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)

We found that treatment of U937 cells with ZnCl(2) resulted in marked inhibition of ricin-induced DNA fragmentation and nuclear morphological change. Zn(2+) also completely inhibited the activation of caspase-3-, caspase-6-, and caspase-9-like proteases in ricin-treated cells, while no significant effect of Zn(2+) on these protease activities was observed when added directly to the lysate of ricin-treated cells, suggesting that Zn(2+) blocks the process of the activation of these caspases rather than the direct inhibition of the already activated enzymes. Fluorescence microscopic observation with Zn(2+) specific fluorescent probe dansylaminoethyl-cyclen suggested that there was a substantial increase in probe-detectable Zn(2+) in ricin-treated cells. Since the differences in the total Zn(2+) contents between ricin-treated and -untreated cells as measured with an atomic absorption spectrophotometer were too small to explain the increase in probe fluorescence in ricin-treated cells, it was suggested that release of Zn(2+) from intracellular stores or metalloproteins may occur rather than enhanced uptake from the medium. The Zn(2+) probe fluorescence change was observed prior to the depletion of intracellular glutathione. Carbobenzoxy-Asp-1-yl-[(2,6-dichlorobenzoyl)oxy]methane (Z-Asp-CH(2)-DCB), a caspase family protease inhibitor, prevented ricin-induced increase in Zn(2+) probe fluorescence. These results suggest that redistribution of intracellular Zn(2+) occurs during ricin-induced apoptosis as early apoptotic event, and exogenously added Zn(2+) may prevent such intracellular Zn(2+) redistribution resulting in the inhibition of apoptosis.
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PMID:Role of zinc ions in ricin-induced apoptosis in U937 cells. 1204 48

We previously reported that two trifluoromethyl ketones, 3,3,3-trifluoro-1-phenyl-1,2-propanedione (TF1) and 1,1,1-trifluoro-3-phenyl-2-propanone (TF2), have neuroprotective effects against low K(+)-induced apoptosis in cerebellar granule neurons (CGNs) exposed at 12-13 days in vitro (DIV). On the other hand, these compounds showed weak neuroprotective potency against 7 DIV CGNs. It is reported that actinomycin D (Act-D), cycloheximide (CHX), and caspase-3 inhibitors prevent the apoptosis of CGNs induced by K+ deprivation. However, these experiments are generally performed using 7 DIV CGNs. We investigated and compared the antiapoptotic efficacy of these drugs and newly-discovered TF1 and TF2 to protect DIV 7 and 12-13 CGNs from death induced by K+ deprivation. Apoptosis of CGNs induced by K+ withdrawal at 13 DIV was potently inhibited by Act-D and CHX similar to those at 7 DIV. Caspase-3 inhibitors moderately suppressed cell death during low K(+)-induced apoptosis both exposed 7 and 13 DIV. Serine protease inhibitor N-tosyl-L-phenylalanyl chloromethylketone (TPCK) had no effect on K(+)-deprivation-induced apoptosis of CGNs at both 7 and 12 DIV. This study showed that there are different pathways of apoptosis in CGNs depending on the culture age.
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PMID:Trifluoromethyl ketones show culture age-dependent inhibitory effects on low K(+)-induced apoptosis in cerebellar granule neurons. 1207 78

Residual oil fly ash (ROFA) is a pollutant dust that stimulates production of reactive oxygen species (ROS) from mitochondria and apoptosis in alveolar macrophages (AM), but the relationship between these two processes is unclear. In this study, human AM were incubated with ROFA or vanadyl sulfate (VOSO(4)), the major metal constituent in ROFA, with or without nitro-L-arginine methyl ester (L-NAME), diphenyleneiodonium (DPI), and mitochondrial electron transport inhibitors. Interactions among production of ROS, nitric oxide (NO), and apoptosis of AM were determined. ROFA-stimulated ROS production was attenuated by DPI, rotenone, antimycin, and NaN(3), but not by L-NAME, a pattern mimicked by VOSO(4). ROFA-induced apoptosis was inhibited by L-NAME and a caspase-3-like protease inhibitor, but not by mitochondrial inhibitors. ROFA enhanced NO-mediated increase in caspase-3-like activity. VOSO(4) had minor effects on apoptosis. Thus ROFA-stimulated production of ROS from mitochondria was independent of apoptosis of AM, which was mediated by activation of caspase-3-like proteases and NO. The pro-oxidant effect but not the proapoptotic effect of ROFA was mediated by vanadium.
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PMID:Mitochondrial oxidant production by a pollutant dust and NO-mediated apoptosis in human alveolar macrophage. 1238 87

