghnad; Kleman, Marika I; Olausson, Michael
Ostensibly ineffectual doses of cadmium and lipopolysaccharide causes liver damage in rats.
Various hepatotoxicants co-treated with lipopolysaccharide (LPS) have the potential to cause severe hepatic damage. Whether co-treatment with ostensibly ineffectual (without effect on customary clinical liver function tests, such as aspartate aminotransferase and alanine aminotransferase) doses of cadmium (Cd) and LPS cause liver damage is still unknown. We examined the effects of treating ostensibly ineffectual doses of Cd and LPS on liver dysfunction as well as on liver histopathology. We injected rats with saline only, Cd only, LPS only, or a single ostensibly ineffectual dose of Cd (100 ?g/kg body weight) plus LPS (0.1 mg/kg body weight). After 6 h, the rats were killed and their liver damage was assessed. Co-treated with ostensibly ineffectual doses of Cd and LPS had higher levels of aspartate aminotransferase and alanine aminotransferase, hepatic lipid peroxidation, peroxynitrite, nitrite, and interleukin-1? (IL-1?), but lower levels of hepatic metallothionein (MT) than did that treated with saline only, Cd only, and LPS only. Histopathological analysis of Cd only and LPS only showed apparent liver damage, but Cd plus LPS showed marked hepatic damage. We conclude that co-treating the rats with ostensibly ineffectual doses of Cd and LPS is hepatotoxic. Cd promotes LPS-initiated oxidative-stress-associated liver damage by increasing IL-1? and decreasing MT levels in rats. PMID:20639273
Srinivasan, Periasamy; Li, Ya-Hui; Hsu, Dur-Zong; Su, Shih-Bin; Liu, Ming-Yie
Objectives: To develop a new ELISA system for liver-type arginase using monoclonal antibodies against the enzyme, and to verify the utility of the arginase in diagnosis of hepatic disorders.Design and Methods: We have developed an enzyme-linked immunosorbent assay (ELISA), using two kinds of monoclonal antibodies (Mo6G3 and Mo9C5) for human liver-type arginase as the first and second antibodies respectively. We
Masaki Ikemoto; Shoji Tsunekawa; Masaaki Awane; Yoshihiro Fukuda; Hiroshi Murayama; Makoto Igarashi; Atsuo Nagata; Yasunari Kasai; Masayuki Totani
Background: The long-term risk of thrombotic and vascular complications is elevated in liver transplant recipients compared to the general population. Patients with cirrhosis are in a hypercoagulable status during and directly after orthotopic liver transplantation, but it is unclear whether this hypercoagulability persists over time. Aim: We aimed to investigate the hemostatic status of liver transplant recipients one year after transplantation. Methods: We prospectively collected blood samples of 15 patients with a functioning graft one year after orthotopic liver transplantation and compared the hemostatic status of these patients with that of 30 healthy individuals. Results: Patients one year after liver transplantation had significantly elevated plasma levels of von Willebrand factor (VWF). Thrombin generation, as assessed by the endogenous thrombin potential, was decreased in patients, which was associated with increased plasma levels of the natural anticoagulants antithrombin and tissue factor pathway inhibitor. �Plasma fibrinolytic potential was significantly decreased in patients and correlated inversely with levels of plasminogen activator inhibitor-1. Conclusion: One year after liver transplantation, liver graft recipients have a dysregulated hemostatic system characterised by elevation of plasma levels of endothelial-derived proteins. Increased levels of von Willebrand factor and decreased fibrinolytic potential may (in part) be responsible for the increased risk for vascular disease seen in liver transplant recipients.
Arshad, Freeha; Adelmeijer, Jelle; Blokzijl, Hans; van den Berg, Aad; Porte, Robert; Lisman, Ton
Dietary amino acid taurine ameliorates liver injury in chronic hepatitis patients
Summary.��The effect of dietary amino acid taurine on the liver function of chronic hepatitis patients was investigated. The 24 chronic\\u000a hepatitis patients with 2�5 times over normal activities of alanine aminotransferase (ALT) or aspartate aminotransferase (AST)\\u000a were selected and equally divided into taurine treatment and control groups. In taurine treatment group, each patient took\\u000a 2?g taurine 3 times a day
Y. H. Hu; C. L. Lin; Y. W. Huang; P. E. Liu; D.-F. Hwang
Lactic acid formation in crustaceans and the liver function of the midgut gland questioned.
1. The possibility of the midgut gland of the crustacean (Cherax destructor) functioning as a liver has been investigated. 2. Seven species of crustaceans accumulate lactic acid in the haemolymph when exercised. The rate of disappearance of lactate in Homarus gammarus and in C. destructor is very slow when compared with man. 3. In the midgut gland of C. destructor no firm evidence was obtained for gluconeogenesis from lactate and for ketogenesis from fatty acids. 4. It is concluded that there is at present no justification for the common practice of calling the midgut gland an hepatopancreas. PMID:318254
Phillips, J W; McKinney, R J; Hird, F J; Macmillan, D L
Potential causes of abnormal liver function tests include viral hepatitis, alcohol intake, nonalcoholic fatty liver disease, autoimmune liver diseases, hereditary diseases, hepatobiliary malignancies or infection, gallstones and drug-induced liver injury. Moreover, the liver may be involved in systemic diseases that mainly affect other organs. Therefore, in patients without etiology of liver injury by screening serology and diagnostic imaging, but who have systemic diseases, the abnormal liver function test results might be caused by the systemic disease. In most of these patients, the systemic disease should be treated primarily. However, some patients with systemic disease and severe liver injury or fulminant hepatic failure require intensive treatments of the liver. PMID:18636653
Shimizu, Yukihiro
Use of ?-alanine as an ergogenic aid.
Despite the large variety of so-called ergogenic supplements used by the sporting community, only few of them are effectively supported by scientific proof. One of the recent evidence-based supplements that entered the market is ?-alanine. ?-Alanine is the rate-limiting precursor for the synthesis of the dipeptide carnosine (?-alanyl-L-histidine) in human muscle. The chronic daily ingestion of ?-alanine can markedly elevate muscle carnosine content, which results in improved exercise capacity, especially in sports that include high-intensity exercise episodes. The use of ?-alanine is exponentially growing in recent years. This chapter aims to (1) discuss the scientific basis and physiological background of ?-alanine and its synthesis product carnosine, and (2) translate these scientific findings to practical applications in sports. PMID:23765354
Derave, Wim
... likely, but will subside once treatment ends. Liver transplant. In cases where tumors have caused the liver to lose all or most function, a transplant from a donor may be necessary. Most liver ...
Accuracy of urine urobilinogen and bilirubin assays in predicting liver function test abnormalities.
Components of the dipstick urinalysis (urine urobilinogen and urine bilirubin) are often used by emergency physicians to screen for the need to obtain liver function tests in many clinical situations. A prospective observational study was conducted to evaluate the sensitivity, specificity, and predictive properties of spot urine bilirubin and urobilinogen assays in the emergency department as screening test for serum liver function test (LFT) abnormalities. Of 122 patients, abdominal pain was the indication for laboratory evaluation in 54%; jaundice and constitutional symptoms were the indication in 29%. Overall sensitivities for both urine assays were 70% to 74% for serum bilirubin, but 43% to 53% for other LFTs; specificities were 77% to 87% for both urine screens. Positive predictive values show that the urine assays were 83% to 86% reliable for detecting at least one LFT abnormality. Negative predictive values were 85% for both urine assays for serum bilirubin elevations, but lower for other LFTs. Urine urobilinogen has its greatest clinical utility as a screen when a normal/abnormal threshold of 2.0/4.0 mg/dL is used. PMID:3662182
Kupka, T; Binder, L S; Smith, D A; Nelson, B K; Wainscott, M P; Glass, B A
Background\\/Aims: Most substances used in experimental models of cirrhosis are chosen either as protectors of lipid peroxidation, as antifibrogenic agents or as vitamins, among others. In this report, we analyze the improvement produced, in established cirrhosis (CCl4 plus phenobarbital) in rats, by intraperitoneal injection of Liver Growth Factor, a hepatic mitogen with activity both in vivo and in vitro.Methods: Following
Juan J D�az-Gil; Javier Mu�oz; Agust�n Albillos; Carmen R�a; Celia Mach�n; Rafael Garc�a-Ca�ero; Rosa M Cereceda; Mar�a C Guijarro; Carolina Trilla; Pedro Escart�n
Flies recycle the photoreceptor neurotransmitter histamine by conjugating it to ?-alanine to form ?-alanyl-histamine (carcinine). The conjugation is regulated by Ebony, while Tan hydrolyses carcinine, releasing histamine and ?-alanine. In Drosophila, ?-alanine synthesis occurs either from uracil or from the decarboxylation of aspartate but detailed roles for the enzymes responsible remain unclear. Immunohistochemically detected ?-alanine is present throughout the fly's entire brain, and is enhanced in the retina especially in the pseudocone, pigment and photoreceptor cells of the ommatidia. HPLC determinations reveal 10.7 ng of ?-alanine in the wild-type head, roughly five times more than histamine. When wild-type flies drink uracil their head ?-alanine increases more than after drinking l-aspartic acid, indicating the effectiveness of the uracil pathway. Mutants of black, which lack aspartate decarboxylase, cannot synthesize ?-alanine from l-aspartate but can still synthesize it efficiently from uracil. Our findings demonstrate a novel function for pigment cells, which not only screen ommatidia from stray light but also store and transport ?-alanine and carcinine. This role is consistent with a ?-alanine-dependent histamine recycling pathway occurring not only in the photoreceptor terminals in the lamina neuropile, where carcinine occurs in marginal glia, but vertically via a long pathway that involves the retina. The lamina's marginal glia are also a hub involved in the storage and/or disposal of carcinine and ?-alanine. PMID:22442379
Borycz, Janusz; Borycz, Jolanta A; Edwards, Tara N; Boulianne, Gabrielle L; Meinertzhagen, Ian A
?-Alanine supplementation for athletic performance: an update.
?-alanine supplementation has become a common practice among competitive athletes participating in a range of different sports. Although the mechanism by which chronic ?-alanine supplementation could have an ergogenic effect is widely debated, the popular view is that ?-alanine supplementation augments intramuscular carnosine content, leading to an increase in muscle buffer capacity, a delay in the onset of muscular fatigue, and a facilitated recovery during repeated bouts of high-intensity exercise. ?-alanine supplementation appears to be most effective for exercise tasks that rely heavily on ATP synthesis from anaerobic glycolysis. However, research investigating its efficacy as an ergogenic aid remains equivocal, making it difficult to draw conclusions as to its effectiveness for training and competition. The aim of this review was to update, summarize, and critically evaluate the findings associated with ?-alanine supplementation and exercise performance with the most recent research available to allow the development of practical recommendations for coaches and athletes. A critical review of the literature reveals that when significant ergogenic effects have been found, they have been generally shown in untrained individuals performing exercise bouts under laboratory conditions. The body of scientific data available concerning highly trained athletes performing single competition-like exercise tasks indicates that this type of population receives modest but potentially worthwhile performance benefits from ?-alanine supplementation. Recent data indicate that athletes may not only be using ?-alanine supplementation to enhance sports performance but also as a training aid to augment bouts of high-intensity training. ?-alanine supplementation has also been shown to increase resistance training performance and training volume in team-sport athletes, which may allow for greater overload and superior adaptations compared with training alone. The ergogenic potential of ?-alanine supplementation for elite athletes performing repeated high-intensity exercise bouts, either during training or during competition in sports which require repeated maximal efforts (e.g., rugby and soccer), needs scientific confirmation. PMID:24276304
Bellinger, Phillip M
BACKGROUND: A clonal cell line that combines both stable hepatic function and proliferation capacity is desirable for in vitro applications that depend on hepatic function, such as pharmacological or toxicological assays and bioartificial liver systems. Here we describe the generation and characterization of a clonal human cell line for in vitro hepatocyte applications. RESULTS: Cell clones derived from human fetal
Tanja Deurholt; Niek P van Til; Aniska A Chhatta; Lysbeth ten Bloemendaal; Ruth Schwartlander; Catherine Payne; John N Plevris; Igor M Sauer; Robert AFM Chamuleau; R. P. J. Oude Elferink; Jurgen Seppen; Ruurdtje Hoekstra
Six Minute Walk Test to assess functional capacity in chronic liver disease patients
AIM: To examine the utility of Six Minute Walk Test (6MWT) in patients with chronic liver disease (CLD). METHODS: Two hundred and fifty subjects between the ages of 18 and 80 (mean 47) years performed 6MWT and the Six Minute Walk Distance (6MWD) was measured. RESULTS: The subjects were categorized into four groups. Group A (n = 45) healthy subjects (control); group B (n = 49) chronic hepatitis B patients; group C (n = 54) chronic hepatitis C patients; group D (n = 98) liver cirrhosis patients. The four groups differed in terms of 6MWDs (P < 0.001). The longest distance walked was 421 � 47 m by group A, then group B (390 � 53 m), group C (357 � 72 m) and group D (306 � 111 m). The 6MWD correlated with age (r = -0.482, P < 0.01), hemoglobin (r = +0.373, P < 0.001) and albumin (r = +0.311, P < 0.001) levels. The Child-Pugh classification was negatively correlated with the 6MWD in cirrhosis (group D) patients (r = -0.328, P < 0.01). At the end of a 12 mo follow-up period, 15 of the 98 cirrhosis patients had died from disease complications. The 6MWD for the surviving cirrhotic patients was longer than for non-survivors (317 � 101 vs 245 � 145 m, P = 0.021; 95% CI 11-132). The 6MWD was found to be an independent predictor of survival (P = 0.024). CONCLUSION: 6MWT is a useful tool for assessing physical function in CLD patients. We suggest that 6MWD may serve as a prognostic indicator in patients with liver cirrhosis. PMID:17663517
Alameri, Hatem F; Sanai, Faisal M; Al Dukhayil, Manal; Azzam, Nahla A; Al-Swat, Khalid A; Hersi, Ahmad S; Abdo, Ayman A
Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds
Background Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying effects caused by these chemicals. Methodology/Principal Findings Sprague-Dawley female rats were exposed via gavage to one of five concentrations of one of five nitrotoluenes [2,4,6-trinitrotoluene (TNT), 2-amino-4,6-dinitrotoluene (2ADNT) 4-amino-2,6-dinitrotoulene (4ADNT), 2,4-dinitrotoluene (2,4DNT) and 2,6-dinitrotoluene (2,6DNT)] with necropsy and tissue collection at 24 or 48 h. Gene expression profile results correlated well with clinical data and liver histopathology that lead to the concept that hematotoxicity was followed by hepatotoxicity. Overall, 2,4DNT, 2,6DNT and TNT had stronger effects than 2ADNT and 4ADNT. Common functional terms, gene expression patterns, pathways and networks were regulated across all nitrotoluenes. These pathways included NRF2-mediated oxidative stress response, aryl hydrocarbon receptor signaling, LPS/IL-1 mediated inhibition of RXR function, xenobiotic metabolism signaling and metabolism of xenobiotics by cytochrome P450. One biological process common to all compounds, lipid metabolism, was found to be impacted both at the transcriptional and lipid production level. Conclusions/Significance A systems biology strategy was used to identify biochemical pathways affected by five nitroaromatic compounds and to integrate data that tie biochemical alterations to pathological changes. An integrative graphical network model was constructed by combining genomic, gene pathway, lipidomic, and physiological endpoint results to better understand mechanisms of liver toxicity and physiological endpoints affected by these compounds. PMID:21346803
Deng, Youping; Meyer, Sharon A.; Guan, Xin; Escalon, Barbara Lynn; Ai, Junmei; Wilbanks, Mitchell S.; Welti, Ruth; Garcia-Reyero, Nat�lia; Perkins, Edward J.
Chondrokola Rosh (CKR) is a traditional metallic Ayurvedic preparation widely used by the rural and ethnic people of Bangladesh in dysuria. It is a preparation of various roasted metals (Hg and Cu), non-metal (sulphur and Mica) and medicinal herbs. Considering the controversy over the risk of toxic heavy metals in Ayurvedic herbo-mineral preparations, toxicological parameters on liver functions were investigated. A single dose of 100mg/kg body weight of the preparation was administered orally to the rats of both sexes for ninety days. In this evaluation a statistically significant (p<0.001) increase of serum albumin levels in male (17%) and female (15%) rat groups were observed. On the other hand, the plasma bilirubin level was decreased 50% and 28% respectively in both rats groups. But no remarkable differences were observed in plasma protein, sGPT, sGOT and ALP activities from their corresponding control values. This study showed that CKR had no remarkable toxic effect on liver of the animals despite the presence of traces of transformed heavy metals. PMID:22754071
Nasrin, S; Bachar, S C; Choudhuri, M S K
Innate Functions of Immunoglobulin M Lessen Liver Gene Transfer with Helper-Dependent Adenovirus
The immune system poses obstacles to viral vectors, even in the first administration to preimmunized hosts. We have observed that the livers of B cell-deficient mice were more effectively transduced by a helper-dependent adenovirus serotype-5 (HDA) vector than those of WT mice. This effect was T-cell independent as shown in athymic mice. Passive transfer of the serum from adenovirus-na�ve WT to Rag1KO mice resulted in a reduction in gene transfer that was traced to IgM purified from serum of adenovirus-na�ve mice. To ascribe the gene transfer inhibition activity to either adenoviral antigen-specific or antigen-unspecific functions of IgM, we used a monoclonal IgM antibody of unrelated specificity. Both the polyclonal and the irrelevant monoclonal IgM inhibited gene transfer by the HDA vector to either cultured hepatocellular carcinoma cells or to the liver of mice in vivo. Adsorption of polyclonal or monoclonal IgMs to viral capsids was revealed by ELISAs on adenovirus-coated plates. These observations indicate the existence of an inborn IgM mechanism deployed against a prevalent virus to reduce early post-infection viremia. In conclusion, innate IgM binding to adenovirus serotype-5 capsids restrains gene-transfer and offers a mechanism to be targeted for optimization of vector dosage in gene therapy with HDA vectors. PMID:24465560
Unzu, Carmen; Morales-Kastresana, Aizea; Sampedro, Ana; Serrano-Mendioroz, Irantzu; Azpilikueta, Arantza; Ochoa, Maria Carmen; Dubrot, Juan; Martinez-Anso, Eduardo
characterize the two chicken liver proteins; and 4) to prepare and validate polyclonal antisera against A-FABP and the two lipid binding proteins in liver. CHAPTER II LITERATURE REVIEW Much scientific as well as popular attention has focused... characterize the two chicken liver proteins; and 4) to prepare and validate polyclonal antisera against A-FABP and the two lipid binding proteins in liver. CHAPTER II LITERATURE REVIEW Much scientific as well as popular attention has focused...
Sams, Gretchen Hubler
Plasma amino-acid patterns in liver disease.
Plasma amino-acid concentrations were measured in 167 patients with liver disease of varying aetiology and severity, all free of encephalopathy, and the results compared with those in 57 control subjects matched for age and sex. In the four groups of patients with chronic liver disease (26 patients with chronic active hepatitis, 23 with primary biliary cirrhosis, 11 with cryptogenic cirrhosis, and 48 with alcoholic hepatitis +/- cirrhosis) plasma concentrations of methionine were significantly increased, while concentrations of the three branched chain amino-acids were significantly reduced. In the first three groups of patients plasma concentrations of aspartate, serine, and one or both of the aromatic amino-acids tyrosine and phenylalanine were also significantly increased, while in the patients with alcoholic hepatitis +/- cirrhosis plasma concentrations of glycine, alanine, and phenylalanine were significantly reduced. In the three groups of patients with minimal, potentially reversible liver disease (31 patients with alcoholic fatty liver, 10 with viral hepatitis, and 18 with biliary disease) plasma concentrations of proline and the three branched chain amino-acids were significantly reduced. Patients with alcoholic fatty liver also showed significantly reduced plasma phenylalanine values. Most changes in plasma amino-acid concentrations in patients with chronic liver disease may be explained on the basis of impaired hepatic function, portal-systemic shunting of blood, and hyperinsulinaemia and hyperglucagonaemia. The changes in patients with minimal liver disease are less easily explained. PMID:7076013
Morgan, M Y; Marshall, A W; Milsom, J P; Sherlock, S
Effect of perches on liver health of hens.
Fatty liver is a common energy metabolic disorder in caged laying hens. Considering that the egg industry is shifting from conventional cages to alternative housing systems such as enriched cages, the objective of this study was to determine the effects of perches on fat deposition and liver health in laying hens. Three hundred twenty-four 17-wk-old White Leghorn hens were housed in 1 of 4 treatments with 9 hens per cage. Treatment 1 hens never had access to perches during their life cycle. Treatment 2 hens had access to perches during the pullet phase only. Treatment 3 hens had access to perches during the laying phase only. Treatment 4 hens always had access to perches. Liver weight, abdominal fat pad weight, BW, liver fat, and circulating alanine transaminase, aspartate transaminase, and adiponectin were determined. Provision of perches during either the rearing or laying phase did not affect liver health in 71-wk-old hens. However, perch access compared with no perch access during the egg laying phase reduced relative fat pad weight. These results suggest that providing perches as a means of stimulating activity reduced abdominal fat deposition in caged hens during the laying period. However, perch access in caged hens was ineffective in reducing fat deposition in the liver and altering enzyme activities related to improved liver function. PMID:24812236
Jiang, S; Hester, P Y; Hu, J Y; Yan, F F; Dennis, R L; Cheng, H W
Gut-liver axis improves with meloxicam treatment after cirrhotic liver resection
AIM: To investigate the effect of meloxicam on the gut-liver axis after cirrhotic liver resection. METHODS: Forty-four male Wistar rats were assigned to three groups: (1) control group (CG); (2) bile duct ligation with meloxicam treatment (BDL + M); and (3) bile duct ligation without meloxicam treatment (BDL). Secondary biliary liver cirrhosis was induced via ligature of the bile duct in the BDL + M and BDL groups. After 2 wk, the animals underwent a 50% hepatectomy. In the BDL + M group 15 min prior to the hepatectomy, one single dose of meloxicam was administered. Parameters measured included: microcirculation of the liver and small bowel; portal venous flow (PVF); gastrointestinal (GI) transit; alanine aminotransferase (ALT); malondialdehyde; interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-?1) and hypoxia-inducible factor 1 alpha (HIF-1?) levels; mRNA expression of cyclooxigenase-2 (COX-2), IL-6 and TGF-?1; liver and small bowel histology; immunohistochemical evaluation of hepatocyte and enterocyte proliferation with Ki-67 and COX-2 liver expression. RESULTS: Proliferative activity of hepatocytes after liver resection, liver flow and PVF were significantly higher in CG vs BDL + M and CG vs BDL group (P < 0.05), whereas one single dose of meloxicam ameliorated liver flow and proliferative activity of hepatocytes in BDL + M vs BDL group. COX-2 liver expression at 24 h observation time (OT), IL-6 concentration and mRNA IL-6 expression in the liver especially at 3 h OT, were significantly higher in BDL group when compared with the BDL + M and CG groups (P < 0.01, P < 0.001, P < 0.01, respectively). Liver and small bowel histology, according to a semi quantitative scoring system, showed better integrity in BDL + M and CG as compared to BDL group. ALT release and HIF-1? levels at 1 h OT were significantly higher in BDL + M compared to CG and BDL group (P < 0.001 and P < 0.01, respectively). Moreover, ALT release levels at 3 and 24 h OT were significantly higher in BDL group compared to CG, P < 0.01. GI transit, enterocyte proliferative activity and number of goblet cells were in favor of meloxicam treatment vs BDL group (P < 0.05, P < 0.001, P < 0.01, respectively). Additionally, villus length were higher in BDL + M as compared to BDL group. CONCLUSION: One single dose of meloxicam administered after cirrhotic liver resection was able to cause better function and integrity of the remaining liver and small bowel. PMID:25356044
Hamza, Astrit R; Krasniqi, Avdyl S; Srinivasan, Pramod Kadaba; Afify, Mamdouh; Bleilevens, Christian; Klinge, Uwe; Tolba, Rene H
MRI-based estimation of liver function: Gd-EOB-DTPA-enhanced T1 relaxometry of 3T vs. the MELD score
Gd-EOB-DTPA is a hepatocyte-specific MRI contrast agent. Due to its hepatocyte-specific uptake and paramagnetic properties, functioning areas of the liver exhibit shortening of the T1 relaxation time. We report the potential use of T1 relaxometry of the liver with Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) for estimating the liver function as expressed by the MELD score. 3 T MRI relaxometry was performed before and 20?min after Gd-EOB-DTPA administration. A strong correlation between changes in the T1 relaxometry and the extent of liver disease, expressed by the MELD score, was documented. Reduced liver function correlates with decreased Gd-EOB-DTPA accumulation in the hepatocytes during the hepatobiliary phase. MRI-based T1 relaxometry with Gd-EOB-DTPA may be a useful method for assessing overall and segmental liver function. PMID:25001391
Haimerl, Michael; Verloh, Niklas; Fellner, Claudia; Zeman, Florian; Teufel, Andreas; Feigl, Stefan Fichtner-; Schreyer, Andreas G.; Stroszczynski, Christian; Wiggermann, Philipp
Liver transplantation is the ultimate treatment for severe hepatic failure to date. However, the limited supply of donor organs has severely hampered this treatment. So far, great potentials of using mesenchymal stem cells (MSCs) to replenish the hepatic cell population have been shown; nevertheless, there still is a lack of an optimal three-dimensional scaffold for generation of well-transplantable hepatic tissues. In this study, we utilized a cryo-chemical decellularization method which combines physical and chemical approach to generate acellular liver scaffolds (ALS) from the whole liver. The produced ALS provides a biomimetic three-dimensional environment to support hepatic differentiation of MSCs, evidenced by expression of hepatic-associated genes and marker protein, glycogen storage, albumin secretion, and urea production. It is also found that hepatic differentiation of MSCs within the ALS is much more efficient than two-dimensional culture in vitro. Importantly, the hepatic-like tissues (HLT) generated by repopulating ALS with MSCs are able to act as functional grafts and rescue lethal hepatic failure after transplantation in vivo. In summary, the cryo-chemical method used in this study is suitable for decellularization of liver and create acellular scaffolds that can support hepatic differentiation of MSCs and be used to fabricate functional tissue-engineered liver constructs. PMID:24462361
Jiang, Wei-Cheng; Cheng, Yu-Hao; Yen, Meng-Hua; Chang, Yin; Yang, Vincent W; Lee, Oscar K
Oxygen uptake rates and liver-specific functions of hepatocyte and 3T3 fibroblast co-cultures.
Bioartificial liver (BAL) devices have been developed to treat patients undergoing acute liver failure. One of the most important parameters to consider in designing these devices is the oxygen consumption rate of the seeded hepatocytes which are known to have oxygen consumption rates 10 times higher than most other cell types. Hepatocytes in various culture configurations have been tested in BAL devices including those formats that involve co-culture of hepatocytes with other cell types. In this study, we investigated, for the first time, oxygen uptake rates (OUR)s of hepatocytes co-cultured with 3T3-J2 fibroblasts at various hepatocyte to fibroblast seeding ratios. OURs were determined by measuring the rate of oxygen disappearance using a ruthenium-coated optical probe after closing and sealing the culture dish. Albumin and urea production rates were measured to assess hepatocyte function. Lower hepatocyte density co-cultures demonstrated significantly higher OURs (2 to 3.5-fold) and liver- specific functions (1.6-fold for albumin and 4.5-fold for urea production) on a per cell basis than those seeded at higher densities. Increases in OUR correlated well with increased liver-specific functions. OURs (V(m)) were modeled by fitting Michaelis-Menten kinetics and the model predictions closely correlated with the experimental data. This study provides useful information for predicting BAL design parameters that will avoid oxygen limitations, as well as maximize metabolic functions. PMID:17054120
Cho, Cheul H; Park, Jaesung; Nagrath, Deepak; Tilles, Arno W; Berthiaume, Fran�ois; Toner, Mehmet; Yarmush, Martin L
Specimens of mullet (Mugil cephalus), a marine fish, were given single doses of 3-methylcholanthrene intraperitoneally and the activity of the microsomal mixed-function oxygenase system in the liver was measured by the metabolism of benzo(a)-pyrene. The enzyme system was found to...
Alanine Aminotransferase-Old Biomarker and New Concept: A Review
Measurement of serum alanine aminotransferase (ALT) is a common, readily available, and inexpensive laboratory assay in clinical practice. ALT activity is not only measured to detect liver disease, but also to monitor overall health. ALT activity is influenced by various factors, including viral hepatitis, alcohol consumption, and medication. Recently, the impact of metabolic abnormalities on ALT variation has raised concern due to the worldwide obesity epidemic. The normal ranges for ALT have been updated and validated considering the metabolic covariates in the various ethnic districts. The interaction between metabolic and demographic factors on ALT variation has also been discussed in previous studies. In addition, an extremely low ALT value might reflect the process of aging, and frailty in older adults has been raised as another clinically significant feature of this enzyme, to be followed with additional epidemiologic investigation. Timely updated, comprehensive, and systematic introduction of ALT activity is necessary to aid clinicians make better use of this enzyme. PMID:25013373
Liu, Zhengtao; Que, Shuping; Xu, Jing; Peng, Tao
Background Deregulated energetics is a property of most cancer cells. This phenomenon, known as the Warburg Effect or aerobic glycolysis, is characterized by increased glucose uptake, lactate export and extracellular acidification, even in the presence of oxygen. ?-alanine is a non-essential amino acid that has previously been shown to be metabolized into carnosine, which functions as an intracellular buffer. Because of this buffering capacity, we investigated the effects of ?-alanine on the metabolic cancerous phenotype. Methods Non-malignant MCF-10a and malignant MCF-7 breast epithelial cells were treated with ?-alanine at 100 mM for 24 hours. Aerobic glycolysis was quantified by measuring extracellular acidification rate (ECAR) and oxidative metabolism was quantified by measuring oxygen consumption rate (OCR). mRNA of metabolism-related genes was quantified by qRT-PCR with corresponding protein expression quantified by immunoblotting, or by flow cytometry which was verified by confocal microscopy. Mitochondrial content was quantified using a mitochondria-specific dye and measured by flow cytometry. Results Cells treated with ?-alanine displayed significantly suppressed basal and peak ECAR (aerobic glycolysis), with simultaneous increase in glucose transporter 1 (GLUT1). Additionally, cells treated with ?-alanine exhibited significantly reduced basal and peak OCR (oxidative metabolism), which was accompanied by reduction in mitochondrial content with subsequent suppression of genes which promote mitochondrial biosynthesis. Suppression of glycolytic and oxidative metabolism by ?-alanine resulted in the reduction of total metabolic rate, although cell viability was not affected. Because ?-alanine treatment reduces extracellular acidity, a constituent of the invasive microenvironment that promotes progression, we investigated the effect of ?-alanine on breast cell viability and migration. ?-alanine was shown to reduce both cell migration and proliferation without acting in a cytotoxic fashion. Moreover, ?-alanine significantly increased malignant cell sensitivity to doxorubicin, suggesting a potential role as a co-therapeutic agent. Conclusion Taken together, our results suggest that ?-alanine may elicit several anti-tumor effects. Our observations support the need for further investigation into the mechanism(s) of action and specificity of ?-alanine as a co-therapeutic agent in the treatment of breast tumors. PMID:24460609
Structures of dense glycine and alanine adlayers on chiral Cu(3,1,17) surfaces.
Density Functional Theory calculations have been used to predict the structures of dense glycine and alanine adlayers on Cu(3,1,17)(S). Facets of this chiral Cu surface result from adsorbate-induced surface reconstruction when glycine or alanine are adsorbed and annealed on Cu(100). We have calculated the surface energy changes associated with this surface reconstruction. Our results allow the enantiospecificity of this reconstruction following adsorption of enantiopure or racemic alanine on Cu(100) to be discussed. The overall stability of glycine and alanine adlayers on Cu(3,1,17)(S) arises from an interplay between the formation of chemical bonds with the Cu surface, deformations in the adsorbed molecules during adsorption, and intermolecular hydrogen bonds within the adlayer; none of these factors individually dominates. PMID:16952247
Rankin, Rees B; Sholl, David S
Given the tremendous importance of mitochondria to basic cellular functions as well as the critical role of mitochondrial impairment in a vast number of disorders, a compelling question is whether 17{beta}-estradiol (E2) modulates mitochondrial function. To answer this question we exposed isolated liver mitochondria to E2. Three groups of rat females were used: control, ovariectomized and ovariectomized treated with tamoxifen. Tamoxifen has antiestrogenic effects in the breast tissue and is the standard endocrine treatment for women with breast cancer. However, under certain circumstances and in certain tissues, tamoxifen can also exert estrogenic agonist properties. We observed that at basal conditions, ovariectomy and tamoxifen treatment do not induce any statistical alteration in oxidative phosphorylation system and respiratory chain parameters. Furthermore, tamoxifen treatment increases the capacity of mitochondria to accumulate Ca{sup 2+} delaying the opening of the permeability transition pore. The presence of 25 {mu}M E2 impairs respiration and oxidative phosphorylation system these effects being similar in all groups of animals studied. Curiously, E2 protects against lipid peroxidation and increases the production of H{sub 2}O{sub 2} in energized mitochondria of control females. Our results indicate that E2 has in general deleterious effects that lead to mitochondrial impairment. Since mitochondrial dysfunction is a triggering event of cell degeneration and death, the use of exogenous E2 must be carefully considered.
