Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxysterols have been shown to induce apoptosis in a variety of cell lines. The mechanism of oxysterol-induced apoptosis is mainly known at the post-mitochondrial level. The aim of the present study was to compare the pathway of apoptosis induced by the oxysterols 7beta-hydroxycholesterol (7beta-OH) and cholesterol-5beta,6beta-epoxide (beta-epoxide) in U937 cells. To this end, we employed a range of inhibitors of apoptosis; a broad-spectrum caspase inhibitor, a specific caspase-3 inhibitor and an inhibitor of cytochrome c release and the antioxidants; trolox, ebselen and resveratrol. The three inhibitors of apoptosis prevented cell death induced by 7beta-OH; however, in beta-epoxide-treated cells, the inhibitor of cytochrome c release did not protect against apoptosis. The cellular antioxidant glutathione was depleted in 7beta-OH-treated cells but not in cells incubated with beta-epoxide. Trolox, a water-soluble synthetic analogue of alpha-tocopherol, prevented 7beta-OH-induced apoptosis but did not protect against cell death induced by beta-epoxide. Ebselen and resveratrol did not protect U937 cells against apoptosis induced by either 7beta-OH or beta-epoxide. Our results suggest that differences occur in the pathways of apoptosis induced by 7beta-OH and beta-epoxide in U937 cells.
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PMID:Comparison of the apoptotic processes induced by the oxysterols 7beta-hydroxycholesterol and cholesterol-5beta,6beta-epoxide. 1568 34

Neonatal hypoxic-ischemic brain injury remains a significant cause of morbidity and mortality and lacks effective therapies for prevention and treatment. Recently, interest in the biology of polyphenol compounds has led to the discovery that dietary supplementation with foods rich in polyphenols (e.g. blueberries, green tea extract) provides neuroprotection in adult animal models of ischemia and Alzheimer's disease. We sought to determine whether protection of the neonatal brain against a hypoxic-ischemic insult could be attained through supplementation of the maternal diet with pomegranate juice, notable for its high polyphenol content. Mouse dams were provided ad libitum access to drinking water with pomegranate juice, at one of three doses, as well as plain water, sugar water, and vitamin C water controls during the last third of pregnancy and throughout the duration of litter suckling. At postnatal day 7, pups underwent unilateral carotid ligation followed by exposure to 8% oxygen for 45 min. Brain injury was assessed histologically after 1 wk (percentage of tissue area loss) and biochemically after 24 h (caspase-3 activity). Dietary supplementation with pomegranate juice resulted in markedly decreased brain tissue loss (>60%) in all three brain regions assessed, with the highest pomegranate juice dose having greatest significance (p < or = 0.0001). Pomegranate juice also diminished caspase-3 activation by 84% in the hippocampus and 64% in the cortex. Ellagic acid, a polyphenolic component in pomegranate juice, was detected in plasma from treated but not control pups. These results demonstrate that maternal dietary supplementation with pomegranate juice is neuroprotective for the neonatal brain.
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PMID:Maternal dietary supplementation with pomegranate juice is neuroprotective in an animal model of neonatal hypoxic-ischemic brain injury. 1577 34

Apples contain several classes of polyphenols: monomers (catechins, epicatechins) and oligomers/polymers, such as the procyanidins. Our aim was (i) to study anti-proliferative mechanisms on human metastatic colon carcinoma (SW620 cells) of apple polyphenol fractions (monomers or procyanidins) and (ii) to evaluate their anti-carcinogenic properties in vivo. Two polyphenol-enriched fractions were isolated from apples. Fraction non-procyanidins contained 73% phenolic monomers and no procyanidins, while fraction procyanidins contained 78% procyanidins and no monomers. Inhibition of SW620 cell growth was only observed with fraction P (IC50 = 45 microg/ml). After a 24-h exposure of cells to fraction P, protein kinase C activity was inhibited by 70% and a significant increase in extracellular signal-regulated kinases 1 and 2 and c-jun N-terminal kinases expression was observed together with the down-regulation of polyamine biosynthesis and the activation of caspase-3. Colon carcinogenesis was induced in rats by intraperitoneal injections of azoxymethane, once a week for 2 weeks. Seven days after the last injection, Wistar rats received fraction P (0.01%) dissolved in drinking water. After 6 weeks of treatment, the colon of rats receiving procyanidins showed a significant (P < 0.01) reduction of the number of preneoplastic lesions when compared with controls receiving water. The total number of hyperproliferative crypts and of aberrant crypt foci was reduced by 50% in rats receiving 0.01% apple procyanidins in their drinking water. Our results show that apple procyanidins alter intracellular signaling pathways, polyamine biosynthesis and trigger apoptosis in tumor cells. These compounds antagonize cancer promotion in vivo. In contrast with absorbable drugs, these natural, non toxic, dietary constituents reach the colon where they are able to exert their antitumor effects.
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PMID:Chemopreventive properties of apple procyanidins on human colon cancer-derived metastatic SW620 cells and in a rat model of colon carcinogenesis. 1579 May 89

