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)

Lithium is widely used for the treatment of bipolar disorder. Recent studies have demonstrated its neuroprotective effect. Ethanol is a potent neurotoxin that is particularly harmful to the developing nervous system. In this study, we evaluated lithium's neuroprotection against ethanol-induced apoptosis. Transient exposure of infant mice to ethanol caused apoptotic cell death in brain, which was prevented significantly by administering a low dose of lithium 15min later. In cultured cerebellar granule neurons, ethanol-induced apoptosis and activation of caspase-3/9, both of which were prevented by lithium. However, lithium's protection is not mediated by its commonly known inhibition of glycogen synthase3beta, because neither ethanol nor lithium has significant effects on the phosphorylation of Akt (ser473) or GSK3beta (ser9). In addition, the selective GSK-3beta inhibitor SB-415286 was unable to prevent ethanol-induced apoptosis. These data suggest lithium may be used as a potential preventive measure for ethanol-induced neurological deficits.
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PMID:Lithium protects ethanol-induced neuronal apoptosis. 1704 45

Ethanol exposure is known to suppress male reproductive activity in laboratory animals and humans. The present study was designed to evaluate whether chronic ethanol exposure decreases proliferative activity or increases apoptosis in the testes. Ethanol (1.5 g/kg or 3 g/kg i.p., 15% v/v in saline) was administrated to adult male rats for 10 days. Proliferating cell nuclear antigen (PCNA) was used as a proliferative marker. Western blot analysis showed that ethanol administration significantly reduced the level of PCNA. Also, immunoreactivity of PCNA-positive cells in the spermatogonia and primary spermatocytes were decreased by ethanol exposure. However, the number of TUNEL-positive cells was significantly increased in the testicular germ cells of ethanol-treated rats. Moreover, ethanol administration significantly increased the level of activated caspase-3 in testes. In conclusion, our findings suggest that ethanol may partly contribute to the suppression of male reproductive activity through a reduction of cell proliferation and an enhancement of cell death in rat testes.
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PMID:Ethanol exposure decreases cell proliferation and increases apoptosis in rat testes. 1708 77

Ethanol (EtOH) is a well-known developmental toxicant that produces a range of abnormal phenotypes in mammalian systems including craniofacial abnormalities, cognitive deficits and growth retardation. While the toxic potential of developmental EtOH exposure is well characterized clinically, the effect of timing on the extent of toxicity remains unknown. Fish models such as the Japanese medaka, Oryzias latipes, provide a convenient system for investigating the effects of developmental EtOH exposure in vivo. In this study, medaka embryo toxicity tests were used to assess temporal variations in developmental EtOH toxicity. Fertilized eggs were collected and incubated during early, middle or late egg development (e.g., 0-3, 3-6 or 6-9 days post-fertilization) with various sub-lethal concentrations of EtOH [0.1% (17.2 mM), 0.5% (86.0 mM) or 1% (172 mM)]. Uptake of EtOH by the embryo was 60-68% of the solution concentration across all windows. Time to hatch, head width, total body length and whole embryo caspase activity were used to assess toxicity. Hatching delays were noted only at the highest concentration of EtOH. Head width was affected at all ethanol levels, regardless of the window of exposure. EtOH-induced decreases in body length, however, appeared to be most pronounced when exposure occurred either during the first or last window. The effect on caspase-3/7 activity also depended on the window of exposure, with increases in caspase noted in embryos treated on days 1 or 2 (first window) and decreases seen in embryos treated on day 6 (second window) or day 8 (third window). In general, these data suggest that critical periods for heightened sensitivity to developmental EtOH exposure may vary according to the specific endpoint used to assess toxicity.
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PMID:Vulnerable windows for developmental ethanol toxicity in the Japanese medaka fish (Oryzias latipes). 1712 51

Ethanol is a well-established irritant inducing inflammation in gastric mucosa, but the effects at the cellular level remain unclear. This study investigates NF-kappaB activation in gastric mucosal cells by ethanol and assesses the effects of heat shock pretreatment in this ulcerogenic situation. Rat gastric mucosal epithelia were exposed to ethanol for different time periods. Heat shock was induced by incubating the cells at 42 degrees C for 1 h prior to the experiments. For evaluation of NF-kappaB activation, the nuclear fraction of the cell lysates was analyzed with an EMSA or an ELISA-based assay. Caspase-3 (a promoter of apoptosis) activity was measured with a time-resolved fluorescence based assay, cell viability with a tetrazolium assay, and cell membrane integrity with a LDH assay. Ethanol (1-5%) induced NF-kappaB activation, reaching a maximum after 3 h, and also led to moderately increased COX-2 expression. Heat shock pretreatment and the intracellular calcium chelator BAPTA were able to inhibit ethanol-induced NF-kappaB activation. Heat shock pretreatment decreased ethanol-induced caspase-3 activation, decreased cell membrane damage, and retained cellular viability. Inhibition of NF-kappaB activation by NEMO-binding peptide, by decreasing RelA expression, or by inhibiting COX-2 activity by CAY-14040 promoted the effects of ethanol, such as increased caspase-3 activity and decreased cell viability. In conclusion, ethanol induces NF-kappaB activation via a calcium-dependent pathway and induces COX-2 expression. Inhibition of the NF-kappaB activation or COX-2 activity potentiates apoptosis and cell damage induced by ethanol, suggesting a protective role for NF-kappaB activation and COX-2 expression.
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PMID:Ethanol induced NF-{kappa}B activation protects against cell injury in cultured rat gastric mucosal epithelium. 1734 52

