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)

When cultured cerebellar granule neurons (CGN) are transferred from 25 mM KCl (K25) to 5 mM KCl (K5) caspase-3 and caspase-8, but not caspase-1 or caspase-9,activities are induced and cells die apoptotically. CGN death was triggered by a [Ca(2+)](i) modification when [Ca(2+)](i) was reduced from 300 nM to 50 nM in a K5 medium. The [Ca(2+)](i) changes were followed by an increase in ROS levels. The generation of both cytosolic and mitochondrial reactive oxygen species (ROS) occurred at three different times, 10 min, 30 min and 3--4 hr but only those ROS produced after 3--4 hr are involved in the process of cell death. When CGN cultured in a K5 medium are treated with different antioxidants like scavengers of ROS (mannitol, DMSO) or antioxidant enzymes (superoxide dismutase and catalase) phosphatidylserine translocation, caspase activity, chromatin condensation and cell death is markedly diminished. The protective effect of antioxidants is not mediated through a modification in [Ca(2+)](i). Caspase activation, PS translocation and chromatin condensation were downstream of ROS production. In contrast to H(2)O(2), ROS produced by a xanthine/xanthine oxidase system in CGN cultured in K25 were able to directly induce caspase-3 activation and death that resulted sensitive to z-VAD, a caspase inhibitor. These findings indicate that a reduction in [Ca(2+)](i) triggers CGN death by inducing a generation of ROS after 3--4 hr, which could play a critical role in the initial phases of the apoptotic process including PS translocation, chromatin condensation and the activation of initiator and executor caspases.
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PMID:Role of oxidative stress in the apoptotic cell death of cultured cerebellar granule neurons. 1131 73

Treatment of neuroblastoma cells with the copper chelator triethylene tetramine tetrahydrochloride induced intracellular decrease of copper content paralleled by diminished activity of the enzymes Cu, Zn superoxide dismutase, and cytochrome c oxidase. This effect appears to be specific for copper-enzymes and the treatment affects neither viability nor growth capability of cells. However, molecular markers of apoptosis Bcl-2, p53, and caspase-3 were slightly affected in these cells. When copper-deficient cells were challenged with oxidative stress generated by paraquat or puromycin, they underwent a higher degree of apoptosis with respect to copper-adequate control cells. The mechanism underlying paraquat-triggered apoptosis implies dramatic activation of caspase-3 and induction of the transcription factor p53. These results demonstrate that impairment of copper balance predisposes neuronal cells to apoptosis induced by oxidative stress. Overall findings represent a contribution to the comprehension of the link between copper-imbalance and neurodegeneration, which has recently been repeatedly suggested for the most invalidating pathologies of the central nervous system.
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PMID:Increased susceptibility of copper-deficient neuroblastoma cells to oxidative stress-mediated apoptosis. 1136 9

Manganese(II) has been shown to exhibit catalase-like activity under physiological conditions. In the course of studies to test the antioxidant activity of Mn(II) on HeLa cells, it was observed at high concentrations (1-2 mM) that Mn(II) also induced apoptosis, as judged by changes in cell morphology, caspase-3 activation, cleavage of poly(ADP) ribose, and DNA condensation. However, in contrast to established mechanisms, the Mn(II)-induced apoptosis is associated with an increase rather than a decrease in mitochondrial inner-membrane potential, as monitored by the fluorescent probe tetramethylrhodamine ethyl ester. Based on immunochemical analysis, Mn(II)-induced apoptosis does not lead to the release of cytochrome c into the cytosol. These and other measurements show that treatment with Mn(II) leads to enhancement of the mitochondrial "membrane mass," has no effect on mitochondrial volume, and does not affect the permeability transition pore. Together, these results support the view that Mn(II)-induced apoptosis occurs by a heretofore unrecognized mechanism. In addition, it was demonstrated that Mn(II) treatment leads to an increase in the production of reactive oxygen species (peroxides) and to the induction of the manganese superoxide dismutase and catalase activities but has no effect on the Cu,Zn-superoxide dismutase level.
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PMID:Mitochondria play no roles in Mn(II)-induced apoptosis in HeLa cells. 1149 12

Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress and causing apoptosis. Our previous studies demonstrated that MG induced apoptosis in Jurkat cells by activating the c-Jun N-terminal kinase (JNK) signal transduction pathway, which induced an obvious decrease in mitochondrial membrane potential, followed by caspase-3 activation. Here, we observed that MG-induced apoptosis was associated with both rapid production of superoxide anion (O(2)(-)) followed by a marked increase in ROS and striking and temporal activation of ASK1. Overexpression of wild-type ASK1 could enhance the rate of apoptosis induced by MG, whereas the expression of the kinase-inactive form of ASK1 notably prevented cells from MG-induced death. NAC and PDTC blocked the activation of ASK1 and MG-induced apoptosis completely. Moreover, nonthiol antioxidants SOD-mimic MnTBAP and catalase together obviously inhibited MG-induced ASK1 activation and apoptosis induction. Correspondingly, MG-mediated ASK1 activation was enhanced by diethyldithiocarbamate (DDC). Addition of antioxidant into the culture of cells at a later stage (4-8 h after the initial MG treatment) failed to prevent their death. These results suggest that activating ASK1 at the early stage linking to production of O(2)(-) is crucial for subsequent progression of apoptosis in MG-treated Jurkat cells.
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PMID:Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process. 1149 80

