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Phytochemicals in Foods: February 2012
Piperine is a phytochemical alkaloid in the class of organosulfur compound, found abundantly in white and black pepper, long pepper, etc.Health Benefits1. Anti bacterial activitiesIn the valuation of novel synthetic analogues of piperine as inhibitors of multidrug efflux pump NorA of Staphylococcus aureus, showed that a newly identified class of compounds derived from a natural amide, piperine, is more potent than the parent molecule in potentiating the activity of ciprofloxacin through the inhibition of the NorA efflux pump. These molecules may prove useful in augmenting the antibacterial activities of fluoroquinolones in a clinical setting, according to "Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus" by Ashwani Kumar, Inshad Ali Khan, Surrinder Koul, Jawahir Lal Koul, Subhash Chandra Taneja, Intzar Ali, Furqan Ali, Sandeep Sharma, Zahid Mehmood Mirza, Manoj Kumar, Pyare Lal Sangwan, Pankaj Gupta, Niranjan Thota and Ghulam Nabi Qazi(1)2. Anti-inflammatory Effect In the investigation of investigate the anti-inflammatory effect of piperine against adjuvant-induced arthritis in rats, an experimental model for rheumatoid arthritis and compared it with that of the non-steroidal anti-inflammatory drug indomethacin, found that Histopathological analysis of joints also revealed that synovial hyperplasia and mononuclear infiltration observed in arthritic rats were alleviated by piperine. Thus, the present study clearly indicated that piperine possesses promising anti-inflammatory effect against adjuvant-induced arthritis by suppressing inflammation and cartilage destruction, according to "Anti-inflammatory Effect of Piperine in Adjuvant-Induced Arthritic Rats-a Biochemical Approach" by Murunikkara V, Pragasam SJ, Kodandaraman G, Sabina EP, Rasool M.(2)3. Murine breast cancer In the investigation of the effects of piperine, a major pungent alkaloid present in Piper nigrum and Piper longum, on the tumor growth and metastasis of mouse 4T1 mammary carcinoma in vitro and in vivo, and elucidation of the underlying mechanisms, showed that Treatment of 4T1 cells with piperine (70-280 μmol/L) dose-dependently induced apoptosis of 4T1 cells, accompanying activation of caspase 3. The cells treated with piperine (140 and 280 μmol/L) significantly increased the percentage of cells in G(2)/M phase with a reduction in the expression of cyclin B1. Piperine (140 and 280 μmol/L) significantly decreased the expression of MMP-9 and MMP-13, and inhibited 4T1 cell migration in vitro. Injection of piperine (2.5 and 5 mg/kg) dose-dependently suppressed the primary 4T1 tumor growth and injection of piperine (5 mg/kg) significantly inhibited the lung metastasis, according to "Piperine suppresses tumor growth and metastasis in vitro and in vivo in a 4T1 murine breast cancer model" by Lai LH, Fu QH, Liu Y, Jiang K, Guo QM, Chen QY, Yan B, Wang QQ, Shen JG.(3)4. Cytotoxicity In the investigation of the protective effect of piperine treatment on corticosterone-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells, showed that piperine co-treatment revealed a differential effect on the cytotoxicity of corticosterone and had its maximum inhibitory effect at 1 μM. Piperine (1 μM) co-treatment also significantly decreased intracellular reactive oxygen species level, and enhanced superoxide dismutase activity and total glutathione level in corticosterone-treated PC12 cells. In addition, piperine (1 μM) co-treatment was found to reverse the decreased brain-derived neurotrophic factor (BDNF) mRNA level caused by corticosterone in PC12 cells, according to "Protective Effects of Piperine Against Corticosterone-Induced Neurotoxicity in PC12 Cells" by Mao QQ, Huang Z, Ip SP, Xian YF, Che CT.(4)5. Human metabolic syndromeIn the examination of the dietary supplementation with piperine, the active principle of black pepper, to high carbohydrate, high fat (HCHF) diet-fed rats as a model of human metabolic syndrome. Rats were fed with either HCHF diet (carbohydrate, 52%; fat, 24%; 25% fructose in drinking water) or cornstarch (CS) diet for a total of 16 weeks. Diets of the treatment groups (CS + piperine and HCHF + piperine) were supplemented with piperine for the last 8 weeks of this protocol, found that After 16 weeks, rats fed with HCHF diet developed hypertension, elevated oxidative stress and inflammation-induced cardiac changes (infiltration of inflammatory cells in heart, increase in count and degranulation of mast cells in heart, cardiac fibrosis and increase in ventricular stiffness), reduced responsiveness of aortic rings, impaired glucose tolerance, abdominal obesity together with liver fibrosis, fat deposition and increased plasma liver enzymes. Supplementation with piperine (375 mg/kg food; approximately 30 mg/kg/day) in HCHF-fed rats normalized blood pressure, improved glucose tolerance and reactivity of aortic rings, reduced plasma parameters of oxidative stress and inflammation, attenuated cardiac and hepatic inflammatory cell infiltration and fibrosis and improved liver function, according to "Piperine Attenuates Cardiovascular, Liver and Metabolic Changes in High Carbohydrate, High Fat-Fed Rats" by Diwan V, Poudyal H, Brown L.(5)6. HypertensionIn the study of the effects of curcuma and black pepper compounds on increased blood pressure and remodeling of aorta in the rat model of experimental NO-deficient hypertension, showed that administration of piperine or curcumin, less their combination, is able to partially prevent the increase of blood pressure caused by chronic L-NAME administration. The spices modify the remodeling of the wall of the aorta induced by hypertension. Our results show that independent administration of curcumin is more effective in preventing negative changes in blood vessel morphology accompanying hypertensive disease, according to"Spice up the hypertension diet - curcumin and piperine prevent remodeling of aorta in experimental L-NAME induced hypertension" by Hlavačková L, Janegová A, Uličná O, Janega P, Cerná A, Babál P.(6)7. Synergistic effectsin the evaluation of the effects of curcumin alone and with adjuvant piperine against benzo(a)pyrene (BaP) induced oxidative stress in lungs of male Swiss albino mice, showed that BaP treatment alone did not alter significantly the GST activity. Pretreatment with curcumin increased the GST activity in BaP treated group, which was enhanced further upon synergistic treatment with piperine and curcumin. Therefore, combined administration of curcumin and piperine shall prove to be more effective in attenuating BaP induced toxicity, according to "Synergistic effects of piperine and curcumin in modulating benzo(a)pyrene induced redox imbalance in mice lungs" by Sehgal A, Kumar M, Jain M, Dhawan DK.(7)8. Antimicrobial, antileishmanial and cytotoxic compounds in the evaluation of the petroleum ether and chloroform extracts of the root of Piper chaba showed antimicrobial, antileishmanial and cytotoxic activities, led to the isolation of Bornyl piperate (1), piperlonguminine (2) and piperine (3), showed that the isolated compounds (1 and 2) showed potent antifungal activity when compared with standard drug Nystatin, and significant cytotoxic activity with the IC(50) values of 0.76 and 0.83 µg mL(-1), respectively. These compounds were also found to have weak antibacterial and antileishmanial activities. This is the first report about the antileishmanial activity of Piper isolates, according to "Antimicrobial, antileishmanial and cytotoxic compounds from Piper chaba" byNaz T, Mosaddik A, Rahman MM, Muhammad I, Haque ME, Cho SK.(8)9. Antigenotoxic effectsIn the investigation of the antigenotoxic effects of curcumin and piperine separately and in combination against benzo(a)pyrene (BaP) induced DNA damage in lungs and livers of mice, found thatPretreatments of curcumin and curcumin plus piperine before administration of single dose of BaP significantly decreased the levels of 8-oxo-dG content and % DNA in the comet tail in both the tissues. Moreover, the genoprotective potential of curcumin plus piperine was significantly higher as compared to curcumin alone against BaP induced DNA damage, according to "Combined effects of curcumin and piperine in ameliorating benzo(a)pyrene induced DNA damage" by Sehgal A, Kumar M, Jain M, Dhawan DK.(9)10. Multidrug resistant cancer cellsOver-expression of P-gp, MRP1 and BCRP in tumor cells is one of the important mechanisms leading to multidrug resistance (MDR), which impairs the efficacy of chemotherapy. P-gp, MRP1 and BCRP are ABC (ATP-Binding Cassette) transporters, piperine can potentiate the cytotoxicity of anti-cancer drugs in resistant sublines, such as MCF-7/DOX and A-549/DDP, which were derived from MCF-7 and A-549 cell lines. At a concentration of 50 μM piperine could reverse the resistance to doxorubicin 32.16 and 14.14 folds, respectively. It also re-sensitized cells to mitoxantrone 6.98 folds. In addition, long-term treatment of cells by piperine inhibits transcription of the corresponding ABC transporter genes, according to "Piperine, a piperidine alkaloid from Piper nigrum re-sensitizes P-gp, MRP1 and BCRP dependent multidrug resistant cancer cells" by Li S, Lei Y, Jia Y, Li N, Wink M, Ma Y.(10)11. Cytosolic isoforms hCA I and IIIn the examination of Caffeine and piperine extracted for inhibition of the human (h) cytosolic isoforms hCA I and II, indicated that The IC(50) values of caffeine against hCA I was of 55 mM, whereas that of piperine of 60 mM. The IC(50) values of caffeine and piperine against hCA II were of 2 mM. Although these are quite weak inhibitors they may constitute leads for developing tighter binding compounds, according to "Carbonic anhydrase I and II inhibition with natural products: caffeine and piperine" by Sethi KK, Sahoo SK, Pichikala JN, Suresh P.(11)12. Etc.Sources(1) http://jac.oxfordjournals.org/content/61/6/1270.full(2) http://www.ncbi.nlm.nih.gov/pubmed/22389056(3) http://www.ncbi.nlm.nih.gov/pubmed/22388073(4) http://www.ncbi.nlm.nih.gov/pubmed/22205277(5) http://www.ncbi.nlm.nih.gov/pubmed/22038304(6) http://www.ncbi.nlm.nih.gov/pubmed/22005253(7) http://www.ncbi.nlm.nih.gov/pubmed/21859361(8) http://www.ncbi.nlm.nih.gov/pubmed/21834629(9) http://www.ncbi.nlm.nih.gov/pubmed/21827816(10) http://www.ncbi.nlm.nih.gov/pubmed/21802927(11) http://www.ncbi.nlm.nih.gov/pubmed/21612376
Allyl isothiocyanate is phytochemical containing sulfur in the class of organosulfur compound, found abundantly in horseradish, mustard, wasabi, etc.Health Benefits1. Brain CancerIn the investigation of that AITC significantly decreased proliferation and viability of human brain malignant glioma GBM 8401 cells in a dose-dependent manner with IC50 9.25+/-0.69 microM for 24 h-treatment, showed that Pretreatment with specific inhibitors of caspase-3 (Z-DEVE-FMK) and -9 (Z-LEHD-FMK) significantly reduced caspase-3 and -9 activity in GBM 8401 cells. Western blot analysis and colorimetric assays also displayed that AITC caused a time-dependent increase in cytosolic cytochrome c, pro-caspase-9, Apaf-1, AIF, Endo G and the stimulated caspase-9 and -3 activity. Our results suggest that AITC is a potent anti-human brain malignant glioma drug and it shows a remarkable action on cell cycle arrest before commitment for apoptosis is reached, according to "Allyl isothiocyanate triggers G2/M phase arrest and apoptosis in human brain malignant glioma GBM 8401 cells through a mitochondria-dependent pathway' by Chen NG, Chen KT, Lu CC, Lan YH, Lai CH, Chung YT, Yang JS, Lin YC.(1)2. Bladder cancerUrinary concentrations of AITC equivalent are at least ten times higher than in the plasma, and tissue levels of AITC equivalent in the urinary bladder were 14-79 times higher than in other organs after oral AITC administration to rats. AITC may be most effective in the bladder as a cancer chemopreventive compound. AITC at high-dose levels also exhibit a low degree of cytotoxicity and genotoxicity in animal studies, but such adverse effects are unlikely in humans exposed to dietary levels of AITC. Overall, AITC exhibits many desirable attributes of a cancer chemopreventive agent, and further studies are warranted in order to elucidate its mechanism of action and to assess its protective activity in humans, according to "Allyl isothiocyanate as a cancer chemopreventive phytochemical" by Zhang Y.(2)3. Antimicrobial effectsIn the investigation of the antimicrobial effect of a chitosan coating+allyl isothiocyanate (AIT) and nisin against Salmonella on whole fresh cantaloupes, showed that The same coating treatment completely inactivated mold and yeast on cantaloupe at day 1 and no regrowth occurred even up to 14days of storage. Scanning electron microscopy revealed that cell membrane damage and leakage of intercellular components occurred as a result of the chitosan-AIT coating treatments. No visual changes in overall appearance and color of cantaloupe rind and flesh due to coating treatments were observed. These results indicate that the application of an antimicrobial coating may be an effective method for decontamination of cantaloupes, according to "Inactivation of Salmonella on whole cantaloupe by application of an antimicrobial coating containing chitosan and allyl isothiocyanate" by Chen W, Jin TZ, Gurtler JB, Geveke DJ, Fan X.(3)4. Stress responseIn the examination of the effects of AITC on heat shock protein (HSP) 70 expression in Caenorhabditis elegans and factors affecting the production of AITC from its precursor, sinigrin, a glucosinolate, in ground Brassica juncea cv. Vulcan seed as mustard has some potential as a biopesticide, found that AITC induced toxicity in C. elegans, as measured by HSP70 expression.