Ginkgolide B is a major active component of Ginkgo biloba extracts, which has been shown to confer anticancer effects by inducing apoptosis or inhibiting oxidative stress generation. Ethanol induces a wide range of cellular toxicities, many of which have been linked to free radical generation. To further elucidate the cellular effects of ginkgolide B, we examined the dose-response effect of ginkgolide B on ethanol-induced toxicity in human Hep G2 cells. TUNEL and MTT assays revealed that ethanol (50-400 mM) induced apoptotic cell death in human Hep G2 cells, and that this effect was inhibited by low (5-25 microM) doses of ginkgolide B, but enhanced by high (50-100 microM) doses of ginkgolide B. Additional experiments revealed that ethanol treatment directly increased intracellular oxidative stress; this effect was enhanced by high doses of ginkgolide B but decreased following treatment with low concentrations of ginkgolide B. The dose-response effects of ginkgolide B on reactive oxygen species (ROS) generation were directly correlated with cell apoptotic biochemical changes including c-Jun N-terminal kinase (JNK) activation, caspase-3 activation, and DNA fragmentation. These results indicate that treatment dosage may determine the effect of ginkgolide B on ethanol-induced ROS generation and cell apoptosis, and support the notion that an appropriate dosage of ginkgolide B may aid in decreasing the toxic effects of ethanol.
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PMID:Dosage effects of ginkgolide B on ethanol-induced cell death in human hepatoma G2 cells. 1740 51

Neuronal death is one of the most prominent consequences of alcohol exposure during development. Ethanol-induced neuronal death appears to involve apoptosis. The objective of the present study was to characterize the effect of ethanol on neuronal cell viability and to determine the mechanism by which ethanol enhances apoptosis in neural cells. For these studies the rat pheochromocytoma (PC12) cells were used. PC12 cells were incubated for 24 h in the presence or absence of 100 mM ethanol. Apoptosis was induced by serum withdrawal. Ethanol in the presence of serum-containing media did not alter cell viability, while incubation of PC12 cells in serum-free media resulted in a significant increase in cell death that was further significantly increased by 35% in cells exposed to ethanol. The temporal response of the PC12 cells to serum withdrawal was studied over a period of 22 h. At least 18 h of ethanol exposure was necessary to observe a significant increase in death for cells incubated in serum-free media. An increase in the caspase-3 activity in PC12 cells deprived of serum was observed that was further increased by ethanol exposure. This increase of caspase-3 activity was correlated with an enhancement of caspase-9 activity. Ethanol exposure increased the amount of cytosolic cytochrome c in PC12 cells incubated in serum-free media but did not alter the level of cytochrome c in cells incubated in serum. Finally, a 26% increase was observed in the number of cells with depolarized mitochondria due to ethanol treatment. The present study implicates an increase in the mitochondrial outer membrane permeability as a potential mechanism of enhancement of apoptosis in serum-deprived PC12 cells by ethanol.
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PMID:Mechanism of ethanol enhancement of apoptosis and caspase activation in serum-deprived PC12 cells. 1770 24

Ethanol metabolism plays a central role in activating the mitogen-activated protein kinase (MAPK) cascade leading to inflammation and apoptosis. Sustained activation of c-Jun N-terminal kinase (JNK), one of the MAPKs, has been shown to induce apoptosis in hepatocytes. MAPK phosphatase-1 (MKP-1) has been shown to dephosphorylate MAPKs in several cells. The aim of the study is to evaluate the role of MKP-1 in sustained JNK activation as a mechanism to explain ethanol-induced hepatocyte apoptosis. VL-17A cells (HepG2 cells overexpressing alcohol dehydrogenase and cytochrome P450-2E1) were exposed to ethanol for different time periods. Western blots were performed for MKP-1, phospho-JNK, phosphotyrosine, and protein kinase Cdelta (PKCdelta). Electrophoretic mobility shift assays for AP-1 were performed. Apoptosis was measured by caspase-3 activity assay, TUNEL, and 4',6-diamidino-2-phenylindole staining. Reactive oxygen species were neutralized by overexpressing both superoxide dismutase-3 and catalase genes using lentiviral vectors in VL-17A cells. Ethanol incubation markedly decreased the MKP-1 protein levels to 15% of control levels and was associated with sustained phosphorylation of p46 JNK and p54 JNK, as well as increased apoptosis. VL-17A cells overexpressing superoxide dismutase-3 and catalase, treatment with a tyrosine kinase inhibitor, or incubation of the cells with PKCdelta small interference RNAs significantly inhibited the ethanol-induced MKP-1 degradation and apoptosis. Ethanol-induced oxidative stress enhanced the tyrosine phosphorylation of PKCdelta, which in turn caused the proteasomal degradation of MKP-1, leading to sustained JNK activation and increased apoptosis in VL-17A cells.
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PMID:Role of MAPK phosphatase-1 in sustained activation of JNK during ethanol-induced apoptosis in hepatocyte-like VL-17A cells. 1784 70