Moreira, Paula I. [Center for Neuroscience and Cell Biology, University of Coimbra, 3005-504 Coimbra (Portugal); Institute of Physiology, Faculty of Medicine, University of Coimbra, 3005-504 Coimbra (Portugal); Custodio, Jose B.A. [Center for Neuroscience and Cell Biology, University of Coimbra, 3005-504 Coimbra (Portugal); Institute of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3005-504 Coimbra (Portugal); Nunes, Elsa [Center for Neuroscience and Cell Biology, University of Coimbra, 3005-504 Coimbra (Portugal); Institute of Physiology, Faculty of Medicine, University of Coimbra, 3005-504 Coimbra (Portugal); Moreno, Antonio [Center for Neuroscience and Cell Biology, University of Coimbra, 3005-504 Coimbra (Portugal); Department of Zoology, Faculty of Sciences and Technology, University of Coimbra, 3005-504 Coimbra (Portugal); Institute of Marine Research, University of Coimbra, 3005-504 Coimbra (Portugal); Seica, Raquel [Center for Neuroscience and Cell Biology, University of Coimbra, 3005-504 Coimbra (Portugal); Institute of Physiology, Faculty of Medicine, University of Coimbra, 3005-504 Coimbra (Portugal); Oliveira, Catarina R. [Center for Neuroscience and Cell Biology, University of Coimbra, 3005-504 Coimbra (Portugal); Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3005-504 Coimbra (Portugal); Santos, Maria S. [Center for Neuroscience and Cell Biology, University of Coimbra, 3005-504 Coimbra (Portugal) and Department of Zoology, Faculty of Sciences and Technology, University of Coimbra, 3005-504 Coimbra (Portugal)]. E-mail: email@example.com
Functional imaging biomarkers for assessing response to treatment in liver and lung metastases
Abstract Management of patients with metastatic cancer and development of new treatments rely on imaging to provide non-invasive biomarkers of tumour response and progression. The widely used size-based criteria have increasingly become inadequate where early measures of response are required to avoid toxicity of ineffective treatments, as biological, physiologic, and molecular modifications in tumours occur before changes in gross tumour size. A multiparametric approach with the current range of imaging techniques allows functional aspects of tumours to be simultaneously interrogated. Appropriate use of these imaging techniques and their timing in relation to the treatment schedule, particularly in the context of clinical trials, is fundamental. There is a lack of consensus regarding which imaging parameters are most informative for a particular disease site and the best time to image so that, despite an increasing body of literature, open questions on these aspects remain. In addition, standardization of these new parameters is required. This review summarizes the published literature over the last decade on functional and molecular imaging techniques in assessing treatment response in liver and lung metastases. PMID:24334562
O'Flynn, Elizabeth A.M.; deSouza, Nandita M.
Patients with hepatitis C infection and normal liver function: an evaluation of cognitive function
Purpose of the study Hepatitis C virus (HCV) is associated with neuropsychiatric complaints. Previous studies have associated cognitive alterations with HCV infection but have often included confounding factors in their samples. This study compares the cognitive performance between patients with HCV infection (HCV patients) and a control group while excluding other factors that may cause cognitive impairment. Study design This cross-sectional study was conducted from March 2010 through June 2011. HCV infected patients and healthy individuals between the ages of 18 and 80?years were considered eligible. The exclusion criteria included well established causes of cognitive impairment such as depression and cirrhosis. Study participants underwent neuropsychological testing involving measures of attention, memory, abstraction, visuoconstructive abilities, and executive function. Results Of 138 initial patients, 47 were excluded because of their medical records, three refused to participate, 23 did not attend the consultation, and 32 were excluded because of having Beck Depression Inventory (BDI) scores >11. In all, 33 patients underwent neuropsychological testing; however, three were excluded because of having hypothyroidism, and one was excluded because of having a cobalamin deficiency. For the control group, of the 33 healthy individuals that were selected, four were excluded because of having BDI scores >11. Thus, the final analysis included 29 HCV patients and 29 control participants. The groups did not differ in education, age, or gender. No statistically significant differences were found between the groups regarding cognitive performance. Conclusions In this study using strict selection criteria, there was no evidence of an association between HCV infection and cognitive impairment. PMID:23625064
Abrantes, Jefferson; Torres, Daniel Simplicio; de Mello, Carlos Eduardo Brandao
Succinate and alanine as anaerobic end-products in the diving turtle ( Chrysemys picta bellii)
The western painted turtle is an extremely anoxia-tolerant vertebrate capable of tolerating blood lactate levels of 150�200 mM. Since lactate increases to such high levels, other fermentation end-products such as succinate and alanine, which have not been previously measured in this species, might also be expected to increase. Therefore, I measured turtle heart, liver, and blood concentrations of lactate, succinate,
L. T Buck
Liver fibrosis in overweight patients
Background & Aims: A common clinical issue is whether overweight patients with abnormal liver function test results should undergo liver biopsy. Although serious liver injury can occur, its prevalence and risk factors are not well known. Methods: Ninety-three consecutive patients with abnormal liver function tests (but without overt liver disease), body mass index (BMI) > 25 kg\\/m2, and no alcoholic,
Vlad Ratziu; Philippe Giral; Frederic Charlotte; Eric Bruckert; Vincent Thibault; Ioannis Theodorou; Lina Khalil; G�rard Turpin; Pierre Opolon; Thierry Poynard
NSDL National Science Digital Library
Students learn the function of the liver and how biomedical engineers can use liver regeneration to help people. Students test the effects of toxic chemicals on a beef liver by adding hydrogen peroxide to various liver and salt solutions. They observe, record and graph their results.
Integrated Teaching And Learning Program
Antioxidative natural product protect against econazole-induced liver injuries.
The study objective of this research is in order to investigate the hepatoprotective and therapeutic effects of propolis ethanol extract (PEE) on acute econazole-induced liver injury. Positive control of various concentrations of PEE on liver function and the dose-response relationship of liver injury induced by various doses of econazole were firstly observed from biochemical assay of serum level of aspartate transaminase (SGOT) and serum alanine transaminase (SGPT) and histopathological microscopic examination. The hepatoprotective effects of various concentration of PEE on liver damage induced by hepatotoxic dose (300 mg/kg) of econazole were observed by the obvious decrement of SGOT and SGPT level and further confirmed by hepatohistological microscopic examination. The inhibitory effects of PEE on FeCl(2)-induced (in vitro) or econazole-induced (in vivo) lipid peroxidation were investigated from the measurement of the formed malonic dialdehyde (MDA) level in the rat liver homogenate. The IC(50) (microM) of various concentrations of PEE in the superoxide scavenging activity in econazole (300 mg/kg)-damaged rat liver homogenate were assessed by cytochrome c reduction method and compared with that of (+)-alpha-tocopherol. It could be postulated that the hepatoprotective effect of PEE may be, at least in part, due to their inhibitory ability on membrane lipid peroxidation and free radical formation or due to their free radical scavenging ability. PMID:15036759
Liu, Chi-Feng; Lin, Chia-Hsien; Lin, Chun-Ching; Lin, Yun-Ho; Chen, Chin-Fa; Lin, Chao-Kuang; Lin, Song-Chow
Objective To evalueate hepatoprotective effects Feronia elephantum (F. elephantum) correa against thioacetamide (TA) induced liver necrosis in diabetic rats. Methods Male wistar rats were made diabetic with alloxan (160 mg/kg) on day 0 of the study. They were intoxicated with hepatotoxicant (thioacetamide, 300 mg/kg, ip) on day 9 of study to produce liver necrosis. Effects of 7 day daily once administration (day 2 to day 9) of EF (400 and 800 mg/kg, po) were evaluated on necorosis of liver in terms of mortality, liver volume, liver weight, serum aspartate aminotransferase (AST) and serum alanine transaminase (ALT), and histopathology of liver sections (for signs of necorosis and inflammation) on day-9 of the study. Separate groups of rats with treated only with alloxan (DA control), thioacetamide (TA control) and both (TA+DA control) were maintained. Results FE significantly lowered the mortality rate and showed improvement in liver function parameters in TA-induced diabetic rats without change in liver weight, volume and serum glucose levels. Conclusions FE showed promising activity against TA-induced liver necorsis in diabetic rats and so might be useful for prevention of liver complications in DM. PMID:23569996
Sharma, Prashant; Bodhankar, Subhash L; Thakurdesai, Prasad A
A prospective observational study of 229 cases was conducted in a busy ambulatory care setting to evaluate the sensitivity, specificity, predictive values, and accuracy of spot urine urobilinogen and urine bilirubin assays as screening tests for serum liver function test (LFT) abnormalities. Both urine tests exhibited remarkably similar characteristics overall once they were adjusted to maximize accuracy and predictive values (occurring at a normal or abnormal "threshold," respectively, of 3.4 or 5.07 mumol/d for urobilinogen and 0 or 1+ for urine bilirubin). The percentage of cases correctly identified were 81% to 83% for serum bilirubin assays, 68% to 72% for other LFTs, but only 62% to 63% for screens for cases with at least one abnormal LFT finding. Poor sensitivities (47% to 49%) limited the detection of abnormal findings by the screen; both screens were reasonably specific (79% to 89%), but negative predictive values were suitable (89%) for serum bilirubin results only and were prohibitively lower (49% to 50%) in predicting all patients without LFT abnormalities. We conclude that spot urine urobilinogen and urine bilirubin determinations, although good screens for isolated serum bilirubin elevations, have unacceptable statistical properties as predictors of other LFT results due to a high proportion of false-negative results. PMID:2642693
Binder, L; Smith, D; Kupka, T; Nelson, B; Glass, B; Wainscott, M; Haynes, J
Functional reconstitution of the canalicular bile salt transport system of rat liver.
Recent studies have suggested that the canalicular bile salt transport system of rat liver corresponds to a 100-kDa membrane glycoprotein. In the present study we attempted to functionally reconstitute the 100-kDa protein into artificial proteoliposomes. Canalicular membrane proteins were solubilized with octyl glucoside in the presence of asolectin phospholipids. The extracts were treated with preimmune serum or the 100-kDa protein selectively immunoprecipitated with a polyclonal antiserum. Proteins remaining in the supernatant were then incorporated into proteoliposomes by gel-filtration chromatography. Canalicular proteoliposomes containing the 100-kDa protein exhibited transstimulatable taurocholate uptake that could be inhibited by 4,4'-diisothiocyanato-2,2'-stilbenedisulfonic acid (DIDS). In contrast, no DIDS-sensitive transstimulatable taurocholate uptake was found in 100-kDa protein-free canalicular proteoliposomes. However, when the immunoprecipitated 100-kDa protein was dissociated from the antibodies and exclusively incorporated into liposomes, reconstitution of DIDS-sensitive transstimulatable and electrogenic taurocholate anion transport was again positive. Although incorporation of solubilized basolateral membrane proteins into liposomes also resulted in a prompt reconstitution of Na+ gradient-driven taurocholate uptake, the anti-100-kDa antibodies had no effects on the reconstituted transport activity of basolateral proteins. Thus, the findings establish that the previously characterized canalicular-specific 100-kDa protein is directly involved in the transcanalicular secretion of bile salts. Images PMID:3413083
Ruetz, S; Hugentobler, G; Meier, P J
Cultured mycelium Cordyceps sinensis (CMCS) was widely used for a variety of diseases including liver injury, the current study aims to investigate the protective effects of CMCS on liver sinusoidal endothelial cells (LSECs) in acute injury liver and related action mechanisms. The mice were injected intraperitoneally with lipopolysaccharide (LPS) and D-galactosamine (D-GalN). 39 male BABL/c mice were randomly divided into four groups: normal control, model control, CMCS treatment and 1,10-phenanthroline treatment groups. The Serum liver function parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were assayed with the commercial kit. The inflammation and scaffold structure in liver were stained with hematoxylin and eosin and silver staining respectively. The LSECs and sub-endothelial basement membrane were observed with the scanning and transmission electronic microscope. The protein expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in liver were analyzed with Western blotting. Expression of von Willebrand factor (vWF) was investigated with immunofluorescence staining. The lipid peroxidation indicators including antisuperoxideanion (ASAFR), hydroxyl free radical (�OH), superoxide dismutase (SOD), malondialdehyde and glutathione S-transferase (GST) were determined with kits, and matrix metalloproteinase-2 and 9 (MMP-2/9) activities in liver were analyzed with gelatin zymography and in situ fluorescent zymography respectively. The model mice had much higher serum levels of ALT and AST than the normal mice. Compared to that in the normal control, more severe liver inflammation and hepatocyte apoptosis, worse hepatic lipid peroxidation demonstrated by the increased ASAFR, �OH and MDA, but decreased SOD and GST, increased MMP-2/9 activities and VCAM-1, ICAM-1 and vWF expressions, which revealed obvious LSEC injury and scaffold structure broken, were shown in the model control. Compared with the model group, CMCS and 1,10-phenanthroline significantly improved serum ALT/AST, attenuated hepatic inflammation and improved peroxidative injury in liver, decreased MMP-2/9 activities in liver tissue, improved integration of scaffold structure, and decreased protein expression of VCAM-1 and ICAM-1. CMCS could protect LSECs from injury and maintain the microvasculature integration in acute injured liver of mice induced by LPS/D-GalN. Its action mechanism was associated with the down-regulation of MMP-2/9 activities and inhibition of peroxidation in injured liver. PMID:24442316
Peng, Yuan; Chen, Qian; Yang, Tao; Tao, Yanyan; Lu, Xiong; Liu, Chenghai
Effect of various alanine analogues on the L-alanine-adding enzyme from Escherichia coli.
An extract from Escherichia coli containing the L-alanine-adding enzyme with a high specific activity was prepared. Several compounds structurally related to L-alanine were tested as inhibitors of this activity. Intact amino and carboxyl groups were necessary for an interaction with the enzyme. Certain halogenated (haloalanines) or unsaturated (L-vinylglycine, L-propargylglycine, 3-cyano-L-alanine) amino acids were good inhibitors. Radioactive glycine, serine and 1-aminoethylphosphonic acid were tested as substrates. Whereas glycine or L-serine gave rise to the formation of the corresponding nucleotide product, no synthesis of UDP-N-acetylmuramyl-L-1-aminoethylphosphonic acid could be detected. PMID:1855644
Liger, D; Blanot, D; van Heijenoort, J
Experimental autoimmune hepatitis was produced by immunizing Wistar rats with syngeneic liver proteins. Mononuclear cells infiltrating the liver tissue were identified by immunohistochemical techniques using monoclonal antibodies specific for subpopulations of rat lymphocytes. The strong infiltration of CD8+ cytotoxic T lymphocytes (CTL) were found in the portal areas. Subpopulations of mononuclear cells infiltrating the liver, spleen cells and peripheral blood lymphocytes were identified by flow cytometry. Flow cytometric analysis revealed the presence of CD5- and CD8+ lymphocytes in the liver tissues. Mononuclear cells infiltrating the liver were isolated from Wistar rats having autoimmune hepatitis to determine whether those exhibit cytotoxicity against syngeneic hepatocytes; they exhibited cytotoxicity against isolated syngeneic hepatocytes, but failed to lyse K562 cells, syngeneic concanavalin A-activated splenocytes and allogeneic hepatocytes. Depletion of CD8+ T cells significantly reduced the cytotoxic ability of mononuclear cells infiltrating into the liver against syngeneic hepatocytes. These findings support the idea that liver cell injury in experimental autoimmune hepatitis may at least in part be mediated by CTL. Images Fig. 1 PMID:2265486
Kohda, H; Sekiya, C; Kanai, M; Yoshida, Y; Uede, T; Kikuchi, K; Namiki, M
In this article, we report on the expression and function of a Na(+)-coupled transporter for citrate, NaCT, in human and rat liver cell lines and in primary hepatocytes from the rat liver. We also describe the polarized expression of this transporter in human and rat livers. Citrate uptake in human liver cell lines HepG2 and Huh-7 was obligatorily dependent on Na+. The uptake system showed a preference for citrate over other intermediates of the citric acid cycle and exhibited a Michaelis constant of approximately 6 mM for citrate. The transport activity was stimulated by Li+, and the activation was associated with a marked increase in substrate affinity. Citrate uptake in rat liver cell line MH1C1 was also Na+ dependent and showed a preference for citrate. The Michaelis constant for citrate was approximately 10 microM. The transport activity was inhibited by Li+. Primary hepatocytes from the rat liver also showed robust activity for Na+-coupled citrate uptake, with functional features similar to those described in the rat liver cell line. Immunolabeling with a specific anti-NaCT antibody showed exclusive expression of the transporter in the sinusoidal membrane of hepatocytes in human and rat livers. This constitutes the first report on the expression and function of NaCT in liver cells. PMID:16973915
Gopal, Elangovan; Miyauchi, Seiji; Martin, Pamela M; Ananth, Sudha; Srinivas, Sonne R; Smith, Sylvia B; Prasad, Puttur D; Ganapathy, Vadivel
Liver bioengineering has been a field of intense research and popular excitement in the past decades. It experiences great interest since the introduction of whole liver acellular scaffolds generated by perfusion decellularization1�3. Nevertheless, the different strategies developed so far have failed to generate hepatic tissue in vitro bioequivalent to native liver tissue. Even notable novel strategies that rely on iPSC-derived liver progenitor cells potential to self-organize in association with endothelial cells in hepatic organoids are lacking critical components of the native tissue (e.g., bile ducts, functional vascular network, hepatic microarchitecture, etc)4. Hence, it is vital to understand the strengths and short comes of our current strategies in this quest to re-create liver organogenesis in vitro. To shed some light into these issues, this review describes the different actors that play crucial roles in liver organogenesis and highlights the steps still missing to successfully generate whole livers and hepatic organoids in vitro for multiple applications. PMID:25102189
Caralt, Mireia; Velasco, Enrique; Lanas, Angel; Baptista, Pedro M
cipitation using anti-HNF6 antibodies was performed on chromatin isolated from Foxa2 loxP\\/loxP Alfp.Cre and control mouse livers, and HNF6 binding to its target, Glut2, was determined by quantitative PCR. In contrast to the current model, we found no significant difference in HNF6 occupancy at the Glut2 promoter between Foxa2-deficient and control livers. In order to evaluate the Foxa2\\/HNF6 interaction model
Nir E. Rubins; Joshua R. Friedman; Phillip P. Le; Liping Zhang; John Brestelli; Klaus H. Kaestner
Biliobiliary fistulas manifested by worsening liver function--a case report.
We report a case of cholecystolithiasis with biliobiliary fistulas from gallbladder to hepatic ducts, which were manifested by worsening liver dysfunction. Although it was not diagnosed preoperatively, it was successfully treated by cholecystectomy with closure of fistulas by the gallbladder wall. This case suggests that an internal biliary fistula may be possible, when the gallbladder wall is thickened and shrunken in the case of cholecystolithiasis, accompanied with liver dysfunction despite no dilatation of the common bile duct. PMID:16001637
Ishikawa, Takashi; Yoshida, Shun; Sekido, Hitoshi; Morioka, Daisuke; Akiyama, Hirotoshi; Ichikawa, Yasushi; Endo, Itaru; Masunari, Hideki; Togo, Shinji; Kobayashi, Hideo; Shimada, Hiroshi
Intrauterine growth retardation (IUGR) leads to the dysfunction in digestive system, as well as the alteration in the expression of some functional proteins. Heat shock protein 70 (Hsp70) could be induced by various stress factors, but whether Hsp70 expression is changed in neonatal IUGR infants has not been demonstrated. This study was conducted to explore the expression of Hsp70 in the liver by using the IUGR piglet model. Liver and plasma samples were obtained from IUGR and normal birth weight (NBW) piglets at birth. The neonatal IUGR piglets had significantly lower liver weight than their counterparts. The activities of aspartate aminotransferase and alanine aminotransferase in serum were enhanced significantly in IUGR indicating liver dysfunction. The activities of superoxide dismutase (p<0.01), glutathione peroxidase (p<0.01) and catalase (p>0.05) were lower and the level of malondialdehybe was higher (p<0.05) in IUGR liver compared with in NBW. According to the results of histological tests, fatty hepatic infiltrates and cytoplasmic vacuolization were present in the liver of IUGR piglets, but not in NBW liver. The expression of Hsp70 protein was significantly higher (p<0.05) in IUGR piglet liver than in NBW. Similar to where the hepatic injuries were observed, location of Hsp70 was mostly in the midzonal hepatic lobule indicating that oxidative stress might be responsible for the increased expression of Hsp70. PMID:25049668
Li, Wei; Zhong, Xiang; Zhang, Lili; Wang, Yuanxiao; Wang, Tian
The architectural arrangement and selected histochemical properties of hepatocytes in the rainbow trout (Salmo gairdneri Richardson) were examined. Light and transmission electron microscopic (TEM) examination following fixation by portal venous perfusion revealed a tubular arrangement of hepatocytes. Lobules, as defined in the adult mammal, were absent. Biliary epithelial cells associated with bile preductules and ductules were a prominent feature of trout liver. Patterns and location of reaction products for glucose-6-phosphatase (G-6-Pase), glucose-6-phosphate dehydrogenase (G-6-PDH), and magnesium-dependent adenosine triphosphatase (ATPase), enzymes preferentially distributed in mammalian liver, were demonstrated in trout liver. A slightly heavier staining pattern for G-6-Pase was seen around presumptive portal venules but all other enzyme reaction patterns were uniform throughout the liver parenchyma. Following ATPase localization, four sizes of biliary passageways (canaliculi, bile preductules, ductules, and ducts) were visualized. Maximum glycogen retention was achieved with freeze-drying and glycolmethacrylate embedding and with this method intense, uniform glycogen staining was observed in all areas of the liver. Companion TEM examinations revealed large depots of glycogen within hepatocytes. The results are important for interpretation and description of the effects of toxic/carcinogenic alteration on trout liver. PMID:3000224
Hampton, J A; McCuskey, P A; McCuskey, R S; Hinton, D E
The objective of this study was to determine the effects of a country liquor Toddy (Coconut palm wine) and an equivalent quantity of ethanol on liver function and lipid metabolism in utero. Female albino rats with an average weight of 125� 5 g were exposed to Toddy from coconut palm (24.5 ml\\/kg-1 body weight\\/day) and ethanol (0.52 ml\\/kg body weight\\/day)
John. J. Lal; C. V. Sreeranjit Kumar; M. V. Suresh; M. Indira; P. L. Vijayammal
Effect of feeding enzymatically detoxified aflatoxin-B1 diet on liver function test of wistar rats
Purpose � The purpose of this paper is to evaluate safety of the enzymatic treatment (garlic peroxidase) for removing aflatoxin B1 (AFB1) from foods. Design\\/methodology\\/approach � An in vivo study was carried out on male wistar rats for three weeks. Since AFB1 is a hepatotoxic; the effect of AFB1 and the enzymatic detoxification of AFB1 on the liver function was
Smita Tripathi; Hari Niwas Mishra
Juvenile white sturgeon (Acipenser transmontanus) were fed three isonitrogenous and isoenergetic diets containing either 35% D-glucose (HC), a mixture of 20% dextrin and\\u000a 10% cellulose (MC), or 23% cellulose (LC), to investigate the effects of dietary carbohydrate on liver function. After 8-week\\u000a feeding, body weight gain of fish fed the HC diet was consistently higher than that of fish fed
Kofi Fynn-Aikins; Silas S. O. Hung; Steven G. Hughes
The present study was carried out to assess the endocrine status and liver function in adult cows reared in polluted environment around different industrial units in India.The effect on endocrine system was examined by determination of plasma level of thyroid hormones, thyroxin (T4) (n=269) and triidothyronin (T3) (n=269), stress hormone cortisol (n=266), and reproductive hormones such as estradiol (n=84) and
D. Swarup; Ram Naresh; V. P. Varshney; M. Balagangatharathilagar; P. Kumar; D. Nandi; R. C. Patra
The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver
LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1�SIK pathway functions as a key gluconeogenic gatekeeper in the liver. PMID:25088745
Patel, Kashyap; Foretz, Marc; Marion, Allison; Campbell, David G.; Gourlay, Robert; Boudaba, Nadia; Tournier, Emilie; Titchenell, Paul; Peggie, Mark; Deak, Maria; Wan, Min; Kaestner, Klaus H.; Goransson, Olga; Viollet, Benoit; Gray, Nathanael S.; Birnbaum, Morris J.; Sutherland, Calum; Sakamoto, Kei
In the current study, the therapeutic effects of zeaxanthin dipalmitate (ZD) on a rat alcoholic fatty liver disease (AFLD) model were evaluated. After-treatment with ZD from the 5th week to the 10th week in a 10-week ethanol intragastric administration in rats significantly alleviated the typical AFLD symptoms, including reduction in rat body weight, accumulation of hepatic fat droplets, occurrence of oxidative stress, inflammation, chemoattractive responses and hepatic apoptosis in the liver. The reduction of liver function abnormalities by ZD was partly through lower expression level of cytochrome P450 2E1 (CYP2E1), diminished activity of nuclear factor kappa B (NF-?B) through the restoration of its inhibitor kappa B alpha (I?B?), and the modulation of MAPK pathways including p38 MAPK, JNK and ERK. ZD treatment alone did not pose obvious adverse effect on the healthy rat. In the cellular AFLD model, we also confirmed the inhibition of p38 MAPK and ERK abolished the beneficial effects of ZD. These results provide a scientific rationale for the use of zeaxanthin and its derivatives as new complementary agents for the prevention and treatment of alcoholic liver diseases. PMID:24740309
Xing, Feiyue; Han, Tao; Jiao, Rui; Liong, Emily C.; Fung, Man-Lung; So, Kwok-Fai; Tipoe, George L.
The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.
LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver. PMID:25088745
Patel, Kashyap; Foretz, Marc; Marion, Allison; Campbell, David G; Gourlay, Robert; Boudaba, Nadia; Tournier, Emilie; Titchenell, Paul; Peggie, Mark; Deak, Maria; Wan, Min; Kaestner, Klaus H; G�ransson, Olga; Viollet, Benoit; Gray, Nathanael S; Birnbaum, Morris J; Sutherland, Calum; Sakamoto, Kei
Purification and properties of alanine racemase from crayfish Procambarus clarkii
Fresh water crayfish Procambarusclarkii is known to accumulate d-alanine remarkably in muscle after seawater acclimation, accompanied by an increase in alanine racemase activity. We have purified alanine racemase from crayfish muscle to homogeneity. The enzyme is a monomeric protein with a molecular mass of 58 kDa. It is highly specific to alanine and does not racemize l-serine, l-aspartate, l-glutamate, l-valine
Kimihiko Shibata; Katsushi Shirasuna; Kengo Motegi; Yoshio Kera; Hiroki Abe; Ryo-hei Yamada
Monitoring hepatic function in children with short bowel syndrome (SBS) and parenteral nutrition-associated liver disease (PNALD) is currently limited to conventional blood testing or liver biopsy. Metabolism of the stable isotope L[1-13C]methionine occurs exclusively in liver mitochondria and can be noninvasively quantified in expired breath samples. We hypothesized that the 13C-methionine breath test (13C-MBT) could be a safe, noninvasive, and valid measure of hepatic mitochondrial function in children with SBS and PNALD. Methods Baseline breath samples were collected in 8 children with SBS before intravenous administration of 2 mg/kg of L[1-13C]methionine. Six paired breath samples were obtained at 20-minute intervals. The 13CO2 enrichment was analyzed using isotope ratio mass spectrometry. Results All 8 patients (5 males; mean age, 8.9 months) tolerated the 13C-MBT without adverse events. Two patients underwent serial testing. One patient, tested before and after resolution of cholestasis, demonstrated increased cumulative percentage dose (4.7% to 6.6%) and area under the curve (AUC) (270�303). A second patient with progressive PNALD demonstrated decreased cumulative percentage dose (from 7.8% to 5.9%) and AUC (from 335 to 288). Conclusion The 13C-MBT is a feasible, safe, and potentially clinically relevant measure of hepatic mitochondrial function in children with SBS and PNALD. PMID:19159749
Duro, Debora; Duggan, Christopher; Valim, Clarissa; Bechard, Lori; Fitzgibbons, Shimae; Jaksic, Tom; Yu, Yong-Ming
Code of Federal Regulations, 2011 CFR
...ADDITION TO FOOD FOR HUMAN CONSUMPTION Flavoring Agents and Related Substances � 172.540 DL-Alanine. DL-Alanine (a racemic mixture of D- and L-alanine; CAS Reg. No. 302-72-7) may be safely used as a flavor enhancer for sweeteners...
Code of Federal Regulations, 2010 CFR
...ADDITION TO FOOD FOR HUMAN CONSUMPTION Flavoring Agents and Related Substances � 172.540 DL-Alanine. DL-Alanine (a racemic mixture of D- and L-alanine; CAS Reg. No. 302-72-7) may be safely used as a flavor enhancer for sweeteners...
Code of Federal Regulations, 2013 CFR
...ADDITION TO FOOD FOR HUMAN CONSUMPTION Flavoring Agents and Related Substances � 172.540 DL-Alanine. DL-Alanine (a racemic mixture of D- and L-alanine; CAS Reg. No. 302-72-7) may be safely used as a flavor enhancer for sweeteners...
Code of Federal Regulations, 2012 CFR
...ADDITION TO FOOD FOR HUMAN CONSUMPTION Flavoring Agents and Related Substances � 172.540 DL-Alanine. DL-Alanine (a racemic mixture of D- and L-alanine; CAS Reg. No. 302-72-7) may be safely used as a flavor enhancer for sweeteners...
On the existence of �L-alanine cadmium bromide'
NASA Astrophysics Data System (ADS)
It is argued that the recently reported nonlinear optical crystal L-alanine cadmium bromide, grown by slow solvent evaporation method at room temperature [P. Ilayabarathi, J. Chandrasekaran, Spectrochim. Acta 96A (2012) 684-689] is the well-known L-alanine crystal. The isolation of L-alanine crystal is explained due to fractional crystallization.
Srinivasan, Bikshandarkoil R.
On the existence of 'L-alanine cadmium bromide'.
