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: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We had earlier shown that higher concentration of hydrogen peroxide (H(2)O(2)) induced p53-dependent apoptosis in glioma cell line with wild type p53 but had minimal effect on cells with mutated p53. Here we show a potentiating effect of hydroxylamine (HA), an inhibitor of catalase, on a nontoxic dose of H(2)O(2) in glioma cells. HA sensitized both p53 wild type and mutated glioma cells to 0.25 mM H(2)O(2). Potentiating effect of HA was independent of p53. Higher levels of reactive oxygen species (ROS) generation were observed in cells treated with HA+H(2)O(2) as compared to cells treated with each component alone in both the cell lines. Dimethyl sulfoxide (DMSO) protected cells. Cytosolic cytochrome c and activated caspase 3 were detected at 4h. The results suggest that higher levels of intracellular ROS, generated by HA+H(2)O(2) act as a molecular switch in activating a rapidly acting p53-independent mitochondrial apoptotic pathway.
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PMID:Hydroxylamine potentiates the effect of low dose hydrogen peroxide in glioma cells independent of p53. 1296 3

In the present study, we investigated the effect of tetraarsenic oxide (As4O6, 2,4,6,8,9,10-Hexaoxa-1,3,5,7-tetraarsatricyclo[3.3.1.13,7]decane) upon induction of apoptosis in arsenic trioxide (diarsenic oxide, As2O3) resistant U937 leukemic cells. As4O6 induced apoptosis in U937 leukemic cells at much lower concentrations than As2O3 via an early increase of cellular reactive oxygen species (ROS), and a decrease in cellular mitochondrial membrane potential, followed by cytochrome c release and caspase-3 activation. As4O6 generated ROS and induced caspase-3 activation more potently than As2O3 in U937 cells. Incubation of the cells with N-acetyl-L-cysteine and catalase resulted in significant suppression of As4O6-induced apoptotic cell death. These results show that the generation of ROS leads to the consequences associated with apoptosis induced by As4O6. In conclusion, As4O6 might be a new arsenic compound which may induce apoptosis in U937 leukemic cells by activating unique apoptotic signaling mediated by ROS more potently than As2O3, and deserves further evaluation.
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PMID:Tetraarsenic oxide induces apoptosis in U937 leukemic cells through a reactive oxygen species-dependent pathway. 1296 72

Reactive oxygen species (ROS) have been suggested as important mediators of cisplatin-induced acute renal failure in vivo. However, our previous studies have shown that cisplatin-induced cell death in vitro could not be prevented by scavengers of hydrogen peroxide and hydroxyl radical in rabbit renal cortical slices. This discrepancy may be attributed to differential roles of ROS in necrotic and apoptotic cell death. We therefore examined, in this study, the roles of ROS in necrosis and apoptosis induced by cisplatin in primary cultured rabbit proximal tubule. Cisplatin induced necrosis at high concentrations over a few hours and apoptosis at much lower concentrations over longer periods. Necrosis induced by high concentration of cisplatin was prevented by a cell-permeable superoxide scavenger (tiron), hydrogen peroxide scavengers (catalase and pyruvate), and antioxidants (Trolox and deferoxamine), whereas hydroxyl radical scavengers (dimethythiourea and thiourea) did not affect the cisplatin-induced necrosis. However, apoptosis induced by lower concentration of cisplatin was partially prevented by tiron and hydroxyl radical scavengers but not by hydrogen peroxide scavengers and antioxidants. Cisplatin-induced apoptosis was mediated by the signaling pathway that is associated with cytochrome c release from mitochondria and caspase-3 activation. These effects were prevented by tiron and dimethylthiourea but not by catalase. Dimethylthiourea produced a significant protection against cisplatin-induced acute renal failure, and the effect was associated with an inhibition of apoptosis. These results suggest that hydrogen peroxide is involved in the cisplatin-induced necrosis, whereas hydroxyl radical is responsible for the cisplatin-induced apoptosis. The protective effects of hydroxyl radical scavengers are associated with an inhibition of cytochrome c release and caspase activation.
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PMID:Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced cell death in renal proximal tubular epithelial cells. 1453 6