This experimental study was designed to determine if caspase-3-like protease is activated during a short period of ischemia - reperfusion (I-R) that did not induce apoptosis, and whether protease-3-protease inhibitor could prevent myocardial I-R injury, especially necrotic cell death. The subjects were 20 isolated rat hearts; 10 were pretreated for 20 min with 100 micromol/L of the protease-3-protease inhibitor, peptide antagonist Asp-Glu-Val-Asp-CHO (DEVD) (Group D), and compared with the 10 no-pretreated hearts (Group C). The hearts were then subjected to 20, 30, 45, and 60 min of normothermic global ischemia followed by 30 min of reperfusion. Caspase-3-like protease was significantly elevated after 45 min and 60 min in ischemic hearts. Group D had reduced levels of caspase-3-like protease activity after 45 min and 60 min (302+/-58%, 378+/-69% of pre-ischemic control, respectively), as compared with Group C (542+/-74%, 689+/-85%, respectively) (p<0.05, p<0.05, respectively). Histological analysis also demonstrated a decrease in cellular damage in Group D, as the count ratio of necrotic cells with total cardiomyocytes was 38%, as compared with 78% in the control group (p<0.05). Caspase-3-like protease participated in I-R injury in rat hearts and inhibition of this protease resulted in a reduction of necrotic cell death.
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PMID:Participation of caspase-3-like protease in necrotic cell death of myocardium during ischemia-reperfusion injury in rat hearts. 1260 76

Caspase-8 is a key effector of death-receptor-triggered apoptosis. In a previous study, we demonstrated, however, that caspase-8 can also be activated in a death receptor-independent manner via the mitochondrial apoptosis pathway, downstream of caspase-3. Here, we show that caspases-3 and -8 mediate a mitochondrial amplification loop that is required for the optimal release of cytochrome c, mitochondrial permeability shift transition, and cell death during apoptosis induced by treatment with the microtubule-damaging agent paclitaxel (Taxol). In contrast, Smac release from mitochondria followed a different pattern, and therefore seems to be regulated independently from cytochrome c release. Taxol-induced cell death was inhibited by the use of synthetic, cell-permeable caspase-3- (zDEVD-fmk) or caspase-8-specific (zIETD-fmk) inhibitors. Apoptosis signaling was not affected by a dominant-negative FADD mutant (FADD-DN), thereby excluding a role of death receptor signaling in the amplification loop and drug-induced apoptosis. The inhibitor experiments were corroborated by the use of BJAB cells overexpressing the natural serpin protease inhibitor, cytokine response modifier A. These data demonstrate that the complete activation of mitochondria, release of cytochrome c, and execution of drug-induced apoptosis require a mitochondrial amplification loop that depends on caspases-3 and -8 activation. In addition, this is the first report to demonstrate death receptor-independent caspase-8 autoprocessing in vivo.
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PMID:Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven mitochondrial amplification loop. 1270 Jun 60

The human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 has been implicated in the pathogenesis of HIV-1 dementia. Thus, inhibition of gp120 activity could reduce HIV toxicity in the brain. We have used primary cultures of rat cerebellar granule cells to examine mechanisms whereby gp120 causes cell death and to characterize neuroprotective agents. gp120 induced a time- and concentration-dependent apoptotic cell death, which was caspase-3-mediated but caspase-1 independent, and was totally blocked by the irreversible caspase-3-like protease inhibitor N-acetyl-Asp-Glu-Val-Asp-chloromethylketone. Caspase-3 activation was observed only in neurons that internalize gp120, indicating that internalization is key to gp120 toxicity. Because brain-derived neurotrophic factor (BDNF) prevents caspase-3-mediated neuronal cell death, we examined whether BDNF could prevent gp120-mediated apoptosis. Preincubation of neurons with BDNF before the addition of gp120 reduced caspase-3 activation, and consequently rescued 80% of neurons from apoptosis. Most importantly, BDNF reduced the levels of CXC chemokine receptor-4 (CXCR4), a receptor that mediates HIV-1 gp120-induced apoptosis. This effect correlated with the ability of BDNF to reduce gp120 internalization and apoptosis. Moreover, BDNF blocked the neurotoxic effect of stromal-derived factor-1alpha, a natural ligand for CXCR4, further establishing a correlation between neuroprotection and downregulation of CXCR4. We propose that BDNF may be a valid therapy to slow down the progression of HIV/gp120-mediated neurotoxicity.
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PMID:Brain-derived neurotrophic factor inhibits human immunodeficiency virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 internalization. 1284 75

N-Tosyl-L-phenylalanyl chloromethyl ketone (TPCK), a chymotrypsin-like serine protease inhibitor, affected apoptosis in human monocytic THP.1 cells differently dependent on both the concentration used and the apoptotic stimulus. TPCK (50 - 75 microM) induced both biochemical and ultrastructural changes characteristic of apoptosis, including proteolysis of poly (ADP-ribose) polymerase (PARP) and lamins together with formation of large kilobase pair fragments of DNA, particularly of 30 - 50 and 200 - 300 kilobase pairs in length but without internucleosomal cleavage of DNA. The induction of apoptosis by TPCK also involved the processing of CPP32 and Mch 3 to their catalytically active subunits. Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.FMK), an ICE-like protease inhibitor, completely prevented all the biochemical and morphological changes induced by TPCK demonstrating the involvement of ICE-like proteases in the execution phase of apoptosis. Lower concentrations of TPCK (5 - 20 microM) prevented internucleosomal cleavage of DNA induced by other apoptotic stimuli. TPCK (10 microM) inhibited cell death induced by etoposide but potentiated that induced by cycloheximide demonstrating that it differentially affected apoptosis in THP.1 cells dependent on the stimulus used. These results are consistent with at least three distinct TPCK targets, one being important for cell survival, the second in facilitating internucleosomal cleavage of DNA and the third in the modulation of apoptosis induced by different apoptotic stimuli.
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PMID:Apoptosis in human monocytic THP.1 cells involves several distinct targets of N-tosyl-L-phenylalanyl chloromethyl ketone (TPCK). 1455 72