It is argued that the recently reported nonlinear optical crystal L-alanine cadmium bromide, grown by slow solvent evaporation method at room temperature [P. Ilayabarathi, J. Chandrasekaran, Spectrochim. Acta 96A (2012) 684-689] is the well-known L-alanine crystal. The isolation of L-alanine crystal is explained due to fractional crystallization. PMID:23973284
Srinivasan, Bikshandarkoil R
Adsorption of alpha-Alanine on Boehmite
The adsorption of alpha-alanine on boehmite is effected at room temperature in aqueous solutions at different pH values (2.5, 6.0, 12.2). The different forms of alpha-alanine prevalent in the different media result in different modes of adsorption, different uptakes that generally increase with pH, and different responses of the pore structure of boehmite. The dominance of the zwitterionic form at pH 6.0 results in an adsorption mode that permits a three-dimensional array of crystalline alpha-alanine to be built on the surface of boehmite while allowing hydrogen bonding with surface hydroxyls through the carboxylate anion end, which acts as a proton acceptor. The formation of a well-crystallized alpha-alanine is less probable at pH 2.5, where the adsorption of the two prevailing forms, CH3CH(N+H3)COO- and CH3CH(N+H3)COOH, makes them unable to interact in a way that permits a three-dimensional framework of hydrogen bonding between COO- as proton acceptor and N+H3 as proton donor. At pH 12.2 the prevailing CH3CH(NH2)COO- is adsorbed coordinately on Lewis acid sites represented by the surface Al ions. Such a mode of adsorption is more disperse than that occurring at lower pH values, causing an increase in the uptake and noncrystallinity of adsorbed alanine. The narrow pores where surface hydroxyl density is high are most affected by adsorption at pH 2.5 and 6.0, which facilitates building the three-dimensional order, due to limited space, of adsorbed alanine. In alkaline medium the adsorption takes place mainly in larger pores, which results in a lower loss of area than expected. The results are compared with those obtained previously using glycine as the adsorbate, and the differences are discussed in terms of the characteristics of hydration in aqueous media. PMID:9056318
El Shafei GMS; Philip
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diagnoses ranging from simple fatty liver (SFL), to non-alcoholic steatohepatitis (NASH). This study aimed to determine the effect of moderate and severe NAFLD on hepatic transporter expression and function in vivo. Rats were fed a high-fat diet (SFL model) or a methionine-choline-deficient diet (NASH model) for eight weeks. Hepatic uptake transporter function was determined by bromosulfophthalein (BSP) disposition. Transporter expression was determined by branched DNA signal amplification assay and western blotting; inflammation was identified by immunostaining of liver slices for interleukin 1 beta (IL-1?). MC- rats showed significant retention of BSP in the plasma when compared to control rats. Hepatic NTCP, OATP1a1, 1a4, 1b2 and 2b1; and OAT 2 and 3 mRNA levels were significantly decreased in high-fat and MC- diet rats when compared to control. Protein expression of OATP1a1 was significantly decreased in high-fat animals, while OATP1a1 and OATP1b2 expression was significantly lower in MC- rats when compared to control. Liver tissue from high-fat and MC- rats stained positive for IL-1?, a pro-inflammatory cytokine known to decrease expression of NTCP, OATP and OAT transporters, suggesting a plausible mechanism for the observed transporter alterations. These data suggest that different stages of NAFLD result in altered hepatic uptake transporter expression that can lead to a functional impairment of xenobiotic uptake from the blood. Furthermore, NAFLD may alter the plasma retention time of clinically relevant drugs that are reliant on these transporters and may increase the potential drug toxicity. PMID:19358839
Fisher, Craig D.; Lickteig, Andrew J.; Augustine, Lisa M.; Oude Elferink, Ronald P.J.; Besselsen, David G.; Erickson, Robert P.; Cherrington, Nathan J.
Regulation of liver metabolism by enzyme phosphorylation during mammalian hibernation.
Kinetic properties of regulatory enzymes of glycolysis in liver of the mouse, Zapus hudsonius, were modified during hibernation, the probable mechanism being covalent modification. Liver glycogen phosphorylase activity was strongly depressed during both short (less than 24 h) and long (5-8 days) term hibernation, the mechanism involving a decrease in both the percentage of enzyme in the active a form and the total amount (a + b) of enzyme expressed. Phosphofructokinase showed kinetic changes (a 2.5-fold increase in Ka for fructose-2,6-P2, 4- and 3.7-fold decreases in I50 values for ATP and citrate, compared to euthermic controls) in liver of hibernators indicative of phosphorylation inactivation of the enzyme. Measured levels of fructose-2,6-P2 in liver did not change during hibernation. Changes in pyruvate kinase kinetics in liver from long term hibernators similarly indicated enzyme phosphorylation in the depressed state (Ka for fructose-1,6-P2 increased 4.4-fold, I50 for L-alanine decreased 6.3-fold). Apparent covalent modification of glycolytic enzymes during hibernation may serve two functions: depression of glycolytic activity as part of the general metabolic rate depression of hibernation, or reorganization of fuel use in the hibernating state to limit carbohydrate catabolism and promote gluconeogenesis. PMID:2948958
Storey, K B
Hepatotoxicity and liver injury induced by hydroxyapatite nanoparticles.
As hydroxyapatite nanoparticles (HA NPs) are increasingly used in biomedical and biotechnological fields, risk assessment of HA NPs has attracted extensive attention. Nevertheless, little is known about the potential adverse effects of HA NPs on normal hepatocytes and the liver. In the present study, we conducted an in vitro study in which 80-nm HA NPs were incubated with normal Buffalo rat liver (BRL) cells. By analyzing the changes in cell viability, apoptosis/necrosis and the mitogen-activated protein kinase (MAPK) signaling pathway, we investigated the cytotoxicity and potential mechanism of HA NPs in hepatocytes. Furthermore, we used the serum hematology and histopathology examinations to explore the in vivo effects of HA NPs on the structure and function of the liver. Our results showed that exposure to HA NPs at a concentration above 200?�g?ml(-1) decreased cell viability, increased levels of lactate dehydrogenase (LDH) leakage, induced apoptosis and necrosis, and triggered the MAPK signaling pathway in BRL cells in a dose-dependent manner. Moreover, our in vivo study indicated that HA NPs increased the white blood cell count (WBC) and the levels of tumor necrosis factor-? (TNF-?), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum, caused inflammatory cell infiltration at the portal area in the liver, and induced hepatic oxidative stress with elevated levels of hydrogen peroxide (H2 O2 ) and malondialdehyde (MDA). These data demonstrate that at certain concentrations, 80-nm HA NPs cause hepatotoxicity and liver injury. Copyright � 2014 John Wiley & Sons, Ltd. PMID:25225040
Chen, Qingqing; Xue, Yang; Sun, Jiao
Metabolism of 2,5-diphenyloxazole (PPO) by trout liver microsomal mixed function monooxygenase.
Metabolism of 2,5-diphenyloxazole (PPO) has been characterized in trout liver microsomes. Trout liver microsomes have been found to metabolize PPO into at least one NaOH extractable flourescing metabolite having a strong excitation peak at 345 nm and an emission peak at about 510 nm. As the metabolite(s) has (have) not been characterized, Vmax has not been determined, however in arbitary fluorescent units (FU) Vmax is several fold higher in the trout than in the male rat hepatic microsomes. Km is 12.7 M, being about twice as high as reported for mouse (Cantrell et al. 1975). Optimum assay conditions have been established for the metabolism of PPO by trout liver microsomes. NADPH generating system is essential and the metabolism was strongly inhibited by alpha-naphthoflavone, but much less markedly by SKF 525 A or metyrapone. PMID:935635
Ahokas, J T
Metastases to the liver; Metastatic liver cancer; Liver cancer - metastatic ... Almost any cancer can spread to the liver. Cancers that can spread to the liver include: Breast cancer Colorectal cancer Esophageal ...
Background and Objectives: Major abdominal procedures are strongly associated with postoperative immunosuppression and subsequent increased patient morbidity. It is believed that laparoscopic surgery causes less depletion of the systemic immune function because of the reduced tissue trauma. Various cytokines and monocytic HLA-DR expression have been successfully implemented to assess postoperative immune function. The aim of our study was to show the difference in immunologic profiles after minimally invasive versus conventional liver resection. Methods: Ten animals underwent either laparoscopic or conventional open left lateral liver resection. Flow cytometric characteristics of HLA-DR expression on monocytes and lipopolysaccharide-stimulated cellular secretion of tumor necrosis factor ?, interferon ?, interleukin 6, and interleukin 8 were measured and analyzed in ex vivo whole blood samples. Intraoperative and postoperative clinical outcome parameters were also documented and evaluated. Results: All animals survived the procedures. Postoperative complications were fever (n = 3), wound infections (n = 2), and biloma (n = 1). Open surgery showed a morbidity rate of 80% compared with 40% after laparoscopic surgery. Laparoscopic liver resection showed no postoperative immunoparalysis. Major histocompatibility complex class II expression in this group was elevated, whereas the open surgery group showed decreased major histocompatibility complex class II expression on postoperative day 1. Postoperative secretion of tumor necrosis factor ?, interleukin 6, and interferon ? was lower in the open surgery group. Elevated transaminase levels after laparoscopy might have resulted from an ischemia/reperfusion injury caused by the capnoperitoneum. Conclusion: Major immunoparalysis depression was not observed in either group. Laparoscopic surgery shows a tendency to improve immunologic recovery after liver resection. PMID:24398205
Haacke, Nadine; Meisel, Christian; Unterwalder, Nadine; Fikatas, Panagiotis; Schmidt, Sven C.
CHARACTERIZATION OF MUGIL CEPHALUS LIVER MICROSOMAL MIXED FUNCTION OXIDASE ENZYMES AND METABOLISM AND THEIR INDUCTION IN RESPONSE TO F2 FUFL OIL WATER SOLUBLE FRACTION AND BENZPYRENE A Thesis by BRUCE RAY WOODIN Submitted to the Graduate... College of Texas ASM University in partial fulfillment of the requirement for the degree of MASTER OF SCIENCE August 1979 Major Subject: Biology CHARACTERIZATION OF I'IUGIL CEPHALUS LIVER MICROSOMAL MIXED FUNCTION OXIDASE ENZY1;ES AND METABOLISl...
Woodin, Bruce Ray
We studied the effects of supernatant from ovarian fibroblasts derived from the progeny of female rats with experimental chronic liver disease of different genesis on the function of cultured allogenic peritoneal macrophages. Addition of fibroblast supernatant derived from animals with liver disease to the culture medium suppressed the function of peritoneal macrophages from intact newborn rats, which manifested in reduction of the adhesion characteristics and decrease of their phagocytic parameter and phagocytic index. PMID:23486594
Bryukhin, G V; Zubarev, I V
Effect of Lactobacillus fermentum MG590 on Alcohol Metabolism and Liver Function in Rats
Alcohol consumption has numerous health consequences for the human body. For example, heavy drinking on a daily basis causes liver diseases, and certain products such as acetaldehyde produced from alcohol metabolism are more toxic than alcohol itself. Accordingly, the current study evaluated the role of Lactobacillus fermentum MG590 to enhance the removal of the toxic effect of alcohol in alcohol
Effect of syrepar and oxaphenamide on liver function in experimental hypokinesia
NASA Technical Reports Server (NTRS)
Experiments on albino rats showed that 30 day hypokinesia changes the reaction of the liver to cholagogues. The choleretic action of oxaphenamide as well as its inhibitory effect on synthesis of bile acids diminishes, while the influence of bilirubin secretion increases.
Skakun, L. N.
Insights into the requirement of phosphatidylcholine synthesis for liver function in mice
Phosphatidylcholine (PC) is made in the liver by the CDP-choline pathway and via phosphatidylethanol- amine N -methyltransferase (PEMT), which catalyzes the con- version of phosphatidylethanolamine to PC. Unexpect- edly, hepatic apolipoprotein B-100 secretion is inhibited in male, but not female, Pemt ? \\/ ? mice (Noga, A. A., Y. Zhao, and D. E. Vance. 2002. J. Biol. Chem. 277: 42358-42365;
Anna A. Noga; Dennis E. Vance
Sixteen adult male squirrel monkeys (Saimiri sciureus) were randomly divided into three treatment groups and one control group. Each treatment group received 10 mg/kg oral doses of diphenylhydantoin and/or chloroquine. Following sacrifice, in vitro assays for activity of liver mi...
Effect of cortisone on aspartate and alanine aminotransferases in a desert lizard.
1. Liver and serum aspartate aminotransferase (GOT) and alanine aminotransferase (GPT) activities were measured in a hibernating desert lizard, Uromastix hardwickii. The levels of both enzymes were found to be lower in hibernation than during the active period, particularly in the liver. 2. After intramuscular injection of 2 mg of cortisone acetate there was a rapid rise in the levels of these enzymes with a peak of 18 hours (GOT) and 12 hours (GPT). 3. The response of both enzymes to cortisone was much greater during the active period than during hibernation. 4. GOT showed a much more rapid and greater response to cortisone than GPT. This is in contrast to the response of rat liver where GPT is more responsive to this hormone. 5. These studies indicate that the transferase enzymes of this lizard differ from those of the rat in their sensitivity and time of response to cortisone. PMID:149452
Aziz, S; Hasnain, S N; Zain, B K
Objective: The purpose of this study was to explore the accuracy of elevated liver function values, age, gender, pancreatitis and cholecystitis as predictors of common bile duct stones (CBDS). Methods: All patients operated on for gallstone disease over a period of 3 years in a Swedish county of 302 564 citizens were registered prospectively. Intraoperative cholangiography (IOC) was used to detect CBDS. Results: A total of 1171 patients were registered; 95% of these patients underwent IOC. Common bile duct stones were found in 42% of patients with elevated liver function values, 20% of patients with a history of pancreatitis and 9% of patients with cholecystitis. The presence of CBDS was significantly predicted by elevated liver function values, but not by age, gender, history of acute pancreatitis or cholecystitis. A total of 93% of patients with normal liver function tests had a normal IOC. The best agreement between elevated liver function values and CBDS was seen in patients undergoing elective surgery without a history of acute pancreatitis or cholecystitis. Conclusions: Although alkaline phosphatase (ALP) and bilirubin levels represented the most reliable predictors of CBDS, false positive and false negative values were common, especially in patients with a history of cholecystitis or pancreatitis, which indicates that other mechanisms were responsible for elevated liver function values in these patients. PMID:21762294
Videhult, Per; Sandblom, Gabriel; Rudberg, Claes; Rasmussen, Ib Christian
In the phototrophic nonsulfur bacterium Rhodobacter capsulatus E1F1, L-alanine dehydrogenase aminating activity functions as an alternative route for ammonia assimilation when glutamine synthetase is inactivated. L-Alanine dehydrogenase deaminating activity participates in the supply of organic carbon to cells growing on L-alanine as the sole carbon source. L-Alanine dehydrogenase is induced in cells growing on pyruvate plus nitrate, pyruvate plus ammonia, or L-alanine under both light-anaerobic and dark-heterotrophic conditions. The enzyme has been purified to electrophoretic and immunological homogeneity by using affinity chromatography with Red-120 agarose. The native enzyme was an oligomeric protein of 246 kilodaltons (kDa) which consisted of six identical subunits of 42 kDa each, had a Stokes' radius of 5.8 nm, an s20.w of 10.1 S, a D20,w of 4.25 x 10(-11) m2 s-1, and a frictional quotient of 1.35. The aminating activity was absolutely specific for NADPH, whereas deaminating activity was strictly NAD dependent, with apparent Kms of 0.25 (NADPH), 0.15 (NAD+), 1.25 (L-alanine), 0.13 (pyruvate), and 16 (ammonium) mM. The enzyme was inhibited in vitro by pyruvate or L-alanine and had two sulfhydryl groups per subunit which were essential for both aminating and deaminating activities. PMID:2722749
Caballero, F J; Cardenas, J; Castillo, F
Background It is of importance to minimize ischemia reperfusion (I/R) injury during liver operations. Reducing the inflammatory reaction is an effective way to achieve this goal. Notably, adiponectin (APN) was found to have anti-inflammatory activity in heart and renal I/R injury. Herein, we investigated the role of APN in liver I/R injury. Methods Wistar rats were randomized to four groups: (1) sham group; (2) I/R control group; (3) I/R+APN group; and (4) I/R+APN+AMPK inhibitor group. Liver and blood samples were collected 6h and 24h after reperfusion. Liver function and histopathologic changes were assessed. Macrophage and neutrophil infiltration was detected by immunohistochemistry staining, while pro-inflammatory cytokines and chemokines released in the liver were measured using ELISA and RT-PCR, respectively. Apoptosis was analyzed by TUNEL staining and caspase-3 expression in the liver. Downstream molecules of APN were investigated by Western blotting. Results Circulatory APN was down-regulated during liver I/R. When exogenous APN treatment was administered during liver I/R, alanine transaminase (ALT) and aspartate aminotransferase (AST) were decreased, and less hepatocyte necrosis was observed. Less inflammatory cell infiltration and pro-inflammatory cytokines/chemokines release were also observed in the I/R+APN group when compared with the I/R control group. APN treatment also reduced hepatocyte apoptosis, evidenced by reduced TUNEL positive cells and less caspase-3 expression in the reperfused liver. Finally, the AMPK/eNOS pathway was found to be activated by APN, and administration of an AMPK inhibitor reversed the beneficial effects of APN. Conclusion APN can protect the liver from I/R injury by reducing the inflammatory response and hepatocyte apoptosis, a process that likely involves the AMPK/eNOS pathway. The current study provides a potential pharmacologic target for liver I/R injury. PMID:23762489
Li, Qiang; Chen, Maogen; Zhao, Qiang; Deng, Ronghai; Wu, Chenglin; Yang, Anli; Guo, Zhiyong; Wang, Dongping; He, Xiaoshun
Use of bone mesenchymal stem cells to treat rats with acute liver failure.
This study aimed to isolate mesenchymal stem cells from bone mesenchymal stem cells (BMSCs), determine their therapeutic potential for treating rats with acute liver failure (ALF), further explore the factors that induce liver failure mechanisms, and elucidate the role of bone marrow stem cell therapy and BMSCs on liver homing. We found that differentiation potential was present in BMSCs expressing high levels of CD29 and CD90. These cells improved liver functioning in vivo after transplantation into rat livers with D-galactosamine damage, as evidenced by the levels of alanine aminotransferase and aspartate aminotransferase returning to normal (low levels) in recipient ALF rats. A significant improvement in the liver functional test and histological findings was observed in the transplantation group after 120 and 168 h of transplantation (P < 0.05). Histological data revealed that hepatocyte cell apoptosis was lower in the transplantation group compared to the control groups (P < 0.05), and that the transplantation of BMSCs reduced liver inflammation, decreased hepatic denaturation and necrosis, and promoted liver regeneration. These ameliorations were not recorded in the control groups. The results of in situ hybridization, immunofluorescence staining, and Western blot confirmed the presence of transplanted BMSCs in recipient rat livers. Stromal cell derived factor-1 alpha and vascular endothelial growth factor were significantly upregulated after the intraportal transplantation of BMSCs, with significantly higher levels being found in the portal vein and the tail vein groups (P < 0.05). In conclusion, BMSCs have a therapeutic effect against ALF rats, evoke endogenous repair mechanisms in the liver, and may represent a novel form of therapeutic intervention for the disease. Furthermore, intraportal transplantation serves as a more effective pathway compared to tail vein transplantation. PMID:24841910
Yuan, S F; Jiang, T; Sun, L H; Zheng, R J; Cao, G Q; Ahat, N Z; Zhang, Y X
The effect of immunonutrition (glutamine, alanine) on fracture healing
Background There have been various studies related to fracture healing. Glutamine is an amino acid with an important role in many cell and organ functions. This study aimed to make a clinical, radiological, and histopathological evaluation of the effects of glutamine on fracture healing. Methods Twenty rabbits were randomly allocated into two groups of control and immunonutrition. A fracture of the fibula was made to the right hind leg. All rabbits received standard food and water. From post-operative first day for 30 days, the study group received an additional 2 ml/kg/day 20% L-alanine L-glutamine solution via a gastric catheter, and the control group received 2 ml/kg/day isotonic via gastric catheter. At the end of 30 days, the rabbits were sacrificed and the fractures were examined clinically, radiologically, and histopathologically in respect to the degree of union. Results Radiological evaluation of the control group determined a mean score of 2.5 according to the orthopaedists and 2.65 according to the radiologists. In the clinical evaluation, the mean score was 1.875 for the control group and 2.0 for the study group. Histopathological evaluation determined a mean score of 8.5 for the control group and 9.0 for the study group. Conclusion One month after orally administered glutamine�alanine, positive effects were observed on fracture healing radiologically, clinically, and histopathologically, although no statistically significant difference was determined.
K���kalp, Abdullah; Durak, Kemal; Bayyurt, Sarp; S�nmez, G�rsel; Bilgen, Muhammed S.
Purification and characterization of alanine aminotransferase from Panicum miliaceum leaves.
Three alanine aminotransferases, two minor (AlaAT-1, AlaAT-3) and one major (AlaAT-2), were detected by native gel electrophoresis of leaf extracts from Panicum miliaceum L. AlaAT-2 was purified to homogeneity and a specific polyclonal antibody was raised against it which did not react with the other two forms of the enzyme. The enzyme, with an apparent molecular size of 102 kDa, appeared to be a dimer of a single 50-kDa polypeptide. The enzyme has a relatively broad pH optima with similar curves for the forward and reverse directions, ranging between 6.5 and 7.5. The Km values of this enzyme were 6.67, 0.15, 5.00, and 0.33 mM for alanine, 2-oxoglutarate, glutamate, and pyruvate, respectively. The activity of AlaAT-2 was found to increase markedly during leaf greening in parallel with the increase of immunochemically titrated protein, and it is suggested to function in the C4 photosynthetic cycle. PMID:1898070
Son, D; Jo, J; Sugiyama, T
[Activity of alanine aminopeptidase in blood and in urine of smoking and non-smoking smelters].
The human body is constantly exposed to xenobiotics. This will include exogenous substances from environmental pollution such as heavy metals and lifestyle such as smoking, which may lead to impaired functioning of many organs. The liver and kidney are the critical organs in the case of a long-term occupational or environmental exposure to heavy metals and tobacco smoke. In diagnostics of liver and kidney damage useful are the methods which determine the activity of enzymes such as alanine aminopeptidase (AAP). AAP is a marker for early detection of acute kidney damage, and presence of AAP derive mainly from proximal tubular brush-border. Activity of AAP in urine allows to assess the damage resulting from the nephrotoxic exposure to heavy metals. In the serum AAP is mainly from hepatic. Activity of AAP may be useful to identify liver cancer. The investigation was shown, that AAP activity in the blood is used to detect hepatic cholestasis and congestive jaundice. The aim of present study was to assess the influence of occupational exposure of copper-foundry workers to heavy metals (arsenic, cadmium, lead) on activity of alanine aminopeptidase in blood and urine. The investigations were performed in blood and urine of 166 subjects: 101 male copper smelters and 65 non-exposed male subjects. The study protocol was approved by Local Bioethics Committee of Wroclaw Medical University (KB No: 469/2008). The data on smoking which had been obtained from a direct personal interview were verified by determination of serum cotinine concentrations. Biological material collected from the control group and smelters was divided into subgroups of nonsmokers and smokers. The concentrations of lead and cadmium were determined in whole blood, whilst the level of arsenic and cadmium were determined in urine using FAAS method (Flame Atomic Absorption Spectrometry) in the acetylate flame on the SOLAAR M6. The activity of AA was determined in blood and in urine. The results showed a 9-fold increase in the concentration of lead and 10-fold elevation of arsenic level in all groups of smelters in comparison to the control group. The highest cadmium, lead and arsenic concentrations were observed in blood and urine of smoking smelters. We have observed a significant increase in the concentrations of lead and cadmium in blood of smoking persons from control group in comparison to the non-smoking persons from this group, which suggest, that tobacco smoking increase the heavy metals concentrations in the organisms. Occupational exposure to heavy metals resulted in an increase of AAP activity in blood and urine of all groups of smelters in comparison to corresponding control groups. The highest value of AAP was observed in serum and urine of smoking smelters. Tobacco smoke also increases the AAP activity the blood and urine of smoking smelters and control group compared to the non-smoking smelters and nonsmoking control group, appropriate. The study was shown that occupational exposure to heavy metals and tobacco. PMID:21360924
Bizo?, Anna; Stasiak, Karolina; Milnerowicz, Halina
Serum levels of DDT and liver function of malaria control personnel.
The levels of DDT and metabolites in serum of 23 applicators involved in malaria control operations in Natal were determined using gas chromatography with electron capture detection. The mean levels (microgram/l, ppb) were 61.7 DDT, 129.3 DDE, 11.0 DDD and 202.0 sigma DDT. Percentage DDT was 33.4%. These levels were higher than for an age matched sample of the general population in KwaZulu, who are protected by DDT against malaria. Percentage DDT correlated negatively with age (P less than 0.05) for the applicators, suggesting a change in pharmacodynamics with age. Mean serum albumin, alkaline phosphatase, aspartate transferase and gamma-glutamyltransferase (GGT) levels did not differ significantly from an age-matched control group, but the mean GGT value for the applicators was higher than the maximum of the laboratory normal range. Although not clinically significant, the alanine transferase was significantly higher in the applicators than in the control group. These higher levels suggest a possible risk to the health of the sprayers, but uncertainties remain. PMID:2017743
Bouwman, H; Cooppan, R M; Botha, M J; Becker, P J
We report a case of symptomatic massive liver echinococcosis due to Echinococcus granulosus, unexpectedly found in a 34 year old woman living in Apulia, Italy. Based on size (max diameter 18 cm), clinical presentation, geographical area, and natural history of echinococcosis, we estimate that the initial infection should have occurred 9-20 yrs before. Presenting symptoms were those of typical mass effect with RUQ pain, pruritus, malaise, and recent weight loss. Abdominal ultrasound diagnosis of probable echinococcal cyst was subsequentely confirmed by positive serology and further detailed by radiological imaging. The cyst was massively occupying subdiaphragmatic liver segments and extending to the omentum and the stomach. The characteristics of the lesion were compatible with the WHO 2003 classification type CE2l, indicating a large active fertile cyst with daughter cysts. The cyst was successfully treated with medical therapy followed by surgery. The prevalence, diagnostic workup, management, and costs of echinococcosis are discussed in this case presentation. PMID:23813143
Bonfrate, L; Giuliante, F; Palasciano, G; Lamont, J T; Portincasa, P
A case of elevated liver function tests after crown-of-thorns (Acanthaster planci) envenomation.
The crown-of-thorns starfish (Acanthaster planci) inhabits coral reefs, largely throughout the Indo-Pacific region. Its dorsal surface is covered with stout thorn-like spines. When handled or stepped on by humans, the spines can puncture the skin, causing an immediate painful reaction, followed by inflammation and possible infection. Initial pain and swelling may last for days. Effects of envenomation on the liver have been demonstrated previously in animal models, but hepatic toxicity has not previously been described in humans. We describe elevated liver enzymes in a 19-year-old female associated with A planci spine puncture wounds. To our knowledge, this is the first documented report of transaminitis in a human after A planci envenomation. PMID:19099322
Lin, Brian; Norris, Robert L; Auerbach, Paul S
Choronic effects of Lamotrigine on liver function in adult male rats
A number of newly developed antiepileptic drugs are currently in use, among them Lamotrigine (LTG) is more common. Despite\\u000a the extensive use of this drug, it has not been possible to predict the side effects especially the hepatotoxic reactions\\u000a after long-term treatment. The present study was designed to find out alterations in the activities of liver enzymes after\\u000a chronic exposure
M. H. Meshkibaf; A. Ebrahimi; R. Ghodsi; A. Ahmadi
Diet, liver function and dimethylhydrazine-induced gastrointestinal tumours in male Wistar rats
Male Wistar rats fed a normal laboratory pelleted diet, when treated s.c. with 1,2-dimethylhydrazine (DMH) 10 mg\\/kg\\/wk survived the 24-week experiment, showed no signs of chemical toxicity or macroscopic liver damage, and developed mainly large-bowel tumours. Conversely, male Wistar rats treated with 20 mg\\/kg\\/wk DMH did not survive the full term of the experiment and developed ascites, pleural effusions and
W M Castleden; K B Shilkin
Isolation, Characterization, and Functional Studies of Rat Liver Iron Regulatory Protein 1
Ferritin mRNAs are translationally regulated by the binding of either of two cytosolic proteins, iron regulatory protein 1 (IRP1) or IRP2, to the iron responsive element (IRE) located in their 5? untranslated region (UTR). Rat liver IRP1 was purified by anion exchange, gel filtration, and affinity chromatography using a concatemerized version of the IRE. Two bands withMrof 95,000 and 100,000
Richard S. Eisenstein; Hugh A. Barton; Warren H. Pettingell; Adrian B. Bomford
Objective��The aim of this study was to investigate the impact of the water-soluble poly-(ADP)-ribose-polymerase (PARP) inhibitor 5-aminoisoquinolinone (5-AIQ) on liver microcirculation and function after haemorrhagic shock and resuscitation.Design��Controlled, randomized animal study.Setting��University animal care facility and research laboratory.Subject��Male Sprague�Dawley rats were subjected to haemorrhagic shock for 1?h, followed by resuscitation with shed blood and crystalloid solution for a�total of 5 h.Interventions��The
J. P. Roesner; D. A. Vagts; T. Iber; C. Eipel; B. Vollmar; G. F. E. N�ldge-Schomburg
Core level study of alanine and threonine.
Core level X-ray photoemission spectra (XPS) and near edge X-ray absorption fine structure (NEXAFS) spectra of alanine and threonine in the gas phase have been measured at the carbon, nitrogen, and oxygen K edges and interpreted in the light of theoretical calculations. For the computations, a set of approximations is made which allows sufficiently accurate calculations of several conformers to be performed in reasonable computing time. The accuracy has been checked by comparing results obtained for proline to our previous, higher level calculations. The photoemission spectra at the carbon and oxygen edges are assigned and compared. The nitrogen 1s photoemission peaks show anomalous broadening which we relate to the populations and types of conformers. The carbon K-edge NEXAFS spectra of alanine and threonine are compared with our previous data on glycine and resonances assigned accordingly. The nitrogen K-edge NEXAFS spectra of alanine and threonine do not show measurable effects due to the population of conformers, in contrast to the photoemission results. At the oxygen K edge, the spectra of these amino acids are similar with two prominent peaks assigned to transitions of O 1s electrons from the oxo and hydroxyl groups to vacant pi* and sigma* orbitals and additional intensity for threonine due to the second OH group. Conformer effects are observable in photoemission but appear to be more difficult to resolve in photoabsorption. We explain this by energetic shifts of opposite sign for the core hole states and unoccupied orbitals, which causes partial cancelation in NEXAFS but not in photoemission. PMID:18671382
Feyer, Vitaliy; Plekan, Oksana; Richter, Robert; Coreno, Marcello; Prince, Kevin C; Carravetta, Vincenzo
Hepatic stem cells in adult rats are activated by chemical injury to the liver, causing hepatic progenitor cells to proliferate, integrate into the hepatic plates, and differentiate into hepatocytes. In an attempt to model ...
Moritz, Joseph M. (Joseph Michael)
Aspartate Aminotransferase (AST/GOT) and Alanine Aminotransferase (ALT/GPT) Detection Techniques
The levels of aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) in serum can help people diagnose body tissues especially the heart and the liver are injured or not. This article provides a comprehensive review of research activities that concentrate on AST/GOT and ALT/GPT detection techniques due to their clinical importance. The detection techniques include colorimetric, spectrophotometric, chemiluminescence, chromatography, fluorescence and UV absorbance, radiochemical, and electrochemical techniques. We devote the most attention on experimental principle. In some methods a few representative devices and important conclusions are presented.
Huang, Xing-Jiu; Choi, Yang-Kyu; Im, Hyung-Soon; Yarimaga, Oktay; Yoon, Euisik; Kim, Hak-Sung
Background��Chronic arsenic exposure has been shown to cause liver damage. However, serum hepatic enzyme activity as recognized on liver\\u000a function tests (LFTs) showing a dose-response relationship with arsenic exposure has not yet been clearly documented. The\\u000a aim of our study was to investigate the dose-response relationship between arsenic exposure and major serum enzyme marker\\u000a activity associated with LFTs in the
Khairul Islam; Abedul Haque; Rezaul Karim; Abul Fajol; Ekhtear Hossain; Kazi Abdus Salam; Nurshad Ali; Zahangir Alam Saud; Matiar Rahman; Mashiur Rahman; Papia Sultana; Mostaque Hossain; Anwarul Azim Akhand; Abul Mandal; Hideki Miyataka; Seiichiro Himeno; Khaled Hossain
A liver biopsy is a medical procedure performed in order to obtain a small sample of the liver. This is accomplished ... scar. The most common reasons for a liver biopsy include the evaluation of: ? Jaundice ? Liver inflammation (hepatitis) ? ...
... you on a waiting list for a liver transplant. Doctors do liver transplants when other treatment cannot keep a damaged liver ... and replaces it with a healthy one. Most transplant livers come from a donor who has died. ...
We have cloned two complementary DNAs (cDNAs), RL-Mtx-1 and RL-Mtx-2, corresponding to the bile acid- sensitive methotrexate carrier from rat liver by direct full-length rapid amplification of cDNA ends polymerase chain reaction (RACE-PCR) using degenerated primers that were deduced from published sequences of tumor cell methotrexate transporters. When expressed in Xenopus laevis oocytes and cosM6 cells, both clones mediate methotrexate and bumetanide transport. RL-Mtx-1 consists of 2,445 bp with an open reading frame of 1,536 bp. The corresponding protein with 512 amino acids has a molecular weight of 58 kd. RL-Mtx-2 (2,654 bp) differs by an additional insert of 203 bp. This insert is located in frame at position 1,196 of the RL-Mtx-1 and contains the typical splice junction sites at the 5' and 3' end, indicating that the RL-Mtx-2 messenger RNA (mRNA) is generated by alternative splicing. The insert contains a stop codon that shortens the RL-Mtx-2 protein to 330 amino acids (38 kd). Both cDNAs contain the binding site sequence for the dioxin/nuclear translocator responsive element (Ah/Arnt-receptor) in conjunction with a barbiturate recognition sequence (Barbie box). Preliminary results show that the Barbie box acts as a negative regulatory element. The two liver cDNA clones show homologies to the published sequences of folate and the reduced folate carriers, but no homology is found to the transport systems for organic anions like the Ntcp1, oatp1, OAT-K1, and OAT1. Expression of the mRNA for the methotrexate carrier is found in liver, kidney, heart, brain, spleen, lung, and skeletal muscle, but not in the testis as revealed by Northern blot analysis. The highest abundance of the mRNA is found in the kidney. PMID:10827155
Honscha, W; D�tsch, K U; Thomsen, N; Petzinger, E
Liver functional genomics in beef cows on grazing systems: novel genes and pathways revealed.
