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)

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

Oxidative stress can be induced neurotoxic insults by increasing intracellular H2O2, which has been implicated in various neurodegenerative diseases in aging. We investigated the mechanism by which Debo protects PC12 cells from serum deprivation-induced apoptosis. PC12 cells underwent apoptotic death in association with increase in caspase 3-like activity, DNA fragmentation, H2O2 production, GSH depletion, and NF-kappaB activation after 24 hr of serum withdrawal. Debo protected cells from a serum deprivation-induced cytotoxicity in a dose dependent manner. Debo recovered the intracellular GSH level decreased by serum deprivation in PC12 cells. Also, Debo inhibited the activation of caspase 3-like protease of serum-deprived PC12 cells in a dose dependent manner. Furthermore, Debo inhibited the transcriptional activation of NF-kappaB by serum deprivation. These findings indicate that Debo may protect PC12 cells against apoptosis by serum deprivation via generation of intracellular GSH to scavenge oxidative radicals including H2O2.
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PMID:Protective effects of Debo on serum-deprived apoptosis of PC12 cells via inhibition of H2O2 generation and caspase 3-like protease activity. 1206 49

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

Tauhe main component of cerebral amyloid angiopathy (CAA) in Alzheimer's disease is the amyloid-beta protein (Abeta), a 4-kDa polypeptide derived from the beta-amyloid protein precursor (APP). The accumulation of Abeta in the basement membrane has been implicated in the degeneration of adjacent vascular smooth muscle cells (VSMC). However, the mechanism of Abeta toxicity is still unclear. In this study, we examined the effect of substrate-bound Abeta on VSMC in culture. The use of substrate-bound proteins in cell culture mimics presentation of the proteins to cells as if bound to the basement membrane. Substrate-bound Abeta peptides were found to be toxic to the cells and to increase the rate of cell death. This toxicity was dependent on the length of time the peptide was allowed to 'age', a process by which Abeta is induced to aggregate over several hours to days. Oxidative stress via hydrogen peroxide (H2O2) release was not involved in the toxic effect, as no decrease in toxicity was observed in the presence of catalase. However, substrate-bound Abeta significantly reduced cell adhesion compared to cells grown on plastic alone, indicating that cell-substrate adhesion may be important in maintaining cell viability. Abeta also caused an increase in the number of apoptotic cells. This increase in apoptosis was accompanied by activation of caspase-3. Homocysteine, a known risk factor for cerebrovascular disease, increased Abeta-induced toxicity and caspase-3 activation in a dose-dependent manner. These studies suggest that Abeta may activate apoptotic pathways to cause loss of VSMC in CAA by inhibiting cell-substrate interactions. Our studies also suggest that homocysteine, a known risk factor for other cardiovascular diseases, could also be a risk factor for hemorrhagic stroke associated with CAA.
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PMID:Toxicity of substrate-bound amyloid peptides on vascular smooth muscle cells is enhanced by homocysteine. 1207 66

We examined the effect of 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene (NOC12), a nitric oxide (NO) donor, on apoptosis in cultured astrocytes. Reperfusion after hydrogen peroxide (H2O2) exposure caused a decrease in cell viability, loss of mitochondrial membrane potential, caspase-3 activation, DNA ladder formation, and nuclear condensation. NOC12 at 10-100 microM significantly attenuated these apoptotic changes, while the NO donor at 1 mM caused cell injury and exacerbated the H202-induced cell injury. NOC12 increased intracellular cGMP levels in a dose dependent manner with the maximal effect at 100 microM. The protective effect of NOC12 was mimicked by the NO-independent guanylate cyclase activator 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole, and was attenuated by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and the cGMP-dependent protein kinase inhibitor KT5823. ODQ and KT5823 did not block but rather exacerbated the cytotoxic effect of NOC12 at 1 mM. These findings demonstrate that lower concentrations of NOC12 inhibit the H2O2-induced apoptosis of astrocytes in a cGMP-dependent way, but higher concentrations of NOC12 show a toxic effect on astrocytes in a cGMP-independent way.
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PMID:The nitric oxide donor NOC12 protects cultured astrocytes against apoptosis via a cGMP-dependent mechanism. 1208 44

