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)

Epithelial-mesenchymal interactions contribute to functionality and integrity of the lung epithelium, which might change during ageing and associated cellular ageing. Therefore, we studied the effect of senescent versus pre-senescent lung fibroblasts (WI-38) on mitogenic and stress-protective factors in lung epithelial cells (H358). By use of conditioned medium, we found a growth promoting impact of fibroblasts compared with control medium from epithelial cells associated with activation of ERK1/2, Akt, p70S6K, and EGF receptor. Although senescent fibroblasts mediated similar growth stimulation compared with pre-senescent cells, we observed less protection against spontaneous mitochondrial dysfunction in vitro, higher production of reactive oxygen species and activation of copper/zinc superoxide dismutase. Moreover, senescent cells induced activation of caspase-3/7 in epithelial cells, which was associated with down-regulation of the caspase-inhibitory protein XIAP. In summary, senescent lung fibroblasts induce moderate stress in lung epithelial cells in vitro without affecting growth signaling.
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PMID:Senescent fibroblasts induce moderate stress in lung epithelial cells in vitro. 1660 May 55

One of the histopathologic hallmarks of early diabetic retinopathy is the selective loss of pericytes. Evidences suggest that the pericyte loss in vivo is mediated by apoptosis. However, the underlying cause of pericyte apoptosis is not fully understood. This study investigated the effect of advanced glycation end products (AGEs) on apoptotic cell death in bovine retinal pericytes (BRPs). After incubation of BRPs with 0.47, 1.88, 7.5, 30 microM of AGE-bovine serum albumin (BSA) for 4 days, we assayed the pericytes apoptosis by FACS (fluorescence activated cell sorting), and further measured the signaling pathway involved. The results showed that AGE-BSA could induce significantly the apoptosis of BRPs in a dose-dependent manner compared with controls, associated with an increase in intracellular malondialdehyde level and caspase-3 activity; a decrease in intracellular catalase, SOD activities and Bcl-2/Bax ratio. SOD and selective caspase-3 inhibitor Z-DEVD-fmk can inhibit pericyte apoptosis induced by AGE-BSA. These data suggest that the pericyte loss in diabetic retinopathy involves an apoptotic process, and that elevated AGE observed in diabetes may cause apoptosis in BRPs through an oxidative stress mechanism. The decreased Bcl-2/Bax ratio and activation of caspase-3 are associated with apoptotic process.
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PMID:Advanced glycation end-products induce apoptosis involving the signaling pathways of oxidative stress in bovine retinal pericytes. 1667 81

Chronic systemic exposure of mice, rats, and Drosophila to D-galactose causes the acceleration of senescence and has been used as an aging model. The underlying mechanism is yet unclear. To investigate the mechanisms of neurodegeneration in this model, we studied cognitive function, hippocampal neuronal apoptosis and neurogenesis, and peripheral oxidative stress biomarkers, and also the protective effects of the antioxidant R-alpha-lipoic acid. Chronic systemic exposure of D-galactose (100 mg/kg, s.c., 7 weeks) to mice induced a spatial memory deficit, an increase in cell karyopyknosis, apoptosis and caspase-3 protein levels in hippocampal neurons, a decrease in the number of new neurons in the subgranular zone in the dentate gyrus, a reduction of migration of neural progenitor cells, and an increase in death of newly formed neurons in granular cell layer. The D-galactose exposure also induced an increase in peripheral oxidative stress, including an increase in malondialdehyde, a decrease in total anti-oxidative capabilities (T-AOC), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px) activities. A concomitant treatment with lipoic acid ameliorated cognitive dysfunction and neurodegeneration in the hippocampus, and also reduced peripheral oxidative damage by decreasing malondialdehyde and increasing T-AOC and T-SOD, without an effect on GSH-Px. These findings suggest that chronic D-galactose exposure induces neurodegeneration by enhancing caspase-mediated apoptosis and inhibiting neurogenesis and neuron migration, as well as increasing oxidative damage. In addition, D-galactose-induced toxicity in mice is a useful model for studying the mechanisms of neurodegeneration and neuroprotective drugs and agents.
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PMID:Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid. 1671 Aug 48