The adaptation of the liver to periods of negative energy balance is largely unknown in beef cattle on grazing systems. We evaluated liver transcriptome throughout gestation and early lactation of purebred and crossbred beef cows [Angus, Hereford, and their F1 crossbreeds (CR)], grazing high or low herbage allowances (HA) of native grasslands (4 and 2.5 kg dry matter/kg body wt annual mean; n = 16) using an Agilent 4 � 44k bovine array. A total of 4,661 transcripts were affected by days [272 ? 2.5-fold difference, false discovery rate (FDR) ? 0.10] and 47 pathways were altered during winter gestation (-165 to -15 days relative to calving), when cows experienced decreased body condition score, decreased insulin, and increased nonesterified fatty acid concentrations. Gluconeogenesis and fatty acid oxidation pathways were upregulated, while cell growth, DNA replication, and transcription pathways were downregulated (FDR ? 0.25). We observed only small changes in the liver transcriptome during early lactation (+15 to +60 days). A total of 225 genes were differentially expressed (47 ? 2-fold difference, FDR ? 0.10) between HA. The majority of those were related to glucose and pyruvate metabolism and were upregulated in high HA, reflecting their better metabolic status. Two genes were upregulated in CR cows, but 148 transcripts (74 ? 2-fold change difference, FDR ? 0.10) were affected by the HA and cow genotype interaction. The transcriptional changes observed indicated a complex and previously unrecognized, hepatic adaptive program of grazing beef cows in different nutritional environments. Novel target candidate genes, metabolic pathways, and regulatory mechanisms were reported. PMID:24326346
Laporta, Jimena; Rosa, Guilherme J M; Naya, Hugo; Carriquiry, Mariana
Fructose 1, 6 bisphosphatase activities in mouse liver as a function of age.
Neutral fructose 1, 6 bisphosphatase activity increases till 7 days, after which, a decline is observed postnatally upto 30 days. Alkaline fructose 1, 6 bisphosphatase follows the same pattern. The optimum activity of fructose 1, 6 bisphosphatase in mouse liver at pH 6.5 and 9.0 of all the periods, suggests the presence of both neutral and alkaline enzyme during the developmental period studied. On the basis of similarity observed in optimum pH, the same properties of enzyme at all the developmental stages studied, could not be ruled out. PMID:6097545
Saxena, S P; Upreti, R K; Sanwal, G G
Molecular determination of liver fibrosis by synchrotron infrared microspectroscopy.
Liver fibrosis is an adaptive response to various injuries and may eventually progress to cirrhosis. Although there are several non-invasive methods available to monitor the progression of liver fibrogenesis, they cannot reliably detect fibrosis in its early stages, when the process can be stopped or reversed by removing or eliminating the underlying etiological agent that cause the hepatic injury. In this study, early fibrosis alterations were characterized biochemically, morphologically, and spectroscopically in a rat bile duct ligation (BDL) model. Progressive elevations in serum alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin levels in the BDL rats were found indicating the dynamic deterioration of hepatocellular function. Immunofluorescence microscopy using monoclonal anti-collagen III antibody further revealed abnormal intertwined networks of collagen fibres surrounding the portal areas and extending into the lobules towards the central veins in all BDL samples starting from week one. Synchrotron infrared microspectroscopy of liver sections was exploited to generate false color spectral maps based upon a unique and strong collagen absorption at 1340 cm(- 1), revealing a collagen distribution that correlated very well with corresponding images provided by immunofluorescence imaging. We therefore suggest that infrared microspectroscopy may provide an additional and sensitive means for the early detection of liver fibrosis. PMID:16806057
Liu, Kan-Zhi; Man, Angela; Shaw, R Anthony; Liang, Binhua; Xu, Zhaolin; Gong, Yuwen
The metabolic syndrome is associated with nonalcoholic fatty liver disease (NAFLD) as well as with insulin resistance, inflammatory adipokines, endothelial dysfunction, and higher plasma levels of nonesterified fatty acids (NEFA), all of which may also affect the development of NAFLD. Therefore, we investigated to what extent the association between the metabolic syndrome and alanine aminotransferase (ALT, as a surrogate of
Marjon Jacobs; Marleen M. J. van Greevenbroek; Isabel Ferreira; Edith J. M. Feskens; Eugene H. J. M. Jansen; Casper G. Schalkwijk; Coen Stehouwer
NASA Astrophysics Data System (ADS)
Light scattering in living tissues is mainly caused by subcellular particles like mitochondria. The size of mitochondria changes according to differences in the functional status. Therefore light scattering should be a useful technique for monitoring the functional state in tissues. We investigated functional parameters in our model of the isolated perfused rat liver. For the measurements of light scattering we used the EMPHO SSK Oxyscan. Backscattered light from tissue is shown in 3D images. We found an interesting relation between structures of the liver and the patterns of the relating 3D images. In addition, our underlying spectra show the redox state of cytochromes. This new method of tissue imaging should give the opportunity of new insights into liver function.
Boehnert, Markus; Rauh, Robert; Kessler, Manfred D.
Human C1 inhibitor attenuates liver ischemia-reperfusion injury and promotes liver regeneration.
Liver ischemia-reperfusion injury (IRI) is a well-known cause of morbidity and mortality after liver transplantation (LT). Activation of the complement system contributes to the pathogenesis of IRI. Effective treatment strategies aimed at reducing hepatic IRI and accelerating liver regeneration could offer major benefits in LT. Herein, we investigated the effect of C1-esterase inhibitor (human) [C1-INH] on IRI and liver regeneration. Mice were subjected to 60-min partial IRI, with or without 70% partial hepatectomy, or CCl4-induced acute liver failure. Before liver injury, the animals were pretreated with intravenous C1-INH or normal saline. Liver IRI was evaluated using serum levels of alanine aminotransferase, serum interleukin-6, and histopathology. Liver samples were stained for specific markers of regeneration (5-bromo-2'-deoxyuridine [BrdU] staining and proliferating cell nuclear antigen [PCNA]). Histology, serum interleukin-6, and alanine aminotransferase release revealed that C1-INH treatment attenuated liver injury compared with controls. Improved animal survival and increased number of BrdU- and PCNA-positive cells were observed in C1-INH-treated animals which underwent IRI + partial hepatectomy or CCl4 injection compared with control group. These data indicate that complement plays a key role in IRI and liver regeneration. C1-INH represents a potential therapeutic strategy to reduce IRI and promote regeneration in LT. PMID:24433870
Saidi, Reza F; Rajeshkumar, Barur; Shariftabrizi, Ahmad; Dresser, Karen; Walter, Otto
Emerging Therapies for Liver Fibrosis
Liver fibrosis occurs as a result of a wide range of injurious processes and in its end-stage results in cirrhosis. This gross disruption of liver architecture is associated with impaired hepatic function, portal hypertension and significant resultant morbidity and mortality. Indeed, liver fibrosis and cirrhosis represent a major worldwide healthcare burden. Recent progress in liver transplantation, the management of portal
Andrew J. Fowell; John P. Iredale
Disordered structure and function of liver in HIV/AIDS--a study of thirty cases.
To study abnormalities in liver associated enzymes and histology in AIDS patients with common infections like hepatotrophic viruses and mycobacteria. 30 cases of HIV/AIDS were studied for any significant pattern emerging. The male:female ratio was 4.26:1, occupation being long-distance truck drivers (30%); migrant goldsmiths (27%); migrant labourers (24%). Duration of illness from onset was within three months (46%) and the maximum duration was 26 months (2%). The most common presentation was fever (90%), weakness (79%), weight loss (62%) and diarrhoea (62%). The CD4 cell count was between 200-500/microL (33%). LFT showed hyperglobulinemia in patients having CD4 cell count <500/microL. Rise of alkaline phosphatase was seen in 63% with CD4 cell count <200/microL. 66.6% had HBsAg reactivity, 33.3% had positive anti-HCV antibody and 50% had abnormal liver histology. One third of these had systemic opportunistic infections like tuberculosis. No correlation could be made between hepatic histology and LFT. PMID:16933722
Bhattacharya, Nandita; Banerjee, Sreeparna; Karmakar, Rupam; Neogi, Dhruba Kumar
Liver kinase B1 (LKB1), known as a serine/threonine kinase, has been identified as a critical cancer suppressor in many cancer cells. It is a master upstream kinase of 13 AMP-activated protein kinase (AMPK)-related protein kinases, and possesses versatile biological functions. LKB1 gene is mutated in many cancers, and its protein can form different protein complexes with different cellular localizations in various cell types. The expression of LKB1 can be regulated through epigenetic modification, transcriptional regulation and post-translational modification. LKB1 dowcnstream pathways mainly include AMPK, microtubule affinity regulating kinase (MARK), salt-inducible kinase (SIK), sucrose non-fermenting protein-related kinase (SNRK) and brain selective kinase (BRSK) signalings, etc. This review, therefore, mainly discusses recent studies about the expression, regulation, downstream signaling and cancer suppressive function of LKB1, which can be helpful for better understanding of this molecular and its significance in cancers. PMID:25244018
Gan, Ren-You; Li, Hua-Bin
Background Previous animal studies have shown that Curcuma longa (turmeric) improves liver function. Turmeric may thus be a promising ingredient in functional foods aimed at improving liver function. The purpose of the study is to investigate the hepatoprotective effect of fermented turmeric powder (FTP) on liver function in subjects with elevated alanine transaminase (ALT) levels. Methods A randomised, double-blind, placebo-controlled trial was conducted between November 2010 and April 2012 at the clinical trial center for functional foods of the Chonbuk National University Hospital. The trial included 60 subjects, 20�years old and above, who were diagnosed mild to moderate elevated ALT levels between 40�IU/L and 200�IU/L. Sixty subjects were randomised to receive FTP 3.0�g per day or placebo 3.0�g per day for 12�weeks. The treatment group received two capsules of FTP three times a day after meals, for 12�weeks. The primary efficacy endpoint was change in the ALT levels in the two groups. The secondary efficacy endpoints included its effect on aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin (TB), and lipid profiles. Safety was assessed throughout the study using ongoing laboratory tests. Adverse events (AEs) were also recorded. Results Sixty subjects were randomised in the study (30 into the FTP group, 30 into the placebo group), and among them, twelve subjects were excluded from the analysis for protocol violation, adverse events or consent withdrawal. The two groups did not differ in baseline characteristics. After 12�weeks of treatment, 48 subjects were evaluated. Of the 48 subjects, 26 randomly received FTP capsules and 22 received placebo. The FTP group showed a significant reduction in ALT levels after 12�weeks of treatment compared with the placebo group (p?=?0.019). There was also observed that the serum AST levels were significantly reduce in the FTP group than placebo group (p?=?0.02). The GGT levels showed a tendency to decrease, while the serum alkaline phosphatase (ALP), TB, and lipids levels were not modified. There were no reported severe AEs during this study, or abnormalities observed on blood glucose, total protein, albumin, blood urea nitrogen (BUN), and creatinine levels. Conclusion The data of this trial indicate that FTP is effective and safe, generally well-tolerated without severe AEs, in the treatment of subjects with elevated ALT levels over a 12�weeks period. Trial registration ClinicalTrials.gov: http://NCT01634256 PMID:23497020
To evaluate the impact of day-and-night rotating shift work (RSW) on liver health, we performed a retrospective analysis of the association between long-term RSW exposure and the normalization of plasma alanine transaminase (ALT) levels over a five-year period. The data from physical examinations, blood tests, abdominal sonographic examinations, personal histories, and occupational records were collected from a cohort of workers in a semiconductor manufacturing company. The sample population was divided into three subgroups for analysis, according to self-reported shift work status over the five-year interval: persistent daytime workers, workers exposed intermittently to RSW (i-RSW), and workers exposed persistently to RSW (p-RSW). Records were analyzed for 1196 male workers with an initial mean age of 32.5 years (SD 6.0 years), of whom 821 (68.7%) were identified as rotating shift workers, including 374 i-RSW (31.3%) and 447 p-RSW workers (37.4%). At the beginning of the follow-up, 275 were found to have elevated ALT (e-ALT): 25.1% daytime workers, 23.0% i-RSW workers, and 21.3% p-RSW workers (p?=?0.098). Of those with e-ALT at the beginning, 101 workers showed normalized serum ALT levels at the end of five-year follow-up: 40 (10.7%) of 375 daytime workers, 32 (8.6%) of 374 i-RSW workers, and 29 (6.5%) of 447 p-RSW workers (p?=?0.016). Compared with the workers having persistent e-ALT at the end of follow-up, the workers normalized serum ALT levels had significantly lesser exposures to RSW during follow-up. By performing multivariate logistic regression analyses, and comparing with the persistent daytime co-workers, after controlling for confounding variables (age, occupational factors, educational levels, lifestyle factors, metabolic syndrome, hepatovirus infection, and fatty liver), analysis indicated that the workers exposed to p-RSW were 46% less likely (OR, 0.54; 95% CI, 0.30-0.95; p?=?0.03) to attain normal ALT levels within a five-year interval. These observations demonstrate that persistent day-and-night RSW pose a vigorous obstacle to the normalization of e-ALT among workers with preexisting abnormal liver function. We suggest that workers and managers approach with caution the consideration of assigning or accepting long-term day-and-night RSW when an employee health screening shows evidence of abnormal liver function. PMID:24354767
Lin, Yu-Cheng; Hsieh, I-Chun; Chen, Pau-Chung
5'-Methylthioadenosine attenuates ischemia reperfusion injury after liver transplantation in rats.
5'-Methylthioadenosine (MTA) is a nucleoside generated from S-adenosylmethionine (SAM) during polyamine synthesis. Previous study has indicated that MTA regulated the production of inflammatory mediators by modulating the activation of nuclear factor-?B (NF-?B) and mitogen-activated protein kinase (MAPK) signal pathway. The objective of this study was to determine whether MTA possessed anti-inflammatory properties during rat liver transplantation. Sprague Dawley (SD) to SD rat orthotropic liver transplantation was performed according to the Kamada's technique. Donors in MTA group were given a single dose of MTA (96 ?mol/kg, intraperitoneal) 30 min before surgery (n?=?36), and the control group were given the same volume of normal saline (n?=?36) intraperitoneally. The histopathologic change in the liver was analyzed. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-?), inhibitors of kappa B alpha (I?B?) degradation, NF-?B transcriptional activity, and MAPK activation were determined at 3, 6, and 24 h after reperfusion. Pretreatment with MTA significantly improved liver function, attenuated hepatic ischemia-reperfusion injury (IRI) by downregulating TNF-? level and suppressing inflammatory reaction after liver transplantation. Moreover, MTA also inhibited the I?B? degradation, NF-?B transcriptional activity, and the activation of MAPK signal. MTA protected against hepatic IRI by suppressing inflammatory reaction following liver transplantation. The mechanism for this effect of MTA is mediated, at least in part, by inhibiting the activation of NF-?B and MAPK signal pathway. PMID:24609837
Tang, Yong; Zhang, Weikang; Zhang, Yu; Wang, Wenjing; Yao, Feng; Yan, Jiaqi; Wan, Chidan
Bees' Honey Protects the Liver of Male Rats against Melamine Toxicity
The protective effect of natural bees' honey to the liver of male albino rats against melamine toxicity was studied. Melamine supplementation at a dose of 20000?ppm in the diet for 28 days induced adverse effects on the liver, decreased serum total protein and increased liver enzyme: alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Histological changes of the melamine supplemented group showed necrosis in the hepatic tissues around the central veins of the liver and precipitation of melamine crystals. Treating the male albino rats (that were presupplemented regularly with 20000?ppm melamine) with natural bees' honey at a dose of 2.5?g/kg body weight for 28 days improved both liver functions and increased serum protein. In addition, a positive impact on the shape of the cells after treatment with honey compared to the positive melamine supplemented group was observed. In conclusion, the results of this study revealed that the use of natural bees' honey has the ability to protect the liver of rats against the toxic effects of melamine. PMID:23971045
El Rabey, Haddad A.; Al-Seeni, Madeha N.; Al-Solamy, Suad M.
Synthesis and evaluation of 18F labeled alanine derivatives as potential tumor imaging agents
Introduction This paper reports the synthesis and labeling of 18F alanine derivatives. We also investigate their biological characteristics as potential tumor imaging agents mediated by alanine-serine-cysteine preferring (ASC) transporter system. Methods Three new 18F alanine derivatives were prepared from corresponding tosylate-precursors through a two-step labelling reaction. In vitro uptake studies to evaluate and to compare these three analogs were carried out in 9L glioma and PC-3 prostate cancer cell lines. Potential transport mechanisms, protein incorporation and stability of 3-(1-[18F]fluoromethyl)-L-alanine (L[18F]FMA) were investigated in 9L glioma cells. Its biodistribution was determined in a rat-bearing 9L tumor model. PET imaging studies were performed on rat bearing 9L glioma tumors and transgenic mouse carrying spontaneous generated M/tomND tumor (mammary gland adenocarcinoma). Results New 18F alanine derivatives were prepared with 7�34% uncorrected radiochemical yields, excellent enantiomeric purity (>99%) and good radiochemical purity (>99%). In vitro uptake of the L-[18F]FMA in 9L glioma and PC-3 prostate cancer cells was higher than those observed for other two alanine derivatives and [18F]FDG in first 1 h. Inhibition of cell uptake studies suggested that L-[18F]FMA uptake in 9L glioma was predominantly via transport system ASC. After entering into cells, L-[18F]FMA remained stable and was not incorporated into protein within 2 h. In vivo biodistribution studies demonstrated that L-[18F]FMA had relatively high uptake in liver and kidney. Tumor uptake was fast, reaching a maximum within 30 min. The tumor-to-muscle, tumor-to-blood and tumor-to-brain ratios at 60 min post injection were 2.2, 1.9 and 3.0, respectively. In PET imaging studies, tumors were visualized with L-[18F]FMA in both 9L rat and transgenic mouse. Conclusion L-[18F]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor proliferation. PMID:22542392
Wang, Limin; Zha, Zhihao; Qu, Wenchao; Qiao, Hongwen; Lieberman, Brian P.; Plossl, Karl; Kung, Hank F.
Background Natural high-density lipoproteins (HDL) possess important physiological functions to the transport of cholesterol from the peripheral tissues to the liver for metabolic degradation and excretion in the bile. Methods and results In this work, we took advantage of this pathway and prepared two different gadolinium (Gd)-DTPA-labeled cholesterol-containing recombinant HDL nanoparticles (Gd-chol-HDL) and Gd-(chol)2-HDL as liver-specific magnetic resonance imaging (MRI) contrast agents. The reconstituted HDL nanoparticles had structural similarity to native HDL, and could be taken up by HepG2 cells via interaction with HDL receptors in vitro. In vivo MRI studies in rats after intravenous injections of 10 ?mol gadolinium per kg of recombinant HDL nanoparticles indicated that both nanoparticles could provide signal enhancement in the liver and related organs. However, different T1-weighted image details suggested that they participated in different cholesterol metabolism and excretion pathways in the liver. Conclusion Such information could be highly useful to differentiate functional changes as well as anatomic differences in the liver. These cholesterol-derived contrast agents and their recombinant HDL preparations may warrant further development as a new class of contrast agents for MRI of the liver and related organs. PMID:22888232
Rui, Mengjie; Guo, Wei; Ding, Qian; Wei, Xiaohui; Xu, Jianrong; Xu, Yuhong
Background Hydrogen sulfide (H2S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H2S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H2S in carbon tetrachloride (CCl4)-induced hepatotoxicity, cirrhosis and portal hypertension. Methods and Findings Sodium hydrosulfide (NaHS), a donor of H2S, and DL-propargylglycine (PAG), an irreversible inhibitor of cystathionine ?-lyase (CSE), were applied to the rats to investigate the effects of H2S on CCl4-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H2S, hepatic H2S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP) 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl4 significantly reduced serum levels of H2S, hepatic H2S production and CSE expression. NaHS attenuated CCl4-induced acute hepatotoxicity by supplementing exogenous H2S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), albumin, tumor necrosis factor (TNF)-?, interleukin (IL)-1?, IL-6 and soluble intercellular adhesion molecule (ICAM)-1, liver histology, hepatic hydroxyproline content and ?-smooth muscle actin (SMA) expression. PAG showed opposing effects to NaHS on most of the above parameters. Conclusions Exogenous H2S attenuates CCl4-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H2S may present a promising approach, particularly for its prophylactic effects, against liver cirrhosis and portal hypertension. PMID:22022478
Tan, Gang; Pan, Shangha; Li, Jie; Dong, Xuesong; Kang, Kai; Zhao, Mingyan; Jiang, Xian; Kanwar, Jagat R.; Qiao, Haiquan; Jiang, Hongchi; Sun, Xueying
Structural and function changes in organelles of liver cells in rats exposed to magnetic fields
Exposure of rats to magnetic fields of 10{sup {minus}3} and 10{sup {minus}2} T for 1 hr daily generated structural changes in hepatocytes mitochondria, endoplasmic reticulum, and ribosomes. Simultaneously there was an increase in the activities of the mitochondrial respiratory enzymes: NADH dehydrogenase, succinic dehydrogenase, and cytochrome oxidase. The extent of the changes in liver cell properties following exposure depend on the duration of exposure to and the strength of the applied magnetic fields. Ultrastructural studies did not reveal any changes in external membranes of hepatocytes or in the membranes of cell nuclei. An increase in the amount of glycogen in hepatocytes of rats exposed to both 10{sup {minus}3} and 10{sup {minus}2} T was noted. The high level of cortisol in serum of exposed rats suggests that magnetic field may be a stress generating factor.
Gorczynska, E. (Pomeranian Medical Academy, Szczecin (Poland)); Wegrzynowicz, R. (Academy of Agriculture, Szczecin (Poland))
One Silastic capsule of 15 mm, 20 mm or 30 mm length was inserted subcutaneously into the ventral aspect of the left forearm or upper arm of 28 healthy women during menstrual bleeding or not later than on the seventh day of the menstrual cycle. A new capsule of the same length was inserted after six months and both capsules were removed twelve months after the first insertion. Side-effects, including changes in body weight, blood pressure, menstrual bleeding and liver function test results, were registered. Blood samples were taken from selected subjects twice a week during the 1st, 2nd, 3rd, 6th, 7th and 12th month of use. Plasma concentrations of ST-1435 were measured by radioimmunoassay and the effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. There were no differences in hormonal side-effects between subjects who had a 30 mm capsule or subjects who had 20 mm or 15 mm capsules, but subjects who had 20 or 15 mm capsules had significantly longer bleeding or spotting periods in comparison with subjects who had a 30 mm capsule. There were no changes in blood pressure, body weight or liver function test results in comparison with pre-insertion values. The plasma level of ST-1435 was not significantly higher during the use of 30 mm capsules than during the use of 20 or 15 mm capsules. During the use of the shorter ST-1435 capsules, plasma estradiol elevation and slightly suppressed FSH were seen, while the use of longer capsules resulted in a slight suppression of LH. Progesterone concentrations during monitored cycles indicated anovulation. No pregnancies occurred during the study period of one year. The continuation rate at one year was 71% in the 30 mm capsule group and 57% in the 20 and 15 mm capsule groups taken together. PMID:3922676
Kurunm�ki, H; Toivonen, J; L�hteenm�ki, P; Luukkainen, T
It was shown recently that proline-beta-naphthylamidase from pig liver resembles the gamma-subunit of pig liver esterase (PLE), which could be functionally expressed in the yeast Pichia pastoris in recombinant form (rPLE). The gene encoding rPLE shares 97% identity with the published nucleotide sequence of porcine intestinal carboxylesterase (PICE). By site-directed mutagenesis, 22 nucleotides encoding 17 amino acids were exchanged stepwise from the PLE gene yielding the recombinant PICE sequence and eight intermediate mutants. All esterases were successfully produced in P.pastoris as extracellular proteins with specific activities ranging from 4 to 377 U/mg and V(max)/K(m) values from 12 to 1000 l min(-1) x 10(-3) using p-nitrophenyl acetate as substrate. Activity-staining of native polyacrylamide gels followed by molecular mass determination suggests that the most active forms of all variants are present as trimers with a molecular mass of 190-210 kDa. All enzymes exhibit the highest activity in the pH range 8-9 and between 60 and 70 degrees C. Almost all esterases show a higher ratio of methyl butyrate hydrolase activity to proline-beta-naphthylamidase activity than rPLE. PMID:14983097
Musidlowska-Persson, Anna; Bornscheuer, Uwe T
Cytochrome P-450 and the electron-donor, NADPH-cytochrome c reductase were isolated from phenobarbital induced rat liver microsomes. Both benzene and its primary metabolite phenol, were substrates for the reconstituted purified phenobarbital induced rat liver mixed function oxidase system. Benzene was metabolized to phenol and the polyhydroxylated metabolites; catechol, hydroquinone and 1,2,4 benzenetriol. Benzene elicited a Type I spectral change upon its interaction with the cytochrome P-450 while phenol's interaction with the cytochrome P-450 produced a reverse Type I spectra. The formation of phenol showed a pH optimum of 7.0 compared with 6.6-6.8 for the production of the polyhyrdoxylated metabolites. Cytochrome P-450 inhibitors, such as metyrapone and SKF 525A, diminished the production of phenol from benzene but not the production of the polyhydroxylated metabolites from phenol. The radical trapping agents, DMSO, KTBA and mannitol, decreased the recovery of polyhydroxylated metabolites, from /sup 14/C-labeled benzene and/or phenol. As KTBA and DMSO interacted with OH. There was a concomitant release of ethylene and methane, which was measured. Desferrioxamine, an iron-chelator and catalase also depressed the recovery of polyhydroxylated metabolites. In summary, benzene and phenol were both substrates for this reconstituted purified enzyme system, but they differed in binding to cytochrome P-450, pH optima and mode of hydroxylation.
Griffiths, J.C.
Given the requirement of professional jockeys to make-weight daily, we tested the hypothesis that Flat and National Hunt (Jump) jockeys would display compromised health markers (bone health, vitamin D, liver and kidney function and mood) compared with established clinical norms, with Flat jockeys affected the greater. Daily energy intake was lower in Flat compared with Jump jockeys (6.11�1.25 vs. 7.47�0.83 MJ.day - 1, P=0.01) whereas there was no difference in urine osmolality (811�198 vs. 678�317 mOsmol x kg(-1) respectively, P=0.13). Serum total 25(OH)D was insufficient in Flat and Jump jockeys (37.6�28 vs. 35.1�14 nmol x L(-1) respectively although there was no difference between groups (P=0.79). Markers of bone metabolism (Plasma ?-carboxy-terminal cross-linked teleopeptide (CTX) and Intact Parathyroid Hormone (PTH) and liver and kidney function were within clinical normative ranges although CTX and PTH were higher than average. Abnormal mood profiles were observed in both groups although significantly poorer in the Flat jockeys (P=0.01). We conclude that the current practices of jockeys to make-weight may have detrimental effects upon their health with Flat jockeys affected more so than Jump jockeys. Future studies should investigate the effects of improved dietary practices on the mental and physical health of Flat and Jump jockeys. PMID:23184478
Wilson, G; Fraser, W D; Sharma, A; Eubank, M; Drust, B; Morton, J P; Close, G L
1. Introduction Alanine-based ionizing radiation dosimetry is firmly
1. Introduction Alanine-based ionizing radiation dosimetry is firmly woven into the fabric of high-dose radiation metrology. Because of its superior attributes, alanine dosimetry was recognized at an early stage of use at the NMI level, confidence in the system has grown such that ala- nine dosimetry use is growing
The objective of the study was to determine the effects of a dietary antioxidant blend (ethoxyquin and propyl gallate) and vitamin E on growth performance, liver function, and oxidative status in pigs fed diets high in oxidants. Crossbred barrows (n = 100, 10.91 � 0.65 kg BW, 36 � 2 d of age, Landrace � Duroc) were allotted to 5 treatments on the basis of BW (5 replicate pens per treatment, 4 pigs per pen). Treatments included 1) HO, high-oxidant diet containing 5% oxidized soybean oil and 10% PUFA source (providing 2.05% docosahexaenoic acid in the diet), 2) VE, the HO diet with 11 IU/kg of added vitamin E, 3) AOX, the HO diet with antioxidant blend (135 mg/kg), 4) VE+AOX, the HO diet with both vitamin E and antioxidant blend, and 5) SC, a standard corn-soy control diet. The trial lasted for 118 d; on d 83, the HO diet pigs were switched to the SC diet because the animals were displaying very poor health. Compared with SC pigs, HO pigs had decreased ADG (0.92 vs. 0.51 kg for d 26 to 55, 1.29 vs. 0.34 kg for d 56 to 82; P < 0.05) and ADFI (1.84 vs. 0.96 kg for d 26 to 55, 3.41 vs. 1.14 kg for d 56 to 82; P < 0.05). However, switching the HO pigs to the SC diet resulted in HO pigs having a greater ADG than VE-fed pigs from d 83 to 118 (0.90 vs. 0.60 kg; P < 0.05). The antioxidant blend restored pig performance to a level similar that of pigs fed the SC diet (P > 0.05) with greater G:F for the entire period (0.44 vs. 0.38; P < 0.05). A greater liver to BW ratio was found in HO compared with other treatments on d 55 and in VE on d 118. Total bilirubin concentration in plasma of HO pigs on d 55 was greater than that in VE+AOX pigs (P < 0.05), whereas on d 118, bilirubin concentration in VE was higher than those in VE+AOX and SC (P < 0.05). A similar trend was observed in aspartate transaminase. Plasma concentrations of thiobarbituric acid reactive substances (TBARS) and carbonyl were elevated (P < 0.05) in the HO pigs compared with the SC pigs on d 55 but not on d 118. Liver TBARS and carbonyl concentrations showed a similar trend, except that HO pigs had the greatest carbonyl concentration on d 118. Pigs fed AOX diets had plasma and liver TBARS and carbonyl concentrations similar to those fed SC diets. In the oxidative stress model used in this study, dietary addition of antioxidant blend or antioxidant blend + vitaimin E was effective in improving growth, liver function, and plasma markers of oxidative stress, but VE alone was not. PMID:25367515
Lu, T; Harper, A F; Zhao, J; Estienne, M J; Dalloul, R A
Tc-99m-sulfur colloid scintigrams were abnormal in four patients with hepatic dysfunction due to chronic alcohol abuse. Minimal uptake of radiocolloid in the liver suggested local reticuloendothelial (RE) cell failure. Imaging with a new hepatobiliary agent, Tc-99m-PIPIDA, revealed rapid hepatic accumulation and excretion of radiotracer with adequate visualization of the organ. Scintigraphic findings in these patients indicated a dissociation of hepatocyte and RE cell functions. Demonstration of adequate hepatocyte function with severe RE failure in alcoholic liver disease using a Tc-99m-labeled hepatobiliary agent has not been previously reported.
Rao, B.K.; Weir, G.J. Jr.; Lieberman, L.M.
The structure of alanine racemase from Acinetobacter baumannii
Acinetobacter baumannii is an opportunistic Gram-negative bacterium which is a common cause of hospital-acquired infections. Numerous antibiotic-resistant strains exist, emphasizing the need for the development of new antimicrobials. Alanine racemase (Alr) is a pyridoxal 5?-phosphate dependent enzyme that is responsible for racemization between enantiomers of alanine. As d-alanine is an essential component of the bacterial cell wall, its inhibition is lethal to prokaryotes, making it an excellent antibiotic drug target. The crystal structure of A. baumannii alanine racemase (AlrAba) from the highly antibiotic-resistant NCTC13302 strain has been solved to 1.9?� resolution. Comparison of AlrAba with alanine racemases from closely related bacteria demonstrates a conserved overall fold. The substrate entryway and active site of the enzymes were shown to be highly conserved. The structure of AlrAba will provide the template required for future structure-based drug-design studies. PMID:25195891
Davis, Emily; Scaletti-Hutchinson, Emma; Opel-Reading, Helen; Nakatani, Yoshio; Krause, Kurt L.