Fluorine compounds are widely used for the prevention of caries, and recently sodium fluorosilicate has been used in water fluorination. The cytotoxic effects of sodium fluorosilicate in several osteosarcoma and oral cancer cells were evaluated in this study by measurement of inhibition of cell proliferation. Human osteogenic sarcoma (HOS) cells were the most sensitive to sodium fluorosilicate treatment. Induction of apoptosis, such as nucleosomal DNA fragmentation and the appearance of apoptotic bodies, were observed in HOS cells by agarose gel electrophoresis and by flow cytometric analysis, respectively. The molecular mechanism of apoptosis induction in HOS was investigated by Western blot analysis. The level of Bcl-2 was decreased and consequent release of cytochrome c was increased. Caspase-3 was activated and the cleavage of poly (ADP-ribosyl) polymerase was increased. In conclusion, sodium fluorosilicate induces apoptosis in HOS cells through decrease in Bcl-2, the release of cytochrome c to the cytosol and activation of caspase-3.
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PMID:Induction of apoptosis by sodium fluorosilicate treatment in human osteogenic sarcoma (HOS) cells. 1581 63

This study examined the effect of Saeng-Ji-Hwang (SJH: Radix Rehmanniae) on cardiac muscle cells. Adriamycin-exposed H9C2 cardiac muscle cells were treated with a water extract of SJH. The adriamycin induced cell death and caspase-3 activation were significantly inhibited by SJH (2 mg/ml), which can be explained by the increase in Bcl-2 expression and the inhibition of Bax expression. Adriamycin reduced the Mn-SOD protein expression level in H9C2 cardiac muscle cells but a SJH treatment partially but significantly reversed this effect. Manganese (Mn)-TBAP or Mn-TMyM--mitochondria-specific SOD mimetic agent--reduced the adriamycin-induced cytotoxicity. It was also shown that SJH inhibits the release of H2O2 and prevents lipid peroxidation in the presence of adriamycin. This study examined the intracellular GSH level, which showed that adriamycin significantly decreased the intracellular GSH level but SJH increased it. BSO, a selective inhibitor of glutamyl cysteinyl ligase, which is a rate-limiting enzyme in GSH synthesis, did not affect the viability of the cardiac muscle cells. However, a combination of BSO with SJH in the presence of adriamycin reversed the SJH-induced protection. Overall, the results suggest that SJH-associated Mn-SOD and GSH are important factors in the mechanism of the SJH-induced protective mechanism in H9C2 cardiac muscle cells.
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PMID:Saeng-Ji-Hwang has a protective effect on adriamycin-induced cytotoxicity in cardiac muscle cells. 1582 71

The mechanism of how fluoride causes fluorosis remains unknown. Exposure to fluoride can inhibit protein synthesis, and this may also occur by agents that cause endoplasmic reticulum (ER) stress. When translated proteins fail to fold properly or become misfolded, ER stress response genes are induced that together comprise the unfolded protein response. Because ameloblasts are responsible for dental enamel formation, we used an ameloblast-derived cell line (LS8) to characterize specific responses to fluoride treatment. LS8 cells were growth-inhibited by as little as 1.9-3.8 ppm fluoride, whereas higher doses induced ER stress and caspase-mediated DNA fragmentation. Growth arrest and DNA damage-inducible proteins (GADD153/CHOP, GADD45alpha), binding protein (BiP/glucose-responsive protein 78 (GRP78), the non-secreted form of carbonic anhydrase VI (CA-VI), and active X-box-binding protein-1 (Xbp-1) were all induced significantly after exposure to 38 ppm fluoride. Unexpectedly, DNA fragmentation increased when GADD153 expression was inhibited by short interfering RNA treatment but remained unaffected by transient GADD153 overexpression. Analysis of control and GADD153(-/-) embryonic fibroblasts demonstrated that caspase-3 mediated the increased DNA fragmentation observed in the GADD153 null cells. We also demonstrate that mouse incisor ameloblasts are sensitive to the toxic effects of high dose fluoride in drinking water. Activated Ire1 initiates an ER stress response pathway, and mouse ameloblasts were shown to express activated Ire1. Ire1 levels appeared induced by fluoride treatment, indicating that ER stress may play a role in dental fluorosis. Low dose fluoride, such as that present in fluoridated drinking water, did not induce ER stress.
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PMID:Fluoride induces endoplasmic reticulum stress in ameloblasts responsible for dental enamel formation. 1584 62