Suppression of activation or proliferation, or induction of apoptosis in hepatic stellate cells (HSCs) have been proposed as therapeutic strategies against liver fibrosis. Salvia miltiorrhiza has been reported to exert antifibrotic effects in rats with hepatic fibrosis, but its mechanisms of action remain to be clarified. We have investigated the effects of salvianolic acid A (Sal A), an active principle from S. miltiorrhiza, on the proliferation-related biomarkers in a cell line of rat HSCs (HSC-T6) stimulated with platelet-derived growth factor-BB homodimer (PDGF-BB). DNA synthesis (bromodeoxyuridine (BrdU) incorporation), cell cycle related proteins and apoptosis markers were determined to evaluate the inhibitory effects of Sal A. The results showed that Sal A (1-10 microM) concentration-dependently attenuated PDGF-BB-stimulated proliferation (BrdU incorporation) in HSC-T6 cells. Sal A at 10 microM induced cell apoptosis in PDGF-BB-incubated HSCs, together with a reduction of Bcl-2 protein expression, induction of cell cycle inhibitory proteins p21 and p27, and down-regulation of cyclins D1 and E, suppression of Akt phosphorylation, reduction in PDGF receptor phosphorylation, and an increase in caspase-3 activity. Sal A exerted no direct cytotoxicity on primary hepatocytes and HSC-T6 cells under experimental concentrations. Our results suggested that Sal A inhibited PDGF-BB-activated HSC proliferation, partially through apoptosis induction.
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PMID:Antiproliferative effect of salvianolic acid A on rat hepatic stellate cells. 1680 53

The overall goal of the current study was to examine the functional activity of the prolyl hydroxylases (PHDs) in maturing chondrocytes. Herein, we show for the first time that the PHDs are expressed in the maturing zone of the growth plate, and by a chondrocytic cell line. We determined if this protein and its substrate, hypoxia inducible factor (HIF)-1alpha, modulated the induction of apoptosis. Using a chondrocyte cell line that matured in culture, we inhibited HIF-1alpha expression using siRNA technology and pharmacologically blocked PHD activity. We noted that PHD suppression sensitized the cells to an apoptotic challenge with H(2)O(2). We next examined the interplay between the PHDs and HIF-1alpha by suppressing HIF-1alpha and blocking PHD activity. We noted reduced killing when the mature HIF-silenced cells were challenged with H(2)O(2). In contrast, there was limited change in the viability of immature cells. Based on these differences in chondrocyte susceptibility, it is concluded that HIF-1alpha sensitizes maturing cells to H(2)O(2)-mediated killing. We next determined if this change in the viability of the PHD-inhibited cells was linked to changes in activation of caspase-3. It was noted that there was a minimal change in enzyme activity of the PHD-inhibited HIF-1alpha suppressed cells. Finally, we found that as the chondrocytes mature, the activities of catalase and SOD were significantly reduced and that there was a decrease in the levels of Bcl-2 and Bcl(XL). This loss of protective activity together with the changes mediated by HIF would be expected to generate conditions that would favor the induction of chondrocyte apoptosis.
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PMID:Expression of HIF prolyl hydroxylase isozymes in growth plate chondrocytes: relationship between maturation and apoptotic sensitivity. 1704 72

Reactive oxygen species (ROS) generated by ultraviolet (UV) irradiation are counterbalanced by endogenous antioxidant systems. To test the hypothesis of a novel photoprotective approach, we irradiated epidermis reconstructed with normal human keratinocytes overexpressing sustainably lentivirus-mediated catalase (CAT), copper/zinc superoxide dismutase (CuZnSOD) or manganese superoxide dismutase (MnSOD) enzymes. We found that following UVB irradiation there was a marked decrease in sunburn cell formation, caspase-3 activation and p53 accumulation in human reconstructed epidermis overexpressing CAT. Moreover, UVA-induced hypertrophy and DNA oxidation (8-oxodeoxyguanosine) were decreased by CAT overexpression. These effects were not achieved by overexpression of CuZnSOD or MnSOD. In conclusion, vector-mediated CAT overexpression could be a promising photoprotective tool against deleterious effects of UV irradiation such skin cancer especially in monogenic/polygenic photosensitive disorders characterized by ROS accumulation.
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PMID:Protection of normal human reconstructed epidermis from UV by catalase overexpression. 1705 17

Evidence has been gathered to suggest that trace amounts of copper induce neurotoxicity by interaction with elevated cholesterol in diet. Copper treatment alone showed no significant learning and memory impairments in behavioral tasks. However, copper-induced neurotoxicity was significantly increased in mice given elevated-cholesterol diet. Trace amounts of copper decreased the activity of SOD and increased the level of malondialdehyde (MDA) in the brain of cholesterol-fed mouse. Copper also caused an increase in amyloid precursor protein (APP) mRNA level and the activation of caspase-3 in the brain of cholesterol-fed mice. The apoptosis-induced nuclear DNA fragmentation was detected in the brain of those mice by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end-labeling staining. These findings suggest that trace amounts of copper induce neurotoxicity in cholesterol-fed mice through apoptosis caused by oxidative stress.
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PMID:Trace amounts of copper induce neurotoxicity in the cholesterol-fed mice through apoptosis. 1713 2