• Conditions required for the conversion of sinigrin to AITC in ground B. juncea seed were determined.• The use of C. elegans as a bioassay to test AITC or mustard biopesticide efficacy is discussed, according to "Allyl isothiocyanate induced stress response in Caenorhabditis elegans" by Saini AK, Tyler RT, Shim YY, Reaney MJ.(4)5. Anti cancersIn the review of whether AITC arrests human bladder cancer cells in mitosis and also induces apoptosis, suggested that AITC induced mitochondrion-mediated apoptosis, as shown by cytochrome c release from mitochondria to cytoplasm, activation of caspase-9 and caspase-3, and formation of TUNEL-positive cells. Inhibition of caspase-9 blocked AITC-induced apoptosis. Moreover, we found that apoptosis induction by AITC depended entirely on mitotic arrest and was mediated via Bcl-2 phosphorylation at Ser-70. Pre-arresting cells in G(1) phase by hydroxyurea abrogated both AITC-induced mitotic arrest and Bcl-2 phosphorylation. Overexpression of a Bcl-2 mutant prevented AITC from inducing apoptosis, according to "Allyl isothiocyanate arrests cancer cells in mitosis, and mitotic arrest in turn leads to apoptosis via Bcl-2 protein phosphorylation' by Geng F, Tang L, Li Y, Yang L, Choi KS, Kazim AL, Zhang Y.(5)6. Anti-inflammatory effectsIn the evaluation of the underlying mechanisms of the potential anti-inflammatory properties of allyl-isothiocyanate (AITC) were analysed in vitro and in vivo, showed that 1. AITC was slightly less potent than sulforaphane (used as a positive control) in down-regulating inflammation in LPS stimulated macrophages. A significant increase in nuclear Nrf2 and heme oxygenase 1 gene expression and only a moderate down-regulation of interleukin 1β and microRNA-155 levels due to AITC was found in mouse liver. Present data suggest that AITC exhibits potent anti-inflammatory activity in cultured macrophages in vitro but has only relatively little anti-inflammatory activity in mice in vivo, according to "Anti-inflammatory potential of allyl-isothiocyanate-role of Nrf2, NFκB and microRNA-155" by Wagner AE, Boesch-Saadatmandi C, Dose J, Schultheiss G, Rimbach G.(6)7. Colorectal CancerIn the study conducted by Department of Biology, Science Centre, The Chinese University of Hong Kong, AITC was shown to inhibit the proliferation of human metastatic colorectal adenocarcinoma SW620 cells in vitro by inducing cell cycle arrest at the G2/M phase, according to "Allyl isothiocyanate induces G2/M arrest in human colorectal adenocarcinoma SW620 cells through down-regulation of Cdc25B and Cdc25C" by Lau WS, Chen T, Wong YS.(7)8. Prostate cancerIn the demonstartion of that allyl isothiocyanate (AITC), a constituent of cruciferous vegetables, significantly inhibits proliferation of cultured PC-3 (androgen-independent) and LNCaP (androgen-dependent) human prostate cancer cells in a dose-dependent manner with an IC(50) of approximately 15-17 micro M, found that A significant reduction in the expression of cyclin B1 protein (approximately 45%) was observed only in LNCaP cells. A 24 h exposure of PC-3 and LNCaP cells to an apoptosis-inducing concentration of AITC (20 micro M) resulted in a significant decrease (31-68%) in the levels of anti-apoptotic protein Bcl-2 in both cell lines, and approximately 58% reduction in Bcl-X(L) protein expression in LNCaP cells. In conclusion, it seems reasonable to hypothesize that AITC, and possibly other ITCs, may find use in the treatment of human prostate cancers, according to "Allyl isothiocyanate, a constituent of cruciferous vegetables, inhibits proliferation of human prostate cancer cells by causing G2/M arrest and inducing apoptosis" by Xiao D, Srivastava SK, Lew KL, Zeng Y, Hershberger P, Johnson CS, Trump DL, Singh SV.(8)9. Health benefitsIn the research of nutritional significance of parent glucosinolate sinigrin 50 μmol/kg b. w./day and its degradation product allyl isothiocyanate 25 μmol/kg b. w./day and 50 μmol/kg b. w./day for their influence on some parameters of carbohydrate and lipid metabolism in an animal rat model in vivo after their single (4 h) and 2 weeks oral administration, showed that the effect of SIN and AITC is multidirectional, indicating its impact on many organs like liver as well as pancreas, intestine in vivo action and rat adipocytes in vitro. Whilst consumption of cruciferous vegetables at levels currently considered "normal" seems to be beneficial to human health, this data suggest that any large increase in intake could conceivably lead to undesirable effect. This effect is potentiated with time of action of the examined compounds, whose influence is rather adverse for the majority of metabolic pathways, according to "Multidirectional time-dependent effect of sinigrin and allyl isothiocyanate on metabolic parameters in rats" by Okulicz M.(9)10. White Blood Cells (WBCs)In the investigation of the effects of AITC (dose=20 mg/kg body weight/day for 10 days, subcutaneous: s.c.) on the number of WBCs (total WBCs, lymphocytes, monocyte, neutrophil, basophil and eosinophil) and plasma corticosterone concentrations in adult male rats, showed that administration of AITC decreased significantly the number of total WBCs on days 1-4 post s.c. injection by 25-27%. AITC also decreased the number of lymphocytes on days 1-10 by 21-36% and monocyte on days 1-8 by 28-78%. However, administration of AITC increased the number of neutrophil on days 8-10 by 61-112%. AITC did not change the number of eosinophil and basophil. Plasma corticosterone concentrations during the experimental period were 4.7-8.4 times significantly higher in the AITC group than in the control group, indicating that AITC induced stress-responses, according to "Allyl isothiocyanate-induced changes in the distribution of white blood cells in rats" by Imaizumi K, Sato S, Sakakibara Y, Mori S, Ohkuma M, Kawashima Y, Ban T, Sasaki H, Tachiyashiki K.(10)11. Liver cancerIn the investigation of the possible protective effect of allyl isothiocyanate (AITC) in nitrite- and nitrosamine-treated human hepatoma cells (HepG2) with the evaluation by cytotoxic effects and genotoxic effects determined by the single-cell gel electrophoresis (SCGE), showed that Allyl isothiocyanate treatment enhanced cell viability and reduced intracellular reactive oxygen species (ROS) production in both nitrite- and nitrosamine-treated cells significantly. In SCGE, when compared to untreated control cells, all of the treated groups caused increases in the tail intensity (%) such as nitrite at 17%, N-nitrosodimethylamine (NDMA) at 279%, N-nitrosodiethylamine (NDEA) at 324%, and N-nitrosomorpholine (NMOR) at 288%, according to "Effect of allyl isothiocyanate (AITC) in both nitrite- and nitrosamine-induced cell death, production of reactive oxygen species, and DNA damage by the single-cell gel electrophoresis (SCGE): does it have any protective effect on HepG2 cells?" by Erkekoğlu P, Baydar T.(11)12. Etc.Sources(1) http://www.ncbi.nlm.nih.gov/pubmed/20596632(2) http://www.ncbi.nlm.nih.gov/pubmed/19960458(3) http://www.ncbi.nlm.nih.gov/pubmed/22361025(4) http://www.ncbi.nlm.nih.gov/pubmed/22093285(5) http://www.ncbi.nlm.nih.gov/pubmed/21778226(6) http://www.ncbi.nlm.nih.gov/pubmed/21692985(7) http://www.ncbi.nlm.nih.gov/pubmed/21472349(8) http://www.ncbi.nlm.nih.gov/pubmed/12771033(9) http://www.ncbi.nlm.nih.gov/pubmed/20809411(10) http://www.ncbi.nlm.nih.gov/pubmed/20686346(11) http://www.ncbi.nlm.nih.gov/pubmed/20448263
Allicin is phytochemical containing sulfur in the class of organosulfur compound, found abundantly in onion and garlic.Health Benefits1. Antibacterial activitiesIn the comparison of those of allicin and several clinically useful antibiotics using two representative bacteria commonly found in the human environment, Gram-positive S. aureus and Gram-negative Escherichia coli, indicated that The garlic extract had more potent anti-staphylococcal activity than an equal amount of allicin. In terms of antibiotic potency against Gram-positive and Gram-negative bacteria, authentic allicin had roughly 1-2% of the potency of streptomycin (vs. S. aureus), 8% of that of vancomycin (vs. S. aureus), and only 0.2% of that of colistin (vs. E. coli), according to "Antibacterial potential of garlic-derived allicin and its cancellation by sulfhydryl compounds" by Fujisawa H, Watanabe K, Suma K, Origuchi K, Matsufuji H, Seki T, Ariga T.(1)2. Cognitive effectsIn the assessment of the effects of allicin on endogenous antioxidant defenses in hippocampus of cognitively impaired aged mouse, showed that treatment of allicin significantly ameliorated ageing-induced cognitive dysfunction through enhancing of Nrf2 antioxidant signaling pathways. Therefore, allicin could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in aging and Alzheimer's disease, according to "Allicin ameliorates cognitive deficits ageing-induced learning and memory deficits through enhancing of Nrf2 antioxidant signaling pathways" by Li XH, Li CY, Lu JM, Tian RB, Wei J.(2)3. Chronic Occupational Lead PoisoningIn the investigation of the therapeutic effects of garlic and comparison with d-penicillamine in patients with chronic lead poisoning, found that garlic seems safer clinically and as effective as d-penicillamine. Therefore, garlic can be recommended for the treatment of mild-to-moderate lead poisoning, according to "Comparison of Therapeutic Effects of Garlic and d-Penicillamine in Patients with Chronic Occupational Lead Poisoning, according to " Kianoush S, Balali-Mood M, Mousavi SR, Moradi V, Sadeghi M, Dadpour B, Rajabi O, Shakeri MT.(3)4. Free radical scavenger capacityIn a theoretical study on the free radical scavenger capacity of α-mangostin in Mangosteen and its monoanion is analyzed using the density functional theory approximation, indicated that In thermodynamics and kinetics, α-mangostin and its deprotonated form are good free radical scavenger through the HAT mechanism, with the anionic (deprotonated) form being more reactive than the neutral one. Their capacity to scavenge OOH free radical is similar to that of carotenes, higher than that of allicin, much higher than that of melatonin and N-acetylcysteine amide, and about 15 times lower than that of 2-propenesulfenic acid, according to "Free radical scavenger properties of α-mangostin: thermodynamics and kinetics of HAT and RAF mechanisms" by Martínez A, Galano A, Vargas R.(4)5. Antimicrobial activity Alliums are inhibitory against all tested microorganisms such as bacteria, fungi, viruses, and parasites. Alliums inhibit multi-drug-resistant microorganisms and often work synergistically with common antimicrobials. Allium-derived antimicrobial compounds inhibit microorganisms by reacting with the sulfhydryl (SH) groups of cellular proteins, according to "Antimicrobial properties of allium species" by Kyung KH.(5)6. Murine T-lymphocytes (EL-4) In the investigation of the anti-proliferative and pro-apoptotic activities of allicin in murine T-lymphocytes (EL-4) and the mechanism of inducing apoptosis in vitro, found that allicin was effective in inhibiting the proliferation of EL-4 cells in vitro in a concentration-dependent manner. Further, allicin could induce the formation of apoptotic bodies, nuclear condensation, DNA spallation, and even activated the expression of caspase-3, -12 and cytochrome C (cyt C). Finally, allicin up-regulated the ratio of Bax/Bcl-2 and induced a mitochondrion membrane potential (MMP) decrease. Allicin induced apoptosis in EL-4 cells in a time- and concentration-dependent manner, in which the mitochondrial pathway might play a central role, according to "Allicin induces apoptosis in EL-4 cells in vitro by activation of expression of caspase-3 and -12 and up-regulation of the ratio of Bax/Bcl-2" by Wang Z, Liu Z, Cao Z, Li L.(6)7. Anti tumor activitiesThe combination treatments using chemotherapeutic agents with distinct molecular mechanisms are considered more promising for higher efficacy; however, using multiple agents contributes to added toxicity, in-vitro and in-vivo studies in the last few decades, showed that some phytochemicals derived from 'natural products' such as fruits, vegetables and certain spices, referred to as chemopreventive agents, including capsaicin, trans-anethole, thymoquinone, diosgenin, allicin, can not only reduce the risk of acquiring specific cancer but also have been shown to suppress cancer cell proliferation, inhibit growth factor signaling pathways, induce apoptosis, inhibit nuclear factor-κB, AP-1, Akt, MAPK, Wnt, Notch, p53, AR, ER, and JAK-STAT, etc., activation pathways, inhibit angiogenesis, suppress the expression of antiapoptotic proteins, and inhibit cyclooxygenase-2, according to "Antitumor promoting potential of selected phytochemicals derived from spices: a review" by Rajput S, Mandal M.(7)8. Antioxidants and anti cancersIn the evaluation of the potential anticancer effects of different type of processed garlic extracts on WEHI-164 tumor cells in inbred BALB/c mice and correlate the tumor growth rates with some garlic constituents, showed that three weeks following tumor inoculation, the mean tumor size in garlic extract-treated groups was reduced with significant reductions observed in the fresh and microwaved extract groups compared with the control group (P<.05). The antioxidant capacity and the amounts of allicin, flavonoids, and phenolic compounds in differentially processed garlic were evaluated and correlated with their anticancer activities, according to "Correlation between antioxidant activity of garlic extracts and WEHI-164 fibrosarcoma tumor growth in BALB/c mice" by Shirzad H, Taji F, Rafieian-Kopaei M.