The stress-activated protein kinase c-Jun NH2-terminal kinase (JNK) is a central signal for interleukin-1beta (IL-1beta)-induced apoptosis in insulin-producing beta-cells. The cell-permeable peptide inhibitor of JNK (JNKI1), that introduces the JNK binding domain (JBD) of the scaffold protein islet-brain 1 (IB1) inside cells, effectively prevents beta-cell death caused by this cytokine. To define the molecular targets of JNK involved in cytokine-induced beta-cell apoptosis we investigated whether JNKI1 or stable expression of JBD affected the expression of selected pro- and anti-apoptotic genes induced in rat (RIN-5AH-T2B) and mouse (betaTC3) insulinoma cells exposed to IL-1beta. Inhibition of JNK significantly reduced phosphorylation of the specific JNK substrate c-Jun (p<0.05), IL-1beta-induced apoptosis (p<0.001), and IL-1beta-mediated c-fos gene expression. However, neither JNKI1 nor JBD did influence IL-1beta-induced NO synthesis or iNOS expression or the transcription of the genes encoding mitochondrial manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase rho (GSTrho), heat shock protein (HSP) 70, IL-1beta-converting enzyme (ICE), caspase-3, apoptosis-inducing factor (AIF), Bcl-2 or Bcl-xL. We suggest that the anti-apoptotic effect of JNK inhibition by JBD is independent of the transcription of major pro- and anti-apoptotic genes, but may be exerted at the translational or posttranslational level.
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PMID:The JNK binding domain of islet-brain 1 inhibits IL-1 induced JNK activity and apoptosis but not the transcription of key proapoptotic or protective genes in insulin-secreting cell lines. 1456 87

A key feature of recovery from liver fibrosis is hepatic stellate cell (HSC) apoptosis, which serves the dual function of removing the major source of neomatrix and tissue inhibitors of metalloproteinases thereby facilitating matrix degradation. The mechanisms regulating HSC apoptosis remain undefined but may include the interaction of nerve growth factor (NGF) with its receptor, p75, on HSC. In this study, by TaqMan polymerase chain reaction in situ hybridization and immunohistochemistry, we demonstrate that NGF is expressed by hepatocytes during fibrotic injury. Peak hepatocyte expression of NGF (48 hours after CCl(4) injection) coincides with maximal rate of apoptosis of HSC by terminal dUTP nick-end labeling staining. Addition of recombinant NGF to HSC in tissue culture causes a dose-dependent increase in apoptosis. NGF regulates nuclear factor (NF)-kappaB activity, reducing p50/p65 binding detected by electromobility shift assay and reduced NF-kappaB CAT reporter activities from both basal unstimulated levels and after NF-kappaB induction by tumor necrosis factor. In each case, a relative reduction in NF-kappaB binding was associated with a significant increase in caspase 3 activity. These data provide evidence that NGF is expressed during fibrotic liver injury and may regulate number of activated HSCs via induction of apoptosis.
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PMID:Hepatocytes express nerve growth factor during liver injury: evidence for paracrine regulation of hepatic stellate cell apoptosis. 1457 85

We previously demonstrated that evening primrose extract (EPE) induced apoptosis in Ehrlich ascites tumor cells, while mouse embryo fibroblast cells (NIH3T3) used as a normal cell model, showed no effect of cell viability by treatment of EPE. Furthermore, our results demonstrated the rapid increase in intracellular peroxides levels, loss of mitochondrial membrane potential and the release of cytochrome c to cytosol, suggesting that the rapid increase in intracellular peroxides levels after addition of EPE triggers off induction of apoptosis. In this study, we identified that EPE elicited the translocation of Bax to mitochondria and apoptosis-inducing factor (AIF) to nuclei, but no activation of caspase-3-like protease. We also demonstrated that the rapid EPE-induced increase in hydrogen peroxide levels caused the translocation of Bax to mitochondria, and then mitochondrial cytochrome c was released. One of the main consequences of mitochondrial cytochrome c release is the activation of caspase-3. However, no caspase-3 activation was observed. On the other hand, AIF was translocated from mitochondria to nuclei. The EPE-induced translocation of AIF was suppressed with the addition of catalase, suggesting that the rapid intracellular peroxide levels after addition of EPE triggers off induction of apoptosis, which is AIF-mediated and caspase-independent.
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PMID:Caspase-independent apoptosis induced by evening primrose extract in Ehrlich ascites tumor cells. 1458 Jun 81

We have explored the impact of nitric oxide (NO) exposure on oxidation damage of lipids, and proteins, and the contribution of this type of damage to the activation of the apoptotic program in insulin secreting RINm5F cells. Exposure of cells to NO donors and to interleukin-1 beta (IL-1beta) led to generation of lipooxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Addition of superoxide dismutase (SOD) and catalase (Cat) to cells decreased by 50% MDA and 4-HNE production induced by IL-1beta. Over-expression of Mn-SOD in cells conferred a remarkable decrease (75%) in IL-1beta-induced lipid peroxidation. These data suggest that peroxynitrite (ONOO(-)) mediates peroxidative damage to lipids in this cell system. Inhibitors of advanced lipooxidation end products (ALEs) formation such as aminoguanidine (AG) and pyridoxamine (PM) prevented partially apoptotic events triggered by NO such as DNA fragmentation, caspase-3 activation and cytochrome c release from mitochondria. These findings indicate that ALEs are involved in NO-induced apoptosis. In fact, NO-induced carbonylation of PARP protein preceded its apoptotic degradation and inhibitors of ALEs formation prevented both events. We thus propose that carbonylation of proteins is instrumental in linking NO-dependent lipid oxidation and apoptosis in this cell system.
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PMID:Involvement of advanced lipooxidation end products (ALEs) and protein oxidation in the apoptotic actions of nitric oxide in insulin secreting RINm5F cells. 1459 54