The tumor suppressor p53 protein is known to play a critical role in apoptosis. In normal human diploid fibroblasts (HDFs), expression of the human papillomaviral (HPV) E6 gene results in a reduction of p53 protein and an inhibition of oxidant induced apoptosis within 24 h. In comparison, expression of the HPV E7 gene causes down-regulation of Rb protein without inhibiting apoptosis. Here we determine whether HDFs expressing E6 undergo cell death with a delayed time course following H2O2 exposure. Appearances of caspase-3 activity, cell detachment, trypan blue uptake and aberrant nuclei were all delayed in E6 cells compared to wild type (wt) or E7 cells. A mutant E6 gene that failed to reduce p53 could not delay cell death. Morphological examination revealed nuclear condensation in dying wt or E7 cells but nuclear fragmentation in E6 cells. Flow cytometry analysis indicated an S phase distribution of dying wt or E7 cells but a G2/M phase distribution of dying E6 cells. An elevation of cyclin B was observed in dying E6 cells but not in apoptotic E7 cells. Dying E6 cells also had elevated levels of cdc-2 protein and histone kinase activity, suggesting that the cells died at mitosis. Electron microscopy studies showed that E6 cells may die at prophase or prometaphase. Overexpression of bcl-2 resulted in an inhibition of both caspase-3 and death of E7 or E6 cells. Inactivating caspases with zVAD-fmk also reduced the death rate of E7 and E6 cells. Our data indicate that expression of HPV E6 causes a delay and morphological modification of cell death induced by oxidants. E6 cells die at mitosis, which can be inhibited by bcl-2 overexpression or caspase inhibition.
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PMID:Down regulation of p53 with HPV E6 delays and modifies cell death in oxidant response of human diploid fibroblasts: an apoptosis-like cell death associated with mitosis. 1214 52

We hypothesized that reactive oxygen species play an important role in avascular/ischemic osteonecrosis. When isolated chick osteocytes were cultured with hydrogen peroxide, annexin V binding, which is the earliest marker of apoptosis, increased in a dose-dependent fashion. Hydrogen peroxide also induced the activation of caspase-3 and increase in cytosolic Ca2+. Treatment with BAPTA/AM (cheletor of cytosolic Ca2+) and Ac-DEVD-cho (caspase inhibitor) attenuated hydrogen peroxide-induced apoptosis. These data demonstrated the signal transduction pathways that participate in this hydrogen peroxide-induced cell damage.
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PMID:Hydrogen peroxide induces apoptosis of osteocytes: involvement of calcium ion and caspase activity. 1215 90

Chronic systemic complex I inhibition caused by rotenone exposure induces features of Parkinson's disease (PD) in rats, including selective nigrostriatal dopaminergic degeneration and formation of ubiquitin- and alpha-synuclein-positive inclusions (Betarbet et al., 2000). To determine underlying mechanisms of rotenone-induced cell death, we developed a chronic in vitro model based on treating human neuroblastoma cells with 5 nm rotenone for 1-4 weeks. For up to 4 weeks, cells grown in the presence of rotenone had normal morphology and growth kinetics, but at this time point, approximately 5% of cells began to undergo apoptosis. Short-term rotenone treatment (1 week) elevated soluble alpha-synuclein protein levels without changing message levels, suggesting that alpha-synuclein degradation was retarded. Chronic rotenone exposure (4 weeks) increased levels of SDS-insoluble alpha-synuclein and ubiquitin. After a latency of >2 weeks, rotenone-treated cells showed evidence of oxidative stress, including loss of glutathione and increased oxidative DNA and protein damage. Chronic rotenone treatment (4 weeks) caused a slight elevation in basal apoptosis and markedly sensitized cells to further oxidative challenge. In response to H2O2, there was cytochrome c release from mitochondria, caspase-3 activation, and apoptosis, all of which occurred earlier and to a much greater extent in rotenone-treated cells; caspase inhibition provided substantial protection. These studies indicate that chronic low-grade complex I inhibition caused by rotenone exposure induces accumulation and aggregation of alpha-synuclein and ubiquitin, progressive oxidative damage, and caspase-dependent death, mechanisms that may be central to PD pathogenesis.
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PMID:An in vitro model of Parkinson's disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. 1217 98


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