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)

Nitric oxide (NO) attenuates hydrogen peroxide (H2O2)-mediated injury to H9C2 cardiomyoblasts. To examine the role of nitric oxide, cultured H9C2 cardiomyoblasts were treated with H2O2 for 2 h in the presence or absence of the NO donor, diethylamine nitric oxide (DEANO). DEANO (30 microM) attenuated H2O2-induced apoptosis in H9C2 cells. H2O2-exposed H9C2 cells resulted in apoptosis in a time-dependent manner estimated by DNA fragmentation assay, nuclear morphology stained with fluorescent dye, Hoechst 33258 and Annexin V staining. Pretreatment with z-VAD-FMK, a pancaspase inhibitor, or z-DEVD-CHO, a specific caspase-3 inhibitor, completely suppressed the DNA ladder in response to H2O2. An increase in caspase-3-like protease (DEVDase) activity was observed during apoptosis, but no caspase-1 activity (YVADase) was detected. Treatment of H9C2 cells with 100 microM H2O2, resulted in a strong activation of JNK/SAPK. However, the activation of JNK/ SAPK was clearly attenuated by 30 microM DEANO. Furthermore, the dominant negative JNK and SEK1-expressing cells displayed a marked decrease in a number of apoptotic cells. This inhibition of JNK1 in the system is involved in the protection of H2O2-induced apoptosis in H9C2 cardiomyoblasts.
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PMID:Signal transduction of nitric oxide donor-induced protection in hydrogen peroxide-mediated apoptosis in H9C2 cardiomyoblasts. 1141 47

Hydrogen peroxide (H2O2) is known to both induce and inhibit apoptosis, however the mechanisms are unclear. We found that H2O2 inhibited the activity of recombinant caspase-3 and caspase-8, half-inhibition occurring at about 17 microM H2O2. This inhibition was both prevented and reversed by dithiothreitol while glutathione had little protective effect. 100-200 microM H2O2 added to macrophages after induction of caspase activation by nitric oxide or serum withdrawal substantially inhibited caspase activity. Activation of H2O2-producing NADPH oxidase in macrophages also caused catalase-sensitive inactivation of cellular caspases. The data suggest that the activity of caspases in cells can be directly but reversibly inhibited by H2O2.
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PMID:Caspases are reversibly inactivated by hydrogen peroxide. 1144 67

Hepatic myofibroblasts (hMFs) play a key role in the development of liver fibrosis associated with chronic liver diseases. Apoptosis of these cells is emerging as a key process in the resolution of liver fibrosis. Here, we examined the effects of cyclopentenone prostaglandins on apoptosis of human hMFs. Cyclopentenone prostaglandins of the J series markedly reduced hMF viability, with 15-deoxy-Delta(12,14)-prostaglandin J2 (15-d-PGJ2) being the most potent. This effect was independent of peroxisome-proliferator-activated receptors (PPARs), because PPARgamma and PPARalpha agonists did not affect hMF cell viability, and PPARgamma, the nuclear receptor for 15-d-PGJ2, was not expressed in hMFs. Moreover, 15-d-PGJ2 did not act via a cell surface G protein-coupled receptor, as shown in guanosine-5'-O-(3-thiotriphosphate) binding assays. Cell death resulted from an apoptotic process, because 15-d-PGJ2-treated hMFs exhibited condensed nuclei, fragmented DNA, and elevated caspase-3 activity. Moreover, the caspase inhibitor Z-Val-Ala-Asp(OCH3)-fluoromethyl ketone blocked the cytotoxic effect of 15-d-PGJ2. The apoptotic effects of 15-d-PGJ2 were reproduced by H2O2 and blocked by the antioxidants N-acetylcysteine (NAC), N-(2-mercapto-propionyl)-glycine (NMPG) and pyrrolidine dithiocarbamate (PDTC). Accordingly, 15-d-PGJ2 generated rapid production of reactive oxygen species in hMFs, via a NAC/NMPG/PDTC-sensitive pathway. In conclusion, 15-d-PGJ2 induces apoptosis of human hMFs via a novel mechanism involving oxidative stress and unrelated to activation of its nuclear receptor PPARgamma. These data underline the antifibrogenic potential of 15-d-PGJ2.
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PMID:15-deoxy-Delta 12,14-prostaglandin J2 induces apoptosis of human hepatic myofibroblasts. A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors. 1147