A prospective observational study of 324 cases was conducted in a busy ambulatory care setting to evaluate the sensitivity, specificity, predictive values, and accuracy of spot urine urobilinogen and urine bilirubin assays as screening tests for serum liver function test (LFT) abnormalities. High positive predictive values (88% for at least one abnormal LFT) make the evaluation of positive urine screens detected during routine health care maintenance examinations imperative. Because extraneous factors may influence both urine and serum test results, however, urine assays obtained as a screening parameter in clinical presentations (abdominal pain, jaundice, constitutional symptoms, etc) have only limited clinical utility. The high proportion of false-negative results for both urine assays renders their statistical properties unacceptable as screens in these clinical situations. PMID:3175729
Binder, L; Smith, D; Kupka, T; Nelson, B; Glass, B; Wainscott, M; Haynes, J
Mycobacterium bovis BCG Vaccines Exhibit Defects in Alanine and Serine Catabolism
Mycobacterium bovis BCG is the only accepted vaccine for the prevention of tuberculosis (TB) in humans. BCG is a live vaccine, and induction of immunity to TB requires productive infection of the host by BCG. However, BCG is not a satisfactory vaccine, because it fails to protect against pulmonary TB in adults. In this study, we found that BCG strains cannot utilize many naturally occurring amino acids as the sole nitrogen source for growth. This defect is caused, at least partially, by the lack of functional metabolic enzymes. All BCG strains are unable to catabolize l-alanine or d-alanine due to a frameshift mutation in the l-alanine dehydrogenase gene (ald). Some BCG strains, such as BCG-Pasteur and BCG-Frappier, cannot catabolize l-serine, apparently due to inadequate expression of l-serine deaminase (sdaA). We also found that undegraded alanine and serine inhibit the growth of BCG through blockage of glutamine synthetase. These results suggest that BCG strains are limited in nitrogen metabolic capacity and predict defects that may restrict multiplication and persistence of the live vaccine within the host. PMID:12540549
Chen, Jeffrey M.; Alexander, David C.; Behr, Marcel A.; Liu, Jun
Background Monocyte-derived macrophages critically perpetuate inflammatory responses after liver injury as a prerequisite for organ fibrosis. Experimental murine models identified an essential role for the CCR2-dependent infiltration of classical Gr1/Ly6C+ monocytes in hepatic fibrosis. Moreover, the monocyte-related chemokine receptors CCR1 and CCR5 were recently recognized as important fibrosis modulators in mice. In humans, monocytes consist of classical CD14+CD16? and non-classical CD14+CD16+ cells. We aimed at investigating the relevance of monocyte subpopulations for human liver fibrosis, and hypothesized that �non-classical� monocytes critically exert inflammatory as well as profibrogenic functions in patients during liver disease progression. Methodology/Principal Findings We analyzed circulating monocyte subsets from freshly drawn blood samples of 226 patients with chronic liver disease (CLD) and 184 healthy controls by FACS analysis. Circulating monocytes were significantly expanded in CLD-patients compared to controls with a marked increase of the non-classical CD14+CD16+ subset that showed an activated phenotype in patients and correlated with proinflammatory cytokines and clinical progression. Correspondingly, CD14+CD16+ macrophages massively accumulated in fibrotic/cirrhotic livers, as evidenced by immunofluorescence and FACS. Ligands of monocyte-related chemokine receptors CCR2, CCR1 and CCR5 were expressed at higher levels in fibrotic and cirrhotic livers, while CCL3 and CCL4 were also systemically elevated in CLD-patients. Isolated monocyte/macrophage subpopulations were functionally characterized regarding cytokine/chemokine expression and interactions with primary human hepatic stellate cells (HSC) in vitro. CD14+CD16+ monocytes released abundant proinflammatory cytokines. Furthermore, CD14+CD16+, but not CD14+CD16? monocytes could directly activate collagen-producing HSC. Conclusions/Significance Our data demonstrate the expansion of CD14+CD16+ monocytes in the circulation and liver of CLD-patients upon disease progression and suggest their functional contribution to the perpetuation of intrahepatic inflammation and profibrogenic HSC activation in liver cirrhosis. The modulation of monocyte-subset recruitment into the liver via chemokines/chemokine receptors and their subsequent differentiation may represent promising approaches for therapeutic interventions in human liver fibrosis. PMID:20548789
Zimmermann, Henning W.; Seidler, Sebastian; Nattermann, Jacob; Gassler, Nikolaus; Hellerbrand, Claus; Zernecke, Alma; Tischendorf, Jens J. W.; Luedde, Tom; Weiskirchen, Ralf; Trautwein, Christian; Tacke, Frank
Extended partial hepatectomy may be needed in cases of large hepatic mass, and can lead to fulminant hepatic failure. Macroporous alginate scaffold is a biocompatible matrix which promotes the growth, differentiation and long-term hepatocellular function of primary hepatocytes in vitro. Our aim was to explore the ability of implanted macroporous alginate scaffolds to protect liver remnants from acute hepatic failure after extended partial hepatectomy. An 87% partial hepatectomy (PH) was performed on C57BL/6 mice to compare non-treated mice to mice in which alginate or collagen scaffolds were implanted after PH. Mice were scarified 3, 6, 24 and 48 h and 6 days following scaffold implantation and the extent of liver injury and repair was examined. Alginate scaffolds significantly increased animal survival to 60% vs. 10% in non-treated and collagen-treated mice (log rank=0.001). Mice with implanted alginate scaffolds manifested normal and prolonged aspartate aminotransferases and alanine aminotransferases serum levels as compared with the 2- to 20-fold increase in control groups (P<0.0001) accompanied with improved liver histology. Sustained normal serum albumin levels were observed in alginate-scaffold-treated mice 48 h after hepatectomy. Incorporation of BrdU-positive cells was 30% higher in the alginate-scaffold-treated group, compared with non-treated mice. Serum IL-6 levels were significantly decreased 3h post PH. Biotin-alginate scaffolds were quickly well integrated within the liver tissue. Collectively, implanted alginate scaffolds support liver remnants after extended partial hepatectomy, thus eliminating liver injury and leading to enhanced animal survival after extended partial hepatectomy. PMID:24607858
Shteyer, Eyal; Ben Ya'acov, Ami; Zolotaryova, Lidia; Sinai, Avital; Lichtenstein, Yoav; Pappo, Orit; Kryukov, Olga; Elkayam, Tsiona; Cohen, Smadar; Ilan, Yaron
Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. To elucidate the molecular basis of NAFLD we performed an exome-wide association study of liver fat content. Three variants were associated with increased liver fat at the exome-wide significance level: two in PNPLA3, an established locus for NAFLD, and one (Glu167Lys) in TM6SF2, a gene of unknown function. The Glu167LysTM6SF2 variant was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and lower levels of LDL-cholesterol, triglycerides and alkaline phosphatase in 3 independent populations (n>80,000). Recombinant Glu167LysTM6SF2 produced 50% less protein than wild-type TM6SF2 when expressed in cultured hepatocytes. Adeno-associated virus-mediated shRNA knockdown of Tm6sf2 in mice increased liver triglyceride content 3-fold and decreased VLDL secretion by 50%. Taken together, these data indicate that TM6SF2 activity is required for normal VLDL secretion, and that impaired TM6SF2 function causally contributes to NAFLD. PMID:24531328
Kozlitina, Julia; Smagris, Eriks; Stender, Stefan; Nordestgaard, B?rge G.; Zhou, Heather H.; Tybjaerg-Hansen, Anne; Vogt, Thomas F.; Hobbs, Helen H.; Cohen, Jonathan C.
Qinggan Huoxue Recipe is a traditional Chinese medicine, which has been usually used to improve liver function in hepatitis. In order to investigate the effects of high-dose Qinggan Huoxue Recipe on acute liver failure and explore the potential mechanism, we had built acute liver failure models in rats by intraperitoneal injection of D-galactosamine (D-GalN). High-dose Qinggan Huoxue Recipe was delivered by gavage. After treatment, the blood alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumin (ALB), cholinesterase (CHE), and prothrombin time (PT) were determined. The pathological score of liver tissue was recorded. Proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and fluorescence quantitative reverse transcription polymerase chain reaction (qRT-PCR) of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-?B), and Caspase-3 were performed. The survival curve was also depicted. Our results demonstrated that high-dose Qinggan Huoxue Recipe could significantly improve liver function and increase survival rates in rats with acute liver failure. These effects were supposed to be mediated by suppressing inflammatory reaction and apoptosis. PMID:23554835
Zhu, Hong; Zhang, Yang; Hu, Xiaoyu; Yi, Cheng; Zhong, Sen; Wang, Yanyan; Yang, Fang
Functional units in rainbow trout (Salmo gairdneri, Richardson) liver: II. The biliary system.
The intrahepatic biliary system was studied in the rainbow trout (Salmo gairdneri), a teleost known to form liver neoplasms after exposure to various carcinogens. Normal adults (N = 25) were examined using light microscopic, enzyme histochemical, and transmission and scanning electron microscopic methods. In light micrographs, longitudinal arrays of hepatocytes appeared as double rows incompletely divided by elongated darkly stained cells. Electron micrographs showed tubules of five to nine pyramidally shaped hepatocytes with their apices directed toward a central biliary passageway and their bases directed toward sinusoids. Sequentially, beginning with hepatocytes, biliary passageways included canaliculi, preductules, ductules, and ducts. Canaliculi were short and joined transitional passageways (preductules) formed by junctional complexes between plasma membranes of hepatocytes and small, electron-dense cells with a high nuclear to cytoplasmic ratio. Ductules, completely lined by biliary epithelial cells, occupied central regions of hepatic tubules. Relatively elongated, ductular cells were intimately associated with surrounding hepatocytes, separated from them by only a thin extracellular space devoid of a basal lamina. Epithelium of bile ducts included cuboidal through mucus-laden columnar cells, surrounded by basal lamina and, in larger ducts, by fibroblasts, smooth muscle cells, and a capillary plexus. Bile ducts and hepatic arterioles, but not venules, were distributed together. The ultrastructure of biliary epithelium, periductular, and periductal cells is presented. PMID:2970812
Hampton, J A; Lantz, R C; Goldblatt, P J; Lauren, D J; Hinton, D E
Chemical modification of a functional arginine residue of rat liver glycine methyltransferase
Rat liver glycine methyltransferase is inactivated irreversibly by phenylglyoxal in potassium phosphate buffer. The inactivation obeys pseudo-first-order kinetics, and the apparent first-order rate constant for inactivation is linearly related to the reagent concentration. A second-order rate constant of 10.54 +/- 0.44 M/sup -1/ min /sup -1/ is obtained at pH 8.2 and 25/sup 0/C. Amino acid analysis shows that only arginine is modified upon treatment with phenylglyoxal. Sodium acetate, a competitive inhibitor with respect to glycine, affords complete protection in the presence of S-adenosylmethionine. Acetate alone has no effect on the rate of inactivation. The value of the dissociation constant for acetate determined from the protection experiment is in good agreement with that obtained by kinetic analysis. Comparison of the amount of (/sup 14/C) phenylglyoxal incorporated into the protein and the number of arginine residues modified in the presence and absence of protecting ligands indicates that modification of one arginine residue per enzyme subunit eliminates the enzyme activity, and this residue is identified as Arg-175 by peptide analysis. The arginine-modified glycine methyltransferase appears to bind S-adenosylmethionine as the native enzyme does, as seen from quenching of the protein fluorescence by S-adenosylmethionine. These results suggest the requirement of Arg-175 in binding the carboxyl group of the substrate glycine.
Konishi, K.; Fujioka, M.
The Oriental hornet Vespa orientalis (Hymenoptera, Vespinae) coordinates its daily activities (e.g. flights out of the nest associated with digging activities and removal of the dug soil from the nest) with the amount of insolation. Thus, the stronger the insolation, the more intense the flight activity and vise versa. The hornet's cuticle bears a few yellow stripes interposed among brown parts of the gastral cuticle. These yellow stripes are composed of two elements, namely, a transparent cuticle and underneath it a layer of yellow granules. When the hornets are exposed to UV light, the layer containing the yellow granules is less active than in hornets kept in the dark. This diminished activity entails a lower production of glucose as well as of several enzymes prevalent also in the liver of mammals, like creatine kinase, alanine aminotransferase, aspartate transaminase. Thus solar irradiation stimulates and produces a change in the metabolic activities of the hornet. The fact that hornets link their flight activity with the insolation leads us to speculate that the sun contributes energetically to the hornet's activity. PMID:19535034
Plotkin, Marian; Volynchik, Stanislav; Itzhaky, Dganit; Lis, Monica; Bergman, David J; Ishay, Jacob S
The addition of lactate to lightly buffered suspensions of resting cells of Escherichia coli caused an increase in the pH of the extracellular phase as lactate and protons entered the cell together. From the magnitude of the pH change and the non-electrogenic character of lactate uptake, we concluded that the stoichiometry of the process was 1 proton/lactate anion. The addition of alanine caused a slow increase in pH, also apparently due to the transport of the amino acid by a symport mechanism with 1 proton/alanine stoichiometry. When cells were grown in the chemostat with alanine as sole carbon source and as limiting nutrient, this stoichiometry was found to alter to 2 protons/alanine, and then to 4 protons/alanine. These increases stoichiometries were due to the selection of mutants. The consequences of these changes on the potential uptake capacity of the cells are discussed. PMID:7547
Collins, S H; Jarvis, A W; Lindsay, R J; Hamilton, W A
Associations between Liver Enzymes, Psychopathological and Clinical Features in Eating Disorders.
Elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels are frequently reported in patients with anorexia nervosa (AN) and in subjects who are overweight or with hyperlipidemia, which can be found to be associated with binge eating disorder (BED) and bulimia nervosa (BN). Liver functioning and psychopathological features have been evaluated in 43 patients with AN, 33 with BN, and 32 with BED. Body mass index was found to be inversely associated with AST and ALT in AN, and directly associated with AST and ALT in BED. A positive association between ALT and AST and body shape concern in AN was observed. Liver enzymes could be considered as an index of severity in AN and BED patients. Copyright � 2014 John Wiley & Sons, Ltd and Eating Disorders Association. PMID:25139759
Lelli, Lorenzo; Castellini, Giovanni; Gabbani, Tommaso; Godini, Lucia; Rotella, Francesco; Ricca, Valdo
Punicalagin and punicalin were isolated from the leaves of Terminalia catappa L., a Combretaceous plant distributed throughout tropical and subtropical beaches, which is used for the treatment of dermatitis and hepatitis. Our previous studies showed that both of these compounds exert antioxidative activity. In this study, the antihepatotoxic activity of punicalagin and punicalin on acetaminophen-induced toxicity in the rat liver was evaluated. After evaluating the changes of several biochemical functions in serum, the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased by acetaminophen administration and reduced by punicalagin and punicalin. Histological changes around the hepatic central vein and oxidative damage induced by acetaminophen were also recovered by both compounds. The data show that both punicalagin and punicalin exert antihepatotoxic activity, but treatment with larger doses enhanced liver damage. These results suggest that even if punicalagin and punicalin have antioxidant activity at small doses, treatment with larger doses will possibly induce some cell toxicities. PMID:11351354
Lin, C C; Hsu, Y F; Lin, T C; Hsu, H Y
The functional state of a sphingomyeline cycle and character of its mutual relations with the processes of free radical lipid oxidation during starvation of animals without any restriction of access to drinking water at 1, 2, 3 day (I phase) and 6 day (II phase of starvation) were studied at the liver of rats. The maximal values of the ceramide/sphingomyeline ratio and activity neutral sphingomyelinase and executive caspase-3 were reached in a liver of animals at the 3rd day of starvation. From the 3rd day of starvation the concentration of the tumour necrosis factor-alpha which is one of activators neutral sphingomyelinase was increase in rats blood serum. During the extent of large part of the I phase of starvation the intensity of free radical lipid peroxidation in a liver had almost the same level as in control group--that was a result of the high-grade functioning of antioxidant defense system. After transition the I phase of starvation into the II phase (6 day of experiment) the oxidative stress was developed as result of an exhaustion of system antioxidant defense potential in a liver. The results of this data can testify that during I phase of starvation in a liver the conditions was raised for display of the ceramide-mediated proapoptotic signalling. We assume that ceramide-mediated apoptosis is one of mechanisms of optimization of liver cellular population at the frames of metabolic adaptation. The I phase of starvation in a liver proves by the ceramide-mediated proapoptotic signaling developing. During the II phase of starvation the oxidative stress process were prevailed. PMID:23289297
Kuz'menko, D I; Burov, P G; Serebrov, V Iu; Fa?t, E A; Perevozchikova, T V
... NIDDK supports and conducts a wide variety of research related to liver diseases, liver failure, and liver transplantation. Examples of studies funded by the NIDDK include those investigating adult- ...
Liver involvement in systemic infection
The liver is often involved in systemic infections, resulting in various types of abnormal liver function test results. In particular, hyperbilirubinemia in the range of 2-10 mg/dL is often seen in patients with sepsis, and several mechanisms for this phenomenon have been proposed. In this review, we summarize how the liver is involved in various systemic infections that are not considered to be primarily hepatotropic. In most patients with systemic infections, treatment for the invading microbes is enough to normalize the liver function tests. However, some patients may show severe liver injury or fulminant hepatic failure, requiring intensive treatment of the liver.
Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro
OBJECTIVES:Altered small-bowel motility, lengthening of the orocecal transit time, and small-intestinal bacterial overgrowth have been described in patients with liver cirrhosis. These changes might be related to the progressive course and poor prognosis of the disease. We investigated the effect of a long-term treatment with cisapride and an antibiotic regimen on small-intestinal motor activity, orocecal transit time, bacterial overgrowth, and
Ana Maria Madrid; Carmen Hurtado; Mauricio Venegas; Francisco Cumsille; Carlos Defilippi
Polyproline II structure in a sequence of seven alanine residues.
A sequence of seven alanine residues-too short to form an alpha-helix and whose side chains do not interact with each other-is a particularly simple model for testing the common description of denatured proteins as structureless random coils. The (3)J(HN alpha) coupling constants of individual alanine residues have been measured from 2 to 56 degrees C by using isotopically labeled samples. The results display a thermal transition between different backbone conformations, which is confirmed by CD spectra. The NMR results suggest that polyproline II is the dominant conformation at 2 degrees C and the content of beta strand is increased by approximately 10% at 55 degrees C relative to that at 2 degrees C. The polyproline II conformation is consistent with recent studies of short alanine peptides, including structure prediction by ab initio quantum mechanics and solution structures for both a blocked alanine dipeptide and an alanine tripeptide. CD and other optical spectroscopies have found structure in longer "random coil" peptides and have implicated polyproline II, which is a major backbone conformation in residues within loop regions of protein structures. Our result suggests that the backbone conformational entropy in alanine peptides is considerably smaller than estimated by the random coil model. New thermodynamic data confirm this suggestion: the entropy loss on alanine helix formation is only 2.2 entropy units per residue. PMID:12091708
Shi, Zhengshuang; Olson, C Anders; Rose, George D; Baldwin, Robert L; Kallenbach, Neville R
Polyproline II structure in a sequence of seven alanine residues
NASA Astrophysics Data System (ADS)
A sequence of seven alanine residuestoo short to form an -helix and whose side chains do not interact with each otheris a particularly simple model for testing the common description of denatured proteins as structureless random coils. The 3JHN coupling constants of individual alanine residues have been measured from 2 to 56�C by using isotopically labeled samples. The results display a thermal transition between different backbone conformations, which is confirmed by CD spectra. The NMR results suggest that polyproline II is the dominant conformation at 2�C and the content of strand is increased by approximately 10% at 55�C relative to that at 2�C. The polyproline II conformation is consistent with recent studies of short alanine peptides, including structure prediction by ab initio quantum mechanics and solution structures for both a blocked alanine dipeptide and an alanine tripeptide. CD and other optical spectroscopies have found structure in longer "random coil" peptides and have implicated polyproline II, which is a major backbone conformation in residues within loop regions of protein structures. Our result suggests that the backbone conformational entropy in alanine peptides is considerably smaller than estimated by the random coil model. New thermodynamic data confirm this suggestion: the entropy loss on alanine helix formation is only 2.2 entropy units per residue.
Shi, Zhengshuang; Olson, C. Anders; Rose, George D.; Baldwin, Robert L.; Kallenbach, Neville R.
In a risk assessment and safety evaluation, the effect of Rauwolfia Vomitoria Afzel (Apocynaceae) extract on serum amino transferase and alkaline phosphatase activities and selected indices of liver and kidney functions were investigated. Ethanolic root and leaf extracts of R. vomitoria Afzel (Apocynaceae) were administered externally by gastric intubation to two groups of rats at dose 524 mg\\/kg body weight
M. U. Eteng; H. A. Ibekwe; A. O. Abolaji; A. I. Okoi; N. C. Osuchukwu
We examined the maintenance of functional and morphological integrity of precision-cut rat liver slices cultured in various incubation systems and conditions for 72 h. Slices were incubated (37�C) for 6, 24, 48, and 72 h in supplemented Williams E medium in 6-well plastic culture plates on a gyratory shaking platform (WPCS) or in a rotating organ culture system (ROCS) using
H. J. Toutain; V. Moronvalle-Halley; J. P. Sarsat; C. Chelin; D. Hoet; D. Leroy
Patients with chronic hepatitis C virus (HCV) infection and persistently normal alanine aminotransferase (PNALT) are generally described to have mild liver disease. The aim of this study was to compare clinical and histological features in HCV-infected patients with PNALT and elevated ALT. Patients presenting to the University of Illinois Medical Center, Chicago, who had biopsy proven HCV, an ALT measurement at the time of liver biopsy, at least one additional ALT measurement over the next 12 months, and liver biopsy slides available for review were identified. PNALT was defined as ALT ? 30 on at least 2 different occasions over 12 months. Of 1200 patients with HCV, 243 met the study criteria. 13% (32/243) of patients had PNALT while 87% (211/243) had elevated ALT. Significantly more patients with PNALT had advanced fibrosis (F3 and F4) compared to those with elevated ALT (P = 0.007). There was no significant difference in the histology activity index score as well as mean inflammatory score between the two groups. In conclusion, in a well-characterized cohort of patients at a tertiary medical center, PNALT did not distinguish patients with mild liver disease. PMID:24891947
Guzman, Grace
Optical and Spectral Studies on ? Alanine Metal Halide Hybrid Crystals
NASA Astrophysics Data System (ADS)
We have synthesized and grown ? alanine metal halide hybrid crystals viz. ? alanine cadmium chloride (BACC), an amino acid transition metal halide complex crystal and ? alanine potassium chloride (BAPC), an amino acid alkali metal halide complex crystal by slow evaporation method. The grown crystals were found to be transparent and have well defined morphology. The optical characteristics of the grown crystals were carried out with the help of UV-Vis Spectroscopy. The optical transmittances of the spectrums show that BAPC is more transparent than BACC. The Photoluminescence of the materials were determined by the Photoluminescent Spectroscopy
Sweetlin, M. Daniel; Selvarajan, P.; Perumal, S.; Ramalingom, S.
Dissociative electron attachment to dialanine and alanine anhydride has been studied in the gas phase utilizing a double focusing two sector field mass spectrometer. We show that low-energy electrons (i.e., electrons with kinetic energies from near zero up to 13 eV) attach to these molecules and subsequently dissociate to form a number of anionic fragments. Anion efficiency curves are recorded for the most abundant anions by measuring the ion yield as a function of the incident electron energy. The present experiments show that as for single amino acids (M), e.g., glycine, alanine, valine, and proline, the dehydrogenated closed shell anion (M-H)(-) is the most dominant reaction product. The interpretation of the experiments is aided by quantum chemical calculations based on density functional theory, by which the electrostatic potential and molecular orbitals are calculated and the initial electron attachment process prior to dissociation is investigated. PMID:21303118
Alizadeh, Elahe; Gschliesser, David; Bartl, Peter; Hager, Michaela; Edtbauer, Achim; Vizcaino, Violaine; Mauracher, Andreas; Probst, Michael; M�rk, Tilmann D; Ptasi?ska, Sylwia; Mason, Nigel J; Denifl, Stephan; Scheier, Paul
NASA Astrophysics Data System (ADS)
Dissociative electron attachment to dialanine and alanine anhydride has been studied in the gas phase utilizing a double focusing two sector field mass spectrometer. We show that low-energy electrons (i.e., electrons with kinetic energies from near zero up to 13 eV) attach to these molecules and subsequently dissociate to form a number of anionic fragments. Anion efficiency curves are recorded for the most abundant anions by measuring the ion yield as a function of the incident electron energy. The present experiments show that as for single amino acids (M), e.g., glycine, alanine, valine, and proline, the dehydrogenated closed shell anion (M-H)- is the most dominant reaction product. The interpretation of the experiments is aided by quantum chemical calculations based on density functional theory, by which the electrostatic potential and molecular orbitals are calculated and the initial electron attachment process prior to dissociation is investigated.
Alizadeh, Elahe; Gschliesser, David; Bartl, Peter; Hager, Michaela; Edtbauer, Achim; Vizcaino, Violaine; Mauracher, Andreas; Probst, Michael; M�rk, Tilmann D.; Ptasi?ska, Sylwia; Mason, Nigel J.; Denifl, Stephan; Scheier, Paul
The physiological role of liver alcohol dehydrogenase
1. Yeast alcohol dehydrogenase was used to determine ethanol in the portal and hepatic veins and in the contents of the alimentary canal of rats given a diet free from ethanol. Measurable amounts of a substance behaving like ethanol were found. Its rate of interaction with yeast alcohol dehydrogenase and its volatility indicate that the substance measured was in fact ethanol. 2. The mean alcohol concentration in the portal blood of normal rats was 0.045mm. In the hepatic vein, inferior vena cava and aorta it was about 15 times lower. 3. The contents of all sections of the alimentary canal contained measurable amounts of ethanol. The highest values (average 3.7mm) were found in the stomach. 4. Infusion of pyrazole (an inhibitor of alcohol dehydrogenase) raised the alcohol concentration in the portal vein 10-fold and almost removed the difference between portal and hepatic venous blood. 5. Addition of antibiotics to the food diminished the ethanol concentration of the portal blood to less than one-quarter and that of the stomach contents to less than one-fortieth. 6. The concentration of alcohol in the alimentary canal and in the portal blood of germ-free rats was much decreased, to less than one-tenth in the alimentary canal and to one-third in the portal blood, but detectable quantities remained. These are likely to arise from acetaldehyde formed by the normal pathways of degradation of threonine, deoxyribose phosphate and ?-alanine. 7. The results indicate that significant amounts of alcohol are normally formed in the gastro-intestinal tract. The alcohol is absorbed into the circulation and almost quantitatively removed by the liver. Thus the function, or a major function, of liver alcohol dehydrogenase is the detoxication of ethanol normally present. 8. The alcohol concentration in the stomach of alloxan-diabetic rats was increased about 8-fold. 9. The activity of liver alcohol dehydrogenase is generally lower in carnivores than in herbivores and omnivores, but there is no strict parallelism between the capacity of liver alcohol dehydrogenase and dietary habit. 10. The activity of alcohol dehydrogenase of gastric mucosa was much decreased in two out of the three germ-free rats tested. This is taken to indicate that the enzyme, like gastric urease, may be of microbial origin. 11. When the body was flooded with ethanol by the addition of 10% ethanol to the drinking water the alcohol concentration in the portal vein rose to 15mm and only a few percent of the incoming ethanol was cleared by the liver. PMID:5481498
Krebs, H. A.; Perkins, J. R.
Quantitative analysis of liver function in percutaneous transhepatic biliary drainage patients
The diagnostic usefulness of Tc-99m DISIDA cholescintigraphy as a predictor of eventual catheter and hepatic function in patients who have undergone percutaneous transhepatic biliary drainage (PTBD) for extrahepatic biliary obstruction was evaluated. Twenty-nine cholescintigrams were performed in 14 patients. The examinations were divided into two groups: Group A (N = 17), in which the patient's clinical status deteriorated within two to three days post-PTBD, and Group B (N = 12), in which the patients did well clinically post-PTBD. No significant difference between the two groups was demonstrated by visual analysis of the analog images or by analysis of serum bilirubin levels. A computer program, developed by the authors, quantitates several parameters of DISIDA kinetics, reflecting hepatic function based upon compartmental analysis. A significant difference (P less than .001) was demonstrated between the mean transport constants (blood clearance constant = k1; hepatic clearance constant = k2) for the two groups. It is concluded that serum bilirubin levels and visual inspection of analog images are inadequate independent predictors of hepatic function in patients post PTBD. The transport constants k1 and k2 are quantitative parameters of hepatic function that may be of prognostic value in patients post PTBD.
Velchik, M.G.; Schwartz, W.; London, J.W.; Makler, P.T. Jr.; Alavi, A.
Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds
BackgroundNitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying
Youping Deng; Sharon A. Meyer; Xin Guan; Barbara Lynn Escalon; Junmei Ai; Mitchell S. Wilbanks; Ruth Welti; Nat�lia Garcia-Reyero; Edward J. Perkins; Vladimir N. Uversky
Ageing-related changes in the in vivo function of rat liver macroautophagy and proteolysis
Autophagy is a universal, highly regulated mechanism responsible for the degradation of long-lived proteins, cytomembranes and organelles during fasting and may be the cell repair mechanism that mediates the anti-ageing effects of calorie restriction (Bergamini and Gori, 1995). The function of autophagy was studied in vivo on male Sprague Dawley rats fed ad libitum or 40% food restricted. Autophagy was
Alessandra Del Roso; Simona Vittorini; Gabriella Cavallini; Alessio Donati; Zina Gori; Matilde Masini; Maria Pollera; Ettore Bergamini
Stable isotope-mass spectrometry (MS)-based metabolomic profiling is a powerful technique for following changes in specific metabolite pool sizes and metabolic flux under various experimental conditions in a test organism or cell type. Here, we use a metabolomics approach to interrogate the mechanism of antibiotic action of d-cycloserine (DCS), a second line antibiotic used in the treatment of multidrug resistant Mycobacterium tuberculosis infections. We use doubly labeled 13C ?-carbon-2H l-alanine to allow tracking of both alanine racemase and d-alanine:d-alanine ligase activity in M. tuberculosis challenged with DCS and reveal that d-alanine:d-alanine ligase is more strongly inhibited than alanine racemase at equivalent DCS concentrations. We also shed light on mechanisms surrounding d-Ala-mediated antagonism of DCS growth inhibition and provide evidence for a postantibiotic effect for this drug. Our results illustrate the potential of metabolomics in cellular drug-target engagement studies and consequently have broad implications in future drug development and target validation ventures. PMID:24478820
d-Cycloserine is an effective second line antibiotic used as a last resort to treat multi (MDR)- and extensively (XDR) drug resistant strains of Mycobacterium tuberculosis . d-Cycloserine interferes with the formation of peptidoglycan biosynthesis by competitive inhibition of alanine racemase (Alr) and d-alanine-d-alanine ligase (Ddl). Although the two enzymes are known to be inhibited, the in vivo lethal target is still unknown. Our NMR metabolomics work has revealed that Ddl is the primary target of DCS, as cell growth is inhibited when the production of d-alanyl-d-alanine is halted. It is shown that inhibition of Alr may contribute indirectly by lowering the levels of d-alanine, thus allowing DCS to outcompete d-alanine for Ddl binding. The NMR data also supports the possibility of a transamination reaction to produce d-alanine from pyruvate and glutamate, thereby bypassing Alr inhibition. Furthermore, the inhibition of peptidoglycan synthesis results in a cascading effect on cellular metabolism as there is a shift toward the catabolic routes to compensate for accumulation of peptidoglycan precursors. PMID:24303782
Halouska, Steven; Fenton, Robert J; Zinniel, Denise K; Marshall, Darrell D; Barletta, Ra�l G; Powers, Robert
The objectives of this work were to evaluate the direct effects of diallysulfide (DAS) and diallyldisulfide (DADS), two major organosulfur compounds of garlic oil, on mitochondrial function and integrity, by using isolated mouse liver mitochondria in a cell-free system. DADS produced concentration-dependent mitochondrial swelling over the range 125�1000 ?M, while DAS was ineffective. Swelling experiments performed with de-energized or energized mitochondria showed similar maximal swelling amplitudes. Cyclosporin A (1 ?M), or ethylene glycol-bis(2-aminoethylether)-N,N,N?,N?-tetraacetic acid (EGTA, 1 mM) were ineffective in inhibiting DADS-induced mitochondrial swelling. DADS produced a minor (12%) decrease in mitochondrial membrane protein thiols, but did not induce clustering of mitochondrial membrane proteins. Incubation of mitochondria with DADS (but not DAS) produced an increase in the oxidation rate of 2?,7? dichlorofluorescein diacetate (DCFH-DA), together with depletion of reduced glutathione (GSH) and increased lipid peroxidation. DADS (but not DAS) produced a concentration-dependent dissipation of the mitochondrial membrane potential, but did not induce cytochrome c release. DADS-dependent effects, including mitochondrial swelling, DCFH-DA oxidation, lipid peroxidation and loss of mitochondrial membrane potential, were inhibited by antioxidants and iron chelators. These results suggest that DADS causes direct impairment of mitochondrial function as the result of oxidation of the membrane lipid phase initiated by the GSH- and iron-dependent generation of oxidants. PMID:22960305
Caro, Andres A.; Adlong, Luke W.; Crocker, Samuel J.; Gardner, Michael W.; Luikart, Emily F.; Gron, Liz U.