The protease inhibitor ritonavir is an integral part of current antiretroviral therapy targeting human immunodeficiency virus. Recent studies demonstrate that ritonavir induces apoptotic cell death with high efficiency in lymphoblastoid cell lines. Moreover, ritonavir can suppress activation of the transcription factor nuclear factor-kappaB and is an inhibitor of interleukin-1beta and tumor necrosis factor-alpha production in peripheral blood mononuclear cells. Thus, ritonavir appears to have anti-inflammatory properties. In the present study, we investigated in DLD-1 colon carcinoma cell effects of ritonavir on apoptotic cell death and expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme that may be critically involved in the modulation of colonic inflammation. Compared to unstimulated control, ritonavir resulted in a moderate increase in the rate of apoptotic cell death as observed after 20 h of incubation. Notably, ritonavir potently synergized with the short-chain fatty acid butyrate for induction of caspase-3-dependent apoptosis in DLD-1 cells. Ritonavir enhanced mRNA and protein expression of HO-1 in DLD-1 cells. Ritonavir-induced HO-1 protein was suppressed by SB203580 or SB202190 and preceded by immediate upregulation of cellular c-Fos and c-Jun protein levels. This process was associated with induction of activator protein-1 as detected by electrophoretic mobility shift analysis. The present data suggest that ritonavir has the potential to curb colon carcinogenesis by reducing cell growth via mechanisms that include apoptosis and by simultaneously modulating colonic inflammation via induction of anti-inflammatory HO-1.
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PMID:The HIV protease inhibitor ritonavir synergizes with butyrate for induction of apoptotic cell death and mediates expression of heme oxygenase-1 in DLD-1 colon carcinoma cells. 1550 50

Although ischemia reperfusion (I/R) induces apoptotic damage of mammalian small intestine, the molecular mechanism is largely unknown. We investigated the appearance of apoptosis at various time-points (0-24 h) of reperfusion after 1-h ischemia and the expression of various apoptosis-related proteins, such as Bcl-2, Bax, Fas, Fas ligand (FasL), activated caspase-3, and cytochrome c, immunohistochemically in rat small intestine. As assessed by TUNEL and electron microscopy, apoptotic cells were increased at 3 h of reperfusion in all intestinal parts (villous epithelium, crypt epithelium, and stroma of intestine). Moreover, the TUNEL-positive cells in the stroma were later identified as T cells. The expression of Fas and FasL as well as activated caspase-3 was markedly increased at 3 h of reperfusion in the stroma. In the villous epithelium, a transient decrease in Bcl-2 expression was found while in the crypt epithelium, Fas expression was induced. Finally, intraperitoneal injection of leupeptin (an SH-protease inhibitor) after I/R resulted in a significant inhibition of the induction of apoptosis in the stroma and crypt epithelium. Our results indicate that the triggering molecules of apoptosis in the I/R rat small intestine may vary depending on cell type and that the use of a broad-spectrum protease inhibitor may reduce intestinal damage.
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PMID:Induction of cell death in rat small intestine by ischemia reperfusion: differential roles of Fas/Fas ligand and Bcl-2/Bax systems depending upon cell types. 1576 13

Apoptotic loss of CD4+ T cells has been proposed as a mechanism of T cell depletion in human immunodeficiency virus (HIV) infections resulting in immunodeficiency. The Env glycoprotein has been implicated in apoptosis of uninfected bystander cells via gp120 binding to CD4/CXC chemokine receptor 4 as well as the fusion/hemifusion process mediated by gp41. Using an in vitro model of coculture of Env-expressing cells as effectors and CD4+ T cells as targets, we find that apoptosis mediated by Env glycoprotein in bystander cells in fact correlates with gp41-induced hemifusion. Further, the apoptotic pathway initiated by this interaction involves caspase-3-dependent mitochondrial depolarization and reactive oxygen species production. HIV gp41-induced mitochondrial depolarization is inhibited by protease inhibitor nelfinavir but not by other HIV protease inhibitors or inhibitors of calpain and cathepsin. This "kiss of death" (hemifusion) signaling pathway is independent of p38 mitogen-activated protein kinase and p53, making it distinct from the apoptosis seen in syncytia. We also show that virion-induced apoptosis is gp41-dependent. Our findings provide new insights into the mechanism via which HIV gp41 mediates apoptosis in bystander cells.
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PMID:HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir. 1633 May 30


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