Leishmania donovani promastigotes introduced into the bloodstream by sandfly vectors, are exposed to reactive oxygen species like H2O2 during phagocytosis by the host macrophages. H2O2 can induce promastigote death, but the mechanism of induction of this death is not known. Studies presented in this paper demonstrate that exposure to 4 mM H2O2 results in a pattern of promastigote death that shares many features with metazoan apoptosis. Motility and cell survival in these parasites show a gradual decline with increasing doses of H2O2. Features common to metazoan apoptosis, such as nuclear condensation, DNA fragmentation with accompanying DNA ladder formation and loss of cell volume, are observed after exposure to 4 mM H2O2. Within 30 minutes of the exposure, there is a significant increase in the ability of the cell lysates to cleave the fluorogenic tetrapeptide acetyl-Asp-Glu-Val-Asp-7-amino-4-trifluoromethyl coumarin, which is a substrate for the CED-3/CPP32 group of proteases. Pretreatment of cells with a specific inhibitor of CED-3/CPP32 group of proteases, Z-DEVD-FMK, reduces the number of cells showing apoptosis-like features, prevents DNA breakage and inhibits cleavage of a PARP-like protein. Activation of the caspase-like proteases is followed at 2 hours by the cleavage of a poly(ADP)ribose-polymerase-like protein and a reduction in intracellular glutathione concentration. DNA breakdown as detected by TdT labelling of cells and agarose gel electrophoresis is visible at 6 hours. Taken together, the above data show for the first time that there is a distinct pathway for apoptosis-like death in L. donovani.
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PMID:Hydrogen peroxide induces apoptosis-like death in Leishmania donovani promastigotes. 1155 54

1. Caspases and calpains are mediators of apoptotic cell death. The objective of this study was to determine the role of caspases and calpains in primary cerebrocortical neuronal (CCN) death in response to a range of stimuli which reportedly induce neuronal apoptosis. 2. Cell death of primary cultures of rat CCN was induced by staurosporine (STS), C2-ceramide (CER), camptothecin (CMT), hydrogen peroxide (H(2)O(2)) or N-methyl-D-aspartate (NMDA). Caspase and calpain activity were assessed by cleavage of alpha-fodrin or fluorogenic substrates. 3. Cell death was analysed by lactate dehydrogenase (LDH) assay in the absence or presence of the pan-caspase inhibitor Boc-Asp-(OMe)-Fluoromethylketone (Baf) and/or the calpain inhibitor calpeptin (CP). Cell death induced by STS, CER or CMT was accompanied by chromatin condensation and activation of multiple caspases, particularly caspase-3-type proteases. Hydrogen peroxide (H(2)O(2)) treatment was accompanied by activation of caspases -1, -6 and -8, but not -3, whereas none of the caspases tested were activated in response to NMDA. 4. With the exception of H(2)O(2), when cell death was accompanied by caspase activation, it was significantly suppressed by Baf. 5. All stimuli also induced calpain activation, but calpeptin only suppressed cell death induced by H(2)O(2). Furthermore, co-treatment with Baf and calpeptin did not alter the cell death relative to either inhibitor alone. 6. These findings suggest the existence of stimulus-dependent routes for the activation of caspases and calpains during death of cortical neurones and imply that although caspases and calpains are activated, their involvement in the execution of cell death varies with the stimulus.
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PMID:Involvement of caspases and calpains in cerebrocortical neuronal cell death is stimulus-dependent. 1186 36

We examined whether generation of H2O2 is a critical event for the apoptotic pathway upstream of mitochondrial involvement and caspase-3 protease activation. Perylquinone photosensitizers such as Hypocrellin A (HA), Hypocrellin B (HB) and Hypericin (HY) induced activation of caspase-3 and apoptosis upon photoactivation. Generation of H2O2 was commonly detected after photoactivation within an hour, and scavenging of H2O2 caused cells to fail to undergo apoptosis. Flow cytometry demonstrated that H2O2 production preceded loss of mitochondrial membrane potential (DeltaPsim) in photoactivated cells treated with HA, HB and HY. Then caspase-3 activity was activated, followed by DNA fragmentation. These findings suggest that HA, HB and HY upon photoactivation induce H2O2 generation, which causes (DeltaPsim) and subsequently caspase-3 activation, resulting in apoptosis. These findings suggest that generation of H2O2 by photoactivation of HA, HB and HY causes activation of caspase-3. Therefore, H2O2 may function as a common mediator for apoptosis induced by HA, HB and HY. The present study also demonstrated that upon photoactivation HA, HB and HY induced a decrease in intracellular acidification, glutathione (GSH) depletion and an array of mitochondrial damage together with apoptotic morphological changes in the irradiated cells.
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PMID:Hypocrellins and Hypericin induced apoptosis in human tumor cells: a possible role of hydrogen peroxide. 1195 50