(8)9. Dental caries and periodontitisIn the testing the antimicrobial activity of garlic allicin on oral pathogens associated with dental caries and periodontitis, found that the result support the traditional medicinal use of garlic and suggest the use of allicin for alleviating dental diseases, according to "Garlic allicin as a potential agent for controlling oral pathogens" by Bachrach G, Jamil A, Naor R, Tal G, Ludmer Z, Steinberg D.(9)10. Prevention and treatment of the common coldIn the review the evidence supporting complementary and alternative medicine approaches to treatment and prevention of the common cold in adults, indicated that for prevention, vitamin C demonstrated benefit in a large meta-analysis, with possibly increased benefit in patients subjected to cold stress. There is inconsistent evidence for Asian ginseng (Panax ginseng) and North American ginseng (Panax quinquefolius). Allicin was highly effective in 1 small trial. For treatment, Echinacea purpurea is the most consistently useful variety; it was effective in 5 of 6 trials. Zinc lozenges were effective in 5 of 9 trials, likely owing to dose and formulation issues. Overall, the evidence suggests no benefit from probiotics for prevention or treatment of the common cold, according to "Complementary and alternative medicine for prevention and treatment of the common cold" by Nahas R, Balla A.(10)11. Neuroprotective diseasesIn the investigation of the neuroproyective effects of (1) flavonoid polyphenols like epigallocatechin 3-gallate (EGCG) from green tea and quercetin from apples; (2) non-flavonoid polyphenols such as curcumin from tumeric and resveratrol from grapes; (3) phenolic acids or phenolic diterpenes such as rosmarinic acid or carnosic acid, respectively, both from rosemary; and (4) organosulfur compounds including the isothiocyanate, L-sulforaphane, from broccoli and the thiosulfonate allicin, from garlic, indicated that alternative mechanisms of action have also been suggested for the neuroprotective effects of these compounds such as modulation of signal transduction cascades or effects on gene expression. Here, we review the literature pertaining to these various classes of nutraceutical antioxidants and discuss their potential therapeutic value in neurodegenerative diseases, according to "Nutraceutical antioxidants as novel neuroprotective agents" by Kelsey NA, Wilkins HM, Linseman DA.(11)12. Etc.Sources(1) http://www.ncbi.nlm.nih.gov/pubmed/19734685(2) http://www.ncbi.nlm.nih.gov/pubmed/22390900(3) http://www.ncbi.nlm.nih.gov/pubmed/22151785(4) http://www.ncbi.nlm.nih.gov/pubmed/21936544(5) http://www.ncbi.nlm.nih.gov/pubmed/21903379(6) http://www.ncbi.nlm.nih.gov/pubmed/21902562(7) http://www.ncbi.nlm.nih.gov/pubmed/21876437(8) http://www.ncbi.nlm.nih.gov/pubmed/21812650(9) http://www.ncbi.nlm.nih.gov/pubmed/21548800(10) http://www.ncbi.nlm.nih.gov/pubmed/21322286(11) http://www.ncbi.nlm.nih.gov/pubmed/21060289
Alliin (S-allyl-L-cysteine-S-oxide) is a phytochemical compound sulfoxide,. a derivative of the amino acid cysteine, belonging to the class of sulfur compounds, found abundantly in fresh garlic and onion.Health Benefits1. Antioxidant propertiesIn the investigation of the antioxidant properties of garlic compounds representing the four main chemical classes, alliin, allyl cysteine, allyl disulfide, and allicin, prepared by chemical synthesis or purification, showed that Alliin scavenged superoxide, while allyl cysteine and allyl disulfide did not react with superoxide. Allicin suppressed the formation of superoxide by the xanthine/xanthine oxidase system, probably via a thiol exchange mechanism. Alliin, allyl cysteine, and allyl disulfide all scavenged hydroxyl radicals; the rate constants calculated based on deoxyribose competitive assay were 1.4-1.7 x 10(10), 2.1-2.2 x 10(9), and 0.7-1.5 x 10(10) M (1) second(1), respectively, according to "The antioxidant properties of garlic compounds: allyl cysteine, alliin, allicin, and allyl disulfide" by Chung LY.(1)2. Anti diabetes In comparison of the production and therapeutic efficiency of alliin extracted from garlic leaves of plants grown under ex situ and in situ conditions, found that Alliin production noted ~50% enhancement in leaves from plants grown under in situ conditions. Serum glucose, triglycerides, total lipids, total cholesterol, low-density lipoprotein (LDL)-, and very low-density lipoprotein (VLDL)-cholesterol in diabetic rats treated with alliin produced from in situ grown plants noted significant reduction of ~54%, 15%, 14%, 20%, 24%, and 15%, while 35%, 14%, 10%, 12%, 17% and 11% reduction was noted in diabetic rats treated with alliin produced from ex situ grown plants in comparison with those administered with distilled water. High-density lipoprotein (HDL)-cholesterol did not show any significant change. Leaf extract of plants lowered serum enzyme levels (alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase) toward the norm better than glibenclamide, according to "Alliin obtained from leaf extract of garlic grown under in situ conditions possess higher therapeutic potency as analyzed in alloxan-induced diabetic rats" by Nasim SA, Dhir B, Kapoor R, Fatima S, Mahmooduzzafar, Mujib A.(2)3. Antibacterial activityIn the investigation of an antimicrobial sulfur compound newly isolated from heated garlic extract, showed that the compound was CH₂=CH-CH₂-S-S-S-CH₂-CH(NH₂)COOH, 3-(allyltrisulfanyl)-2-aminopropanoic acid, a derivative of cysteine, presumably derived from alliin (S-allyl-L-cysteine sulfoxide). This novel compound has comparatively potent anti-yeast activity and rather weak antibacterial activity, similar to other antimicrobial compounds in garlic, according to "3-(allyltrisulfanyl)-2-aminopropanoic acid, a novel nonvolatile water-soluble antimicrobial sulfur compound in heated garlic" by Kang SS, Lim DR, Kyung KH.(3)4. Ovarian cancerIn the investigation of a chemical conjugate between daidzein and the garlic enzyme alliinase and its effect on human ovarian cancer cells, suggest that the targeted alliinase conjugates in the presence of alliin, generated therapeutically effective levels of allicin which were capable of suppressing tumor progression of intraperitoneal ovarian cancer in an animal model, according to "Conjugates of daidzein-alliinase as a targeted pro-drug enzyme system against ovarian carcinoma" by Appel E, Rabinkov A, Neeman M, Kohen F, Mirelman D.(4)5. Mitochondrial dysfunctionIn the evaluation of the preventive role of S-allyl cysteine sulphoxide (SACS) in isoproterenol (ISO)-induced cardiotoxicity in male Wistar rats, showed that oral administration of SACS for a period of 35 days to the normal control rats did not show any significant effect. Histopathological studies of the myocardial tissue showed a protective role of SACS in the myocardial-infarcted rats. The effect at a dose of SACS 80 mg/kg was more effective than the dose 40 mg/kg. The results of the study conclude that SACS protect the mitochondria of the ISO-induced myocardial-infarcted rats, according to 'Preventive effect of S-allyl cysteine sulphoxide (Alliin) on mitochondrial dysfunction in normal and isoproterenol induced cardiotoxicity in male Wistar rats: a histopathological study" by Sangeetha T, Darlin Quine S.(5)6. Anti-fungal efficacy In the evaluation of the in vitro anti-fungal efficacy of the active principle of garlic, pure allicin and polybutylcyanoacrylate (PBCA) nanoparticles (NPs) loaded with allicin.found that that pure allicin has stronger in vitro anti-fungal efficacy to six tested fungi than alliinase and alliin. Moreover, it has improved significantly after pure allicin being wrapped into PBCA NP, which may be due to the NP's good prolonged release effect and nano-scale dimensions, according to "Anti-fungal efficacy of polybutylcyanoacrylate nanoparticles of allicin and comparison with pure allicin" by Luo DQ, Guo JH, Wang FJ, Jin ZX, Cheng XL, Zhu JC, Peng CQ, Zhang C.(6)7. Antithrombotic and anticancer effectsIn the review of modern scientific research has revealed that the wide variety of dietary and medicinal functions of garlic can be attributed to the sulfur compounds present in or generated from garlic, indicated that although garlic produces more than 20 kinds of sulfide compounds from a few sulfur-containing amino acids, their functions are different from one another; e.g., allicin, methyl allyl trisulfide, and diallyl trisulfide have antibacterial, antithrombotic, and anticancer activities, respectively, according to "Antithrombotic and anticancer effects of garlic-derived sulfur compounds: a review" by Ariga T, Seki T. (7)8. Anti-angiogenesisIn the demonstartion of dose-dependent of Alliin, a compound derived from garlic, in inhibition of fibroblast growth factor-2 (FGF2)-induced human endothelial cell (EC) tube formation and angiogenesis in the chick chorioallantoic membrane (CAM) model, showed that these data indicated a synergistic effect of antioxidants on the anti-angiogenesis and anticancer efficacy of alliin. These data also suggest the implication of cellular NO and p53 as mediators of anti-angiogenesis and anticancer effects of alliin, according to "Anti-angiogenesis efficacy of the garlic ingredient alliin and antioxidants: role of nitric oxide and p53" by Mousa AS, Mousa SA.(8)9. Serum lipids, blood pressure and arterial stiffness in the testing the effect of dried garlic (Allium sativum) powder on blood lipids, blood pressure and arterial stiffness in a 12-week randomised, double-blind, placebo-controlled trial. Seventy-five healthy, normo-lipidaemic volunteers (men and women aged 40-60 years) were assigned to dried garlic powder tablets (10.8 mg alliin (3-(2-propenylsulfinyl)-L-alanine)/d, corresponding to about three garlic cloves) or placebo, showed that garlic powder was associated with a near-significant decrease (12 %) in triacylglycerol concentration (P=0.07). In conclusion, garlic powder tablets have no clinically relevant lipid-lowering and blood pressure-lowering effects in middle-aged, normo-lipidaemic individuals. The putative anti-atherosclerotic effect of garlic may be linked to risk markers other than blood lipids, according to "Effect of garlic (Allium sativum) powder tablets on serum lipids, blood pressure and arterial stiffness in normo-lipidaemic volunteers: a randomised, double-blind, placebo-controlled trial" by Turner B, Mølgaard C, Marckmann P.(9)10. Hepatoprotective effectIn the study of the interaction of the non-protein amino acid alliin with the enzyme alliinase (alliin lyase, EC 4.4.1.4). D-Galactosamine highly sensitizes the host response of the experimental animal to endotoxin (lipopolysaccharide) and causes fulminant hepatitis within 8h after administration, indicated that In D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced hepatitis rats, a significant increase of lipid peroxidation and decreased liver antioxidant enzyme levels are observed. Pretreatment with allicin, the active component of freshly crushed garlic cloves, prevented these alterations, according to "Hepatoprotective effect of allicin on tissue defense system in galactosamine/endotoxin challenged rats" by Vimal V, Devaki T.(10)11. Etc.Sources(1) http://www.ncbi.nlm.nih.gov/pubmed/16822206(2) http://www.ncbi.nlm.nih.gov/pubmed/21391887(3) http://www.ncbi.nlm.nih.gov/pubmed/20828317(4) http://www.ncbi.nlm.nih.gov/pubmed/20678009(5) http://www.ncbi.nlm.nih.gov/pubmed/19262997(6) http://www.ncbi.nlm.nih.gov/pubmed/19105898(7) http://www.ncbi.nlm.nih.gov/pubmed/16823096(8) http://www.ncbi.nlm.nih.gov/pubmed/16351512(9) http://www.ncbi.nlm.nih.gov/pubmed/15522140(10) http://www.ncbi.nlm.nih.gov/pubmed/14698523
Sinigrin is a phytochemical glucosinolate, belongs to the family of glucosides found abundantly in Brussels sprouts, broccoli, the seeds of black mustard, etc.Health Benefits1. Bladder cancerIn the design of testing the hypothesis of AITC-containing cruciferous vegetables also inhibit bladder cancer development, indicated that Comparison between hydrated MSP-1 and pure sinigrin with added myrosinase suggested that the anticancer effect of MSP-1 was derived principally, if not entirely, from the AITC generated from sinigrin. In an orthotopic rat bladder cancer model, oral MSP-1 at 71.5 mg/kg (sinigrin dose of 9 μmol/kg) inhibited bladder cancer growth by 34.5% (P < 0.05) and blocked muscle invasion by 100%, according to "Allyl isothiocyanate-rich mustard seed powder inhibits bladder cancer growth and muscle invasion" by Bhattacharya A, Li Y, Wade KL, Paonessa JD, Fahey JW, Zhang Y.(1)2. Multidirectional time-dependent effect In a research of nutritional significance of parent glucosinolate sinigrin 50 μmol/kg b. w./day and its degradation product allyl isothiocyanate 25 μmol/kg b. w./day and 50 μmol/kg b. w./day was studied by the evaluation of their influence on some parameters of carbohydrate and lipid metabolism in an animal rat model in vivo after their single (4 h) and 2 weeks oral administration, showed that the effect of SIN and AITC is multidirectional, indicating its impact on many organs like liver as well as pancreas, intestine in vivo action and rat adipocytes in vitro. Whilst consumption of cruciferous vegetables at levels currently considered "normal" seems to be beneficial to human health, this data suggest that any large increase in intake could conceivably lead to undesirable effect, according to "Multidirectional time-dependent effect of sinigrin and allyl isothiocyanate on metabolic parameters in rats" by Okulicz M.(2)3. Postprandial hypertriglyceridemiaIn the examination of the bioactivity of Yamato-mana (Brassica rapa L. Oleifera Group) constituent glucosinolates with 3-butenyl glucosinolate (gluconapin) decreased the plasma triglyceride gain induced by corn oil administration to mice, indicated that phenethyl glucosinolate (gluconasturtiin) had little effect. 