Dimethylformamide-induced liver damage among synthetic leather workers
Prevalence of liver injury associated with dimethylformamide (DMF) exposure was determined. Medical examinations, liver function tests, and creatine phosphokinase (CPK) determinations were performed on 183 of 204 (76%) employees of a synthetic leather factory. Air concentrations of solvents were measured with personal samplers and gas chromatography. The concentration of DMF in air to which each worker was exposed was categorized. High exposure concentrations of DMF (i.e., 25-60 ppm) were significantly associated with elevated alanine aminotransferase (ALT) levels (ALT greater than or equal to 35 IU/l), a result that did not change even after stratification by hepatitis B carrier status. Modeling by logistic regression demonstrated that exposure to high concentrations of DMF was associated with an elevated ALT (p = .01), whereas hepatitis B surface antigen (HBsAg) was slightly but independently associated with an elevated ALT (p = .07). In those workers who had normal ALT values, there occurred still significantly higher mean ALT and aspartate aminotransferase (AST) activities, especially among those who were not HBsAg carriers. A significant association existed between elevated CPK levels and exposure to DMF. However, an analysis of the CPK isoenzyme among 143 workers did not reveal any specific damage to muscles. This outbreak of liver injury among synthetic leather workers is ascribed to DMF. It is recommended that the occupational standard for DMF and its toxicity among HBsAg carriers be evaluated further.
Wang, J.D.; Lai, M.Y.; Chen, J.S.; Lin, J.M.; Chiang, J.R.; Shiau, S.J.; Chang, W.S. (Center for the Research of Environmental and Occupational Disease, Graduate Institute of Public Health and Department of Internal Medicine, National Taiwan University, College of Medicine (China))
Natural Circular Dichroism Spectra of Alanine and Valine Films in Vacuum Ultraviolet Region
NASA Astrophysics Data System (ADS)
Natural circular dichroism (CD) of alanine (Ala) and valine (Val) films were measured in vacuum ultraviolet region using a polarizing undulator as a circularly polarized light source. Compared with absorption spectra, CD spectra showed clear differences between Ala and Val films. In order to explain these differences, a time-dependent density functional theory was applied to calculated CD spectra. The calculated CD spectra showed good agreement with the experimental CD spectra.
Kaneko, Fusae; Yagi-Watanabe, Kazutoshi; Tanaka, Masahito; Nakagawa, Kazumichi
SUMMARY Background Non-alcoholic steatohepatitis (NASH) is a common cause of serum alanine aminotransferase (ALT) elevations and chronic liver disease, but it is unclear how well ALT elevations reflect the liver injury. Aim To assess how well changes in ALT elevations reflect improvements in liver histology in response to vitamin E therapy. Methods The vitamin E and placebo arms of the Pioglitazone vs. Vitamin E vs. Placebo in Non-alcoholic Steatohepatitis (PIVENS) trial were reassessed for associations among changes in ALT levels, body weight and liver histology. An ALT response was defined as a decrease to ?40 U/L and by ?30% of baseline. Liver biopsies taken before and after treatment were scored for non-alcoholic fatty liver disease activity (NAS) and fibrosis. Results ALT responses were more frequent among vitamin E (48%) than placebo (16%) recipients (P < 0.001). Among vitamin E recipients, ALT responses were associated with decreases in NAS (P < 0.001), but not fibrosis scores (P = 0.34), whereas among placebo recipients, ALT responses were associated with significant decreases in both (P < 0.05). Weight loss (?2 kg) was also associated with ALT response (P < 0.001), improvements in NAS (P < 0.001) and fibrosis (P < 0.02), but vitamin E had an added effect both with and without weight loss. Weight gain (?2 kg) was associated with lack of ALT response and worsening NAS and fibrosis scores in patients not on vitamin E. Conclusions Decrease of ALT levels to normal in patients with NASH is usually associated with improved histological activity. Management should stress the value of weight loss and strongly discourage weight gain. Vitamin E can improve both ALT levels and histology with and without weight loss. Clinical Trial Number: NCT00063622. PMID:23718573
Hoofnagle, J. H.; Van Natta, M. L.; Kleiner, D. E.; Clark, J. M.; Kowdley, K. V.; Loomba, R.; Neuschwander-Tetri, B. A.; Sanyal, A. J.; Tonascia, J.
Oxygen is an important component of the cellular microenvironment, mediating cell survival, differentiation, and function. Oxygen supply is a limit- ing factor during culture of highly metabolic cells such as hepatocytes. Here we present a simple formulation of a fluorocarbon-based oxygen carrier embedded in collagen gel that increases oxygen concentration in culture 6-fold. Rat hepatocytes cultured on oxygen carrier-collagen showed
Yaakov Nahmias; Yiannos Kramvis; Laurent Barbe; Monica Casali; Francois Berthiaume; Martin L. Yarmush
Background\\/Aims: The relationship between nitric oxide production, endotoxemia, renal function and hyperdynamic circulatory syndrome has not been yet investigated in patients with cirrhosis.Methods: Serum and urine nitrate, endotoxemia and cardiac index were measured in 59 patients with cirrhosis.Results: Patients with a tense ascites had higher serum nitrate levels than health control subjects (39�7 vs 19�4 ?mol\\/l, p<0.01). Patients with mild
Bernard Campillo; Phuong Nhi Bories; Christophe Benvenuti; Catherine Dupeyron
Transplantable liver production plan
Organ grafts developed in the xenogeneic pig scaffold are expected to resolve most issues of donor safety and ethical concerns about living-donor liver transplantation in Japan. We have been working on so-called �Yamaton� projects to develop transplantable organs using genetically engineered pigs. Our goal is to produce chimeric livers with human parenchyma in such pigs. The Yamaton-Liver project demonstrated the proof of concept by showing that rat�mouse chimeric livers could develop in mice and be successfully transplanted into syngeneic or allogeneic rats. Under conventional immunosuppression, the transplanted livers showed long-term function and protection against rejection. Because chimeric liver grafts have xenogeneic components, additional strategies, such as humanization of pig genes, induction of hematopoietic chimeras in donors, and replacement of pig endothelial cells with human ones, might be required in clinical use. Our projects still need to overcome various hurdles but can bring huge benefits to patients in the future. PMID:23896578
Hata, Toshiyuki; Uemoto, Shinji; Kobayashi, Eiji
Biochemical effects of three carcinogenic chlorinated methanes in rat liver
Three chlorinated methanes, carbon tetrachloride, chloroform and methylene chloride known to cause liver tumors in rodents, were given by oral gavage to adult female rats both 21 and 4 hours before sacrifice. Then hepatic DNA damage, ornithine decarboxylase, cytochrome P-450, glutathione content and serum alanine aminotransferase activity assays were performed. Carbon tetrachloride increased rat hepatic ornithine decarboxylase activity and decreased cytochrome P-450 content at doses both below and above cytotoxicity (as measured by increased serum alanine aminotransferase activity). At 54 and 160 mg/kg, chloroform increased hepatic ornithine decarboxylase activity with minimal or no elevation in serum alanine aminotransferase activity. After oral administration of 480 mg/kg of chloroform, hepatic ornithine decarboxylase activity, serum alanine aminotransferase activity and hepatic DNA damage were increased while hepatic cytochrome P-450 content was decreased. The results with methylene chloride varied between replicates done on three different days.
Kitchin, K.T.; Brown, J.L.
Background Carnosine is a dipeptide that improves exercise performance. The carnosine synthesis mechanism through carnosine and �-alanine ingestion remains unclear. Therefore, we investigated the tissue distribution of carnosine synthase, ATP-grasp domain-containing protein-1 (ATPGD1) mRNA, and ATPGD1 and carnosine specific dipeptidase (CN1) gene expression profiles in mice that were given carnosine or �-alanine orally. Methods ddY mice (7-week-old) were randomly divided into three groups (n?=?6 to 8 animals per group) and were orally given 2 g/kg body weight of carnosine, �-alanine, or water. After 15, 30, 60, 120, 180, or 360 min of treatment, the tissues (brain, blood, liver, kidneys, olfactory bulbs, hindleg muscles) were collected. The obtained tissues measured the expression of ATPGD1 and CN1 genes using quantitative PCR methods. Results The ATPGD1 gene was expressed in muscle and to a lesser extent in brain. The expression of ATPGD1 in the vastus lateralis muscle increased significantly at 180 min (P?=?0.023) after carnosine ingestion and 60 (P?=?0.023) and 180 min (P?=?0.025) after �-alanine ingestion. Moreover, the carnosine group showed a significantly increased renal expression of the CN1 gene 60 min after ingestion (P?=?0.0015). Conclusions The ATPGD1 gene showed high expression levels in brain and muscle. The �-alanine or carnosine administration significantly increased ATPGD1 and CN1 expression in mice. PMID:22510233
Pathogenesis in alcoholic liver disease (ALD) is complicated and multifactorial but clearly involves oxidative stress and inflammation. Currently, conflicting reports exist regarding the role of endoplasmic reticulum (ER) stress in the etiology of ALD. The glucose-regulated protein 78 (GRP78) is the ER homolog of HSP70 and plays a critical role in the cellular response to ER stress by serving as a chaperone assisting protein folding and by regulating the signaling of the unfolded protein response (UPR). Comprising three functional domains, an ATPase, a peptide-binding, and a lid domain, GRP78 folds nascent polypeptides via the substrate-binding domain. Earlier work has indicated that the ATPase function of GRP78 is intrinsically linked and essential to its chaperone activity. Previous work in our laboratory has indicated that GRP78 and the UPR are not induced in a mouse model of ALD but that GRP78 is adducted by the lipid electrophiles 4-hydroxynonenal (4-HNE) and 4-oxononenal (4-ONE) in vivo. As impairment of GRP78 has the potential to contribute to pathogenesis in ALD, we investigated the functional consequences of aldehyde adduction on GRP78 function. Identification of 4-HNE and 4-ONE target residues in purified human GRP78 revealed a marked propensity for Lys and His adduction within the ATPase domain and a relative paucity of adduct formation within the peptide-binding domain. Consistent with these findings, we observed a concomitant dose-dependent decrease in ATP-binding and ATPase activity without any discernible impairment of chaperone function. Collectively, our data indicate that ATPase activity is not essential for GRP78-mediated chaperone activity and is consistent with the hypothesis that ER stress does not play a primary initiating role in the early stages of ALD. PMID:24924946
Galligan, James J; Fritz, Kristofer S; Backos, Donald S; Shearn, Colin T; Smathers, Rebecca L; Jiang, Hua; MacLean, Kenneth N; Reigan, Philip R; Petersen, Dennis R
It has been shown that a three-week feeding of rats with oil derived from seeds of amaranth (Amaranthus cruentus L.) leads to a moderate activation of respiration of coupled and uncoupled rat liver mitochondria (MCh) that oxidize succinate and succinate + glutamate, as well as alpha-ketoglutarate and alpha-ketoglutarate + malonate. In animals receiving the amaranth oil, the injection of adrenaline did not affect the oil-activated respiration of MCh during succinate oxidation; i. e., animals prepared by an oil-enriched diet were resistant to the action of adrenaline, which prevented from possible hyperactivation of mitochondrial functions. In the group of control animals, which received no oil, the injection of adrenaline activated the rate of phosphorylating respiration of MCh during oxidation of succinate or succinate + glutamate: the rate of oxygen uptake in state 3 respiration (by Chance) increased, and the phosphorylation time decreased. The injection of adrenaline did not affect the parameters of respiration of MCh that oxidize a-ketoglutarate; however, in the presence of malonate, the oxidation of alpha-ketoglutarate in state 3 and uncoupled respiration have shown mild but significant increase in response to adrenaline. In animals receiving the amaranth oil, the oil-induced activation of respiration of MCh in response to adrenaline retained but did not increase; however, the phosphorylation time significantly decreased. Thus, concentrated oil of seeds activates the respiration of MCh. In addition, it enhances an energetic function of MCh, which prevents from the hyper-activation of mitochondrial respiration by adrenaline. Therefore an activation of energetic function of MCh by amaranth oil could explain its adaptogenic effect on rats. PMID:18357794
Sirota, T V; Eliseeva, O P; Khunderiakova, N V; Kaminski?, D V; Makhotina, O A; Kondrashova, M N
Liver physiology and liver diseases in the elderly
The liver experiences various changes with aging that could affect clinical characteristics and outcomes in patients with liver diseases. Both liver volume and blood flow decrease significantly with age. These changes and decreased cytochrome P450 activity can affect drug metabolism, increasing susceptibility to drug-induced liver injury. Immune responses against pathogens or neoplastic cells are lower in the elderly, although these individuals may be predisposed to autoimmunity through impairment of dendritic cell maturation and reduction of regulatory T cells. These changes in immune functions could alter the pathogenesis of viral hepatitis and autoimmune liver diseases, as well as the development of hepatocellular carcinoma. Moreover, elderly patients have significantly decreased reserve functions of various organs, reducing their tolerability to treatments for liver diseases. Collectively, aged patients show various changes of the liver and other organs that could affect the clinical characteristics and management of liver diseases in these patients. PMID:24379563
Tajiri, Kazuto; Shimizu, Yukihiro
Misoprostol hepatoprotection against ischemia-reperfusion-induced liver injury in the rat
The hepatoprotective effects of misoprostol, a PGE1 analog, against ischemiareperfusion liver injury were studied using a rat partial liver ischemia model. Serum ornithine carbamoyltransferase (OCT) and alanine aminotransferase (ALT) levels were determined as biochemical indices of injury. Hepatic cell necrosis was assessed histologically using tetranitroblue tetrazolium (TNBT) and hematoxylin and eosin (H&E) staining. With placebo treatment, 90 min of partial
Sook Ping Lim; Fiona J. Andrews; Chris Christophi; Paul E. O'Brien
In order to delineate the location of the tumor both before and during operation, we developed targeted bi-functional polymeric micelles for magnetic resonance (MR) and fluorescence imaging in liver tumors. Hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) were loaded into the polymeric micelles through self-assembly of an amphiphilic block copolymer poly(ethylene glycol)-poly(?-caprolactone). After, transferrin (Tf) and near-infrared fluorescence molecule Cy5.5 were conjugated onto the surface of the polymeric micelles to obtain the nanosized probe SPIO@PEG-b-PCL-Tf/Cy5.5 (SPPTC). Imaging capabilities of this nanoprobe were evaluated both in vitro and in vivo. The accumulation of SPPTC in HepG2 cells increased over email@example.com (SPPC) by confocal microscopy. The targeted nanoprobe SPPTC possessed favorable properties on the MR and fluorescence imaging both in vitro and in vivo. The MTT results showed that the nanoprobes were well tolerated. SPPTC had the potential for pre-operation evaluation and intra-operation navigation of tumors in clinic.
Surface interaction of L-alanine on hematite: an astrobiological implication.
In the present work, surface interaction of L-alanine (L-ala) has been investigated on hematite (?-Fe2O3), an abundant mineral on Mars, as a function of time (5 min-48 h), pH (4.0 and 6.20 � 0.10) and concentration (1 � 10(-3) M-10 � 10(-3) M) with optical absorbance and energy-dispersive spectroscopy (EDS). Adsorption parameters (XM and KL) were calculated from Langmuir adsorption isotherms. L-alanine has maximum affinity (65.31 %) in its zwitterionic form at pH 6.20, while it is only 29.86 % adsorbed at pH 4.0. Possible astrobiological implications are discussed. PMID:24402033
Pandey, Pramod; Pant, Chandra Kala; Gururani, Kavita; Arora, Priyanka; Kumar, Sumit; Sharma, Yogesh; Pathak, Hari Datt; Mehata, Mohan Singh
Energy landscapes and global thermodynamics for alanine peptides
NASA Astrophysics Data System (ADS)
We compare different approaches for computing the thermodynamics of biomolecular systems. Techniques based on parallel replicas evolving via molecular dynamics or Monte Carlo simulations produce overlapping histograms for the densities of states. In contrast, energy landscape methods employ a superposition partition function constructed from local minima of the potential energy surface. The latter approach is particularly powerful for systems exhibiting broken ergodicity, and it is usually implemented using a harmonic normal mode approximation, which has not been extensively tested for biomolecules. The present contribution compares these alternative approaches for small alanine peptides modelled using the CHARMM and AMBER force fields. Densities of states produced from canonical sampling using multiple temperature replicas provide accurate reference data to evaluate the effect of the harmonic normal mode approximation in the superposition calculations. This benchmarking lays foundations for the application of energy landscape methods to larger biomolecules. It will also provide well characterised model systems for developing enhanced sampling methods, and for the treatment of anharmonicity corresponding to individual local minima.
Somani, Sandeep; Wales, David J.
The title compound, {beta}-alanine zinc chloride-a new semiorganic nonlinear optical crystal was grown by slow evaporation technique. Single crystals of {beta}-alanine zinc chloride have been subjected to X-ray diffraction analysis to determine the crystal structure. The powder X-ray diffractogram of the crystal has also been recorded. The amount of carbon, nitrogen and hydrogen in the crystals was also estimated. Fourier Transform Infrared and Raman spectral measurements have been carried out on the grown crystals in order to identify the functional groups. The presence of hydrogen and carbon in the {beta}-alanine zinc chloride was confirmed by using proton and carbon nuclear magnetic resonance spectral analyses. The percentage of zinc in the crystal was determined by atomic absorption spectroscopy. Optical behavior such as ultraviolet-vis-near infrared transmittance spectrum and second harmonic generation has been investigated. The mechanical strength and thermal behavior of the grown crystal have been analyzed.
Anbuchezhiyan, M. [Department of Physics, Valliammai Engineering College, S.R.M. Nagar, Kattankulathur, Chennai 603203 (India)] [Department of Physics, Valliammai Engineering College, S.R.M. Nagar, Kattankulathur, Chennai 603203 (India); Ponnusamy, S., E-mail: firstname.lastname@example.com [Centre for Material Science and Nano Devices, Department of Physics, SRM University, Kattankulathur, Kanchipuram, Chennai 603203 (India); Muthamizhchelvan, C. [Centre for Material Science and Nano Devices, Department of Physics, SRM University, Kattankulathur, Kanchipuram, Chennai 603203 (India)] [Centre for Material Science and Nano Devices, Department of Physics, SRM University, Kattankulathur, Kanchipuram, Chennai 603203 (India); Sivakumar, K. [Department of Physics, Anna University, Chennai 600 025 (India)] [Department of Physics, Anna University, Chennai 600 025 (India)
Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. Although such rhythms have been extensively studied at the level of transcription and mRNA accumulation, little is known about the accumulation patterns of proteins. Here, we quantified temporal profiles in the murine hepatic proteome under physiological light�dark conditions using stable isotope labeling by amino acids quantitative MS. Our analysis identified over 5,000 proteins, of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night and related to core hepatic physiological functions. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulate with reduced amplitudes and significant delays, consistent with protein half-life data. Moreover, a group comprising about one-half of the rhythmic proteins showed no corresponding rhythmic mRNAs, indicating significant translational or posttranslational diurnal control. Such rhythms were highly enriched in secreted proteins accumulating tightly during the night. Also, these rhythms persisted in clock-deficient animals subjected to rhythmic feeding, suggesting that food-related entrainment signals influence rhythms in circulating plasma factors. PMID:24344304
Mauvoisin, Daniel; Wang, Jingkui; Jouffe, Celine; Martin, Eva; Atger, Florian; Waridel, Patrice; Quadroni, Manfredo; Gachon, Frederic; Naef, Felix
Background The aim of this study was to evaluate the actions of coenzyme Q10 (CoQ10) on rats with a cholesterol-rich diet (HD) and high doses of atorvastatin (ATV, 0.2, 0.56 or 1.42�mg/day). Methods Two experiments were done, the first one without coenzyme Q10 supplementation. On the second experiment all groups received coenzyme Q10 0.57�mg/day as supplement. After a 6-week treatment animals were sacrificed, blood and liver were analyzed and liver mitochondria were isolated and its oxygen consumption was evaluated in state 3 (phosphorylating state) and state 4 (resting state) in order to calculate the respiratory control (RC). Results HD increased serum and hepatic cholesterol levels in rats with or without CoQ10. ATV reduced these values but CoQ10 improved even more serum and liver cholesterol. Triacylglycerols (TAG) were also lower in blood and liver of rats with ATV?+?CoQ10. HDL-C decreased in HD rats. Treatment with ATV maintained HDL-C levels. However, these values were lower in HD?+?CoQ10 compared to control diet (CD)?+?CoQ10. RC was lessened in liver mitochondria of HD. The administration of ATV increased RC. All groups supplemented with CoQ10 showed an increment in RC. In conclusion, the combined administration of ATV and CoQ10 improved biochemical parameters, liver function and mitochondrial respiration in hypercholesterolemic rats. Conclusions Our results suggest a potential beneficial effect of CoQ10 supplementation in hypercholesterolemic rats that also receive atorvastatin. This beneficial effect of CoQ10 must be combined with statin treatment in patient with high levels of cholesterol. PMID:24460631
Zajdela hepatoma cells are poorly-adherent cells derived from an undifferentiated tumour and transplanted into rat. We compared the biosynthesis, structure and function of the fibronectin receptor in normal rat hepatocytes with that in Zajdela hepatoma cells. The rat hepatocyte fibronectin receptor has been isolated. It is composed of two subunits: alpha 5 (molecular mass 155 kDa) and beta 1 (molecular mass 115 kDa). However, its biosynthesis has not yet been described. Using polyclonal antibodies raised against each of the subunits of the receptor, we observed that the alpha 5-subunit was synthesized as a 155-kDa polypeptide in normal rat hepatocytes and Zajdela hepatoma cells. In contrast, the molecular mass of the beta 1-subunit was 130 kDa in Zajdela hepatoma cells versus 115 kDa in normal rat hepatocytes. Pulse-chase experiments showed that the apparent transition time from the 100-kDa beta 1-precursor to the 130-kDa mature form was abnormally prolonged in Zajdela hepatoma cells since the latter was not detected until 24 h, while the transition from the 100-kDa precursor to the 115-kDa mature form began within 3 h in normal rat hepatocytes. Digestion of both the normal rat hepatocytes and Zajdela hepatoma cells 100-kDa beta 1-precursors with endo-beta-N-acetylglucosaminidase H and peptide N-glycosidase yielded products from 100 kDa to 84 kDa and 82 kDa, respectively, as judged by SDS/PAGE, suggesting that the same polypeptide chain is synthesized in normal rat hepatocytes and in Zajdela hepatoma cells. Incubation of the mature normal rat hepatocyte beta 1-subunit with peptide N-glycosidase reduced its molecular mass from 115 kDa to 82 kDa, as judged by SDS/PAGE, while the molecular mass of the abnormal mature Zajdela hepatoma cell beta 1-subunit decreased from 130 to 110 kDa. Thus, in addition to alterations in the Asn-linked oligosaccharide processing, 'ascitic growth' induced other post-translational modifications in the Zajdela hepatoma cell beta 1-subunit. Furthermore, both the abnormal mature 130-kDa and precursor 100-kDa beta 1-subunits were detected on the surface of Zajdela hepatoma cells, associated with the alpha 5-subunit. The relationship between these structural alterations in the fibronectin receptor and the impaired Zajdela hepatoma cell binding to soluble fibronectin or to a coated fibronectin matrix that was observed in this study is discussed. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:8471041
Decastel, M; Doyennette-Moyne, M A; Gouet, E; Aubery, M; Codogno, P
Zajdela hepatoma cells are poorly-adherent cells derived from an undifferentiated tumour and transplanted into rat. We compared the biosynthesis, structure and function of the fibronectin receptor in normal rat hepatocytes with that in Zajdela hepatoma cells. The rat hepatocyte fibronectin receptor has been isolated. It is composed of two subunits: alpha 5 (molecular mass 155 kDa) and beta 1 (molecular mass 115 kDa). However, its biosynthesis has not yet been described. Using polyclonal antibodies raised against each of the subunits of the receptor, we observed that the alpha 5-subunit was synthesized as a 155-kDa polypeptide in normal rat hepatocytes and Zajdela hepatoma cells. In contrast, the molecular mass of the beta 1-subunit was 130 kDa in Zajdela hepatoma cells versus 115 kDa in normal rat hepatocytes. Pulse-chase experiments showed that the apparent transition time from the 100-kDa beta 1-precursor to the 130-kDa mature form was abnormally prolonged in Zajdela hepatoma cells since the latter was not detected until 24 h, while the transition from the 100-kDa precursor to the 115-kDa mature form began within 3 h in normal rat hepatocytes. Digestion of both the normal rat hepatocytes and Zajdela hepatoma cells 100-kDa beta 1-precursors with endo-beta-N-acetylglucosaminidase H and peptide N-glycosidase yielded products from 100 kDa to 84 kDa and 82 kDa, respectively, as judged by SDS/PAGE, suggesting that the same polypeptide chain is synthesized in normal rat hepatocytes and in Zajdela hepatoma cells. Incubation of the mature normal rat hepatocyte beta 1-subunit with peptide N-glycosidase reduced its molecular mass from 115 kDa to 82 kDa, as judged by SDS/PAGE, while the molecular mass of the abnormal mature Zajdela hepatoma cell beta 1-subunit decreased from 130 to 110 kDa. Thus, in addition to alterations in the Asn-linked oligosaccharide processing, 'ascitic growth' induced other post-translational modifications in the Zajdela hepatoma cell beta 1-subunit. Furthermore, both the abnormal mature 130-kDa and precursor 100-kDa beta 1-subunits were detected on the surface of Zajdela hepatoma cells, associated with the alpha 5-subunit. The relationship between these structural alterations in the fibronectin receptor and the impaired Zajdela hepatoma cell binding to soluble fibronectin or to a coated fibronectin matrix that was observed in this study is discussed. PMID:8471041
Decastel, M; Doyennette-Moyne, M A; Gouet, E; Aubery, M; Codogno, P
Variations in broiler growth and efficiency have been explained in part by differences in mitochondrial function and biochemistry in broilers. To further our knowledge in this regard, 2 experiments were carried out to determine the relationships of a) mitochondrial function and activities of various electron transport chain (ETC) complexes; b) production of H2O2, a reactive oxygen species (ROS), and its association with protein oxidation; and c) mitochondrial protein expression in liver of a single line male broilers with low or high feed efficiency (FE, n = 5 to 8 per group). Mitochondrial function and complex activities were measured polarographically and spectrophotometrically, respectively. H2O2 was measured fluorimetrically, whereas oxidized protein (carbonyls) and specific mitochondrial proteins were analyzed using Western blots. Mitochondrial function (ETC coupling) and activities of ETC complexes (I, II, III, and IV) were higher in high FE compared with low FE broilers. H2O2 and protein carbonyls were higher in the livers of low FE broilers than in high FE broilers. Whereas the expression of 4 immunoreactive proteins [NAD3 (complex I), subunit VII (complex III), cytochrome c oxidase subunits (COX) II, and COX IVb (complex IV)] were higher in low FE liver mitochondria and 2 proteins [subunit 70 (complex II) and a-ATP synthase (complex V)] were higher in high FE birds, there were no differences between groups in the expression of 18 other mitochondrial proteins. In conclusion, increases in oxidative stress in low FE broilers were caused by or may contribute to differences in mitochondrial function (ETC coupling and complex activities) or the differential expression of steady-state levels of some mitochondrial proteins in the liver. Understanding the role of oxidative stress in Low FE broilers will provide clues in understanding the cellular basis of feed efficiency. PMID:15971533
Iqbal, M; Pumford, N R; Tang, Z X; Lassiter, K; Ojano-Dirain, C; Wing, T; Cooper, M; Bottje, W
Upper Limits of Normal for Serum Alanine Aminotransferase Levels in Chinese Han Population
Background and Objectives Serum alanine aminotransferase (ALT) activity is the most common tool for the assessment of liver diseases. However, it is not clear whether the current normal ALT range really discriminate patients with or without liver diseases. The present study was to establish a new normal range of ALT and examine its ability to identify patients with hepatitis B or nonalcoholic fatty liver disease (NAFLD) in Chinese Han population. Methods 53037 adults were included in this study from January 1st 2008 to August 31st 2010. The 95th percentile of ALT in population with relative low risk factors for liver diseases was set as the new upper limits of normal ALT in gender-specific manner. Results The 95th percentile levels at low risk factors for liver diseases were achieved at 35 U/L for men and 23 U/L for women. The concordance statistics for detection were 0.873 (95%CI: 0.865�0.881) for HBV and 0.932 (95%CI: 0.927�0.937) for NAFLD in men while 0.857 (95%CI: 0.850�0.864) for HBV and 0.909 (95%CI: 0.903�0.915) for NAFLD in women. The median sensitivity of the current used ALT upper limit (40 U/L) was 6.6% for HBV and 29.7% for NAFLD and median specificity was 98.7% for men and 99.4% for women. Using our new-derived thresholds, the sensitivities ranged from 35.3% to 61.1% and the specificities were 94.8% for men and 94.6% for women. Conclusions Our results suggest that upper limits of ALT 35 U/L for men and 23 U/L for women in Chinese Han population. Re-consideration of normal limits of ALT should be recommended. Trial Registration ChiCTR.org ChiCTR-OCS-11001173 PMID:22962588
Zheng, Ming-Hua; Shi, Ke-Qing; Fan, Yu-Chen; Liu, Wen-Yue; Lin, Xian-Feng; Li, Ling-Fei; Chen, Yong-Ping
Effect of ginkgo biloba extract on livers in aged rats
AIM: To investigate the protective effect of ginkgo biloba extract (GBE) on livers of aged rats and the associated mechanisms. METHODS: Two-mo- and 20-mo-old rats were treated with GBE/saline for 3 mo. Liver tissue samples from 5-mo-old rats treated with saline (group Y) and 23-mo-old rats treated with GBE (group E) or saline (group N) were used for histopathological examinations (hematoxylin-eosin and Masson staining, Lipofuscin staining-Schmorl staining) and determination of expression of tissue inhibitor-1 of metalloproteinase (TIMP-1) and the level of malondialdehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD). Blood samples were collected for determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and albumin. RESULTS: Microscopic studies with Masson staining revealed mild liver fibrosis in aged rats (group N), while the livers of aged rats receiving GBE (group E) showed amelioration in fibrosis (2.2�0.1 vs 2.8�0.1, P<0.01) and deposition of lipofuscin (33.7�5.3 vs 62.8�5.7, P<0.01). The expression of TIMP-1 and the level of liver MDA (1.0�0.1 vs 1.2�0.2, P<0.05) also decreased but the activity of GPx (97.1�15.3 vs 61.8�14.5, P<0.01) increased in group E. Compared with group Y, the level of liver MDA (0.8�0.1 vs 1.2�0.2, P<0.01), lipofuscin (32.4�6.0 vs 62.8�5.7, P<0.01) and TIMP-1 expression were increased, while the activity of GPx (103.2�17.6 vs 61.8�14.5, P<0.01) and SOD (16.7�4.4 vs 11.8�3.9, P<0.05) was decreased in group N. There was no difference in liver function among these three groups. CONCLUSION: GBE has protective effects on aging liver. The possible mechanisms might be its antioxidant activity and inhibition of TIMP-1 expression. PMID:15609412
Huang, Shang-Zhen; Luo, Yan-Jun; Wang, Li; Cai, Ke-Yin
The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease. PMID:25386057
Suzuki, Tomohiro; Shinjo, Satoko; Arai, Takatomo; Kanai, Mai; Goda, Nobuhito
Liver injury is common among chronic abusers of ketamine.
