Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure to ultraviolet (UV) light poses a health risk for eye disease, and solar ultraviolet in the B range (UVB, 280-320 nm) is known to be related to various corneal disorders. In this study, we investigated whether pre-conditioning of cells with arsenite (AsO2(-1)) can reduce UVB-induced apoptosis in human corneal epithelial cells, and whether the anti-apoptotic activity of 27 kDa heat shock protein (HSP27), a small heat shock protein, plays a role in this protection. UVB at levels comparable to physiologic solar exposure induces apoptosis of corneal epithelial cells in culture, demonstrated by activation of caspase 9 and caspase 3, and DNA fragmentation. When cells were pre-conditioned with arsenite prior to UVB exposure, the UVB-induced cell death was reduced, and UVB-induced activation of caspases and DNA fragmentation was inhibited. When cells were pre-treated with SB 203580, which inhibits HSP27 phosphorylation through inhibition of p38 MAP kinase activation, the arsenite-induced reduction of UVB-induced apoptosis was partially reversed. Arsenite pre-conditioning inhibited UVB-induced apoptosis in a two-phase pattern, which was temporally correlated with arsenite-induced HSP27 expression and phosphorylation. Neutralization of intracellular HSP27 with its antibody reduced arsenite's inhibition of UVB-induced caspase3 activation. Our results suggest that forms of stress that upregulate HSP27 and its phosphorylation may be useful as novel approaches to prevent adverse ocular effects arising from UV exposure in humans.
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PMID:Arsenite pre-conditioning reduces UVB-induced apoptosis in corneal epithelial cells through the anti-apoptotic activity of 27 kDa heat shock protein (HSP27). 1611 12

Beta-amyloid peptide (Abeta) is considered responsible for the pathogenesis of Alzheimer's disease (AD). Several lines of evidence support that Abeta-induced cytotoxicity is mediated through the generation of reactive oxygen species (ROS). Thus, agents that scavenge ROS level may usefully impede the development or progress of AD. Green tea extract has been known to have such antioxidant properties. Our previous studies demonstrate that green tea extract protected ischemia/reperfusion-induced brain cell death by scavenging oxidative damages of macromolecules. In this study, we investigated the effects of green tea extract on Abeta-induced oxidative cell death in cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with Abeta25-35 (10-50 microM) showed intracellular ROS elevation, the formation of 8-oxodG (an oxidized form of DNA), and underwent apoptotic cell death in a dose-dependent manner. Abeta(25-35) treatment upregulated pro-apoptotic p53 at the gene level, and Bax and caspase-3 at the protein level, but downregulated anti-apoptotic Bcl-2 protein. Interestingly, co-treated green tea extract (10-50 microg/ml) dose-dependently attenuated Abeta(25-35) (50 microM)-induced cell death, intracellular ROS levels, and 8-oxodG formation, in addition to p53, Bax, and caspase-3 expression, but upregulated Bcl-2. Furthermore, green tea extract prevented the Abeta(25-35)-induced activations of the NF-kappaB and ERK and p38 MAP kinase pathways. Our study suggests that green tea extract may usefully prevent or retard the development and progression of AD.
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PMID:Inhibitory effect of green tea extract on beta-amyloid-induced PC12 cell death by inhibition of the activation of NF-kappaB and ERK/p38 MAP kinase pathway through antioxidant mechanisms. 1615 42

Sodium butyrate (NaBu) has an inhibitory effect on histone deacetylases (HDACs). The mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAP, kinase are known to be modulated during NaBu-induced apoptosis. In the present study, we showed that low concentrations of NaBu could induce apoptosis synergistically with the inhibition of p38 MAP kinase as proven by using specific p38 MAP kinase inhibitor and dominant negative p38 transfection in a ras-transformed rat liver epithelial cell line (WB-ras). There were no changes in HDAC1, suggesting that NaBu might be able to kill transformed cells bypassing the HDAC inhibitory effect. We further demonstrated that inhibition of p38 MAP kinase potentiated apoptotic cascades, including cleavage of poly(ADP-ribose) polymerase, caspase-3, and decrease in Bcl-2/Bax ratio even at a lower concentration of NaBu. Thus, p38 MAP kinase played inhibitory roles in NaBu-induced apoptosis, and simultaneous modulation of MAP kinases in NaBu treatment could increase the efficiency of the chemotherapeutic effect of NaBu.
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PMID:Augmentation of sodium butyrate-induced apoptosis by p38 MAP kinase inhibition in rat liver epithelial cells. 1635 38

