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)

Endothelin-1 (ET-1) acts not only as a growth-promoting peptide but also as a potent survival factor against myocardial cell apoptosis. However, the signaling pathways leading to myocardial cell protection by ET-1 are poorly understood. Using a culture system of primary cardiac myocytes derived from neonatal rats, we show in the present study that ET-1 almost completely blocked the hydrogen peroxide-induced increase in the percentage of TdT-mediated dUTP-biotin nick-end labeling-positive myocytes. Apoptosis inhibition by ET-1 was confirmed by cytofluorometric analysis as well as by examination of the ladder formation, morphological features, and caspase-3 cleavage. We have found that ET-1 converts the nuclear factor of activated T lymphocytes (NFATc) in cardiac myocytes into high-mobility forms and translocates cytoplasmic NFATc to the nuclei. In addition, ET-1 stimulates the interaction between NFATc and the cardiac-restricted zinc-finger protein GATA4 in these cells. The immunosuppressants cyclosporin A and FK506, which antagonize calcineurin, negated the inhibitory effect of ET-1 on apoptosis. Calcineurin activation de novo was sufficient to inhibit hydrogen peroxide-induced apoptosis. ET-1 induced the expression of an antiapoptotic protein bcl-2 in cardiac myocytes in a cyclosporin A-dependent manner, but it did not alter the expression of bax. Cyclosporin A also attenuated the ET-1-stimulated transcription of the bcl-2 gene in these cells. These findings demonstrate that the calcineurin pathway is required for the inhibitory effect of ET-1 on oxidant stress-induced apoptosis in cardiac myocytes.
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PMID:Calcineurin pathway is required for endothelin-1-mediated protection against oxidant stress-induced apoptosis in cardiac myocytes. 1142 Feb 94

This study was designed to detect apoptosis in the human amnion and to elucidate the signalling pathway involved in its regulation. Samples of human amnion were obtained from 34 women (weeks 11-42 of gestation) and studied using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) method with light microscopy (LM) and transmission electron microscopy (TEM). Apoptotic regulators in the samples were studied by immunohistochemistry and caspase activity assay. The TUNEL method with LM demonstrated that the percentage of TUNEL-positive cells in the amniotic epithelium was the highest in weeks 40-41 of gestation (P < 0.05) independent of the onset of labour, and the cells were often detached from the epithelium into the amniotic cavity at term. The TUNEL method with TEM clearly showed the characteristic features of apoptosis such as the nuclear condensed chromatin with abundant free 3'-OH DNA ends, cell shrinkage and a decrease in the number of desmosomes, except for the presence of apoptotic bodies. Fas and Fas ligand (FasL) were constantly expressed on apical membranes of amniotic epithelial cells from weeks 16-27 through to 40-41 of gestation, while no Bcl-2 expression was observed throughout the gestational periods. Activities of caspase-3 and caspase-8, but not of caspase-9, were higher in weeks 40-41 than those from weeks 16-27 of gestation (P < 0.01). We conclude that apoptosis in term amniotic epithelium is independent of Bcl-2 regulation and onset of labour, and may play an important role in the fragility and rupture of human fetal membranes at term.
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PMID:Apoptosis in the normal human amnion at term, independent of Bcl-2 regulation and onset of labour. 1142 Mar 92

Hepatic apoptosis has been shown to occur in both experimental and clinical alcoholic liver disease, but the signaling pathway remains unknown. This study was undertaken to examine specifically the involvement of the upstream signals, Fas and cytochrome c, in alcohol-induced caspase-3 activation and apoptosis in the liver. Male FVB mice were administrated intragastrically a single dose of alcohol at 6 g/kg, which has been shown to represent binge drinking in humans. Hepatic apoptosis was detected by a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Active form of caspase-3 was identified by immunoperoxidase staining and confirmed by immunogold labeling and was found to be in the cytosol and nucleus. Enzymic assay further confirmed caspase-3 activation and nucleus localization. Systemic administration of caspase-3 inhibitor, Ac-DEVD-FMK, inhibited caspase-3 activity and abrogated apoptosis. Elevation of cytosolic cytochrome c was found by immunoperoxidase staining, immunogold labeling, and Western blot. Increased Fas ligand expression was detected by immunoperoxidase staining. Intravenous administration of a neutralizing Fas ligand monoclonal antibody resulted in suppression of caspase-3 activation and attenuation of apoptosis, but did not inhibit mitochondrial cytochrome c release. The results thus demonstrate that Fas/Fas ligand system-mediated caspase-3 activation plays a central role in the ethanol-induced hepatic apoptosis.
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PMID:Ethanol-induced apoptosis in mouse liver: Fas- and cytochrome c-mediated caspase-3 activation pathway. 1143 80