AMP-activated protein kinase influences cellular metabolism, glucose-regulated gene expression, and insulin secretion of pancreatic beta cells. Its sustained activation by culture at low glucose concentrations or in the presence of 5-aminoimidazole-4-carboxamide riboside (AICAR) was shown to trigger apoptosis in beta cells. This study shows that both low glucose- and AICAR-induced apoptosis are associated with increased formation of mitochondrial superoxide-derived radicals and decreased mitochondrial activity. Mitochondrial dysfunction was reflected by an increased oxidized state of the mitochondrial flavins (FMN/FAD) but not of NAD(P)H. It was accompanied by suppression of glucose oxidation and glucose-induced insulin secretion, while palmitate oxidation appeared unaffected. When the cellular accumulation of superoxide-derived radicals was quenched by the ROS scavengers vitamin E, N-acetylcysteine, or the SOD-mimetic compound MnTBAP, apoptosis was significantly inhibited. Both low glucose and AICAR also elevated the expression of BH3-domain-only Bcl-2 antagonists, and induced caspase-3 activation, causing caspase-dependent truncation of Bcl-2. Overexpression of recombinant human Bcl-2 prevented caspase-3 activation, endogenous Bcl-2 processing, and apoptosis, but did not attenuate oxygen radical formation, AMPK activation, or JNK phosphorylation. We conclude that apoptosis by prolonged AMPK activation in beta cells results from enhanced production of mitochondria-derived oxygen radicals and onset of the intrinsic mitochondrial apoptosis pathway, followed by caspase activation and Bcl-2 cleavage which may amplify the death signal.
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PMID:Increased oxygen radical formation and mitochondrial dysfunction mediate beta cell apoptosis under conditions of AMP-activated protein kinase stimulation. 1715 94

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its vasculoprotective effects are not completely understood. Because oxidative stress and endothelial cell injury play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits oxidative stress-induced endothelial apoptosis. We found that oxidized LDL and TNF-alpha elicited significant increases in caspase-3/7 activity in endothelial cells and cultured rat aortas, which were prevented by resveratrol pretreatment (10(-6)-10(-4) mol/l). The protective effect of resveratrol was attenuated by inhibition of glutathione peroxidase and heme oxygenase-1, suggesting a role for antioxidant systems in the antiapoptotic action of resveratrol. Indeed, resveratrol treatment protected cultured aortic segments and/or endothelial cells against increases in intracellular H(2)O(2) levels and H(2)O(2)-mediated apoptotic cell death induced by oxidative stressors (exogenous H(2)O(2), paraquat, and UV light). Resveratrol treatment also attenuated UV-induced DNA damage (comet assay). Resveratrol treatment upregulated the expression of glutathione peroxidase, catalase, and heme oxygenase-1 in cultured arteries, whereas it had no significant effect on the expression of SOD isoforms. Resveratrol also effectively scavenged H(2)O(2) in vitro. Thus resveratrol seems to increase vascular oxidative stress resistance by scavenging H(2)O(2) and preventing oxidative stress-induced endothelial cell death. We propose that the antioxidant and antiapoptotic effects of resveratrol, together with its previously described anti-inflammatory actions, are responsible, at least in part, for its cardioprotective effects.
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PMID:Resveratrol increases vascular oxidative stress resistance. 1722 Jan 79

Mutations in copper/zinc superoxide dismutase (SOD1) have been implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 protein likely gains a novel cytotoxic property, leading to the death of motor neurons. We therefore investigated whether caspase-mediated apoptosis is associated with novel cytotoxic properties in a rodent model for familial ALS (G93A SOD1 transgenic mice). Caspase-9 (an effecter in the mitochondrial apoptotic pathway), caspase-8 (an effecter in the Fas apoptotic pathway), and caspase-3 (an executioner of both pathways) proteins were all present in nonactive forms in the spinal cords of wild-type mice during the early stage of the disease (8 weeks), at which time the mice had not yet exhibited motor paralysis. In transgenic mice, however, these proteins were present in their active forms, and their mRNA levels were significantly upregulated in the represent to this conversion from nonactive to active forms. During the advanced stage of the disease (16 weeks), when paralysis was evident, the active caspase levels were further elevated. On the other hand, the mRNA and protein levels of survivin, a counteraction protein against caspases, were significantly suppressed during the early stage, and sharply increased during the advanced stage. Although the mRNA and protein levels of X-linked inhibitor of apoptosis protein (XIAP) remained at the same levels as those seen in the control (wild-type mice) during the early stage, they were significantly depressed at an age of 16 weeks. These findings were observed exclusively in the spinal cord, the region responsible for the disease, and not in the cerebellum, a non-responsible region. We conclude that conditions facilitating the apoptotic process during the early stage of the disease play causative roles in the pathogenesis of ALS and that the suppression of XIAP levels during the advanced stage could contribute to disease expression and/or progression.
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PMID:Dysequilibrium between caspases and their inhibitors in a mouse model for amyotrophic lateral sclerosis. 1739 13


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