The antioxidant and anticancer properties of a medicinal plant, Betula platyphylla var. japonica were investigated. The total methanol extract of B. platyphylla var. japonica had protective effects against hydrogen peroxide (H2O2) in the Chinese hamster lung fibroblast (V79-4) cell line and induced apoptotic cell death in human promyelocytic leukemia (HL-60) cells, a cancer cell line. B. platyphylla var. japonica extract significantly increased cell viability against H2O2. The extract also showed high 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity (IC50 2.4 microg/ml) and lipid peroxidation inhibitory activity (IC50 below 4.0 microg/ml). Furthermore, B. platyphylla var. japonica extract reduced the number of V79-4 cells arrested in G2/M in response to H2O2 treatment and increased the activities of several cellular antioxidant enzymes, including superoxide dismutase, catalase and glutathione peroxidase. Treatment with B. platyphylla var. japonica extract induced cytotoxicity and apoptosis in HL-60 cells, as shown by nucleosomal DNA fragmentation, increases in the subdiploid cell population, and fluorescence microscopy. B. platyphylla var. japonica extract gradually increased the expression of pro-apoptotic Bax and led to the activation of caspase-3 and cleavage of PARP. These findings suggest that B. platyphylla var. japonica exhibits potential antioxidant and anticancer properties.
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PMID:Antioxidant and anticancer activity of extract from Betula platyphylla var. japonica. 1467 57

Although Haemophilus somnus causes septicemia and vasculitis in cattle, relatively little is known about how H. somnus affects endothelial cells in vitro. We previously reported that H. somnus lipooligosaccharide (LOS)-induced activation of caspases-3, -8 and -9, and apoptosis of bovine pulmonary artery endothelial cells (BPAEC) in vitro. Previous reports indicate that the generation of reactive oxygen species (ROS) or reactive nitrogen intermediates (RNI) can contribute to the induction of apoptosis. In the present study, we sought to determine whether ROS and RNI are involved in LOS-mediated apoptosis of BPAEC. We found that H. somnus LOS induced the generation of ROS in BPAEC, which was blocked by pretreatment with membrane permeable ROS scavengers, such as dimethylsulfoxide (DMSO) and allopurinol (AP). Addition of DMSO or AP significantly reduced H. somnus LOS-mediated caspase-3 activation. Addition of membrane impermeable ROS scavengers (e.g. catalase and superoxide dismutase), failed to block LOS-mediated caspase-3 activation, suggesting a role for intracellular generation of ROS in LOS-induced apoptosis of BPAEC. Addition of N(G)-nitro-L-arginine methyl ester (L-NAME) or aminoguanidine, which are selective inhibitors of nitric oxide synthase, blocked NO release and significantly reduced caspase-3 activation in LOS treated BPAEC. These data suggest H. somnus LOS triggers endogenous ROS and RNI production by endothelial cells, which contributes to apoptosis.
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PMID:Reactive oxygen and nitrogen intermediates contribute to Haemophilus somnus lipooligosaccharide-mediated apoptosis of bovine endothelial cells. 1474 Nov 39

The pro-apoptotic ability of conjugated linoleic acid (CLA) has been partly accounted for its anticarcinogenic effect although the precise mechanism of action remains elusive. In this study we characterized the biochemical events governing CLA-mediated apoptosis in Jurkat T cells. CLA induced a time-and dose-dependent activation of caspase-3. Pre-treatment with antioxidant molecules (trolox and quercetin), antioxidant enzymes (catalase and superoxide dismutase) metal chelator (EDTA), reducing agent (N-acetyl-L-cysteine), NADPH oxidase or protein kinase C (PKC) inhibitor (diphenyleneiodinium and G 6976, respectively) suppressed CLA-mediated caspase-3 activation. Moreover, CLA treatment increased the NADPH oxidase activity and depleted the intracellular pool of reduced glutathione. These results suggested that CLA can trigger apoptosis through an oxidative stress mediated by the PKC/NADPH oxidase pathway. The proposed mechanism provides a new insight into the anticancer activity of CLA.
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PMID:Conjugated linoleic acid--mediated apoptosis in Jurkat T cells involves the production of reactive oxygen species. 1497 7


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