We tested the hypothesis that endotoxemia and fasting are associated with increased gut apoptotic activity, gut permeability, and inflammation in a distant organ. Fed or fasted CD-1 mice were studied 6 h after intraperitoneal injection of either saline (sham) or endotoxin (4 mg/kg of 0111:B4 Escherichia coli lipopolysaccharide). We found that endotoxin increased gut caspase-3 and -6 activity by 4.9 +/- 0.6- and 4.5 +/- 0.5-fold, respectively (P < 0.001), and increased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) staining of mucosal cells (P < 0.05). Feeding decreased caspase-3 activity by 40% (P < 0.05) and decreased endotoxin-induced TUNEL staining (P < 0.05). Endotoxin increased gut poly(ADP-ribose) polymerase activity by 15% (P < 0.05). Endotoxin increased gut permeability by 44% (P < 0.05), an effect reduced 36% by feeding (P < 0.05). Similarly, endotoxin increased pulmonary neutrophil infiltration (6.0 +/- 1.0-fold, P < 0.001) and increased lung interleukin (IL)-6 (5.9 +/- 0.1-fold, P < 0.001) and macrophage inflammatory protein (MIP)-2 expression (290 +/- 40-fold, P < 0.001), whereas feeding decreased this effect by 43% for neutrophils, 40% for IL-6 (P < 0.05), and 35% for MIP-2 (P < 0.05). Thus endotoxin increases gut apoptotic activity, gut permeability, and pulmonary inflammation. Enteral feeding may decrease the distant organ inflammation by reducing gut apoptosis, thereby maintaining gut mucosal function during endotoxemia.
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PMID:Enteral feeding decreases gut apoptosis, permeability, and lung inflammation during murine endotoxemia. 1144 38

Severe hyperhomocysteinemia is associated with endothelial cell injury that may contribute to an increased incidence of thromboembolic disease. In this study, homocysteine induced programmed cell death in human umbilical vein endothelial cells as measured by TdT-mediated dUTP nick end labeling assay, DNA ladder formation, induction of caspase 3-like activity, and cleavage of procaspase 3. Homocysteine-induced cell death was specific to homocysteine, was not mediated by oxidative stress, and was mimicked by inducers of the unfolded protein response (UPR), a signal transduction pathway activated by the accumulation of unfolded proteins in the lumen of the endoplasmic reticulum. Dominant negative forms of the endoplasmic reticulum-resident protein kinases IRE1alpha and -beta, which function as signal transducers of the UPR, prevented the activation of glucose-regulated protein 78/immunoglobulin chain-binding protein and C/EBP homologous protein/growth arrest and DNA damage-inducible protein 153 in response to homocysteine. Furthermore, overexpression of the point mutants of IRE1 with defective RNase more effectively suppressed the cell death than the kinase-defective mutant. These results indicate that homocysteine induces apoptosis in human umbilical vein endothelial cells by activation of the UPR and is signaled through IRE1. The studies implicate that the UPR may cause endothelial cell injury associated with severe hyperhomocysteinemia.
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PMID:Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. 1144 14