Abuse of ketamine leads to liver injury. We investigated the histopathologic and radiologic features of ketamine abusers with significant liver injury in a cross-sectional survey of 297 consecutive chronic abusers of ketamine with urinary tract dysfunction. Liver biopsy and magnetic resonance cholangiopancreatography were performed in patients with liver injury (concentrations of bilirubin, alkaline phosphatase, and/or alanine aminotransferase >2-fold the upper limit of normal). The prevalence of liver injury was 9.8% (all cases cholestatic). Bile duct injury was observed in all 7 patients assessed by liver biopsy. Two patients had bridging fibrosis despite their young age. Three of 6 patients who underwent magnetic resonance cholangiopancreatography examination were found to have prominent or dilated common bile ducts without obstructions or extrinsic compressions. Ketamine abuse therefore appears to lead to common bile duct dilatation, microscopic bile duct injury, and even significant liver fibrosis. PMID:24534547
Wong, Grace Lai-Hung; Tam, Yuk-Him; Ng, Chi-Fai; Chan, Anthony Wing-Hung; Choi, Paul Cheung-Lung; Chu, Winnie Chiu-Wing; Lai, Paul Bo-San; Chan, Henry Lik-Yuen; Wong, Vincent Wai-Sun
Conventional US imaging is playing a key role for the diagnosis and the therapeutic management of chronic liver diseases. Nevertheless, conventional US imaging is facing many limitations: operator-dependency, subjective assessment, variable detectability of nodules depending on accessibility to the US beam and spontaneous contrast to surrounding normal parenchyma, limited characterization capabilities. Conventional US imaging is taking advantage of major technological improvements including contrast-enhanced US (CEUS), elastography and volume and fusion imaging techniques. CEUS allows real-time detection of contrast enhancement and improves identification of the hypervascular pattern, major diagnostic criteria of hepatocellular carcinoma. Its kinetics is different from those of benign lesions (regenerative nodules, hemangioma�). CEUS is an excellent technique for focal liver lesion characterization (lesion detected previously at either conventional US or any imaging modality) while its performance remains limited for HCC detection. US contrast agent tolerance is excellent is routine clinical practise with no contraindication related to liver or renal dysfunction. US elastography is a non invasive technique that allows detection and quantification of liver fibrosis and is extending its application toward characterization of focal liver diseases. Volumetric and fusion imaging should improve the therapeutic management of malignant liver lesions and particularly percutaneous guidance of thermo-ablation procedures. PMID:22153061
Correas, Jean-Michel; Pol, Stanislas
The aim of this study was to examine the accumulation of cadmium (Cd) incorporated in radish bulb and its effects on liver and kidney functions in male rats. Control animals were given diet containing ordinary radish bulb for 4, 8 and 12 weeks, while contaminated animals were given diet containing Cd-polluted radish bulb (1.1?gCd\\/g of diet) for the same periods
Samir Haouem; Najla Hmad; Mohamed Fathel Najjar; Abdelhamid El Hani; Rachid Sakly
Inhibition of Mycobacterial Alanine Racemase Activity and Growth by Thiadiazolidinones
The genus Mycobacterium includes non-pathogenic species such as M. smegmatis, and pathogenic species such as M. tuberculosis, the causative agent of tuberculosis (TB). Treatment of TB requires a lengthy regimen of several antibiotics, whose effectiveness has been compromised by the emergence of resistant strains. New antibiotics that can shorten the treatment course and those that have not been compromised by bacterial resistance are needed. In this study, we report that thiadiazolidinones, a relatively little-studied heterocyclic class, inhibit the activity of mycobacterial alanine racemase, an essential enzyme that converts L-alanine to D-alanine for peptidoglycan synthesis. Twelve members of the thiadiazolidinone family were evaluated for inhibition of M. tuberculosis and M. smegmatis alanine racemase activity and bacterial growth. Thiadiazolidinones inhibited M. tuberculosis and M. smegmatis alanine racemases to different extents with 50% inhibitory concentrations (IC50) ranging from <0.03 to 28 �M and 23 to >150 �M, respectively. The compounds also inhibited the growth of these bacteria, including multidrug resistant strains of M. tuberculosis. The minimal inhibitory concentrations (MIC) for drug-susceptible M. tuberculosis and M. smegmatis ranged from 6.25 �g/ml to 100 �g/ml, and from 1.56 to 6.25 �g/ml for drug-resistant M. tuberculosis. The in vitro activities of thiadiazolidinones suggest that this family of compounds might represent starting points for medicinal chemistry efforts aimed at developing novel antimycobacterial agents. PMID:23680030
Lee, Yashang; Mootien, Sara; Shoen, Carolyn; Destefano, Michelle; Cirillo, Pier; Asojo, Oluwatoyin A.; Yeung, Kacheong R.; Ledizet, Michel; Cynamon, Michael H.; Aristoff, Paul A.; Koski, Raymond A.; Kaplan, Paul A.; Anthony, Karen G.
Evaluation of Conformation and Association Behavior of Multivalent Alanine-Rich Polypeptides
Purpose Helical alanine-rich polypeptides with functional groups displayed along the backbone can display desired molecules such as saccharides or therapeutic molecules at a prescribed spacing. Because these polypeptides have promise for application as biomaterials, the conformation and association of these molecules have been investigated under biologically relevant conditions. Methods Three polypeptide sequences, 17-H-3, 17-H-6, and 35-H-6, have been produced through recombinant techniques. Circular dichroic (CD) spectroscopy was used to monitor the secondary structure of the polypeptides in PBS (phosphate buffered saline, pH 7.4). The aggregation behavior in PBS was monitored via analytical ultracentrifugation and non-denaturing polyacrylamide gel electrophoresis. Results The three polypeptides adopt a highly helical structure at low and ambient temperatures, and when heated, undergo a helix-to-coil transition, typical of other alanine-rich peptide sequences. The melting temperatures and van�t Hoff enthalpies, extracted from the CD data, suggest similar stability of the sequences. Although alanine-rich sequences can be prone to aggregation, there is no indication of aggregation for the three polypeptides at a range of concentrations relevant for possible biological applications. Conclusions The helical polypeptides are monomeric under biologically relevant conditions enabling application of these polypeptides as useful scaffolds for ligand or drug display. PMID:17674161
Farmer, Robin S.; Top, Ayben; Argust, Lindsey M.; Liu, Shuang; Kiick, Kristi L.
Biopsy - liver; Percutaneous biopsy ... prevent pain or to calm you (sedative). The biopsy may be done through the abdominal wall: You ... provider will find the correct spot for the biopsy needle to be inserted into the liver. This ...
Insulin resistance and obesity are components of the metabolic syndrome that includes development of cardiovascular disease and diabetes with advancing age. The thrifty phenotype hypothesis suggests that offspring of poorly nourished mothers are predisposed to the various components of the metabolic syndrome due to adaptations made during fetal development. We assessed the effects of maternal nutrient restriction in early gestation on feeding behavior, insulin and glucose dynamics, body composition, and liver function in aged female offspring of ewes fed either a nutrient-restricted [NR 50% National Research Council (NRC) recommendations] or control (C: 100% NRC) diet from 28 to 78 days of gestation, after which both groups were fed at 100% of NRC from day 79 to lambing and through lactation. Female lambs born to NR and C dams were reared as a single group from weaning, and thereafter, they were fed 100% NRC recommendations until assigned to this study at 6 yr of age. These female offspring were evaluated by a frequently sampled intravenous glucose tolerance test, followed by dual-energy X-ray absorptiometry for body composition analysis prior to and after ad libitum feeding of a highly palatable pelleted diet for 11 wk with automated monitoring of feed intake (GrowSafe Systems). Aged female offspring born to NR ewes demonstrated greater and more rapid feed intake, greater body weight gain, and efficiency of gain, lower insulin sensitivity, higher insulin secretion, and greater hepatic lipid and glycogen content than offspring from C ewes. These data confirm an increased metabolic �thriftiness� of offspring born to NR mothers, which continues into advanced age, possibly predisposing these offspring to metabolic disease. PMID:22277936
George, Lindsey A.; Zhang, Liren; Tuersunjiang, Nuermaimaiti; Ma, Yan; Long, Nathan M.; Uthlaut, Adam B.; Smith, Derek T.; Nathanielsz, Peter W.
The liver can precisely regulate its growth and mass. Surgical resection of hepatic lobes or hepatocyte loss caused by viral or chemical injury triggers hepatocyte replication while enlarged liver mass is corrected by apoptosis. Hepatocytes have a great replicative capacity and are capable of repopulating the liver. However, �stem-like� cells proliferate when hepatocyte replication is blocked or delayed. Detailed studies
Nelson Fausto
An emulsion of perfluorotributylamine (Fluosol-43) was used as substitute for the gas-carrying function of erythrocytes in a synthetic medium for perfusion of isolated rat liver. The efficiency and effect of this synthetic gas-carrier were evaluated from measurements of the concentrations of rat albumin, the unsaturated vitamin B12-binding capacity of small-molecular-size vitamin B12-binding proteins (UBBC of SBP), urea nitrogen, glucose, sodium, potassium, alanine amino transferase (ALAT) in the medium, and the incorporation of 14C-lysine into the circulating proteins. Secretion of bile, portal pressure, PO2, PCO2 and pH in the affluent and the effluent mediums were also measured. The results demonstrate that the oxygen-carrying capacity of the medium and the metabolic functions of the liver were higher, and the liver damage less, when the medium included Fluosol-43 than without it. The albumin synthesis and the secretion of bile were as high as has been reported for perfusions with erythrocytes. This indicates that the oxygen carried by the Fluosol-43 was utilised by the liver, and that the metabolic functions were not adversely affected during 4 h of perfusion by the medium containing Fluosol-43. PMID:998284
Nov�kov�, V; Birke, G; Plantin, L O; Wretlind, A
DPP-4 Inhibitors Improve Liver Dysfunction in Type 2 Diabetes Mellitus
Background Dipeptidyl peptidase-4 (DPP-4) inhibitors might have pleiotropic effects because receptors for incretin exist in various tissues, including liver. We examined whether DPP-4 inhibitors affect liver function in patients with type 2 diabetes. Material/Methods A retrospective review of 459 patients with type 2 diabetes who were prescribed DPP-4 inhibitors was performed. After exclusion of patients with hepatitis B or C, steroid use, and other diseases that might affect liver function and diabetes status, 224 patients were included in the analysis. Results Forty-four patients (19.6%) with liver injury defined by aspartate transaminase (AST) or alanine transaminase (ALT) over the normal level of 40 U/L. In the patients with liver injury, AST and ALT were significantly decreased after 6 months from the first date of DPP-4 prescription, with mean changes of ?6.2 U/L [95% confidence interval (CI) ?10.9 to ?1.4, p=0.012] and of ?11.9 U/L (95%CI ?19.5 to ?4.2, p=0.003), respectively. Percent changes in AST were significantly and negatively correlated with baseline AST and ALT (r=?0.27, p<0.001 and r=?0.23, p=0.002, respectively), and percent changes in ALT were also negatively correlated with them (r=?0.23, p=0.001 and r=?0.27, p<0.001, respectively). Conclusions DPP-4 inhibitors improved liver dysfunction in patients with type 2 diabetes. PMID:25228119
Kanazawa, Ippei; Tanaka, Ken-ichiro; Sugimoto, Toshitsugu
The therapeutic efficacy of interleukin-22 (IL-22) on liver injury and hematological disturbances was studied in rat model of acute liver failure (ALF) induced by D-galactosamine/lipopolysaccharide (D-GalN/LPS). The following parameters were investigated: (1) survival rate, (2) serum levels of liver function enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)), total bilirubin (TBILI), and total albumen (ALB), (3) blood clotting tests (prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen level (FIB)) and white blood cells (WBCs), red blood cells (RBCs), and platelet counts, (4) hepatic levels of tumor necrosis factor-? (TNF-?) and cyclooxygenase-2 (COX-2), and (5) liver histopathology. After 48 hours of D-GalN/LPS, the rats exhibited 20% mortality, significant increases in AST, ALT, ALP, TBILI, PT, and aPTT, TNF-?, and COX-2 and significant decreases in FIB, WBCs, and RBCs. By contrast, therapy with IL-22 prevented the lethal effect of D-GalN/LPS by 100% and efficiently alleviated all the biochemical and hematological abnormalities that were observed in ALF untreated group. Furthermore, IL-22 treatment decreased the hepatic contents of TNF-? and COX-2. The histopathological findings also supported the hepatoprotective effect of IL-22. Taken together, therapy with IL-22 can represent a promising therapeutic tool against liver injury and its associated hemostasis disturbances. PMID:24799907
Ashour, Tariq Helal
Serum Liver Enzyme Pattern in Birth Asphyxia Associated Liver Injury
Purpose To study temporal pattern of serum liver enzymes levels in newborns with hepatic injury associated with birth asphyxia (BA). Methods Singleton term newborns with BA and ?72 hours of age admitted to neonatal intensive care unit were prospectively enrolled. Term newborns with physiological jaundice and without BA were studied as controls. Serum liver enzymes were measured at <24 hours, 24-72 hours, and at 6-12 days of age for cases and at 1-6 days of age for controls. BA was defined by 1 minute Apgar score <7 or delayed or absent cry with hypoxic ischemic encephalopathy. BA-associated liver injury was defined as serum alanine aminotransferase (ALT) elevation beyond +2 standard deviation (ALT > +2 SD) above the mean of control subjects at any of the three time points. Results Sixty controls and 62 cases were enrolled. Thirty-five cases (56%) developed BA-associated liver injury (ALT>81 IU/L). They had higher serum levels of ALT, aspartate aminotransferase, lactate dehydrogenase than the control infants, with peak at 24-72 hours. In controls, serum liver enzyme levels were significantly higher in appropriate-for-date (AFD) babies than small-for-date (SFD) babies. Serum enzyme pattern and extent of elevation were comparable between SFD and AFD babies. Degree of serum liver enzyme elevation had no relationship with severity of hypoxic encephalopathy. Conclusion Serum liver enzyme elevation is common in BA; it peaks at 24-72 hours followed by a sharp decline by 6-12 days of age. Pattern and extent of enzyme elevation are comparable between SFD and AFD babies. PMID:25349832
Chhavi, Nanda; Zutshi, Kiran; Singh, Niranjan Kumar; Awasthi, Ashish
Purpose To determine if volumetric changes of diffusion-weighted and contrast material�enhanced magnetic resonance (MR) imaging can help assess early tumor response to intraarterial therapy (IAT) in neuroendocrine liver metastasis (NELM). Materials and Methods This retrospective single-center comprehensive imaging analysis was performed in compliance with HIPAA and was institutional review board approved. Informed patient consent was waived. Seventy-one patients (39 men; mean age, 62.3 years) with NELM treated with IAT were analyzed retrospectively. MR studies were performed before and 3�4 weeks after therapy. The index lesion was segmented to provide volumetric functional analysis of apparent diffusion coefficient (ADC) and contrast-enhanced MR imaging in the hepatic arterial phase (HAP) and portal venous phase (PVP). Tumor response was defined as increase in volumetric ADC of 15% or greater and decrease in volumetric enhancement of 25% or greater during the HAP or of 50% or greater during the PVP. Patient overall survival was the primary end point after therapy initiation. Univariate analysis included Kaplan-Meier survival curves. The Cox proportional hazards regression model was used to detect interactions between volumetric ADC and contrast-enhanced MR imaging and to calculate the hazard ratio. Results There was significant increase in mean volumetric ADC (27%, P < .0001) and significant decrease in mean volumetric enhancement during the HAP (?25.3%, P < .0001) and the PVP (?22.4%, P < .0001) in all patients. Patients who had 15% or greater volumetric ADC increase (n = 49) after therapy had better prognosis than those who had less than 15% increase in volumetric ADC (n = 22) (log-rank test, P < .002). Patients who had 25% or greater decrease in volumetric arterial enhancement (n = 40) or 50% or greater decrease in venous enhancement (n = 18) had better prognosis than those who had less than 25% decrease in volumetric arterial enhancement (n = 31) or less than 50% decrease in venous enhancement (n = 53) (log-rank test, P < .02). Conclusion Volumetric functional MR imaging criteria may act as biomarkers of early response, indicating that these criteria may be important to incorporate in future NELM clinical trials. PMID:23192780
Halappa, Vivek Gowdra; Corona-Villalobos, Celia Pamela; Bonekamp, Susanne; Li, Zhen; Reyes, Diane; Cosgrove, David; Pawlik, Timothy M.; Diaz, Luis Alberto; Bhagat, Nikhil; Eng, John; Geschwind, Jean-Francois; Kamel, Ihab R.
Atomic Layer Deposition of l-Alanine Polypeptide.
l-Alanine polypeptide thin films were synthesized via atomic layer deposition (ALD). Instead of using an amino acid monomer as the precursor, an l-alanine amino acid derivatized with a protecting group was used to prevent self-polymerization, increase the vapor pressure, and allow linear cycle-by-cycle growth emblematic of ALD. The successful deposition of a conformal polypeptide film has been confirmed by FTIR, TEM, and Mass Spectrometry, and the ALD process has been extended to polyvaline. PMID:25355683
Fu, Yaqin; Li, Binsong; Jiang, Ying-Bing; Dunphy, Darren R; Tsai, Andy; Tam, Siu-Yue; Fan, Hongyou; Zhang, Hongxia; Rogers, David; Rempe, Susan; Atanassov, Plamen; Cecchi, Joseph L; Brinker, C Jeffrey
Background The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. Principal Findings Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OST?, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. Conclusions FXR antagonism in vivo results in a positive modulation of MRP4 expression in the liver and is a feasible strategy to target obstructive cholestasis. PMID:22291955
Renga, Barbara; Mencarelli, Andrea; D'Amore, Claudio; Cipriani, Sabrina; D'Auria, Maria Valeria; Sepe, Valentina; Chini, Maria Giovanna; Monti, Maria Chiara; Bifulco, Giuseppe; Zampella, Angela; Fiorucci, Stefano
Orthotopic liver transplantation (OLT) involves the substitution of a diseased native liver with a normal liver (or part of one) taken from a deceased or living donor. Considered an experimental procedure through the 1980s, OLT is now regarded as the treatment of choice for a number of otherwise irreversible forms of acute and chronic liver disease. The first human liver transplantation was performed in the United States in 1963 by Prof. T.E.�Starzl of the University of Colorado. The first OLT to be performed in Italy was done in 1982 by Prof. R. Cortesini. The procedure was successfully performed at the Policlinico Umberto I of the University of Rome (La Sapienza). The paper reports the indications for liver transplantation, donor selection and organ allocation in our experience, surgical technique, immunosuppression, complications and results of liver transplantation in our center. PMID:23396075
Rossi, M.; Mennini, G.; Lai, Q.; Ginanni Corradini, S.; Drudi, F.M.; Pugliese, F.; Berloco, P.B.
MPS IIIA is a lysosomal storage disorder caused by mutations in the sulphamidase gene, resulting in the accumulation of heparan sulphate glycosaminoglycans (HS GAGs). Symptoms predominantly manifest in the CNS and there is no current therapy that effectively addresses neuropathology in MPS IIIA patients. Recent studies in MPS IIIA mice have shown that rhodamine B substrate deprivation therapy (SDT) (also termed substrate reduction therapy/SRT) inhibits GAG biosynthesis and, improves both somatic and CNS disease pathology. Acute overexposure to high doses of rhodamine B results in liver toxicity and is detrimental to reproductive ability. However, the long-term effects of decreasing GAG synthesis, at the low dose sufficient to alter neurological function are unknown. A trans-generational study was therefore initiated to evaluate the continuous exposure of rhodamine B treatment in MPS IIIA mice over 4 generations, including treatment during pregnancy. No alterations in litter size, liver histology or liver function were observed. Overall, there are no long-term issues with the administration of rhodamine B at the low dose tested and no adverse effects were noted during pregnancy in mice. PMID:20650670
Roberts, Ainslie L K; Fletcher, Janice M; Moore, Lynette; Byers, Sharon
Orthotopic liver transplantation is the only available treatment for severe liver failure, but it is currently limited by organ shortage. One technical challenge that has thus far limited the development of a tissue-engineered liver graft is oxygen and nutrient transport. Here we demonstrate a novel approach to generate transplantable liver grafts using decellularized liver matrix. The decellularization process preserves the structural and functional characteristics of the native microvascular network, allowing efficient recellularization of the liver matrix with adult hepatocytes and subsequent perfusion for in vitro culture. The recellularized graft supports liver-specific function including albumin secretion, urea synthesis and cytochrome P450 expression at comparable levels to normal liver in vitro. The recellularized liver grafts can be transplanted into rats, supporting hepatocyte survival and function with minimal ischemic damage. These results provide a proof of principle for the generation of a transplantable liver graft as a potential treatment for liver disease. PMID:20543851
Uygun, Basak E; Soto-Gutierrez, Alejandro; Yagi, Hiroshi; Izamis, Maria-Louisa; Guzzardi, Maria A; Shulman, Carley; Milwid, Jack; Kobayashi, Naoya; Tilles, Arno; Berthiaume, Francois; Hertl, Martin; Nahmias, Yaakov; Yarmush, Martin L; Uygun, Korkut
AIM: To evaluate and compare the clinical usefulness of 13C-phenylalanine and 13C-methacetin breath tests in quantitating functional hepatic mass in patients with chronic liver disease and to further compare these results with those of conventional tests, Child-Pugh score and serum bile acid levels. METHODS: One hundred and forty patients (50 HCV- related chronic hepatitis, 90 liver cirrhosis patients) and 40 matched healthy controls were studied. Both breath test and routine liver test, serum levels of cholic and chenodeoxycholic acid conjugates were evaluated. RESULTS: Methacetin breath test, expressed as 60 min cumulative percent of oxidation, discriminated the hepatic functional capacity not only between controls and liver disease patients, but also between different categories of chronic liver disease patients. Methacetin breath test was correlated with liver function tests and serum bile acids. Furthermore, methacetin breath test, as well as serum bile acids, were highly predictive of Child-Pugh scores. The diagnostic power of phenylalanine breath test was always less than that of methacetin breath test. CONCLUSION: Methacetin breath test represents a safe and accurate diagnostic tool in the evaluation of hepatic functional mass in chronic liver disease patients. PMID:15609414
Festi, D.; Capodicasa, S.; Sandri, L.; Colaiocco-Ferrante, L.; Staniscia, T.; Vitacolonna, E.; Vestito, A.; Simoni, P.; Mazzella, G.; Portincasa, P.; Roda, E.; Colecchia, A.
Anabasis articulata (Forssk) Moq. (Chenopodiaceae) is an herb, grows in Egypt, and used in folk medicine to treat diabetes, fever, and kidney infections. The protective and therapeutic effects of the ethanol extract of A. articulata aerial parts were evaluated against dimethylnitrosamine (DMN)-induced liver fibrosis, compared with the standard drug, silymarin. Hepatic hydroxyproline content, serum transforming growth factor-?1 (TGF-?1), interleukin 10 (IL-10) and fructosamine were measured as liver fibrosis markers. Hepatic malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), glutathione reductase (GR) and glutathione content (GSH) were measured as oxidant/antioxidant markers. Parallel histopathological investigations were also performed. Protective and therapeutic administration of A. articulata (100�mg/kg daily for 4�weeks), markedly prevented DMN-induced loss in body and liver weights. The extract significantly inhibited the elevation of hepatic hydroxyproline, NO and MDA (P�<�0.05), as well as serum fructosamine, and TGF-?1 (P�<�0.05) induced by DMN while it restored IL-10 to normal level in both protective and therapeutic groups. Furthermore, A. articulata prevented the depletion in CAT, GR, and GSH levels (P�?�0.05). In addition, oral administration of A. articulata extract and silymarin to both protective and therapeutic groups reduced the increase in liver function enzyme activities; alanine and aspartate amintransferases, gamma-glutamyl transferase in addition to alkaline phosphatase, and caused significant increase in serum albumin concentration as compared to DMN group. These data corresponded closely with those obtained for the drug silymarin. Histopathological studies confirmed the biochemical data and revealed remarkable improvement in liver architecture. Thus, it could be concluded that, A. articulata extract exhibited in vivo hepatoprotective and therapeutic effects against DMN-induced liver injury and may act as a useful agent in controlling the progression of hepatic fibrosis through reduction of oxidative stress and improving liver function. PMID:25298623
Mohamed, Azza M; Abdalla, Mohga S; Rizk, Maha Z; Mahdy, El-Sayed M E; Farrag, Abdel-Razik H; El-Sharabasy, Fatma S; Aly, Hanan F; Mohamed, Mohamed R
Background RNA editing encompasses a post-transcriptional process in which the genomically templated sequence is enzymatically altered and introduces a modified base into the edited transcript. Mammalian C-to-U RNA editing represents a distinct subtype of base modification, whose prototype is intestinal apolipoprotein B mRNA, mediated by the catalytic deaminase Apobec-1. However, the genome-wide identification, tissue-specificity and functional implications of Apobec-1-mediated C-to-U RNA editing remain incompletely explored. Results Deep sequencing, data filtering and Sanger-sequence validation of intestinal and hepatic RNA from wild-type and Apobec-1-deficient mice revealed 56 novel editing sites in 54 intestinal mRNAs and 22 novel sites in 17 liver mRNAs, all within 3? untranslated regions. Eleven of 17 liver RNAs shared editing sites with intestinal RNAs, while 6 sites are unique to liver. Changes in RNA editing lead to corresponding changes in intestinal mRNA and protein levels for 11 genes. Analysis of RNA editing in vivo following tissue-specific Apobec-1 adenoviral or transgenic Apobec-1 overexpression reveals that a subset of targets identified in wild-type mice are restored in Apobec-1-deficient mouse intestine and liver following Apobec-1 rescue. We find distinctive polysome profiles for several RNA editing targets and demonstrate novel exonic editing sites in nuclear preparations from intestine but not hepatic apolipoprotein B RNA. RNA editing is validated using cell-free extracts from wild-type but not Apobec-1-deficient mice, demonstrating that Apobec-1 is required. Conclusions These studies define selective, tissue-specific targets of Apobec-1-dependent RNA editing and show the functional consequences of editing are both transcript- and tissue-specific. PMID:24946870
PGC-1? plays pleiotropic roles in regulating intermediary metabolism and has been shown to regulate both catabolic and anabolic processes in liver. We sought to evaluate the effects of PGC-1? on liver energy metabolism by generating mice with postnatal, liver-specific deletion of PGC-1? (LS-PGC-1??/? mice). LS-PGC-1??/? mice were outwardly normal, but exhibited a significant increase in hepatic triglyceride content at 6 weeks of age. Hepatic steatosis was due, at least in part, to impaired capacity for fatty acid oxidation and marked mitochondrial dysfunction. Mitochondrial DNA content and the expression of genes encoding multiple steps in mitochondrial fatty acid oxidation and oxidative phosphorylation pathways were significantly diminished in LS-PGC-1??/? mice. Liquid chromatography mass spectrometry-based analyses also revealed that acetylcarnitine and butyrylcarnitine levels were depleted whereas palmitoylcarnitine content was increased in LS-PGC-1??/? liver, which is consistent with attenuated rates of fatty acid oxidation. Interestingly, loss of PGC-1? also significantly impaired inducible expression of glycolytic and lipogenic enzymes that occurs with high carbohydrate diet refeeding after a prolonged fast. These results suggest that PGC-1? plays dual roles in regulating hepatic fatty acid metabolism by controlling the expression of programs of genes involved in both fatty acid oxidation and de novo fatty acid synthesis. PMID:23285128
Chambers, Kari T.; Chen, Zhouji; Crawford, Peter A.; Fu, Xiaorong; Burgess, Shawn C.; Lai, Ling; Leone, Teresa C.; Kelly, Daniel P.; Finck, Brian N.
The objective of this study was to evaluate the role of minerals on lead-induced effect on the liver. Differentiation of minerals and heavy metals pose an inherent problem due to certain common properties shared by them. With this approach to the problem of heavy metal toxicity, in the present study two groups of male Wistar albino rats, one group (well-nourished)
D'souza Sunil Herman; Menezes Geraldine; Venkatesh T
Quantitative radioautographic studies were made of the dose-response of ; desoxyribonucleic acid synthesis in the liver of rats exposed to x radiation. ; Thymidine-H³ was used as a tracer for DNA synthesis. Results are compared ; with those from similar dose-response studies of radiation effects in a number of ; in vivo and in vitro systems. (C.H.);
W. B. Looney; M. L. Pardue; F. W. Banghart
Hepatic injury and regeneration of the liver are associated with activation of hepatic stellate cells (HSC). Fibroblast growth factors (FGFs) and their receptors are important regulators of repair in various tissues. HSC express FGFR3IIIc as well as FGFGR4 and different spliced FGFR1IIIc and FGFR2IIIc isoforms which differ in the presence or absence of the acid box and of the first Ig-like domain. Expression of FGF9, known to be capable to activate the HSC FGFR2/3-isoforms, was increased in HSC in liver slice cultures after exposition to carbon tetrachloride, as an acute liver injury model. FGF9 significantly stimulated 3-H thymidine incorporation of hepatocytes, but failed to induce DNA synthesis in HSC despite the fact that FGF9 induced a sustained activation of extracellular signal-related kinases (ERK) 1/2. FGF9 induced an increased phosphorylation of Tyr436 of the fibroblast growth factor receptor substrate (FRS) 2, while phosphorylation of Tyr196 which is required for efficient Grb2 recruitment remained unchanged. Our findings suggest that HSC FGF9 provide a paracrine mitogenic signal to hepatocytes during acute liver injury, while the autocrine FGF9 signaling appears to be not sufficient to induce cell proliferation.
Antoine, Marianne [Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg (Germany); Wirz, Werner [Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen D-52073 (Germany); Tag, Carmen G. [Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen D-52073 (Germany); Gressner, Axel M. [Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen D-52073 (Germany); Marvituna, Meltem [Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen D-52073 (Germany); Wycislo, Mathias [Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen D-52073 (Germany); Hellerbrand, Claus [Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg (Germany); Kiefer, Paul [Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg (Germany)]. E-mail: email@example.com
Primary Hyperoxaluria Type I (PH1) is a severe rare disorder of metabolism due to inherited mutations on liver peroxisomal alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme whose deficiency causes the deposition of calcium oxalate crystals in the kidneys and urinary tract. PH1 is an extremely heterogeneous disease and there are more than 150 disease-causing mutations currently known, most of which are missense mutations. Moreover, the molecular mechanisms by which missense mutations lead to AGT deficiency span from structural, functional to subcellular localization defects. Gly161 is a highly conserved residue whose mutation to Arg, Cys or Ser is associated with PH1. Here we investigated the molecular bases of the AGT deficit caused by Gly161 mutations with expression studies in a mammalian cellular system paired with biochemical analyses on the purified recombinant proteins. Our results show that the mutations of Gly161 (i) strongly reduce the expression levels and the intracellular half-life of AGT, and (ii) make the protein in the apo-form prone to an electrostatically-driven aggregation in the cell cytosol. The coenzyme PLP, by shifting the equilibrium from the apo- to the holo-form, is able to reduce the aggregation propensity of the variants, thus partly decreasing the effect of the mutations. Altogether, these results shed light on the mechanistic details underlying the pathogenicity of Gly161 variants, thus expanding our knowledge of the enzymatic phenotypes leading to AGT deficiency. PMID:24055001
Oppici, Elisa; Roncador, Alessandro; Montioli, Riccardo; Bianconi, Silvia; Cellini, Barbara
... How many people get liver cancer? What is liver cancer? Liver cancer starts in the liver. To understand ... on what type of tumor you have. Primary liver cancers (cancers that start in the liver) Hepatocellular carcinoma ( ...
Formation of {gamma}-alumina nanorods in presence of alanine
Graphical abstract: Nanorod aluminas with a possible hexagonal symmetry, high surface area and relatively narrow pore size distribution were obtained. Research highlights: {yields} Research highlights {yields} Boehmite was prepared using a green sol-gel process in the presence of alanine. {yields} Nanorod aluminas with a high surface area were obtained. {yields} Addition of alanine would shape the size of the holes and crevices. {yields} The morphologies of the nanorods were revealed by transmission electron microscope. -- Abstract: Boehmite and alumina nanostructures were prepared using a simple green sol-gel process in the presence of alanine in water medium at room temperature. The uncalcined (dried at 200 {sup o}C) and the calcined materials (at 500, 600 and 700 {sup o}C for 4 h) were characterized using XRD, TEM, SEM, N{sub 2} physisorption and TGA. Nanorod aluminas with a possible hexagonal symmetry, high surface area and relatively narrow pore size distribution were obtained. The surface area was enhanced and crystallization was retarded as the alanine content increased. The morphologies of the nanoparticles and nanorods were revealed by a transmission electron microscope (TEM).