2-Propenyl glucosinolate (sinigrin) also reduced the plasma triglyceride level, which suggests that alkenyl glucosinolates might be promising agents to prevent postprandial hypertriglyceridemia, according to "Suppressive effect of Yamato-mana (Brassica rapa L. Oleifera Group) constituent 3-butenyl glucosinolate (gluconapin) on postprandial hypertriglyceridemia in mice" by Washida K, Miyata M, Koyama T, Yazawa K, Nomoto K.(3)4. Antimicrobial effectsIn the investigation of Allyl isothiocyanate (AIT) derived from the glucosinolate sinigrin found in plants of the family Brassicaceae and its antimicrobial agent against a variety of organisms, including foodborne pathogens such as Escherichia coli O157:H7, found that it can be postulated that: 1) AIT is a more effective antimicrobial at low pH values and its degradation reduces this activity; 2) decomposition products in water might not participate in the antimicrobial action of AIT; and 3) AIT seems to have a multi-targeted mechanism of action, perhaps inhibiting several metabolic pathways and damaging cellular structures, according to "Enzymatic inhibition by allyl isothiocyanate and factors affecting its antimicrobial action against Escherichia coli O157:H7" by Luciano FB, Holley RA.(4)5. Liver cancerIn the determination of the inhibitory effects of AITC and its NAC conjugate on cell proliferation, the expression of matrix metalloproteinases (MMPs), adhesion, invasion, and migration in SK-Hep 1 human hepatoma cells, found that AITC and NAC-AITC suppress SK-Hep 1 cell proliferation in a dose-dependent manner; by 25% and 30% for 10 microM AITC and 10 microM NAC-AITC, respectively. The influence of AITC and NAC-AITC on the gene expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). Gelatin zymography also revealed a significant downregulation of MMP-2/-9 expression in SK-Hep1 cells treated with 0.1-5 microM AITC and NAC-AITC compared with controls. Reverse transcriptase polymerase chain reaction revealed dose-dependent decreases in MMP-2/-9 messenger RNA levels in both AITC-treated and NAC-AITC-treated cells, according to "Allyl isothiocyanate and its N-acetylcysteine conjugate suppress metastasis via inhibition of invasion, migration, and matrix metalloproteinase-2/-9 activities in SK-Hep 1 human hepatoma cells" by Hwang ES, Lee HJ.(5)6. Detoxication enzymesIn the examination of the ability of allyl nitrile, a hydrolysis product of the glucosinolate sinigrin, to increase tissue levels of the phase 2 detoxication enzymes glutathione S-transferase and quinone reductase and GSH in a variety of mouse tissues, found that show that allyl nitrile displays its maximum potency in the stomach and lungs, which is of interest in light of epidemiological studies demonstrating an inverse association between crucifer intake and the incidence of stomach and lung cancers, according to "Induction of detoxication enzymes in mice by naturally occurring allyl nitrile" by Tanii H, Higashi T, Nishimura F, Higuchi Y, Saijoh K.(6)7. Anti-SARS coronavirus 3C-like protease effectsIn the study, Isatis indigotica root extract, five major compounds of I. indigotica root, and seven plant-derived phenolic compounds were tested for anti-SARS-CoV 3CLpro effects using cell-free and cell-based cleavage assays, found that Cleavage assays with the 3CLpro demonstrated that IC50 values were in micromolar ranges for I. indigotica root extract, indigo, sinigrin, aloe emodin and hesperetin. Sinigrin (IC50: 217 microM) was more efficient in blocking the cleavage processing of the 3CLpro than indigo (IC50: 752 microM) and beta-sitosterol (IC50: 1210 microM) in the cell-based assay. Only two phenolic compounds aloe emodin and hesperetin dose-dependently inhibited cleavage activity of the 3CLpro, in which the IC50 was 366 microM for aloe emodin and 8.3 microM for hesperetin in the cell-based assay, according to "Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds" by Lin CW, Tsai FJ, Tsai CH, Lai CC, Wan L, Ho TY, Hsieh CC, Chao PD.(7)8. Colorectal cancerIn the investigation of raw juice extracted from Brussels sprouts rich in the glucosinolate sinigrin to explore the effect of naturally occurring glucosinolate breakdown products on cell cycle progression and apoptosis in human colorectal carcinoma cells (HT29), found that the main glucosinolate breakdown products were as follows: the sinigrin breakdown product, 1-cyano-2,3-epithiopropane (ca. 38 mM); the gluconapin hydrolysis product, 3-butenyl isothiocyanate (ca. 2.2.mM); the glucobrassicin metabolite, ascorbigen (ca. 8 mM); and low concentrations of other indole glucosinolate-derived hydrolysis products such as neoascorbigen and 3,3'-diindolylmethane. A variety of biologically active glucosinolate breakdown products are released by mechanical disruption of raw Brussels sprout tissue, but contrary to previous assumptions, allyl isothiocyanate is not the main compound responsible for the inhibition of cell proliferation, according to "Effects of Brussels sprout juice on the cell cycle and adhesion of human colorectal carcinoma cells (HT29) in vitro" by Smith TK, Lund EK, Clarke RG, Bennett RN, Johnson IT.(8)9. Tumor cell proliferation and cyclooxygenase inhibitoryIn the investigation of Cyclooxygenase and human tumor cell growth inhibitory from 5 compounds, namely plastoquinone-9 (1), 6-O-acyl-beta-d-glucosyl-beta-sitosterol (2), 1,2-dilinolenoyl-3-galactosylglycerol (3), linolenoyloleoyl-3-beta-galactosylglycerol (4), and 1,2-dipalmitoyl-3-beta-galactosylglycerol (5). 3-Acyl-sitosterols, sinigrin, gluconasturtiin, and phosphatidylcholines isolated from horseradish and alpha-tocopherol and ubiquinone-10 from wasabi rhizomes, showed that Compounds 3, 4, and 5 gave 75, 42, and 47% inhibition of COX-1 enzyme, respectively, at a concentration of 250 microg/mL. In a dose response study, compound 3 inhibited the proliferation of colon cancer cells (HCT-116) by 21.9, 42.9, 51.2, and 68.4% and lung cancer cells (NCI-H460) by 30, 39, 44, and 71% at concentrations of 7.5, 15, 30, and 60 microg/mL, respectively. At a concentration of 60 microg/mL, compound 4 inhibited the growth of colon, lung, and stomach cancer cells by 28, 17, and 44%, according to "Tumor cell proliferation and cyclooxygenase inhibitory constituents in horseradish (Armoracia rusticana) and Wasabi (Wasabia japonica)" by Weil MJ, Zhang Y, Nair MG.(9)10. Antioxidants In the examination of the effect of an aqueous extract of cooked Brussels sprouts on formation of 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) in calf thymus DNA in vitro, found that Sinigrin, a glucosinolate abundant in Brussels sprouts, co-eluted with the most effective fraction and had DNA protective effects. In comparison with other antioxidants the patterns of effect of the extract in the five damage systems were more similar to that of sodium azide than to those of dimethylsulfoxide and vitamin C, according to "Inhibition of oxidative DNA damage in vitro by extracts of brussels sprouts" by Zhu C, Poulsen HE, Loft S.(10)11. Etc.Sources(1) http://www.ncbi.nlm.nih.gov/pubmed/20889681(2) http://www.ncbi.nlm.nih.gov/pubmed/20809411(3) http://www.ncbi.nlm.nih.gov/pubmed/20530888(4) http://www.ncbi.nlm.nih.gov/pubmed/19346022(5) http://www.ncbi.nlm.nih.gov/pubmed/16565438(6) http://www.ncbi.nlm.nih.gov/pubmed/16277393(7) http://www.ncbi.nlm.nih.gov/pubmed/16115693(8) http://www.ncbi.nlm.nih.gov/pubmed/15884814(9) http://www.ncbi.nlm.nih.gov/pubmed/15740020(10) http://www.ncbi.nlm.nih.gov/pubmed/10885626 Posted by
3,3'-Diindolylmethane or DIM are phytochemicals derived from the digestion of indole-3-carbinol, belonging to the group of Indoles, found abundantly in broccoli, Brussels sprouts, cabbage and kale, etc.Health Benefits1. Antiinflammatory and chemopreventive effects on SkinIn the examination of the effects of 3,3'-Diindolylmethane (DIM) on antiinflammatory and antitumor promotion activity in mouse skin and explored the relevant mechanism, indicated that Several lead compounds, such as genistein (from soybeans), lycopene (from tomatoes), brassinin (from cruciferous vegetables), sulforaphane (from asparagus), indole-3-carbinol (from broccoli), and resveratrol (from grapes and peanuts) are in preclinical or clinical trials for cancer chemoprevention. Phytochemicals have great potential in cancer prevention because of their safety, low cost, and oral bioavailability. In this review, we discuss potential natural cancer preventive compounds and their mechanisms of action, according to "3,3'-diindolylmethane suppresses 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and tumor promotion in mouse skin via the downregulation of inflammatory mediators" by Kim EJ, Park H, Kim J, Park JH.(1)2. Antileukemic ActivityIn the study of 3,3'-diindolylmethane (DIM), one of the active products derived from Brassica plants, for it antitumor effects, showed that DIM significantly induced apoptosis in U937 human leukemia cells in dose- and time-dependent manners. These events were also noted in other human leukemia cells (Jurkat and HL-60) and primary human leukemia cells (AML) but not in normal bone marrow mononuclear cells. DIM-induced lethality is associated with caspases activation, myeloid cell leukemia-1 (Mcl-1) down-regulation, p21(cip1/waf1) up-regulation, and Akt inactivation accompanied by c-jun NH2-terminal kinase (JNK) activation. Enforced activation of Akt by a constitutively active Akt construct prevented DIM-mediated caspase activation, Mcl-1 down-regulation, JNK activation, and apoptosis, according to "3, 3'-Diindolylmethane Exhibits Antileukemic Activity In Vitro and In Vivo through a Akt-Dependent Process" by Gao N, Cheng S, Budhraja A, Liu EH, Chen J, Chen D, Yang Z, Luo J, Shi X, Zhang Z.(2)3. Cervical CancerIn the examination of 3,3'-Diindolylmethane (DIM) prevention or inhibition of the progression from cervical dysplasia to Human papilloma viral causes of cervical neoplasia (CIN), found that significant increases in IFN-γ serum concentrations that correlate with the percentage of CIN free mice in each group indicate that 1000 ppm of DIM in food may be the most effective dose for future studies. These results may eventually lead to new and effective vaccination strategies in women already infected with the human papilloma virus, according to '3,3'-Diindolylmethane Increases Serum Interferon-γ Levels in the K14-HPV16 Transgenic Mouse Model for Cervical Cancer" by Sepkovic DW, Raucci L, Stein J, Carlisle AD, Auborn K, Ksieski HB, Nyirenda T, Bradlow HL.(3)4. Esophageal cancerIn the study of 3,3'-Diindolylmethane (DIM), an active metabolite of indole-3-carbinol, and its antitumor effects in experimental animals and induction of apoptosis in various cancer cells, showed that DIM significantly inhibited the proliferation of ESCC cells in a dose- and time-dependent manner. The percentage of G1 phase cells increased 48 h after being treated with DIM. DIM also reduced cyclin D1, cyclin E2, cyclin-dependent kinase (CDK) 4 and CDK 6 activities, and increased p15 and p27 levels. Additionally, DIM diminished pro-caspase-9 protein expression levels and induced increased cleaved poly (ADP-ribose) polymerase levels, accoridng to "3,3'-Diindolylmethane suppresses growth of human esophageal squamous cancer cells by G1 cell cycle arrest"by Kim SJ, Lee JS, Kim SM.(4)5. Prostate cancerIn the stuidy of whether DIM inhibits the development of prostate cancer using the transgenic adenocarcinoma mouse prostate (TRAMP) model, showed that DIM induced a substantial reduction in the numbers of viable cells and induced apoptosis in LNCaP and DU145 cells. DIM increased the cleavage of caspase-9, -7, -3, and poly (ADP-ribose) polymerase (PARP). DIM increased mitochondrial membrane permeability and the translocation of cytochrome c and Smac/Diablo from the mitochondria. Additionally, DIM induced increases in the levels of cleaved caspase-8, truncated Bid, Fas, and Fas ligand, and the caspase-8 inhibitor Z-IETD-FMK was shown to mitigate DIM-induced apoptosis and the cleavage of caspase-3, PARP, and Bid, according to '3,3'-Diindolylmethane inhibits prostate cancer development in the transgenic adenocarcinoma mouse prostate model" by Cho HJ, Park SY, Kim EJ, Kim JK, Park JH.(5)6. Oral CancerIn the investigation of the antitumor activity of 3,3'-diindolylmethane (DIM), an active metabolite of the phytochemical indole-3-carbinol (I3C), in oral squamous cell carcinoma (OSCC), showed that DIM stimulated the activation of p53 via Ser-15 phosphorylation, leading to increased expression of the BH3-only proapoptotic Bcl-2 members Puma and Noxa. Together, these changes decreased the mitochondrial threshold for apoptosis. G2/M arrest might be attributable to the suppressive effect of DIM on the expression of cyclin B1 and cdc25c. As many downstream effectors of the Akt-NF-κB pathway, including glycogen synthase kinase 3β, IκB kinase α, and cyclooxygenase-2, have been shown to promote oral tumorigenesis, the ability of DIM to inhibit this signaling axis underscores its chemopreventive potential in oral cancer, according to "The dietary phytochemical 3,3'-diindolylmethane induces G2/M arrest and apoptosis in oral squamous cell carcinoma by modulating Akt-NF-κB, MAPK, and p53 signaling" by Weng JR, Bai LY, Chiu CF, Wang YC, Tsai MH.(6)7. Ovarian cancerIn the delineation of the mechanism by which DIM suppressed the growth of SKOV3, OVCAR-3 and TOV-21G human ovarian cancer cells, found that DIM treatment also inhibited the kinase activity of ERK as observed by the down regulation of p-ELK in all the three ovarian cancer cell lines. DIM significantly suppressed the growth of ovarian tumors in vivo. Tumor growth suppressive effects of DIM in SKOV-3 tumor xenografts were associated with reduced phosphorylation of EGFR, MEK and ERK, according to "Blocking EGFR activation suppresses ovarian tumor growth in vitro and in vivo" by Kandala PK, Wright SE, Srivastava SK.