An important aspect in alcohol abuse-associated immune suppression is the loss of T helper CD4(+) lymphocytes, leading to impairment of multiple immune functions. Our work has shown that ethanol can sensitize CD4(+) T lymphocytes to caspase-3-dependent activation-induced cell death (AICD). It has been demonstrated that the formation of S-adenosylmethionine (SAMe) catalyzed by methionine adenosyltransferase (MAT) II is essential for CD4(+) T-cell activation and proliferation. Since ethanol is known to affect SAMe metabolism in hepatocytes, we investigated the effect of ethanol on MAT II activity/expression, SAMe biosynthesis and cell survival in CD4(+) T lymphocytes. We demonstrate for the first time that ethanol at a physiologically relevant concentration (25 mM) substantially decreased the enzymatic activity of MAT II in T lymphocytes. Ethanol was observed to decrease the transcription of MAT2A, which encodes the catalytic subunit of MAT II and is vital for MAT II activity and SAMe biosynthesis. Furthermore, correspondent to its effect on MAT II, ethanol decreased intracellular SAMe levels and enhanced caspase-3-dependent AICD. Importantly, restoration of intracellular SAMe levels by exogenous SAMe supplementation considerably decreased both caspase-3 activity and apoptotic death in T lymphocytes. In conclusion, our data show that MAT II and SAMe are critical molecular components essential for CD4(+) T-cell survival that are affected by ethanol, leading to enhanced AICD. Furthermore, these studies provide a clinical paradigm for the development of much needed therapy using SAMe supplementation in the treatment of immune dysfunction induced by alcohol abuse.
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PMID:Ethanol inhibits methionine adenosyltransferase II activity and S-adenosylmethionine biosynthesis and enhances caspase-3-dependent cell death in T lymphocytes: relevance to alcohol-induced immunosuppression. 1786 84

Hepatocyte apoptosis has been documented in both clinical and experimental alcoholic liver disease. This study was undertaken to examine the effect of dietary zinc supplementation on hepatic apoptosis in mice subjected to a long-term ethanol exposure. Male adult 129S6 mice fed an ethanol-containing liquid diet for 6 months developed hepatitis, as indicated by neutrophil infiltration and elevation of hepatic keratinocyte chemoattractant (KC) and monocyte chemoattractant protein-1 (MCP-1) levels. Apoptotic cell death was detected in ethanol-exposed mice by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and was confirmed by the increased activities of caspase-3 and -8. Zinc supplementation attenuated alcoholic hepatitis and reduced the number of TUNEL-positive cells in association with inhibition of caspase activities. Ethanol exposure caused oxidative stress, as indicated by reactive oxygen species accumulation, mitochondrial glutathione depletion, and decreased metallothionein levels in the liver, which were suppressed by zinc supplementation. The mRNA levels of tumor necrosis factor (TNF)-alpha, TNF-R1, FasL, Fas, Fas-associated factor-1, and caspase-3 in the liver were upregulated by ethanol exposure, which were attenuated by zinc supplementation. Zinc supplementation also prevented ethanol-elevated serum and hepatic TNF-alpha levels and TNF-R1 and Fas proteins in the liver. In conclusion, zinc supplementation prevented hepatocyte apoptosis in mice subjected to long-term ethanol exposure, and the action of zinc is likely through suppression of oxidative stress and death receptor-mediated pathways.
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PMID:Zinc supplementation inhibits hepatic apoptosis in mice subjected to a long-term ethanol exposure. 1837 24

Ethanol-induced hepatocyte necrosis and apoptosis are valid in vitro models to investigate the modulatory effects of hepatoprotective/toxic agents such as curcumin. In this study, suspension and monolayer cultures of isolated rat hepatocytes were used. Levels of trypan blue uptake, reduced glutathione, and lipid peroxidation were quantified. Chromatin condensation, caspase-3 activity, and cytochrome c extramitochondrial translocation were also evaluated. Results revealed that curcumin did not protect against either ethanol-induced necrosis or glutathione depletion. Neither did curcumin reduce caspase-3 activation nor chromatin condensation. In contrast, curcumin induced glutathione depletion, caspase-3 activation, necrosis, and apoptosis. Fortunately, all tested curcumin concentrations (1 microM-10 mM) diminished the ethanol-induced lipid peroxidation. In addition, 1 microM curcumin decreased cytochrome c translocation in hepatocyte monolayers. In conclusion, low concentrations of curcumin may protect hepatocytes by reducing lipid peroxidation and cytochrome c release. Conversely, higher concentrations provoke glutathione depletion, caspase-3 activation, and hepatocytotoxicity.
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PMID:Effects of curcumin on ethanol-induced hepatocyte necrosis and apoptosis: implication of lipid peroxidation and cytochrome c. 1871 59


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