Neuronal apoptosis induced by staurosporine (STS) involves multiple cellular and molecular events, such as the production of reactive oxygen species (ROS). In this study, we tested the efficacy of two synthetic superoxide dismutase/catalase mimetics (EUK-134 and EUK-189) on neuronal apoptosis, oxidative stress, and mitochondrial dysfunction produced by STS in primary cortical neuronal cultures. Exposure of cultures to STS for 24 h increased lactate dehydrogenase (LDH) release, the number of apoptotic cells, and decreased trypan blue exclusion. Pretreatment with 20 microM EUK-134 or 0.5 microM EUK-189 significantly attenuated STS-induced neurotoxicity, as did pretreatment with the caspase-1 inhibitor, Ac-YVAD-CHO, but not the caspase-3 inhibitor, Ac-DEVD-CHO. Posttreatment (1-3 h following STS exposure) with 20 microM EUK-134 or 0.5 microM EUK-189 significantly reduced STS-induced LDH release, in a time-dependent manner. Exposure of cultures to STS for 1 h produced an elevation of ROS, as determined by increased levels of 2,7-dichlorofluorescein (DCF). This rapid elevation of ROS was followed by an increase in lipid peroxidation, and both the increase in DCF fluorescence and in lipid peroxidation were significantly blocked by pretreatment with EUK-134. STS treatment for 3-6 h increased cytochrome c release from mitochondria into the cytosol, an effect also blocked by pretreatment with EUK-134. These results indicate that intracellular oxidative stress and mitochondrial dysfunction are critically involved in STS-induced neurotoxicity. However, there are additional cellular responses to STS, which are insensitive to treatment with radical scavengers that also contribute to its neurotoxicity.
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PMID:Attenuation of staurosporine-induced apoptosis, oxidative stress, and mitochondrial dysfunction by synthetic superoxide dismutase and catalase mimetics, in cultured cortical neurons. 1152 Jan 23

Oxysterols have been shown in a number of cell lines to induce apoptosis by a mechanism as yet unclear. The induction of apoptosis by certain agents has been associated with the generation of oxidative stress and the depletion of the endogenous antioxidant, glutathione, which may result in cytochrome c release and caspase activation. The aim of the present study was to determine whether 7 beta-hydroxycholesterol (7 beta-OH) alters glutathione levels or the activities of catalase, superoxide dismutase (SOD) or caspase-3 in association with cell death in either the U937 or the HepG2 cell lines. 7 beta-OH, which induced significant apoptosis at 12 h in the U937 cell line, was shown to cause a significant decrease in glutathione levels and an increase in the activity of SOD at this time point. An increase in caspase-3 activity was also observed in the U937 cell line following a 24-h incubation with 7 beta-OH. Glutathione concentration, SOD activity and caspase-3 activity were unchanged in the HepG2 cell line, which underwent necrosis following incubation with 7 beta-OH. The activity of the enzyme catalase remained unchanged in both cell lines. These results provide evidence that the generation of an oxidative stress may be a significant event occurring during 7 beta-OH-induced apoptosis.
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PMID:Characteristics of 7 beta-hydroxycholesterol-induced cell death in a human monocytic blood cell line, U937, and a human hepatoma cell line, HepG2. 1202 May 97

There have been very few investigations as to whether mitochondrial-mediated apoptosis in vivo is the underlying mechanism of doxorubicin cardiotoxicity. Moreover, no investigations have been conducted to determine whether there are adaptive responses after doxorubicin treatment. We administered a single dose of doxorubicin (20 mg/kg) to male rats and isolated intact mitochondria from their hearts 4 days later. Apoptosis, as determined by the amount of cytosolic mononucleosomal and oligonucleosomal DNA fragments (180 bp or multiples), was significantly increased after doxorubicin treatment. In contrast, Troponin-T, a cardiac-specific marker for necrotic damage, was unaltered 4 days after doxorubicin treatment. Cytosolic cytochrome c increased 2-fold in the doxorubicin-treated rats and was significantly correlated (r = 0.88; P < 0.01) with the increase in caspase-3 activity observed. Moreover, the level of bleomyocin-detectable iron in serum was significantly increased and may have contributed to the increase in oxidative stress, which was indicated by an increase in cytosolic 8-iso prostaglandin F(2alpha). Cytosolic copper zinc superoxide dismutase activity also increased significantly further supporting the notion that doxorubicin increases superoxide radical production. In addition to adaptations to antioxidant defenses, other adaptive mechanisms occurred in the mitochondria such as an increase in the respiratory P/O ratio and an increase in the Bcl-2:Bax ratio. These findings demonstrate that doxorubicin induces oxidative stress and mitochondrial-mediated apoptosis, as well as adaptive responses by the mitochondria to protect cardiac myocytes in vivo.
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PMID:Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. 1218 13