Dabbagh, Hossein A., E-mail: firstname.lastname@example.com [Catalysis Research Laboratory, Department of Chemistry, Isfahan University of Technology, 8415483111 Isfahan (Iran, Islamic Republic of); Rasti, Elham [Catalysis Research Laboratory, Department of Chemistry, Isfahan University of Technology, 8415483111 Isfahan (Iran, Islamic Republic of)] [Catalysis Research Laboratory, Department of Chemistry, Isfahan University of Technology, 8415483111 Isfahan (Iran, Islamic Republic of); Yalfani, Mohammad S. [Departament d'Enginyeria Quimica, Universitat Rovira i Virgili, Av. Paisos Catalans 26, 43007 Tarragona (Spain)] [Departament d'Enginyeria Quimica, Universitat Rovira i Virgili, Av. Paisos Catalans 26, 43007 Tarragona (Spain); Medina, Francesc, E-mail: firstname.lastname@example.com [Departament d'Enginyeria Quimica, Universitat Rovira i Virgili, Av. Paisos Catalans 26, 43007 Tarragona (Spain)] [Departament d'Enginyeria Quimica, Universitat Rovira i Virgili, Av. Paisos Catalans 26, 43007 Tarragona (Spain)
CW THz spectroscopy of alanyl valine and valyl alanine
CW THz spectroscopy has been used to investigate the lowest frequency vibrational modes of a pair of isostructural dipeptide nanotubes. THz spectra were obtained from 2 cm-1 to 100 cm-1 at 4.2 K for several different preparations of alanyl valine and valyl alanine, as a means of studying effects of cocrystallized solvent molecules on the spectra of these hydrophobic nanotubes.
K. Siegrist; V. Podobedov; A. Schwarzkopf; C. Pfefferkorn; D. F. Plusquellic
Enzyme activities in plasma, liver and kidney of black ducks and mallards.
Activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine phosphokinase (CPK), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were measured in plasma, liver, and kidney, and gamma-glutamyl transferase (GGT) was measured in liver and kidney of black ducks (Anas rubripes). Activities of ALT, AST, GGT, and ornithine carbamyl transferase (OCT) were assayed in plasma, liver, and kidney of game-farm mallards (Anas platyrhynchos). Appreciable OCT and AST activity occurred in both liver and kidney. Activities of ALT, CPK, ALP and GGT were higher in kidney, while LDH was higher in liver, GGT was detected in plasma from one of four mallards. PMID:6130168
Franson, J C
Enzyme activities in plasma, liver, and kidney of black ducks and mallards
Activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine phosphokinase (CPK), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were measured in plasma, liver, and kidney, and gamma-glutamyl transferase (GGT) was measured in liver and kidney of black ducks (Anas rubripes). Activities of ALT, AST, GGT, and ornithine carbamyl transferase (OCT) were assayed in plasma, liver, and kidney of game-farm mallards (Anas platyrhynchos). Appreciable OCT and AST activity occurred in both liver and kidney. Activities of ALT, CPK, ALP and GGT were higher in kidney, while LDH was higher in liver, GGT was detected in plasma from one of four mallards.
Franson, J.C.
Arterial complications after liver transplantation are frequent. Hepatic artery thrombosis (HAT) is usually associated with biliary complications. Herein we have reported a case of a patient who was admitted for jaundice, itch, and elevated aspartate aminotransferase and alanine aminotransferase levels at 6 weeks after liver transplantation. HAT associated with a biloma was diagnosed and an urgent operation performed requiring a
J. H. P. Garcia; J. B. M. Vasconcelos; B. P. A. Gon�alves; P. E. G. Costa; M. A. P. Barros; C. F. G. Viana; I. R. C. Brasil; P. M. Lopes; T. D. Rocha; C. R. F. Forte; G. R. Coelho
Study on the EPR/dosimetric properties of some substituted alanines
NASA Astrophysics Data System (ADS)
Polycrystalline phenyl-alanine and perdeuterated L- ?-alanine ( L- ?-alanine-d 4) were studied as potential high-energy radiation-sensitive materials (RSM) for solid state/EPR dosimetry. It was found that phenyl-alanine exhibits a linear dose response in the dose region 0.1-17 kGy. However, phenyl-alanine is about 10 times less sensitive to ?-irradiation than standard L- ?-alanine irradiated at the same doses. Moreover, the EPR response from phenyl-alanine is unstable and, independent of the absorbed dose, decreases by about 50% within 20 days after irradiation upon storage at room temperature. ?-irradiated polycrystalline perdeuterated L- ?-alanine (CD 3CD(NH 2)COOH) has not previously been studied at room temperature by EPR spectroscopy. The first part of the present analysis was with respect to the structure of the EPR spectrum. By spectrum simulations, the presence of at least two radiation induced free radicals, R 1=CH 3C �(H)COOH and R 2=H 3N +-C �(CH 3)COO -, was confirmed very clearly. Both these radicals were suggested previously from EPR and ENDOR studies of standard alanine crystals. The further investigations into the potential use of alanine-d 4 as RSM, after choosing optimal EPR spectrometer settings parameters for this purpose, show that it is ca. two times more sensitive than standard L- ?-alanine.
Gancheva, Veselka; Sagstuen, Einar; Yordanov, Nicola D.
The urea cycle and related pathways in the liver of Walker-256 tumor-bearing rats.
The urea cycle was evaluated in perfused livers isolated from cachectic tumor-bearing rats (Walker-256 tumor). Urea production in livers of tumor-bearing rats was decreased in the presence of the following substrates: alanine, alanine + ornithine, alanine + aspartate, ammonia, ammonia + lactate, ammonia + pyruvate and glutamine. Urea production from arginine was higher in livers of tumor-bearing rats. No difference was found with aspartate, aspartate + ammonia, citrulline, citrulline + aspartate and glutamine + aspartate. Ammonia consumption was smaller in livers from cachectic rats when the substance was infused together with lactate and pyruvate. Glucose production was smaller in the cachectic condition only when alanine was the gluconeogenic substrate. Blood urea was higher in tumor-bearing rats, suggesting higher rates of urea production. The availability of aspartate seems to be critical for urea synthesis in the liver of tumor-bearing rats, which is possibly unable to produce this amino acid in sufficient amounts from endogenous sources. The liver of tumor-bearing rats may have a different exogenous substrate supply of nitrogenous compounds. Arginine could be one of these compounds in addition to aspartate which seems to be essential for an efficient ureogenesis in tumor-bearing rats. PMID:15062868
Corbello Pereira, Sandra Regina; Darronqui, Elaine; Constantin, Jorgete; da Silva, M�rio Henrique da Rocha Alves; Yamamoto, Nair Seiko; Bracht, Adelar
Abnormal hematological indices (HIs), a complication of liver cirrhosis (LC), present difficulties in the treatment of LC and pose a serious threat to the survival of patients. LC is a dynamic wound-healing process that occurs in response to repeated liver injury and is a chronic disorder associated with changes in various organs and tissues. It has been reported that humoral inhibitor in the formation of LC could affect the hematogenic functions of bone marrow (BM) by acting on erythroid differentiation. This indicates that the BM microenvironment is affected by humoral inhibitor in LC. Bone marrow endothelial cells (BMECs) are very important components of the BM microenvironment that function as the cytoskeleton to support the adhesion of hematopoietic stem cells (HSCs). In addition, they can secrete cytokines, which have important functions in regulating positioning, homing, proliferation, differentiation and other functions of HSCs on the BM microenvironment. These functions of BMECs may be affected due to direct contact with blood and long-term exposure to an environment with humoral inhibitor in the presence of LC. Multiple studies have shown that during the formation of LC, hepatic sinusoid endothelial cells were damaged and secreted cytokines and matrix proteins. Moreover, these cytokines and matrix proteins were involved in the formation and development of LC. Similar in function to mature-stage BM, liver at the embryonic stage also functions as a type of hematogenic organ. With similar anatomical position and functions to that of hepatic sinusoid endothelial cells, BMECs may undergo similar changes and impair hematogenic function of BM. More importantly, we found even more convincing evidence in that the humoral inhibitor in LC could lead to the ultrastructural damage of BMECs that were positively related to the degree of severity of LC. Therefore, we hypothesise the existence of a novel mechanism for abnormal HIs in LC: the continuous humoral inhibitor may lead to abnormal cytokine secretion of BMECs and attenuate their supporting functions, and such alterations of BMECs may lead to BM microenvironment disorder and dysfunction of HSCs, finally causing abnormal HIs. PMID:24388557
Gao, Bo; Li, Zhi-tuo; Xue, Dong-bo; Zhang, Wei-hui
Bone marrow-derived mesenchymal stem cell therapy for decompensated liver cirrhosis: A meta-analysis
AIM: To assess the efficacy and safety of bone marrow-derived mesenchymal stem cell (BM-MSC) in the treatment of decompensated liver cirrhosis. METHODS: The search terms �bone marrow stem cell� �chronic liver disease� �transfusion� and �injection� were used in the Cochrane Library, Med-Line (Pub-Med) and Embase without any limitations with respect to publication date or language. Journals were also hand-searched and experts in the field were contacted. The studies which used BM-MSC in the treatment of any chronic liver disease were included. Comprehensive Review Manager and Meta-Analyst software were used for statistical analysis. Publication bias was evaluated using Begg�s test. RESULTS: Out of 78 studies identified, five studies were included in the final analysis. The studies were conducted in China, Iran, Egypt and Brazil. Analysis of pooled data of two controlled studies by Review Manager showed that the mean decline in scores for the model for end-stage liver disease (MELD) was -1.23 [95%CI: -2.45-(-0.01)], -1.87 [95%CI: -3.16-(-0.58)], -2.01 [95%CI: -3.35-(-0.68)] at 2, 4 and 24 wk, respectively after transfusion. Meta-analysis of the 5 studies showed that the mean improvement in albumin levels was -0.28, 2.60, 5.28, 4.39 g/L at the end of 8, 16, 24, and 48 wk, respectively, after transfusion. MELD scores, alanine aminotransferase, total bilirubin levels and prothrombin times improved to some extent. BM-MSC injections resulted in no serious adverse events or complications. CONCLUSION: BM-MSC infusion in the treatment of decompensated liver cirrhosis improved liver function. At the end of year 1, there were no serious side effects or complications. PMID:25320545
Pan, Xing-Nan; Zheng, Lian-Qiu; Lai, Xiao-Huan
The unresolved puzzle why alanine extensions cause disease.
The prospective increase in life expectancy will be accompanied by a rise in the number of elderly people who suffer from ill health caused by old age. Many diseases caused by aging are protein misfolding diseases. The molecular mechanisms underlying these disorders receive constant scientific interest. In addition to old age, mutations also cause congenital protein misfolding disorders. Chorea Huntington, one of the most well-known examples, is caused by triplet extensions that can lead to more than 100 glutamines in the N-terminal region of huntingtin, accompanied by huntingtin aggregation. So far, nine disease-associated triplet extensions have also been described for alanine codons. The extensions lead primarily to skeletal malformations. Eight of these proteins represent transcription factors, while the nuclear poly-adenylate binding protein 1, PABPN1, is an RNA binding protein. Additional alanines in PABPN1 lead to the disease oculopharyngeal muscular dystrophy (OPMD). The alanine extension affects the N-terminal domain of the protein, which has been shown to lack tertiary contacts. Biochemical analyses of the N-terminal domain revealed an alanine-dependent fibril formation. However, fibril formation of full-length protein did not recapitulate the findings of the N-terminal domain. Fibril formation of intact PABPN1 was independent of the alanine segment, and the fibrils displayed biochemical properties that were completely different from those of the N-terminal domain. Although intranuclear inclusions have been shown to represent the histochemical hallmark of OPMD, their role in pathogenesis is currently unclear. Several cell culture and animal models have been generated to study the molecular processes involved in OPMD. These studies revealed a number of promising future therapeutic strategies that could one day improve the quality of life for the patients. PMID:23612654
Winter, Reno; Liebold, Jens; Schwarz, Elisabeth
Changes in liver gluconeogenesis during the development of Walker-256 tumour in rats
Few studies have investigated liver gluconeogenesis in cancer and there is no agreement as to whether the activity of this pathway is increased or decreased in this disease. The aim of this study was to evaluate gluconeogenesis from alanine, pyruvate and glycerol, and related metabolic parameters in perfused liver from Walker-256 tumour-bearing rats on days 5 (WK5 group), 8 (WK8 group) and 12 (WK12 group) of tumour development. There was reduction (P < 0.05) of liver glucose production from alanine and pyruvate in WK5, WK8 and WK12 groups, which was accompanied by a decrease (P < 0.05) in oxygen consumption. Moreover, there was higher (P < 0.05) pyruvate and lactate production from alanine in the WK5 group and a marked reduction (P < 0.05) of pyruvate and urea production from alanine in the WK12 group. In addition, liver glucose production and oxygen consumption from glycerol were not reduced in WK5, WK8 and WK12 groups. Thus the, the results show inhibition of hepatic gluconeogenesis from alanine and pyruvate, but not from glycerol, on days 5, 8 and 12 of Walker-256 tumour development, which can be attributed to the metabolic step in which the substrate enters the gluconeogenic pathway. PMID:23317353
Moreira, Carolina Campos Lima; Cassolla, Priscila; Dornellas, Ana Paula Segantini; Morais, Hely; Souza, Camila Oliveira; Borba-Murad, Glaucia Regina; Bazotte, Roberto Barbosa; Souza, Helenir Medri
Changes in liver gluconeogenesis during the development of Walker-256 tumour in rats.
Few studies have investigated liver gluconeogenesis in cancer and there is no agreement as to whether the activity of this pathway is increased or decreased in this disease. The aim of this study was to evaluate gluconeogenesis from alanine, pyruvate and glycerol, and related metabolic parameters in perfused liver from Walker-256 tumour-bearing rats on days 5 (WK5 group), 8 (WK8 group) and 12 (WK12 group) of tumour development. There was reduction (P < 0.05) of liver glucose production from alanine and pyruvate in WK5, WK8 and WK12 groups, which was accompanied by a decrease (P < 0.05) in oxygen consumption. Moreover, there was higher (P < 0.05) pyruvate and lactate production from alanine in the WK5 group and a marked reduction (P < 0.05) of pyruvate and urea production from alanine in the WK12 group. In addition, liver glucose production and oxygen consumption from glycerol were not reduced in WK5, WK8 and WK12 groups. Thus the, the results show inhibition of hepatic gluconeogenesis from alanine and pyruvate, but not from glycerol, on days 5, 8 and 12 of Walker-256 tumour development, which can be attributed to the metabolic step in which the substrate enters the gluconeogenic pathway. PMID:23317353
Moreira, Carolina Campos Lima; Cassolla, Priscila; Dornellas, Ana Paula Segantini; de Morais, Hely; de Souza, Camila Oliveira; Borba-Murad, Glaucia Regina; Bazotte, Roberto Barbosa; de Souza, Helenir Medri
Recently, suppressor of cytokine signaling-3 (SOCS3) has been shown to be an inducible endogenous negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway which is relevant in inflammatory response, while its functions in acute liver failure and HBV-induced acute-on-chronic liver failure (HBV-ACLF) have not been fully elucidated. In this study, we explored the role of SOCS3 in the development of mouse hepatitis virus strain 3 (MHV-3)-induced acute liver failure and its expression in liver and peripheral blood mononuclear cells (PBMCs) of patients with HBV-ACLF. Inflammation-related gene expression was detected by real-time PCR, immunohistochemistry and Western blotting. The correlation between SOCS3 level and liver injury was studied. Our results showed that the SOCS3 expression was significantly elevated in both the liver tissue and PBMCs from patients with HBV-ACLF compared to mild chronic hepatitis B (CHB). Moreover, a time course study showed that SOCS3 level was increased remarkably in the liver of BALB/cJ mice at 72 h post-infection. Pro-inflammatory cytokines, interleukin (IL)-1?, IL-6, and tumor necrosis factor (TNF)-?, were also increased significantly at 72 h post-infection. There was a close correlation between hepatic SOCS3 level and IL-6, and the severity of liver injury defined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, respectively. These data suggested that SOCS3 may play a pivotal role in the pathogenesis of MHV-3-induced acute liver failure and HBV-ACLF. PMID:24939297
Li, Yong; Han, Mei-fang; Li, Wei-na; Shi, Ai-chao; Zhang, Yuan-ya; Wang, Hong-yan; Wang, Fa-xi; Li, Lan; Wu, Ting; Ding, Lin; Chen, Tao; Yan, Wei-ming; Luo, Xiao-ping; Ning, Qin
Objective: To assess the effects of preoperative systemic chemo- therapy on remnant liver parenchyma, liver function, and morbidity after major liver resection for colorectal liver metastases. Background: Many patients operated upon for colorectal cancer liver metastases receive previous chemotherapy. Whether systemic chemotherapy alters liver parenchyma in such way that it increases the risks of liver resection remains unclear. Patients and
Mehdi Karoui; Christophe Penna; Mohamed Amin-Hashem; Emmanuel Mitry; Stephane Benoist; Brigitte Franc; Philippe Rougier; Bernard Nordlinger
D-Alanine-D-alanine ligase (DDL) catalyzes the biosynthesis of d-alanyl-d-alanine, an essential bacterial peptidoglycan precursor, and is an important drug target for the development of antibacterials. We determined four different crystal structures of DDL from Xanthomonas oryzae pv. oryzae (Xoo) causing Bacteria Blight (BB), which include apo, ADP-bound, ATP-bound, and AMPPNP-bound structures at the resolution between 2.3 and 2.0 �. Similarly with other DDLs, the active site of XoDDL is formed by three loops from three domains at the center of enzyme. Compared with d-alanyl-d-alanine and ATP-bound TtDDL structure, the ?-phosphate of ATP in XoDDL structure was shifted outside toward solution. We swapped the ?-loop (loop3) of XoDDL with those of Escherichia coli and Helicobacter pylori DDLs, and measured the enzymatic kinetics of wild-type XoDDL and two mutant XoDDLs with the swapped ?-loops. Results showed that the direct interactions between ?-loop and other two loops are essential for the active ATP conformation for D-ala-phosphate formation. PMID:24440607
Doan, Thanh Thi Ngoc; Kim, Jin-Kwang; Ngo, Ho-Phuong-Thuy; Tran, Huyen-Thi; Cha, Sun-Shin; Min Chung, Kyung; Huynh, Kim-Hung; Ahn, Yeh-Jin; Kang, Lin-Woo
Background & Aims Hepatitis C virus (HCV) screening can provide opportunities to reduce disease progression through counseling against alcohol use, but empirical data on this issue are sparse. We determined the efficacy of a behavioral intervention in reducing alcohol use among young, HCV-infected injection drug users (IDUs) (n=355) and assessed whether changes in liver enzymes were associated with changes in alcohol consumption. Methods Both the intervention and attention-control groups were counseled to avoid alcohol use, but the intervention group received enhanced counseling. Logistic regression, ANOVA, and continuous time Markov models were used to identify factors associated with alcohol use, changes in mean ALT and AST levels and change in alcohol use post-intervention. Results Six months post-intervention, alcohol abstinence increased 22.7% in both groups, with no difference by intervention arm. Transition from alcohol use to abstinence was associated with a decrease in liver enzymes, with a marginally greater decrease in the intervention group (p=0.05 for ALT; p=0.06 for AST). In multivariate Markov models, those who used marijuana transitioned from alcohol abstinence to consumption more rapidly than non-users (RR=3.11); those who were homeless transitioned more slowly to alcohol abstinence (RR=0.47); and those who had ever received a clinical diagnosis of liver disease transitioned more rapidly to abstinence (RR=1.88). Conclusions Although, behavioral counseling to reduce alcohol consumption among HCV-infected IDUs had a modest effect, reductions in alcohol consumption were associated with marked improvements in liver function. Interventions to reduce alcohol use among HCV-infected IDUs may benefit from being integrated into clinical care and monitoring of HCV infection. PMID:21145862
Drumright, Lydia N.; Hagan, Holly; Thomas, David L.; Latka, Mary H.; Golub, Elizabeth T.; Garfein, Richard S.; Clapp, John D.; Campbell, Jennifer V.; Bonner, Sebastian; Kapadia, Farzana; Thiel, Thelma King; Strathdee, Steffanie A.
Diagnosis of alcoholic liver disease.
Alcohol is a hepatotoxin that is commonly consumed worldwide and is associated with a spectrum of liver injury including simple steatosis or fatty liver, alcoholic hepatitis, fibrosis, and cirrhosis. Alcoholic liver disease (ALD) is a general term used to refer to this spectrum of alcohol-related liver injuries. Excessive or harmful alcohol use is ranked as one of the top five risk factors for death and disability globally and results in 2.5 million deaths and 69.4 million annual disability adjusted life years. All patients who present with clinical features of hepatitis or chronic liver disease or who have elevated serum elevated transaminase levels should be screened for an alcohol use disorder. The diagnosis of ALD can generally be made based on history, clinical and laboratory findings. However, the diagnosis of ALD can be clinically challenging as there is no single diagnostic test that confirms the diagnosis and patients may not be forthcoming about their degree of alcohol consumption. In addition, clinical findings may be absent or minimal in early ALD characterized by hepatic steatosis. Typical laboratory findings in ALD include transaminase levels with aspartate aminotransferase greater than alanine aminotransferase as well as increased mean corpuscular volume, gamma-glutamyltranspeptidase, and IgA to IgG ratio. In unclear cases, the diagnosis can be supported by imaging and liver biopsy. The histological features of ALD can ultimately define the diagnosis according to the typical presence and distribution of hepatic steatosis, inflammation, and Mallory-Denk bodies. Because of the potential reversible nature of ALD with sobriety, regular screening of the general population and early diagnosis are essential. PMID:25206273
Torruellas, Cara; French, Samuel W; Medici, Valentina
Diagnosis of alcoholic liver disease
Alcohol is a hepatotoxin that is commonly consumed worldwide and is associated with a spectrum of liver injury including simple steatosis or fatty liver, alcoholic hepatitis, fibrosis, and cirrhosis. Alcoholic liver disease (ALD) is a general term used to refer to this spectrum of alcohol-related liver injuries. Excessive or harmful alcohol use is ranked as one of the top five risk factors for death and disability globally and results in 2.5 million deaths and 69.4 million annual disability adjusted life years. All patients who present with clinical features of hepatitis or chronic liver disease or who have elevated serum elevated transaminase levels should be screened for an alcohol use disorder. The diagnosis of ALD can generally be made based on history, clinical and laboratory findings. However, the diagnosis of ALD can be clinically challenging as there is no single diagnostic test that confirms the diagnosis and patients may not be forthcoming about their degree of alcohol consumption. In addition, clinical findings may be absent or minimal in early ALD characterized by hepatic steatosis. Typical laboratory findings in ALD include transaminase levels with aspartate aminotransferase greater than alanine aminotransferase as well as increased mean corpuscular volume, gamma-glutamyltranspeptidase, and IgA to IgG ratio. In unclear cases, the diagnosis can be supported by imaging and liver biopsy. The histological features of ALD can ultimately define the diagnosis according to the typical presence and distribution of hepatic steatosis, inflammation, and Mallory-Denk bodies. Because of the potential reversible nature of ALD with sobriety, regular screening of the general population and early diagnosis are essential. PMID:25206273
Torruellas, Cara; French, Samuel W; Medici, Valentina
The main goal of the present work was to better understand the molecular mechanisms underlying liver hypertrophy (LH), a recurrent finding observed following acute or repeated drug administration to animals, using transcriptomic technologies together with the results from conventional toxicology methods. Administration of 5 terminated proprietary drug candidates from participating companies involved in the EU Innomed PredTox Project or the reference hepatotoxicant troglitazone to rats for up to a 14-day duration induced LH as the main liver phenotypic toxicity outcome. The integrated analysis of transcriptomic liver expression data across studies turned out to be the most informative approach for the generation of mechanistic models of LH. In response to a xenobiotic stimulus, a marked increase in the expression of xenobiotic metabolizing enzymes (XME) was observed in a subset of 4 studies. Accumulation of these newly-synthesized proteins within the smooth endoplasmic reticulum (SER) would suggest proliferation of this organelle, which most likely is the main molecular process underlying the LH observed in XME studies. In another subset of 2 studies (including troglitazone), a marked up-regulation of genes involved in peroxisomal fatty acid {beta}-oxidation was noted, associated with induction of genes involved in peroxisome proliferation. Therefore, an increase in peroxisome abundance would be the main mechanism underlying LH noted in this second study subset. Together, the use of transcript profiling provides a means to generate putative mechanistic models underlying the pathogenesis of liver hypertrophy, to distinguish between subtle variations in subcellular organelle proliferation and creates opportunities for improved mechanism-based risk assessment.
Boitier, Eric, E-mail: firstname.lastname@example.com [sanofi aventis R and D, Disposition, Safety and Animal Research, Vitry sur Seine (France); Amberg, Alexander [sanofi aventis R and D, Disposition, Safety and Animal Research, Frankfurt (Germany); Barbie, Valerie [Merck Serono S.A., Stratified Medicine, Geneva (Switzerland); Blichenberg, Arne [Nycomed GmbH, Institute for Pharmacology and Preclinical Drug Safety, Barsbuettel (Germany); Brandenburg, Arnd; Gmuender, Hans [Genedata AG, Basel (Switzerland); Gruhler, Albrecht [Novo Nordisk A/S, Protein Science, Malov (Denmark); McCarthy, Diane [Bio-Rad Laboratories, Hercules, CA (United States); Meyer, Kirstin; Riefke, Bjoern; Raschke, Marian [Bayer Schering Pharma AG, Investigational Toxicology, Berlin (Germany); Schoonen, Willem [MSD, Toxicology and Drug Disposition, Oss (Netherlands); Sieber, Maximilian [Universitaet Wuerzburg, Institut fuer Toxikologie, Wuerzburg (Germany); Suter, Laura [Hoffmann-La Roche Ltd., Investigative Toxicology, Basel (Switzerland); Thomas, Craig E. [Eli Lilly and Company, Investigative Toxicology, Indianapolis, IN (United States); Sajot, Nicolas [Servier, Drug Safety Assessment, Orleans-Gidy (France)
The main goal of the present work was to better understand the molecular mechanisms underlying liver hypertrophy (LH), a recurrent finding observed following acute or repeated drug administration to animals, using transcriptomic technologies together with the results from conventional toxicology methods. Administration of 5 terminated proprietary drug candidates from participating companies involved in the EU Innomed PredTox Project or the reference hepatotoxicant troglitazone to rats for up to a 14-day duration induced LH as the main liver phenotypic toxicity outcome. The integrated analysis of transcriptomic liver expression data across studies turned out to be the most informative approach for the generation of mechanistic models of LH. In response to a xenobiotic stimulus, a marked increase in the expression of xenobiotic metabolizing enzymes (XME) was observed in a subset of 4 studies. Accumulation of these newly-synthesized proteins within the smooth endoplasmic reticulum (SER) would suggest proliferation of this organelle, which most likely is the main molecular process underlying the LH observed in XME studies. In another subset of 2 studies (including troglitazone), a marked up-regulation of genes involved in peroxisomal fatty acid ?-oxidation was noted, associated with induction of genes involved in peroxisome proliferation. Therefore, an increase in peroxisome abundance would be the main mechanism underlying LH noted in this second study subset. Together, the use of transcript profiling provides a means to generate putative mechanistic models underlying the pathogenesis of liver hypertrophy, to distinguish between subtle variations in subcellular organelle proliferation and creates opportunities for improved mechanism-based risk assessment. PMID:21315101
Boitier, Eric; Amberg, Alexander; Barbi�, Val�rie; Blichenberg, Arne; Brandenburg, Arnd; Gmuender, Hans; Gruhler, Albrecht; McCarthy, Diane; Meyer, Kirstin; Riefke, Bjoern; Raschke, Marian; Schoonen, Willem; Sieber, Maximilian; Suter, Laura; Thomas, Craig E; Sajot, Nicolas
Respiration parameters of liver mitochondria (MCh) in rats fed with amaranth seed oil for 3 weeks have been evaluated. Thirty\\u000a minutes before decapitation, adrenaline was injected intraperitoneally at a low dose (350 ?g\\/kg body weight) to both control\\u000a and experimental animals. It was shown that in animals that were injected with adrenaline and did not receive oil, the rate\\u000a of
T. V. Sirota; O. P. Yelisyeyeva; N. V. Khunderyakova; O. A. Makhotina
Shortage in tissue availability from cadaver donors and the need for life-long immunosuppression severely restrict the large-scale application of cell-replacement therapy for diabetic patients. This study suggests the potential use of adult human liver as alternate tissue for autologous beta-cell-replacement therapy. By using pancreatic and duodenal homeobox gene 1 (PDX-1) and soluble factors, we induced a comprehensive developmental shift of
Tamar Sapir; Keren Shternhall; Irit Meivar-Levy; Tamar Blumenfeld; Hamutal Cohen; Ehud Skutelsky; Smadar Eventov-Friedman; Iris Barshack; Iris Goldberg; Sarah Pri-Chen; Lya Ben-Dor; Sylvie Polak-Charcon; Avraham Karasik; Ilan Shimon; Eytan Mor; Sarah Ferber
D-Alanine:D-alanine ligase (EC 220.127.116.11; Ddl) catalyzes the ATP-driven ligation of two D-alanine (D-Ala) molecules to form the D-alanyl:D-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis, making Ddl an attractive target for drug development. D-Cycloserine (DCS), an analog of D-Ala and a prototype Ddl inhibitor, has shown promise for the treatment of tuberculosis. Here, we report the crystal structure of Mycobacterium tuberculosis Ddl at a resolution of 2.1 {angstrom}. This structure indicates that Ddl is a dimer and consists of three discrete domains; the ligand binding cavity is at the intersection of all three domains and conjoined by several loop regions. The M. tuberculosis apo Ddl structure shows a novel conformation that has not yet been observed in Ddl enzymes from other species. The nucleotide and D-alanine binding pockets are flexible, requiring significant structural rearrangement of the bordering regions for entry and binding of both ATP and D-Ala molecules. Solution affinity and kinetic studies showed that DCS interacts with Ddl in a manner similar to that observed for D-Ala. Each ligand binds to two binding sites that have significant differences in affinity, with the first binding site exhibiting high affinity. DCS inhibits the enzyme, with a 50% inhibitory concentration (IC{sub 50}) of 0.37 mM under standard assay conditions, implicating a preferential and weak inhibition at the second, lower-affinity binding site. Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more-effective Ddl inhibitors.
Bruning, John B.; Murillo, Ana C.; Chacon, Ofelia; Barletta, Ra�l G.; Sacchettini, James C. (TAM); (UNL)
Nonalcoholic fatty liver disease in human obesity is characterized by the multifactorial nature of the underlying pathogenic mechanisms, which include misregulation of PPARs signaling. Liver PPAR-? downregulation with parallel PPAR-? and SREBP-1c up-regulation may trigger major metabolic disturbances between de novo lipogenesis and fatty acid oxidation favouring the former, in association with the onset of steatosis in obesity-induced oxidative stress and related long-chain polyunsaturated fatty acid n-3 (LCPUFA n-3) depletion, insulin resistance, hypoadiponectinemia, and endoplasmic reticulum stress. Considering that antisteatotic strategies targeting PPAR-? revealed that fibrates have poor effectiveness, thiazolidinediones have weight gain limitations, and dual PPAR-?/? agonists have safety concerns, supplementation with LCPUFA n-3 appears as a promising alternative, which achieves both significant reduction in liver steatosis scores and a positive anti-inflammatory outcome. This latter aspect is of importance as PPAR-? downregulation associated with LCPUFA n-3 depletion may play a role in increasing the DNA binding capacity of proinflammatory factors, NF-?B and AP-1, thus constituting one of the major mechanisms for the progression of steatosis to steatohepatitis. PMID:23304111
Videla, Luis A.; Pettinelli, Paulina
Hot topics in liver anesthesia.
Anesthetic techniques for liver surgery still have many controversial issues for anesthesiologists who want to provide optimal care for their patients. There are unanswered questions: What is the best technique to prevent excessive blood loss during live donor liver dissection? What is the proper compromise of filling pressures to reduce bleeding and not compromise vital organ function? Epidural analgesia, an established method for pain relief, carries a risk of epidural hematoma formation in liver resections and especially liver transplantation because of compromised coagulation. New inhalation anesthetics would be ideal for liver surgery except for their potential for renal failure, and the IV agent propofol may have insufficient metabolism when liver function is absent. Several recent studies are reviewed to elucidate these questions. PMID:18555145
Lukanovic, N P
Advancements in accuracy of the alanine dosimetry system. Part 1. The eects of environmental of alanine dosimetry by changing the resonant cavity Q-factor. This is particularly important when irradiated is demonstrated. # 2000 Elsevier Science Ltd. All rights reserved. Keywords: Alanine; EPR dosimetry; Humidity