(7)8. Colon cancerIn the analyzing the expression pattern of N-myc downstream regulated gene-1 following treatment of human colonic cancer cell lines, suggested that N-myc downstream regulated gene-1 expression is enhanced by 3,3'-diindolylmethane in poorly differentiated cells and followed by induction of apoptosis. 3,3'-diindolylmethane induced apoptosis may represent a new regulator of N-myc downstream regulated gene-1 in poorly differentiated colonic cancer cells, according to "The indolic diet-derivative, 3,3'-diindolylmethane, induced apoptosis in human colon cancer cells through upregulation of NDRG1" by Lerner A, Grafi-Cohen M, Napso T, Azzam N, Fares F.(8)9. Osteosarcoma In the investigation of the effect of the natural product 3,3'-diindolylmethane (DIM) on cytosolic Ca(2+) concentrations ([Ca(2+) ](i) ) and viability in MG63 human osteosarcoma cells, found that DIM-evoked Ca(2+) entry was suppressed by nifedipine, econazole, SK&F96365 and protein kinase C modulators. In the absence of extracellular Ca(2+) , incubation with the endoplasmic reticulum Ca(2+) pump inhibitors thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) inhibited or abolished DIM-induced [Ca(2+) ](i) rise. Incubation with DIM also inhibited thapsigargin or BHQ-induced [Ca(2+) ](i) rise. Inhibition of phospholipase C with U73122 abolished DIM-induced [Ca(2+) ](i) rise. At concentrations of 10-50 μM, DIM killed cells in a concentration-dependent manner, according to "3,3'-Diindolylmethane Alters Ca(2+) Homeostasis and Viability in MG63 Human Osteosarcoma Cells" by Lu YC, Chen IS, Chou CT, Huang JK, Chang HT, Tsai JY, Hsu SS, Liao WC, Wang JL, Lin KL, Liu SI, Kuo CC, Ho CM, Jan CR.(9)10. Breast cancerin the assessment of the effects of DIM on cell-cycle regulation in both estrogen-dependent MCF-7 and estrogen receptor negative p53 mutant MDA-MB-468 human breast cancer cells,showed that DIM inhibited the breast cancer cell growth in vitro and in vivo, and caused cell-cycle arrest by down-regulating protein levels of cell-cycle related kinases CDK1, CDK2, CDK4, and CDK6, as well as Cyclin B1 and Cdc25A. Meanwhile, it was revealed that Ser(124) phosphorylation of Cdc25A is primarily responsible for the DIM-induced Cdc25A degradation. Furthermore, treatment of MCF-7 cells with DIM increased miR-21 expression and down-regulated Cdc25A, resulting in an inhibition of breast cancer cell proliferation, according to " 3,3'-Diindolylmethane inhibits breast cancer cell growth via miR-21-mediated Cdc25A degradation' by Jin Y.(10)11. Thyroid cancerIn the investigation of the property of a natural dietary compound found in cruciferous vegetables, 3,3'-diindolylmethane (DIM), to target the metastatic phenotype of thyroid cancer cells through a functional estrogen receptor, found that DIM inhibits estrogen mediated increase in thyroid cell migration, adhesion and invasion, which is also supported by ER-α downregulation (siRNA) studies. Western blot and zymography analyses provided direct evidence for this DIM mediated inhibition of E(2) enhanced metastasis associated events by virtue of targeting essential proteolytic enzymes, namely MMP-2 and MMP-9, according to "Estrogen induced metastatic modulators MMP-2 and MMP-9 are targets of 3,3'-diindolylmethane in thyroid cancer' by Rajoria S, Suriano R, George A, Shanmugam A, Schantz SP, Geliebter J, Tiwari RK.(11)12. Etc.Sources(1) http://www.ncbi.nlm.nih.gov/pubmed/20564344(2) http://www.ncbi.nlm.nih.gov/pubmed/22363731(3) http://www.ncbi.nlm.nih.gov/pubmed/22351660(4) http://www.ncbi.nlm.nih.gov/pubmed/22293900(5) http://www.ncbi.nlm.nih.gov/pubmed/21229607(6) http://www.ncbi.nlm.nih.gov/pubmed/22290291(7) http://www.ncbi.nlm.nih.gov/pubmed/22205686(8) http://www.ncbi.nlm.nih.gov/pubmed/22187533(9) http://www.ncbi.nlm.nih.gov/pubmed/21995587(10) http://www.ncbi.nlm.nih.gov/pubmed/21761201(11) http://www.ncbi.nlm.nih.gov/pubmed/21267453
Indole-3-carbinol is a phytochemical in the class of Indoles, found abundantly in cabbage, kale, brussels sprouts, rutabaga, mustard greens, broccoli, etc.Health Benefits1. Breast cancerIn the investigation of treatment of highly tumorigenic MDA-MB-231 human breast cancer cells with indole-3-carbinol (I3C) directly inhibited the extracellular elastase-dependent cleavage of membrane-associated CD40, showed that I3C directly inhibits the elastase-mediated proteolytic processing of CD40, which alters downstream signaling to disrupt NF-kappaB-induced cell survival and proliferative responses. Furthermore, the establish of a new I3C-mediated antiproliferative cascade has significant therapeutic potential for treatment of human cancers associated with high levels of elastase and its CD40 membrane substrate, according to "Direct inhibition of elastase activity by indole-3-carbinol triggers a CD40-TRAF regulatory cascade that disrupts NF-kappaB transcriptional activity in human breast cancer cells" by Aronchik I, Bjeldanes LF, Firestone GL.(1)2. Lung cancerIn the examination of the inhibitory effects of N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine (PEITC-NAC), myo-inositol (MI) and indole-3-carbinol (I3C) or 3,3'-diindolylmethane (DIM), alone and in combination, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (BaP)-induced A/J mouse lung tumorigenesis and proliferation of A549 cells and human bronchial epithelial cells (HBECs) and relevant potential mechanisms, found that the assessment of the anti-proliferative effects of the individual agents or their combinations showed significant reductions in the proliferation of cigarette smoke condensate (CSC)-pretreated HBEC (reduction by 30-41% at 48 h and 41-58% at 72 h) and A549 cells (30-43% at 48 h and 40-59% at 72 h), but not in dimethyl sulfoxide-pretreated HBEC. Combinatorial treatment with the agents also caused marked reductions in the activation of Akt, extracellular signal-regulated kinase and nuclear factor-kappaB in lung tumor tissues, CSC-pretreated HBEC and A549 cells, according to "Inhibition of lung carcinogenesis and critical cancer-related signaling pathways by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine, indole-3-carbinol and myo-inositol, alone and in combination" by Kassie F, Melkamu T, Endalew A, Upadhyaya P, Luo X, Hecht SS.(2)3. Pancreatic cell linesIn the examination of the possible mechanism of I3C-enhanced efficacy on pancreatic cell lines (BxPC-3, Mia Paca-2, PL-45, AsPC-1 and PANC-1) for modulation of human equilibrative nucleoside transporter 1 (hENT1) expression, showed that Gemcitabine alone showed no effect on hENT1 expression. However, combining gemcitabine with I3C further increased hENT1 expression. Cell viability assays revealed no effect of I3C on normal cells, hTERT-HPNE. hENT1-specific inhibitor, nitrobenzylthioinosine, significantly abrogated I3C-induced gemcitabine cytotoxicity, further demonstrating its specificity, according to "Enhanced efficacy of gemcitabine by indole-3-carbinol in pancreatic cell lines: the role of human equilibrative nucleoside transporter 1" by Wang H, Word BR, Lyn-Cook BD.(3)4. Prostate cancerIn the examination of the chemopreventive effects and the molecular mechanism of I3C, particularly the anti-oxidative stress pathway regulated by nuclear erythroid related factor 2 (Nrf2), found that treatments of transgenic adenocarcinoma of mouse prostate, TRAMP C1 cells with I3C also resulted in the induction of Nrf2-mediated genes. I3C significantly suppressed the incidence of palpable tumor and reduced the genitourinary weight in TRAMP mice. Western blots and qPCR analyses of prostate tissues showed that I3C induced the expression of Nrf2, NAD(P)H quinine oxidoreductase 1 (NQO-1) as well as cell cycle and apoptosis related biomarkers in I3C-fed TRAMP mice, according to "In vivo pharmacodynamics of indole-3-carbinol in the inhibition of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: Involvement of Nrf2 and cell cycle/apoptosis signaling pathways" by Wu TY, Saw CL, Khor TO, Pung D, Boyanapalli SS, Kong AN.(4)5. Vulval intraepithelial neoplasiaIn the evaluation of the effectiveness and safety of medical interventions for high grade Vulval intraepithelial neoplasia (VIN), a pre-malignant condition of the vulval skin, associated with infection with human papilloma virus (HPV) infection, indicated that four trials met our inclusion criteria: three assessed the effectiveness of topical imiquimod versus placebo in women with high grade VIN; one examined low versus high dose indole-3-carbinol in similar women. Meta-analysis of three trials found that the proportion of women who responded to treatment at 5 to 6 months was much higher in the group who received topical imiquimod than in the group who received placebo (relative risk (RR) = 11.95, 95% confidence interval (CI) 3.21 to 44.51), according to "Medical interventions for high grade vulval intraepithelial neoplasia" by Pepas L, Kaushik S, Bryant A, Nordin A, Dickinson HO.(5)6. Estrogen MetabolismIn the investigation of determine whether a breast health supplement containing indole-3-carbinol and hydroxymatairesinol lignan would alter estrogen metabolism to favour C-2 hydroxylation and reduce C-16 hydroxylation, found that Supplementation with a mixture of indole-3-carbinol and HMR lignan in women significantly increased estrogen C-2 hydroxylation. This may constitute a mechanism for the reduction of breast cancer risk as well as risk for other estrogen-related cancers. Further studies with higher numbers of subjects are indicated, according to "Effects of A Breast-Health Herbal Formula Supplement on Estrogen Metabolism in Pre- and Post-Menopausal Women not Taking Hormonal Contraceptives or Supplements: A Randomized Controlled Trial" by Laidlaw M, Cockerline CA, Sepkovic DW.(6)7. Oral cancerIn the investigation ofthe antitumor effects of OSU-A9, a structurally optimized I3C derivative, in a panel of oral squamous cell carcinoma cell lines, SCC4, SCC15, and SCC2095, showed that The antiproliferative effect of OSU-A9 was approximately two-orders-of-magnitude higher than that of I3C. Importantly, normal human oral keratinocytes were less sensitive to OSU-A9 than oral cancer cells. This antiproliferative effect of OSU-A9 was attributable to the induction of mitochondrial-dependent apoptosis as evidenced by sub-G1 accumulation of cells, poly ADP-ribose polymerase cleavage, and cytochrome c release from the mitochondria. OSU-A9 down regulates Akt and NF-κB signaling pathways, leading to changes in many downstream effectors involved in regulating cell cycle and apoptosis, according to "A novel indole-3-carbinol derivative inhibits the growth of human oral squamous cell carcinoma in vitro" by Weng JR, Bai LY, Omar HA, Sargeant AM, Yeh CT, Chen YY, Tsai MH, Chiu CF.(7)8. Cancer preventionIn the review of botanical and nutritional compounds have been used for the treatment of cancer throughout history, indicated that several lead compounds, such as genistein (from soybeans), lycopene (from tomatoes), brassinin (from cruciferous vegetables), sulforaphane (from asparagus), indole-3-carbinol (from broccoli), and resveratrol (from grapes and peanuts) are in preclinical or clinical trials for cancer chemoprevention. Phytochemicals have great potential in cancer prevention because of their safety, low cost, and oral bioavailability, according to "Cancer prevention with natural compounds" by Gullett NP, Ruhul Amin AR, Bayraktar S, Pezzuto JM, Shin DM, Khuri FR, Aggarwal BB, Surh YJ, Kucuk O.(8)9. Nasopharyngeal cancerIn the examination of the apoptotic effects of indole-3-carbinol (I3C) in many human cancer cells, found that Treatment with I3C significantly suppressed XIAP, c-IAP1 and Survivin protein, while elevated the expression of Omi, Smac and Cyto-c. Fas/FasL and MAPK pathway were involved in the induction of apoptosis. Taken together, these results demonstrated that I3C may induce mitochondria-mediated apoptosis via the Fas death receptor in CNE-2 cells. This molecular mechanism for apoptotic effect of I3C on nasopharyngeal cancer cells suggested that I3C might become a preventive and therapeutic agent against nasopharyngeal cancer, according to "Indole-3-carbinol (I3C)-induced apoptosis in nasopharyngeal cancer cells through Fas/FasL and MAPK pathway" by Xu Y, Zhang J, Dong WG.(9)10. Colon cancerIn an easy two-step synthesis for 4-methoxyindole-3-carbinol (4MeOI3C), the expected breakdown product of 4-methoxyglucobrassicin during ingestion. 4MeOI3C inhibited the proliferation of human colon cancer cells DLD-1 and HCT 116 with IC(50) values of 116 microM and 96 microM, respectively, found that after 48 h in vitro, and is therefore a more potent inhibitor than indole-3-carbinol (I3C). 4MeOI3C and I3C combined in different molar ratios inhibited proliferation in a nearly additive to slightly synergistic manner. Proliferation was inhibited by 100 microM 4MeOI3C after 48 h without affecting cell cycle phase distribution, indicating an overall-slowdown effect on the cell cycle, according to "Effect of 4-methoxyindole-3-carbinol on the proliferation of colon cancer cells in vitro, when treated alone or in combination with indole-3-carbinol" by Kronbak R, Duus F, Vang O.(10)11. Etc. Sources(1) http://www.ncbi.nlm.nih.gov/pubmed/20530686(2) http://www.ncbi.nlm.nih.gov/pubmed/20603442(3) http://www.ncbi.nlm.nih.gov/pubmed/21965724(4) http://www.ncbi.nlm.nih.gov/pubmed/21837756(5) http://www.ncbi.nlm.nih.gov/pubmed/21491403(6) http://www.ncbi.nlm.nih.gov/pubmed/21234288(7) http://www.ncbi.nlm.nih.gov/pubmed/20843730(8) http://www.ncbi.nlm.nih.gov/pubmed/20709209(9) http://www.ncbi.nlm.nih.gov/pubmed/20628834(10) http://pubs.acs.org/doi/abs/10.1021/jf101806t Posted by