Reactive oxygen species not only modulate important signal transduction pathways, but also induce DNA damage and cytotoxicity in keratinocytes. Hydrogen peroxide and organic peroxides are particularly important as these chemicals are widely used in dermally applied cosmetics and pharmaceuticals, and also represent endogenous metabolic intermediates. Lipid peroxidation is of fundamental interest in the cellular response to peroxides, as lipids are extremely sensitive to oxidation and lipid-based signaling systems have been implicated in a number of cellular processes, including apoptosis. Oxidation of specific phospholipid classes was measured in normal human epidermal keratinocytes exposed to cumene hydroperoxide after metabolic incorporation of the fluorescent oxidation-sensitive fatty acid, cis-parinaric acid, using a fluorescence high-performance liquid chromatography assay. In addition, lipid oxidation was correlated with changes in membrane phospholipid asymmetry and other markers of apoptosis. Although cumene hydroperoxide produced significant oxidation of cis-parinaric acid in all phospholipid classes, one phospholipid, phosphatidylserine, appeared to be preferentially oxidized above all other species. Using fluorescamine derivatization and annexin V binding it was observed that specific oxidation of phosphatidylserine was accompanied by phosphatidylserine translocation from the inner to the outer plasma membrane surface where it may serve as a recognition signal for interaction with phagocytic macrophages. These effects occurred much earlier than any detectable changes in other apoptotic markers such as caspase-3 activation, DNA fragmentation, or changes in nuclear morphology. Thus, normal human epidermal keratinocytes undergo profound lipid oxidation with preference for phosphatidylserine followed by phosphatidylserine externalization upon exposure to cumene hydroperoxide. It is therefore likely that normal human epidermal keratinocytes exposed to similar oxidative stress in vivo would under go phosphatidylserine oxidation/translocation. This would make them targets for macrophage recognition and phagocytosis, and thus limit their potential to invoke inflammation or give rise to neoplastic transformations.
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PMID:Selective peroxidation and externalization of phosphatidylserine in normal human epidermal keratinocytes during oxidative stress induced by cumene hydroperoxide. 1206 Mar 96

Caspases have an active site cysteine whose oxidation blocks catalytic activity. Caspase activity, measured in lysates of apoptotic cells, was inhibited by H2O2 with an IC50 of 7 microM. Recombinant caspase-3 was directly inhibited by H2O2, with an estimated second-order rate constant of 750 M-1 s-1. These values were determined when H2O2 was added while the caspases were cleaving a peptide substrate. There was a 40-fold decrease in sensitivity to inactivation if the substrate was absent at the time of H2O2 addition. These results rationalise conflicting reports of the sensitivity of caspase-3 to H2O2, and identify a novel mechanism for sensitising a thiol enzyme to oxidative inactivation.
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PMID:Interaction with substrate sensitises caspase-3 to inactivation by hydrogen peroxide. 1206 43

Arsenic trioxide (As2O3) can induce clinical remission in patients with acute promyelocytic leukemia (APL) through induction of apoptosis. To investigate the potential therapeutic usage of As2O3 in cervical cancer and its possible mechanisms, human cervical cancer cell line HeLa was employed. The cells underwent apoptosis in response to As2O3, accompanied by a decrease of mitochondrial membrane potential and caspase-3 activation. Overexpression of Bcl-2, however, prevented the dissipation of mitochondrial membrane potential, subsequently protecting the cells from As2O3-induced apoptosis. As2O3 increased cellular content of reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), and the antioxidant N-acetyl-L-cysteine completely suppressed As2O3-induced apoptosis. Furthermore, incubation of the cells with catalase resulted in significant suppression of As2O3-induced apoptosis. The above results indicate that the induction of HeLa cell apoptosis by As2O3 involved an early decrease in cellular mitochondrial membrane potential and increase in ROS content, predominantly H2O2, followed by caspase-3 activation and DNA fragmentation.
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PMID:Arsenic trioxide induces apoptosis through a reactive oxygen species-dependent pathway and loss of mitochondrial membrane potential in HeLa cells. 1206 50

D-galactosamine (D-GalN) toxicity is a useful experimental model of liver failure in human. It has been previously observed that PGE1 treatment reduced necrosis and apoptosis induced by D-GalN in rats. Primary cultured rat hepatocytes were used to evaluate if intracellular oxidative stress was involved during the induction of apoptosis and necrosis by D-GalN (0-40mM). Also, the present study investigated if PGE1 (1 microM) was equally potent reducing both types of cell death. The presence of hypodiploid cells, DNA fragmentation and caspase-3 activation were used as a marker of hepatocyte apoptosis. Necrosis was measured by lactate dehydrogenase (LDH) release. Oxidative stress was evaluated by the intracellular production of hydrogen peroxide (H2O2), the disturbances on the mitochondrial transmembrane potential (MTP), thiobarbituric-reacting substances (TBARS) release and the GSH/GSSG ratio. Data showed that intermediate range of D-GalN concentrations (2.5-10mM) induced apoptosis in association with a moderate oxidative stress. High D-GalN concentration (40 mM) induced a reduction of all parameters associated with apoptosis and enhanced all those related to necrosis and intracellular oxidative stress, including a reduction of GSH/GSSG ratio and MTP in comparison with D-GalN (2.5-10 mM)-treated cells. Although PGE1 reduced apoptosis induced by D-GalN, it was not able to reduce the oxidative stress and cell necrosis induced by the hepatotoxin in spite to its ability to abolish the GSH depletion.
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PMID:PGE1 protection against apoptosis induced by D-galactosamine is not related to the modulation of intracellular free radical production in primary culture of rat hepatocytes. 1207 54


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