Previous studies using transgenic mice in which metallothionein (MT) was overexpressed only in the heart have demonstrated that MT protects from oxidative cardiac injury induced by doxorubicin (DOX), an important anticancer agent. MT cardioprotection is associated with its antiapoptotic effect. The present study was undertaken to test the hypothesis that MT suppresses DOX-induced apoptosis through inhibition of mitochondrial cytochrome c release and caspase-3 activation. Primary cultures of cardiomyocytes isolated from the hearts of transgenic neonatal mice and nontransgenic controls were treated with DOX at a clinically relevant concentration (1.0 microM) for varying time periods. Apoptosis was detected in nontransgenic cardiomyocyte cultures by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and Annexin V-fluorescein isothiocyanate binding. This apoptotic effect was significantly suppressed in the MT-overexpressing transgenic cardiomyocytes. Western blot analysis revealed that DOX caused mitochondrial cytochrome c release. Furthermore, caspase-3 activation was observed. The activation of this apoptotic pathway by DOX was dramatically inhibited in the MT-overexpressing cardiomyocytes. To elucidate the role of reactive oxygen species (ROS) in the activation of the cytochrome c-mediated caspase-3 activation pathway, the intracellular levels of ROS and their localization were detected by fluorescent confocal microscopy. Mitochondrial ROS concentrations were dramatically elevated by DOX in nontransgenic cardiomyocytes. This elevation was completely inhibited almost in the MT-overexpressing cardiomyocytes. Thus, these results demonstrate that MT suppresses DOX-induced apoptosis in cardiomyocytes through, at least in part, inhibition of the cytochrome c-mediated apoptotic pathway.
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PMID:Metallothionein inhibits doxorubicin-induced mitochondrial cytochrome c release and caspase-3 activation in cardiomyocytes. 1145 6

The evolution of brain injury was examined in mice subjected to focal cerebral ischemia as induced by 30 min of intraluminar thread occlusion of the middle cerebral artery, followed by 3 h to 3 days of reperfusion. Metabolic dysfunctions were studied by 3H-leucine autoradiography for the measurement of cerebral protein synthesis and by regional ATP bioluminescent imaging. Metabolic changes were compared with responses of the genes c-fos, c-jun, heat-shock protein gene (hsp)72, p53-activated gene (pag)608 and caspase-3, which were investigated by in situ hybridization histochemistry and immunocytochemistry, and correlated with the degree of DNA fragmentation, as assessed by the terminal TdT-mediated dUTP-biotin nick end labeling method. Intraluminar thread occlusion led to a reproducible reduction of cerebral laser Doppler flow to 20-30% of control. Thread withdrawal was followed by a short-lasting post-ischemic hyperperfusion to approximately 120%. In non-ischemic control animals, fractional protein synthesis values of 0.81+/-0.26 and 0.94+/-0.23 were obtained. Thread occlusion resulted in a suppression of protein synthesis throughout the territory of the middle cerebral artery after 3 h of reperfusion (0.04+/-0.08 in caudate-putamen and 0.14+/-0.19 in somatosensory cortex, P<0.05). Protein synthesis partly recovered in the cortex after 24 h and 3 days (0.71+/-0.40 and 0.63+/-0.26, respectively), but remained suppressed in the caudate-putamen (0.14+/-0.22 and 0.28+/-0.28). Regional ATP levels did not show any major disturbances at the reperfusion times examined. Thread occlusion resulted in a transient increase of c-fos mRNA levels in ischemic and non-ischemic parts of the cortex and caudate-putamen at 3 h after ischemia, which suggests that spreading depressions were elicited in the tissue. At the same time, c-jun and hsp72 mRNAs were elevated only in ischemic brain areas showing inhibition of protein synthesis. C-fos and c-jun responses completely disappeared within 24 h of reperfusion. Hsp72 mRNA levels remained elevated in the cortex after 24 h, but decreased to basal values in the caudate-putamen. Twenty-four hours after reperfusion, pag608 and caspase-3 mRNA levels increased in the caudate-putamen, where protein synthesis rates were still reduced, and remained elevated even after 3 days. However, pag608 and caspase-3 mRNA levels did not increase in the cortex, where protein synthesis recovered. After 24 h and 3 days, functionally active p20 fragment of caspase-3 was detected in the caudate-putamen, closely associated with the appearance of DNA fragmented cells. Neither activated caspase-3 nor DNA fragmentation were noticed in the cortex.In summary, the suppression of protein synthesis is reversible in the ischemia-resistant cortex following 30 min of thread occlusion in mice, but persists in the vulnerable caudate-putamen. In the caudate-putamen, apoptotic programs are induced, closely in parallel with the manifestation of delayed cell death. Thus, the recovery of protein synthesis may be a major factor influencing tissue survival after transient focal ischemia.
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PMID:Relationship between metabolic dysfunctions, gene responses and delayed cell death after mild focal cerebral ischemia in mice. 1145 82