Pramipexole, a novel non-ergot dopamine (DA) agonist, has been successfully applied to the treatment of Parkinson's disease (PD). Although the specific cause of PD remains unknown, recent studies have provided evidence that oxidative stress plays a role in the parthenogenesis of the disease. In the present study, we examined the effect of pramipexole on hydrogen peroxide (H2O2, 100 microM)-induced PC12 cell death, and the intracellular mechanism of this effect. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay revealed that pretreatment of PC12 cells with pramipexole (1-100 microM) resulted in significant protection against H2O2-induced cell death in a concentration-dependent manner. The protective effect of pramipexole was not affected by pretreatment with the DA receptor antagonists sulpiride, spiperone or domperidone, suggesting that the effect of pramipexole is not mediated by DA receptors. In PC12 cells, pramipexole inhibited H2O2-induced lactate dehydrogenase (LDH) leakage, as well as H2O2-induced cytochrome c release and caspase-3 activation with the resultant apoptosis. It was also observed in PC12 cells that H2O2 stimulated phosphorylation of mitogen-activated protein (MAP) kinases, i.e., extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase. Pramipexole inhibited H2O2-induced JNK and p38 MAP kinase, but not ERK1/2 phosphorylation. Furthermore, in these cells experiments with a fluorescent probe, 2-[6-(4'-amino)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid, revealed that pramipexole, the JNK inhibitor SP600125 and the p38 MAP kinase inhibitor SB203580 inhibited the generation of H2O2-induced reactive oxygen species. Caspase inhibitors Z-DEVD-FMK and Z-IETD-FMK, as well as SP600125 and SB203580, inhibited H2O2-induced PC12 cell death to a similar extent as pramipexole. These results suggest that pramipexole exerts a protective effect against oxidative stress-induced PC12 cell death in part through an inhibition of JNK and p38 MAP kinase.
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PMID:Pramipexole protects against H2O2-induced PC12 cell death. 1636 28

Acetaldehyde, the major metabolite of ethanol, which is far more toxic and reactive than ethanol, may be responsible for alcohol-induced cardiac damage. This study was designed to examine the impact of facilitated acetaldehyde metabolism using transfection of human aldehyde dehydrogenase-2 (ALDH2) transgene on acetaldehyde- and ethanol-induced cell injury. Fetal human cardiac myocytes were transfected with ALDH2, the efficacy of which was verified by flow cytometry, Western blot and ALDH2 activity assays. Generation of reactive oxygen species (ROS) was detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA). Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride (DAPI) fluorescence microscopy, quantitative DNA fragmentation ELISA and caspase 3 activity. Acetaldehyde and ethanol elicited overt ROS generation and apoptosis in human cardiac myocytes following 24-48 h of incubation. Immunostaining revealed activation of the MAP kinase cascades ERK1/2, SAPK/JNK and p38 MAP kinase in acetaldehyde-treated myocytes. Interestingly, ALDH2 transgene significantly attenuated acetaldehyde-induced ROS generation, apoptosis and phosphorylation of ERK1/2 and SAPK/JNK. Time-dependent response (0-12 h) revealed ROS accumulation and activation of MAP kinases prior to acetaldehyde-induced apoptosis. In addition, acetaldehyde-induced ROS generation and apoptosis were antagonized by non-enzymatic antioxidants. Our results suggested that ALDH2 transgene overexpression may effectively alleviate acetaldehyde-elicited cell injury through an ERK1/2 and SPAK/JNK-dependent mechanism. Our data are consistent with the notion of acetaldehyde as a contributor to alcoholic cardiomyopathy and implicate the therapeutic potential of ALDH2 enzyme in alcoholic complications.
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PMID:Attenuation of acetaldehyde-induced cell injury by overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene in human cardiac myocytes: role of MAP kinase signaling. 1640 13

Red wine polyphenol, trans-resveratrol (trans-3,4',5-trihydroxy stilbene), has potent chemopreventive effects against various tumors. In this study, we found for the first time that resveratrol rapidly induces S phase cell cycle arrest of human malignant B cells including myeloma cells in dose- and time-dependent manners, followed by S phase cell cycle arrest through ATM/Chk pathway. Resveratrol-induced apoptosis occurs in association with the activation of caspase-3 and the loss of mitochondrial transmembrane potentials. In addition, resveratrol induces the phosphorylation of p38 MAP kinase, and specific inhibition of p38 MAP kinase abolishes the resveratrol-induced apoptosis, indicating that activation of the p38 MAP kinase pathway is required for inducing apoptosis in malignant B cells. These results suggest that resveratrol may have potential as a novel therapeutic agent for the patients with B cell malignancies including multiple myeloma.
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PMID:Resveratrol induces apoptosis of human malignant B cells by activation of caspase-3 and p38 MAP kinase pathways. 1642 27

Hydrogen sulfide, together with carbon monoxide and nitric oxide, is now considered a gasotransmitter able to induce specific cellular responses. As hydrogen sulfide is a component of several natural compounds known to be effective in many inflammatory pathologies, particularly of the respiratory tract, we studied its effects in vitro on the survival and bactericidal activity of purified human neutrophils. We found that (1) HS(-) ions promote the survival of granulocytes, but not that of lymphocytes or eosinophils, cultured in serum-free medium; (2) the pro-survival effect of HS(-) is due to inhibition of caspase-3 cleavage and p38 MAP kinase phosphorylation; (3) the bactericidal activity of neutrophils is not impaired by hydrogen sulfide. We conclude that HS(-) promotes the short-term survival of neutrophils potentially accelerating the resolution of inflammatory processes and preventing the occurrence of new ones.
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PMID:Hydrogen sulfide prevents apoptosis of human PMN via inhibition of p38 and caspase 3. 1644 3