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Zippy's Zone: September 2013
I just cannot believe how quickly this year is going! Seems only like yesterday I was sat out in the glorious sun and enjoying the warmth, now its Autumn and Winter is just round the corner! Having said that, today is a lovely day, sun is shining and even though it is breezy and quite cool it is lovely. But the colder days and darker nights are a reminder to me that Christmas is on its way and time to get started on the Christmas cards!
I have decided this year as I have so many to do and I am always struggling to get them finished that I would do clean and simple cards like the ones below:
The images are from Lili of the Valley's new Christmas range and are coloured with a mixture of Promarkers and Spectrum Noir pens. The papers are just some scraps I found in my scraps box. The red card and ribbon are from stash.
Posted by Zippy at 13:35 5 comments:
Hello everyone, its that time of the week again for Crafty Little Fairies Challenge! This week it is New Baby:
I have used an image from Joanna Sheen's House Mouse CD and the papers also come from the same CD. I just love this little mouse! Everything else used is from stash.
Some do come along and play with Crafty Little Fairies, you now use any image you wish and we would all love to see you fab designs!
Posted by Zippy at 09:00 2 comments:
Hello lovely bloggers, sorry not been around much, don't know what happened but I just simply lost the desire to craft, just could not be bothered and it felt like a chore. So I decided to have a bit of a break and have not even looked at crafty mags! Anyway, this weekend I got the urge to make some quick Christmas cards, I always have loads of cards to make at Christmas so I have decided this year they are going to be clean and simple:
The stamps used are from the Crafters Companion Barkley range and coloured with Promarkers. The paper and ribbon are all from stash.
Hope you are all keeping well lovely blog buddies and I am hoping to be visiting you sooner rather than later!
Posted by Zippy at 15:51 3 comments:

type: global

value: Blogger is an American online content management system (CMS) which enables multi-user blogs with time-stamped entries. Pyra Labs developed it before being acquired by Google in 2003.


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Property Q&A: How much is a home with water views near St. George in Staten Island? - Trulia Voices
Asked by Michele, Brooklyn, NY
There is a home listed at 420k, but it appears to have a broken link, does anyone know anything about this property?
This question is about this property: http://www.trulia.com/property/1073293590--Staten-Island-NY-10301
1Fam Homes in near St. George range from $379,000-$599,000
2Fam Homes in near St. George range from $299,000-$699,000
Condos in near St. George range from $325,000-$793,000
Co-ops in near St. George range from $110,000-$485,000
92 hecker st staten island ny 10307

value: Trulia is an American online real estate marketplace which is a subsidiary of Zillow. It facilitates buyers and renters to find homes and neighborhoods across the United States through recommendations, local insights, and map overlays that offer details on a commute, reported crime, schools, churches and nearby businesses.Founded in 2005, Trulia is based in San Francisco, and owned and operated by Zillow Group, Inc.


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The Last Word: Meltdown
SJ6K23NXMZQ6
No, not the bad kind of meltdown, the spring kind! It's mid-February and I'm not naive enough to belief that this temporary burst of mild weather is going to last, but it's a nice reminder that spring is not too far off.
On Saturday, we decided to go to a local trail so that Frank could work on his half marathon training. That left me with the dog and my iPod and I couldn't have been happier. I crave the outdoors all winter long, and being able to walk for 45 minutes without needing a giant puffy coat and gloves sounded like heaven.
The trail is made of crushed limestone, so the melting ice mixed with mud and stone made certain spots feel like quicksand. It made for one muddy puppy belly and almost ruined my new boots. But it was worth it. Here are some pictures I took with my iPhone.
JewelsFebruary 16, 2011 at 5:13 PMwhat beautiful pictures. I love this time of year...knowing that Spring is soon to come. The sun stays out longer and the thoughts of summer and basking in the sun are starting to look like they aren't impossible.ReplyDeleteAngelaFebruary 16, 2011 at 11:16 PMBeautiful pictures!!! We've been hitting 60 here for the last three days, but like you I know it's not going to actually last until a little later on in the year!!! But oh, these last few days have been BLISS!!!ReplyDeleteAdd commentLoad more...


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50% Off @ White Rabbit Brewery - Angier, NC | Groupon
$26 for brewery tour for two ($52 total value)
Two flights of four beer tastings ($10 value)
Two servings or bombers of beer ($18 value)
Two stickers, key chain bottle-openers, and posters ($18 value)
Two brewery tours ($6 value)
$52 for brewery tour for four ($104 total value)
Four flights of four beer tastings ($20 value)
Four servings bombers of beer ($36 value)
Four stickers, key chain bottle-openers, and posters ($36 value)
Four brewery tours ($12 value)
Olive walls flank White Rabbit Brewing Company's taproom, a simple space with a polished wooden bar and a tabletop supported by kegs instead of traditional human legs. On Friday and Saturday evenings, bartenders pour pints and four-ounce samples of the brewery's ales and lagers, which borrow their titles and labels from Alice in Wonderland characters. There's the Double Trouble Belgian Dubbel, a malty, medium-bodied brew, and the Cheshire's Pumpkin Ale, a spiced, light-bodied brew with an "almost cidery" mouthfeel, according to the brewers. White Rabbit Brewery
May be repurchased every 90 days. Limit 1 per person, may buy 2 additional as gifts. Limit 1 per visit. Valid only for option purchased. Promotional value expires 120 days. Subject to availability; substitutions will be offered as necessary.
In and Around Angier Durham

value: Groupon is an American global e-commerce marketplace connecting subscribers with local merchants by offering activities, travel, goods and services in 15 countries. Based in Chicago, Groupon was launched there in November 2008, launching soon after in Boston, New York City and Toronto.


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Press Release Watch: #JKFloods: Online auction by Aditya Birla Group for flood victims of Jammu and Kashmir
#JKFloods: Online auction by Aditya Birla Group for flood victims of Jammu and Kashmir
Through an online auction Aditya Birla Group aims to raise funds for those affected by recent floods in Jammu and Kashmir.The auction will be held on StoryLTD, a service of auction house Saffronart, from October 8 – 9, 2014. Bidding on lots will begin at 7:00 p.m. on October 8 at www.storyltd.com. To encourage people to step in to contribute to the cause, there will be no buyer’s premium charged to buyers by StoryLTD on any of the lots, and some lots do not have a minimum price, known as a reserve price, in order to sell.
The auction features a total of 50 artworks by some of the most renowned Modern Masters such as F.N. Souza, Ram Kumar, K.G. Subramanyan and Sakti Burman, among others. Among the contemporaries, there are works by renowned artists such as Ranbir Kaleka, Manjunath Kamath, G.R. Iranna, Hema Upadhyay, and Dhruva Mistry, to name a few.
Tags J&K