During the last few years, adenoviral gene transfer techniques have achieved increasing interest in the treatment of neurodegenerative diseases. However, gene therapy requires that delivered genes are translated into proteins. This may pose a problem in focal ischemia where protein synthesis is compromized. The present study was conducted to find out the feasibility of adenoviral GDNF and CNTF delivery in transient focal ischemia, as induced by 30 min of intraluminar middle cerebral artery (MCA) occlusion in mice. Injections of vehicle, of an adenoviral vector deleted in the E1 region (Ad-dE1) and of vectors expressing the GDNF (Ad-GDNF), CNTF (Ad-CNTF), or GFP (Ad-EGFP) gene from a CMV promoter were stereotactically placed in the dorsolateral striatum, i.e., the core of the MCA territory, and focal ischemia was induced seven days later. Thread occlusion resulted in disseminated injury of the striatum, but not the overlying cortex. The number of viable neurons was significantly increased after 1 and 3 days of reperfusion both in Ad-GDNF and Ad-CNTF as compared with vehicle or Ad-dE1-treated animals, whereas the number of injured cells was significantly reduced, as shown by cresyl violet staining, terminal transferase biotinylated-dUTP nick end-labeling (TUNEL), and immunocytochemistry for activated caspase-3. Interestingly, the protective effects of Ad-GDNF were similarly strong in areas of the striatum adjacent and remote of the adenoviral infusion site, while Ad-CNTF showed pronounced rescue effects in the surrounding, but rather little effects distant to the infusion. The present study demonstrates that adenoviral delivery of neurotrophic factors may be a useful tool for the treatment of focal ischemia.
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PMID:Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice. 1149 30

Zinc is proposed to be antiapoptotic for it has been shown to inhibit late events of apoptotic pathways such as Ca(2+)/Mg(2+)-dependent endonuclease cleavage of chromatin DNA, poly-ADP ribose polymerase cleavage, and caspase-3 activity. Because caspase-3 is a critical executioner caspase in apoptosis, this study was undertaken to examine specifically a correlation between zinc inhibition of caspase-3 activation and apoptosis in HeLa cells. Cultured HeLa cells were exposed to 100 microM ZnCl(2) for 1 h prior to 12 h treatment with 1.0 microM doxorubicin (DOX), an important anticancer agent that causes apoptosis in a wide variety of tumor cells. Western blot analysis of HeLa cells treated with DOX for 12 h revealed that DOX caused proteolytic activation of caspase-3 and zinc inhibited this activation. Interestingly, zinc did not inhibit DOX-induced apoptosis as measured by a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Furthermore, a microculture tetrazolium assay confirmed that cell death occurred in the presence of zinc. These results demonstrate that zinc specifically inhibits DOX-induced activation of caspase-3 in HeLa cells, but does not suppress DOX-induced apoptosis or otherwise cell death, thus suggesting DOX-induced caspase-3 activation may not play a major role in overall cell death and/or non-caspase-3 pathways are involved in DOX-induced apoptosis in HeLa cells.
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PMID:Zinc inhibition of caspase-3 activation does not protect HeLa cells from apoptotic cell death. 1150 31

Apoptosis of neuronal cells is a proposed cause of certain neurological disorders. Here, we report on a 5- to 6-fold increase in apoptosis by exposure to prostaglandin D2 synthase (PGD2S) in PC12 neuronal cells. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and appears to be mediated via caspase-3 activation. Neutralization with anti-PGD2S antibody or pre-treatment with selenium, which inhibits PGD2S enzymatic activity, both significantly inhibited the PGD2S-induced apoptosis, however, neither had any effect on the apoptosis induced by the known neuronal apoptotic inducer, glutamate. In addition, prostaglandins E1, E2, and F2alpha all inhibited the PGD2S-induced apoptosis while prostaglandin H2 had no significant effect. Furthermore, PGD2S isolated from human serum was more effective at inducing apoptosis then recombinantly expressed protein, presumably due to glycosylation. This novel role of PGD2S, as an inducer of apoptosis, may have implications in PC12 differentiation and possibly some neurological disorders.
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PMID:Prostaglandin D2 synthase induces apoptosis in PC12 neuronal cells. 1152 37


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