Airway epithelial cells (AEC) contain both pro- and anti-apoptotic factors but little is known about mechanisms regulating apoptosis of these cells. In this study we have examined the localization of pro-caspase-3 and Zn(2+), a cellular regulator of pro-caspase-3, in primary sheep and human AEC. Zn(2+) was concentrated in both cytoplasmic vesicles and ciliary basal bodies, in the vicinity of both pro-caspase-3 and the antioxidant Cu/Zn superoxide dismutase (Cu/Zn SOD). Depletion of intracellular Zn(2+) in sheep AEC, using the membrane permeant Zn(2+) chelator TPEN, increased lipid peroxidation in the apical cell membranes (as assessed by immunofluorescence with anti-hydroxynonenal) as well as increasing activated pro-caspase-3 and apoptosis. There were smaller increases in caspase-2 and -6 but not other caspases. Activation of caspase-3 in TPEN-treated AEC was inhibited strongly by N-acetylcysteine and partially by vitamin C and vitamin E. These findings suggest that cytoplasmic pro-caspase-3 is positioned near the lumenal surface of AEC where it is under the influence of Zn(2+) and other anti-oxidants.
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PMID:Involvement of redox events in caspase activation in zinc-depleted airway epithelial cells. 1235 64

Apoptosis of vascular smooth muscle cells (VSMCs) is an integral part of cardiovascular diseases including atherosclerosis, hypertension and restenosis. Here we studied the fate of VSMCs in response to intracellular superoxide stimulation. Diethyldithiocarbamic acid (DDC) was used to inhibit copper-zinc superoxide dismutase thereby increasing intracellular superoxide levels. The results show that DDC at a dose from 25-100 micro M is able to induce VSMC apoptosis. Superoxide was found to be responsible for DDC-induced apoptosis. In the apoptotic process mitochondrial membrane potential was decreased and caspase-3, -8 and -9 were activated. Surprisingly, neither cytochrome c release nor Bid cleavage could be observed. These data suggest a role for intracellular superoxide in the regulation of VSMCs apoptosis.
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PMID:Intracellular superoxide induces apoptosis in VSMCs: role of mitochondrial membrane potential, cytochrome C and caspases. 1237 Apr 93

Resolution of inflammation requires clearance of activated neutrophils by phagocytes in a manner that protects adjacent tissues from injury. Mechanisms governing apoptosis and clearance of activated neutrophils from inflamed areas are still poorly understood. We used dimethylsulfoxide-differentiated HL-60 cells showing inducible oxidase activity to study NADPH oxidase-induced apoptosis pathways typical of neutrophils. Activation of the NADPH oxidase by phorbol myristate acetate caused oxidative stress as shown by production of superoxide and hydrogen peroxide, depletion of intracellular glutathione, and peroxidation of all three major classes of membrane phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. In addition, phorbol myristate acetate stimulation of the NADPH oxidase caused apoptosis, as evidenced by apoptosis-specific phosphatidylserine externalization, increased caspase-3 activity, chromatin condensation, and nuclear fragmentation. Furthermore, phorbol myristate acetate stimulation of the NADPH oxidase caused recognition and ingestion of dimethylsulfoxide-differentiated HL-60 cells by J774A.1 macrophages. To reveal the apoptosis-related component of oxidative stress in the phorbol myristate acetate-induced response, we pretreated cells with a pancaspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk), and found that it caused partial inhibition of hydrogen peroxide formation as well as selective protection of only phosphatidylserine, whereas more abundant phospholipids, phosphatidylcholine and phosphatidylethanolamine, were oxidized to the same extent in the absence or presence of z-VAD-fmk. In contrast, inhibitors of NADPH oxidase activity, diphenylene iodonium and staurosporine, as well as antioxidant enzymes, superoxide dismutase/catalase, completely protected all phospholipids against peroxidation, inhibited expression of apoptotic biomarkers and externalization of phosphatidylserine, and reduced phagocytosis of differentiated HL-60 cells by J774A.1 macrophages. Similarly, zymosan-induced activation of the NADPH oxidase resulted in the production of superoxide and oxidation of different classes of phospholipids of which only phosphatidylserine was protected by z-VAD-fmk. Accordingly, zymosan caused apoptosis in differentiated HL-60 cells, as evidenced by caspase-3 activation and phosphatidylserine externalization. Finally, zymosan triggered caspase-3 activation and extensive SOD/catalase-inhibitable phosphatidylserine exposure in human neutrophils. Overall, our results indicate that NADPH oxidase-induced oxidative stress in neutrophil-like cells triggers apoptosis and subsequent recognition and removal of these cells through pathways dependent on oxidation and externalization of phosphatidylserine.
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PMID:NADPH oxidase-dependent oxidation and externalization of phosphatidylserine during apoptosis in Me2SO-differentiated HL-60 cells. Role in phagocytic clearance. 1237 50


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