Although short-chain fatty acid (SCFA)-induced heat shock protein 25 (Hsp25) is associated with increased cellular resistance to injury, withdrawal of lumenal butyrate in vivo is associated with intestinal epithelial injury and apoptosis. Recognizing that SCFA-dependent posttranslational modification of Hsp25 may involve altered Hsp25 phosphorylation, we hypothesized that butyrate regulates Hsp25 phosphorylation and secondarily affects cellular responses to apoptosis-inducing agents. Intestinal epithelial crypt IEC-18 cells were treated with butyrate, propionate, or the histone deacetylase inhibitor trichostatin A for 6-24 h. Immunolocalization of Hsp25 was examined by confocal laser microscopy. Hsp25 phosphorylation was characterized using two-dimensional isoelectric focusing gel electrophoresis. Hsp25 accumulation in cytoskeletal- and mitochondrial-enriched fractions was examined by immunoblotting. The activation of p38 MAP kinase was determined using phospho-specific antibodies and MAPKAPK 2 kinase assays. The effects of SCFA on apoptosis were studied by ELISA detection of cleaved DNA and using antibodies recognizing cleaved caspase-3. Five-millimolar butyrate induced no significant injury to IEC-18 cells. Hsp25 did not accumulate in Triton X-100-insoluble cytoskeletal fractions with butyrate treatment but did localize to mitochondria in a p38 MAP kinase-dependent manner. Hsp25 phosphorylation was induced by butyrate, propionate, and trichostatin A. Butyrate-mediated changes in Hsp25 phosphorylation coincide with the activation of the p38 MAP kinase and MAPKAPK 2. Butyrate, propionate, and low-dose trichostatin A confer significant protection from camptothecin-induced apoptosis, which was not reversed by the p38 inhibitor SB203580. We conclude that butyrate-mediated phosphorylation of Hsp25 is associated with significant resistance to apoptosis, which appears to be independent of p38-mediated targeting of Hsp25 to mitochondria.
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PMID:Short-chain fatty acid mediated phosphorylation of heat shock protein 25: effects on camptothecin-induced apoptosis. 1646 26

Glycogen synthase kinase (GSK) 3beta is a multifunctional protein that positively regulates myocardial apoptosis and negatively regulates hypertrophy. However, the role of GSK3beta in the diabetic myocardium is largely unknown. We found that GSK3beta became more active (less phosphorylated at serine 9) via decreased Akt phosphorylation, in parallel to c-Jun NH2 terminal kinase activation, which correlated with increased activated caspase 3 and myocardial apoptosis 3 days after streptozotocin (STZ) injection in mice. However, 28 days after STZ injection, GSK3beta became inactive, which correlated with the enhanced protein kinase C beta2 and p38 mitogen activated protein kinase expression, nuclear translocation of nuclear factor of activated T cells c3, cardiac hypertrophy and fibrosis. All of the above parameters were exacerbated in dominant-negative 14-3-3 transgenic mice. Our results suggest that GSK3beta together with 14-3-3 protein plays essential roles in the signaling of diabetic cardiomyopathy, and treatment with either losartan or tempol prevents these changes.
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PMID:Glycogen synthase kinase 3beta together with 14-3-3 protein regulates diabetic cardiomyopathy: effect of losartan and tempol. 1653 Jan 86

Thrombospondin-1 (TSP1) is an endogenous inhibitor of angiogenesis, which limits blood vessel density in normal tissues and curtails tumor growth. Previous studies of the molecular and cellular effects of TSP1 in angiogenesis have been contradictory. Here, we show that retinal endothelial cells (REC) prepared from TSP1-deficient (TSP1-/-) mice are more proliferative and migratory compared to the wild type REC. We observed up-regulation of the cell cycle regulators, including cyclin A, D1, and Cdk2, as well as the enhanced sequential activities of Src, PI3-kinase, Akt/PKB, Rac1/Cdc42 GTPases, and p38 MAP kinase in TSP1-/- REC. The increased levels of fibronectin and active Akt/PKB were also observed in retinal vasculature of TSP1-/- mice in vivo. Inhibition of Src/PI3-kinase/P38 MAP kinase activities in TSP1-/- REC resulted in decreased migration. Furthermore, TSP1-/- REC showed decreased intracellular levels of active Fyn and JNK2 without affecting caspase-3 activity. Thus, our results demonstrate that in the absence of TSP1, the proangiogenic signaling is enhanced, possibly through up-regulation of fibronectin expression. The enhanced signaling further promotes EC proliferation, migration, and survival. These novel observations support the TSP1's role as an endogenous inhibitor of angiogenesis whose endothelium expression promotes a quiescent, differentiated phenotype.
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PMID:Enhanced proangiogenic signaling in thrombospondin-1-deficient retinal endothelial cells. 1662 39


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