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In the chilly bureaucratic confines of the social services office where I worked before college, few people had it in them to waste energy on politeness. Poverty and dependence tended to take a toll on good manners.So it was that Gary distinguished himself right away. On his way in, he held the door for the old woman leaving with her bag full of food from our pantry. He smiled at me, gave a little bow, sat and waited for his appointment.After a minute or two I noticed out of the corner of my eye that he was no longer facing me. His head down and cocked to one side, the old man was shaking quietly in his chair. When I called for my boss, she emerged into the waiting room, declared imperturbably that he was having a seizure, and went back to her office.Not knowing what else to do, I called 911 and sat by his side to wait for an ambulance. After several minutes, Gary stopped shaking and stared at his construction boots, a column of saliva connecting his shirt and his mouth. We sat there for a while longer before the ambulance came, Gary staring downward and mumbling angrily, me patting his shoulder and producing a meaningless series of sounds and words in as calm a voice as I could muster.Our conversation was disjointed and unintelligible. He was probably not aware of it and would not remember it later. And yet there was some kind of clarity between us in those murmuring minutes before he was laid on a stretcher and taken to the hospital. If Gary did not remember them, I would. We took care of each other during those moments, keeping each other still.
Kelly Blair In medical school I worked with a young infectious-disease physician from India. She was consulting on the case of a middle-aged Indian man who had cancer and a hospital-acquired infection. His infection had improved, but his cancer had become quite aggressive, and I accompanied her to his room to discuss what had become a very poor prognosis.To learn how to carry on this kind of end-of-life discussion, medical students practice on actors trained to simulate dying patients. It’s a valuable exercise, but a difficult one. I always found myself hung up on the details of what I was supposed to say — important details, like the patient’s life expectancy, remaining treatment options and the logistics of palliative care and hospice services.When it came to real patients, I found myself similarly fixated on the particulars, doing my best to learn the drill: What lab or exam findings let the physician know it was time for this discussion? Would insurance pay for hospice care? Could she wait for her daughter to fly in from Phoenix before making the decision?The Indian patient lay quietly in his hospital bed, his wife beside him, elegant in an embroidered dress and a sheer blue headscarf. The doctor began speaking to them in English as the husband and wife took turns translating unfamiliar words into Hindi. I listened closely as always, concentrating on the facts of the case.I suspect the English was on my account, for when it became clear that the couple was having too much difficulty understanding, the doctor gave up and began speaking in fluent Hindi. I kept listening, but now the music of the language was all I could follow.English words were peppered in only occasionally — a sentence punctuated by the word “suffering,” then a paragraph weaving “comfortable” and “hospice” into a string of Hindi. I was behind a veil, seeing the dialogue only in silhouettes.Yet somehow, being outside the language finally allowed me into the heart of it. The conversation was beautiful, hypnotic, meditative. With words out of the way, I could focus on the elements I had always been too distracted to notice — the doctor’s slow and lilting tone, her attentiveness to the patient’s body language, the white-knuckled hands of the husband and wife locked together, a lifetime of love, fear, resignation and hope flickering back and forth in the glances they exchanged.

value: The New York Times (N.Y.T. or N.Y. Times) is an American daily newspaper based in New York City with a worldwide readership. Founded in 1851, the Times has since won 132 Pulitzer Prizes (the most of any newspaper), and has long been regarded within the industry as a national "newspaper of record".


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UPDATE 2-Rugby-Rugby Australia intends to sack Folau over 'discriminatory' post - Reuters
April 11, 2019 / 9:11 AM / a year ago
UPDATE 2-Rugby-Rugby Australia intends to sack Folau over 'discriminatory' post
* Folau to be sacked if no ‘compelling mitigating factors’ for posting meme
* Club and country unable to contact player
* Folau warned over sharing material that vilifies over sexuality (Adds background, detail)
SYDNEY, April 11 (Reuters) - Rugby Australia said on Thursday it would terminate the contract of Israel Folau, the country’s best-known and best-paid player, if he cannot offer a good reason for a social media post that said gay people would go to “hell” if they did not “repent”.
“This unprecedented course of action sends a strong message of what will and will not be tolerated in rugby – and they’ve made it clear that homophobia and transphobia has no place in the sport,” said Andrew Purchas, founder of the Sydney Convicts, Australia’s first and most successful gay rugby club. (Editing by Sudipto Ganguly)

value: Reuters ( (listen)) is an international news organisation now owned by Thomson Reuters. It employs around 2,500 journalists and 600 photojournalists in about 200 locations worldwide.


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Stealing Commas: Bill Towner: Electrician and Adventurer
Posted by chris the cynic at 11:02 PM
Lonespark December 14, 2014 at 1:04 AM
Completely agree about this type of character. And I think woman ones are great...sometimes there is a character like that who's someone's grandmother, it seems like...
Bill reminds me a bit of Harry Tuttle from Brazil. I think Tuttle is a workman serious about his craft, which means he needs to defy the government, who do not prioritize quality HVAC work... (possibly he has a card that says "Rogue Heating Engineer"? I haven't watched it in a while...) Not a nice person, helpful only insofar as doing his thing may improve your life. No kid. Played by Robert DeNiro, so perhaps we can imagine in a different world he would be someone more like Captain Shakespeare?
Firedrake January 16, 2015 at 5:01 PM
I suspect that part of the problem is the Campbellian monomyth, which (particularly post Star Wars) has been such a huge influence on writers of anything fantastic that it's now hard to get away from it. One of the key points there is that the hero has to leave normal life to go and do fantastic stuff, and then later come back to normal life on slightly different terms. The idea of someone who isn't doing a Hero's Journey but instead has a season ticket is a tough one to fit into this framework.
Nancy Jorden June 12, 2015 at 10:25 AM
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Amazon.co.uk: £5 - £10 - Spanish / Sociology / Social Sciences: Books Amazon Your Amazon.co.uk Today's Deals Gift Cards Sell Help Shop by Department Hello. Sign in Your Account Try Prime Basket 0 Wish List Search Sociology Sociology All Departments Amazon Instant Video Apps for Android Baby Beauty Books Car & Motorbike CDs & Vinyl Classical Clothing Computers & Accessories Digital Music DIY & Tools DVD & Blu-ray Electronics & Photo Garden & Outdoors Gift Cards Grocery Health & Personal Care Jewellery Kindle Store Kitchen & Home Large Appliances Lighting LOVEFiLM by Post Luggage Musical Instruments & DJ PC & Video Games Pet Supplies Shoes & Bags Software Sports & Outdoors Stationery & Office Supplies Toys & Games VHS Watches Books
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Aquinas Academy Adventures: What a sweetie!
My 11 year old paid me quite the compliment today."Mom," he said, "Thanks for answering most of my completely meaningless questions!"At least he notices that I try to meet his need for a walking, talking encyclopedia - most of the time!
Ha, today Miriam asked me when I was cleaning up their toys, "What are you doing?" I shot her a look and asked, "Why are you asking me that?" She said, "Because I love asking you stupid questions." LOL.
3/26/2008 8:55 PM
LOL! That is an amazing boy you have there!Kelly
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Metalsmith – Page 2 – Hammermarks
Metalsmith’s Little Known Tools Compendium
October 7, 2013 October 7, 2013 | Wendy Edsall-Kerwin
This summer I introduced you to a number of tools that aren’t normally associated with metalsmithing, but are nevertheless one’s that I need to complete my pieces. In case you missed them, here is a recap of those posts.
More Tools – Sinking Stump
And some older posts about tools:
The Overlooked Metalsmith’s Tool
My Smallest Tool
My Smallest Stake
Using Tools (an existential tool post)
And some toolmaking tutorials:
How to Make a Tubing Jig
How to Make a Wooden Draw Plate
And of course, a link to the list of Better Know Your Hammer posts I did:
November 19, 2012 | Wendy Edsall-Kerwin
Sheet Metal Drawer – Thankfully it all came this way!
If you look at my in process posts, you see that all of my pieces start out as wire or flat sheet. I buy my bronze, brass, copper, nickel, and silver this way. Prior to the industrial age this wasn’t possible. So as much time as I spend forming each piece now, it’s nothing compared to what metalsmiths from the past had to do.
In pre-industrial times a jeweler or metalsmith would have to form their own sheet and wire. They would melt
What my sheet becomes…
down gold, silver, etc. into ingots. These ingots were then hammered down by hand. After hours and hours of making the sheet or wire, it was then possible to begin actually forming the piece.
Thank goodness I can buy nice, even thickness metal in the gauge (thickness) that I want. I like to make things using hand tools, but there is a line even I won’t cross. It takes enough time to actually form my pieces. In fact, I should be getting back into the studio right now…

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Clinton Gives Gays Historic Political Clout - tribunedigital-chicagotribune
April 18, 1993|By Mitchell Locin, a member of the Tribune's Washington bureau.
WASHINGTON — Three months into his presidency, Bill Clinton already has done more to nurture the civil rights and liberties of homosexuals than any other president in the nation's history.
Even though his desire to integrate openly gay men and lesbians into the armed forces has been derailed and delayed, Clinton has raised discrimination against homosexuals into a civil rights issue that he believes requires presidential leadership and governmental intervention.
Clinton has appointed openly gay men and lesbians to key posts, including Roberta Actenberg as assistant secretary of housing and urban development, and Bob Hattoy as deputy White House personnel director. He is searching for an AIDS czar and has asked for a 28 percent increase-$585 million-in funding for AIDS-related research, prevention and health care.
On Jan. 29, after his proposal to remove the armed services ban against gays met military and congressional resistance, Clinton delivered an unequivocal, personal statement rejecting discrimination against homosexuals and lesbians.
"The issue is not whether there should be homosexuals in the military. Everyone concedes that there are," the president said. "The issue is whether men and women, who can and have served with real distinction, should be excluded from military service solely on the basis of their status. And I believe they should not."
Clinton said he will issue an executive order ending the ban July 15, giving the Defense Department and Congress time to examine the issue.
From the Oval Office on down, according to administration members, there is a new culture of openness and comfort for homosexuals serving in government, although some activists argue that politically, some White House advisers wish the issue would disappear.
But over these 10 weeks Clinton also learned that public sentiment has not rallied to his decision to press the military issue, and that it could erode support badly needed to pass his economic program and health-care plan, the cornerstones of his presidency.
It has clouded his role as commander in chief, already suspect by many in the service because he avoided the draft and opposed the Vietnam War.
By threatening to write the ban into law and then passing a prohibition against admitting refugees carrying the AIDS-causing HIV virus, Congress, including many of his fellow Democrats, has signaled a deep division with the president on the matter of homosexual rights.
Next Sunday, gay and lesbian groups plan a march in Washington that they predict will be the largest civil rights demonstration in history, surpassing those on abortion and minority rights.
The march underscores the delicate politics of the president's decision. On one hand, he is accused of moving too slowly to satisfy some homosexual-rights activists; on the other, his commitment to the interests of a relatively narrow segment of the population could be contributing to the erosion of his broad national support.
White House press secretary Dee Dee Myers said Clinton is proceeding with the agenda he set out during the campaign, moving to keep his promises to powerful and vocal segment of his winning coalition and a personal commitment to equality.
Clinton has knowingly thrust himself into a national debate that touches on individuals' deepest personal fears, misconceptions and beliefs regarding sexuality, family and religion.
"No president of the United States has ever forged a closer friendship and working relationship with the gay and lesbian community as Bill Clinton has," said Gregory King, spokesman for the Human Rights Campaign Fund, the largest political organization devoted to promoting gay and lesbian rights.
Rep. Barney Frank (D-Mass.), who is gay, said, "It's the first time in history the president, even a major presidential nominee, has committed himself."
If the march draws one million participants, as its planners expect, it could provide a measure of reassurance for the president to proceed with his campaign vows in the face of angry and emotional opposition.
"Everyone who is coming to the march expects to see the president on stage," said Scout, a Chicagoan who is co-chair of the march organizing committee. But they are likely to be disappointed; Clinton plans to be in Boston, where he will be addressing newspaper executives.
Nor should he attend, Frank argued, because "a small percentage of people in the march will act in ways they hope will outrage people . . . I don't want the president on television any way linked with that."
Clinton's hero, President John F. Kennedy, also grappled with how far he could go in support of civil rights-in his case for blacks-in the face of a recalcitrant Congress.

value: The Chicago Tribune is a daily newspaper based in Chicago, Illinois, United States, owned by Tribune Publishing. Founded in 1847, and formerly self-styled as the "World's Greatest Newspaper" (a slogan for which WGN radio and television are named), it remains the most-read daily newspaper of the Chicago metropolitan area and the Great Lakes region.