Our group has previously shown that polyamine depletion delays apoptosis in rat intestinal epithelial (IEC-6) cells (Ray RM, Viar MJ, Yuan Q, and Johnson LR, Am J Physiol Cell Physiol 278: C480-C489, 2000). Here, we demonstrate that polyamine depletion inhibits gamma-irradiation-induced apoptosis in vitro and in vivo. Pretreatment of IEC-6 cells with 5 mM alpha-difluoromethylornithine (DFMO) for 4 days significantly reduced radiation-induced caspase-3 activity and DNA fragmentation. This protective effect was prevented by the addition of 10 muM exogenous putrescine. Radiation exposure to mice resulted in a high frequency of apoptosis over cells positioned fourth to seventh in crypt-villus units. Pretreatment of mice with 2% DFMO in drinking water significantly reduced apoptotic cells from approximately 2.75 to 1.61 per crypt-villus unit, accompanied by significant decreases in caspase-3 levels. Further examination showed that DFMO pretreatment inhibited the radiation-induced increase in the proapoptotic protein Bax. Moreover, DFMO pretreatment significantly enhanced the intestinal crypt survival rate by 2.1-fold subsequent to radiation and ameliorated mucosal structural damage. We conclude that polyamine depletion by DFMO inhibits gamma-irradiation-induced apoptosis of intestinal epithelial cells both in vitro and in vivo through inhibition of Bax and caspase-3 activity, which leads to attenuation of radiation-inflicted intestinal injury. These data indicate that DFMO may be therapeutically useful to counteract the gastrointestinal toxicity caused by chemoradiotherapy. This is the first demonstration that polyamines are required for apoptosis in vivo.
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PMID:Polyamine depletion inhibits irradiation-induced apoptosis in intestinal epithelia. 1586 Jun 39

This study examined the protective effects of Ginkgo biloba extract (GbE) on the learning and memory function in aluminum-treated rats and potential mechanisms. Wistar rats were given daily aluminum chloride 500 mg/kg, i.g, for one month, followed by continuous exposure via the drinking water containing 1600 ppm aluminum chloride for up to 5 months. The ability of spatial learning and memory was tested by Morris water maze. Aluminum administration significantly increased escape latency and searching distance, indicative of brain dysfunction. GbE treatment (50-200 mg/kg, i.g) significantly protected against aluminum-induced brain dysfunction, as evidenced by decreased escape latency and searching distance compared with the Al alone group. To examine the mechanisms of the protection, the expressions of amyloid precursor protein (APP) and caspase-3 in brain regions were examined by immunohistochemistry. GbE treatment reduced the contents of APP and caspase-3 in hippocampus of aluminum-treated rats in a dose-dependent manner. At the highest dose of GbE (200 mg/kg), the immunostain for APP and caspase-3 was returned to normal levels. In summary, this study demonstrates that GbE is effective in improving the ability of spatial learning and memory of aluminum-intoxicated rats. This protection appears to be due to a decreased expression of APP and caspase-3 in rat brain, resulting in a decrease in the production of insoluble fragments of Abeta-amyloid.
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PMID:Protective effects of Ginkgo biloba leaf extract on aluminum-induced brain dysfunction in rats. 1586 99

The volatile extract from dried pericarp of Zanthoxylum schinifolium that was obtained by simultaneous distillation with dichloromethane and water was composed of 29.9% geranyl acetate, 15.8% citronella, 15.4% sabinene and the minor volatile components included beta-myrcene, linalool, (-)-isopulegol, citronellyl acetate, 1,4-dimethyl pyrazole, alpha-terpinene, 3-methyl-6-(1-methylethyl)-2-cyclo-hexene-1-o1 and trans-geraniol. The volatile extract decreased the cell viability and induced apoptotic death in HepG2 human hepatoma cells in a concentration- and time-related manner. In addition, the volatile extract increased the production of reactive oxygen species in a dose-dependent manner. Pretreatment of the cells with Trolox, a well-known antioxidant, significantly suppressed the generation of reactive oxygen species and cell death induced by the extract. However, caspase-3 activity was not changed in the extract-treated cells, suggesting that the extract-induced apoptosis of HepG2 cells is caspase-3 independent. Furthermore, in nude mice inoculated with Huh-7 human hepatoma cells, the extract significantly inhibited tumor development. These results suggest that the volatile extract from Zanthoxylum schinifolium pericarpium is a good candidate for hepatocellular carcinoma (HCC) therapy and that reactive oxygen species are the key signaling molecules in the volatile extract-induced cell death in HepG2 cells.
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PMID:The essential oils from Zanthoxylum schinifolium pericarp induce apoptosis of HepG2 human hepatoma cells through increased production of reactive oxygen species. 1586 82

Andrographolide was extracted and purified from Andrographis panicula using hexane and water partitioning followed by ethyl acetate extraction and chromatography. It showed selective cytotoxicity to prostate cancer PC-3 cells in vitro. The morphological and biochemical changes induced by the extract in carcinoma PC-3 cell death were studied. In andrographolide-treated cells, evidence of apoptosis such as cell shrinkage and surface microvilli loss after 4-hour treatment and chromatin condensation and fragmentation in H&E-stained cells between 4 to 8 hours after treatment were observed. Under electron microscopy, membrane blebbing and apoptotic bodies formation were seen after 8-hour treatment. Using immunocytochemistry staining and cellular caspase-3 activity assay, andrographolide-treated cells showed considerable caspase-3 activation and caspase-8 in PC-3 cells at 4 and 2 hours after treatment, respectively. This suggests andrographolide-induced cell death was achieved through the apoptotic pathway, via the activation of an extrinsic caspase cascade.
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PMID:Morphological and biochemical changes of andrographolide-induced cell death in human prostatic adenocarcinoma PC-3 cells. 1587 75


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