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)

Manganese superoxide dismutase (MnSOD, SOD2) is an essential primary antioxidant enzyme which converts superoxide radical to hydrogen peroxide within the mitochondrial matrix. MnSOD plays a prominent role in protection against many apoptotic stimuli. Its absence may therefore impair the cellular redox balance and enhance apoptosis. Our data show that in Jurkat T cells, following oligomerization of the Fas receptor, MnSOD is selectively degraded during apoptosis. In the presence of cycloheximide, an inhibitor of protein synthesis, the rates of cell death and MnSOD degradation were accelerated. Fas-induced MnSOD cleavage was partially inhibited in the presence of the pan-caspase inhibitor, z-VAD-fmk. MnSOD in the mitochondrial fractions was cleaved in vitro by treatment with the cytosolic fraction of Fas-activated cells. Moreover, two possible cleavage sites of recombinant hMnSOD by direct interaction with recombinant caspase-3 were noted. Cellular and mitochondrial factors were found to be necessary for the interaction. These factors include intracellular mobilization of calcium. Our data indicate that inactivation of MnSOD in receptor-mediated apoptosis by caspase-specific degradation would render the mitochondria sensitive to the steady-state production of superoxide, decrease the steady-state flux of H(2)O(2), expedite the loss of mitochondrial function, and potentiate apoptosis.
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PMID:Manganese superoxide dismutase inactivation during Fas (CD95)-mediated apoptosis in Jurkat T cells. 1715 82

Cells typically die by either apoptosis or necrosis. However, the consequences of apoptosis and necrosis are quite different for a whole organism. In the case of apoptosis, the cell content remains packed in the apoptotic bodies that are removed by macrophages, and thereby inflammation does not occur; during necrosis, the cell membrane is ruptured, and the cytosolic constituents are released into the extracellular space provoking inflammation. Recently, inflammation and necrosis have been suggested to promote tumor growth. We investigated the molecular mechanism underlying cell death in response to glucose depletion (GD), a common characteristic of the tumor microenvironment. GD induced necrosis through production of reactive oxygen species (ROS) in A549 lung carcinoma cells. Inhibition of ROS production by N-acetyl-L-cysteine and catalase prevented necrosis and switched the cell death mode to apoptosis that depends on mitochondrial death pathway involving caspase-9 and caspase-3 activation, indicating a critical role of ROS in determination of GD-induced cell death mode. We demonstrate that protein kinase C-dependent extracellular regulated kinase 1/2 (ERK1/2) activation also switched GD-induced necrosis to apoptosis through inhibition of ROS production possibly by inducing manganese superoxide dismutase (SOD) expression and by preventing GD-induced degradation of copper zinc SOD. Thus, these results suggest that GD-induced cell death mode is determined by the protein kinase C/ERK1/2 signal pathway that regulates MnSOD and CuZnSOD and that these antioxidants may exert their known tumor suppressive activities by inducing necrosis-to-apoptosis switch.
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PMID:Protein kinase C-ERK1/2 signal pathway switches glucose depletion-induced necrosis to apoptosis by regulating superoxide dismutases and suppressing reactive oxygen species production in A549 lung cancer cells. 1730 78

Pancreatic islets are commonly isolated for research and transplantation without taking into consideration that they undergo mechanical or chemical stress during this process. In order to counteract both types of injuries, the compound AEOL10150, a novel MnSOD mimic, was added during isolation of islet at concentrations ranging from 18 to 100 microM. Mechanical or chemical stress-related pro-apoptotic signals were then studied. We demonstrate that this MnSOD mimic diminishes the negative effects of mechanical stress by blocking insulin impairment, production of non-specific islet beta-cell proteins, transcription of iNOS and FAS, activation of caspase-3 and -9 and, ultimately, apoptosis. Moreover, the effects of the MnSOD mimic on isolated islets were greatly influenced by dosage: the best dose able to fully counteract mechanical stress was found to be 100 microM; doses > or =150 microM were themselves highly toxic for islet cells. On the other hand, rIL-1beta-induced chemical stress is rather complex, and there was no protection in this scenario. Therefore, contrarily to what has been previously reported, MnSOD mimic administration is only capable of counteracting mechanical stress, and not cytokine-induced cytotoxicity, and that this drug acts within a limited concentration range.
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PMID:MnSOD mimic compounds can counteract mechanical stress and islet beta cell apoptosis, although at appropriate concentration ranges. 1731 Dec 87

The present study elucidates a possible mechanism by which chronic organophosphate exposure (dichlorvos 6 mg/kg bw, s.c. for 12 weeks) causes neuronal degeneration. Mitochondria, as a primary site of cellular energy generation and oxygen consumption represent itself a likely target for organophosphate poisoning. Therefore, the objective of the current study was planned with an aim to investigate the effect of chronic dichlorvos exposure on mitochondrial calcium uptake, oxidative stress generation and its implication in the induction of neuronal apoptosis in rodent model. Mitochondrial preparation from dichlorvos (DDVP) treated rat brain demonstrated significant increase in mitochondrial Ca(2+) uptake (644.2 nmol/mg protein). Our results indicated decreased mitochondrial electron transfer activities of cytochrome oxidase (complex IV) along with altered mitochondrial complex I, and complex II activity, which might have resulted from elevated mitochondrial calcium uptake. The alterations in the mitochondrial calcium uptake and mitochondrial electron transfer enzyme activities in turn might have caused an increase in malondialdehyde, protein carbonyl and 8-hydroxydeoxyguanosine formation as a result of enhanced lipid peroxidation, and as well as protein and mtDNA oxidation. All this could have been because of enhanced oxidative stress, decreased GSH levels and also decreased Mn-SOD activity in the mitochondria isolated from dichlorvos treated rat brain. Thus, chronic organophosphate exposure has the potential to disrupt cellular antioxidant defense system which in turn triggers the release of cytochrome c from mitochondria to cytosol as well as caspase-3 activation in dichlorvos treated rat brain as revealed by immunoblotting experiments. Low-level long-term organophosphate exposure finally resulted in oligonucleosomal DNA fragmentation, a hallmark of apoptosis. These studies provide an evidence of impaired mitochondrial bioenergetics and apoptotic neuronal degeneration after chronic low-level exposure to dichlorvos.
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PMID:Impaired mitochondrial energy metabolism and neuronal apoptotic cell death after chronic dichlorvos (OP) exposure in rat brain. 1785 Aug 75

Transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes, through a mechanism mediated by reactive oxygen species (ROS) production. Numerous tumoral cells develop mechanisms to escape from the TGF-beta-induced tumor suppressor effects. In this work we show that in FaO rat hepatoma cells inhibition of the epidermal growth factor receptor (EGFR) with the tyrphostin AG1478 enhances TGF-beta-induced cell death, coincident with an elevated increase in ROS production and GSH depletion. These events correlate with down-regulation of genes involved in the maintenance of redox homeostasis, such as gamma-GCS and MnSOD, and elevated mitochondrial ROS. Nonetheless, not all the ROS proceed from the mitochondria. Emerging evidences indicate that ROS production by TGF-beta is also mediated by the NADPH oxidase (NOX) system. TGF-beta-treated FaO cells induce nox1 expression. However, the treatment with TGF-beta and AG1478 greatly enhanced the expression of another family member: nox4. NOX1 and NOX4 targeted knock-down by siRNA experiments suggest that they play opposite roles, because NOX1 knockdown increases caspase-3 activity and cell death, whilst NOX4 knock-down attenuates the apoptotic process. This attenuation correlates with maintenance of GSH and antioxidant enzymes levels. In summary, EGFR inhibition enhances apoptosis induced by TGF-beta in FaO rat hepatoma cells through an increased oxidative stress coincident with a change in the expression pattern of NOX enzymes.
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PMID:The inhibition of the epidermal growth factor (EGF) pathway enhances TGF-beta-induced apoptosis in rat hepatoma cells through inducing oxidative stress coincident with a change in the expression pattern of the NADPH oxidases (NOX) isoforms. 1884 61

Peroxisome proliferator-activated receptor (PPAR)-gamma is a ligand-activated transcription factor of nuclear hormone receptor superfamily. Thiazolidinedione rosiglitazone is a potent agonist of PPARgamma which was shown to induce neuroprotection in animal models of focal ischemia and spinal cord injury. We currently evaluated the therapeutic potential of rosiglitazone (6 mg/kg at 5 min, 6 h and 24 h; i.p.) following controlled cortical impact (CCI)-induced traumatic brain injury (TBI) in adult mice. CCI injury increased the cortical PPARgamma mRNA levels which were further elevated by rosiglitazone treatment. In addition, rosiglitazone treatment significantly decreased the cortical lesion volume measured at 7 days compared to vehicle treatment (by 56+/-7%; p<0.05; n=6/group). Following TBI, the spared cortex of the rosiglitazone group showed significantly less numbers of GSI-B4(+) activated microglia/macrophages and ICAM1(+) capillaries, and curtailed induction of pro-inflammatory genes IL6, MCP1 and ICAM1 compared to vehicle group. Rosiglitazone-treated mice also showed significantly less number of TUNEL(+) apoptotic neurons and curtailed induction of caspase-3 and Bax, compared to vehicle control. In addition, rosiglitazone significantly enhanced the post-TBI expression of the neuroprotective chaperones HSP27, HSP70 and HSP32/HO1, and the anti-oxidant enzymes catalase, Cu/Zn-SOD and Mn-SOD, compared to vehicle. Treatment with GW9662 (a specific PPARgamma antagonist) prevented all the above PPARgamma-mediated actions. Thus, PPARgamma activation confers neuroprotection after TBI by anti-inflammatory, anti-apoptotic and anti-oxidative mechanisms.
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PMID:PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. 1894 87

Flavonoids are considered therapeutic agents in neurodegenerative disease because of their neuroprotective activity. This study investigated the neuroprotective effects of hesperetin in the brains of mice administered hesperetin at 10 or 50 mg/kg body weight (BW) for five weeks. Hesperetin inhibited biomarkers of oxidative stress, such as the level of thiobarbituric acid-reactive substance (TBARS) and carbonyl content, although there was a significant reduction at the higher dose of hesperetin. Moreover, at the higher dose, hesperetin significantly activated the catalase and total superoxide dismutase (SOD) activities. The same patterns were observed in the protein expression, and the expression of CuZn-SOD was more pronounced than that of Mn-SOD. The reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio was increased significantly in a dose-dependent manner, as well as the glutathione peroxidase (GSH-px) and glutathione reductase (GR) activities. Moreover, hesperetin did not induce apoptosis, even at the higher dose, as evidenced by caspase-3 expression and its activity. Based on these results, hesperetin may have a neuroprotective effect via the inhibition of oxidative damage, together with activation of the antioxidant enzyme system.
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PMID:Neuroprotective effects of chronic hesperetin administration in mice. 1902 42

Atherosclerosis is a chronic inflammatory process with increased oxidative stress in vascular endothelium. Ginkgo biloba extract (GbE), extracted from Ginkgo biloba leaves, has commonly been used as a therapeutic agent for cardiovascular and neurological disorders. The aim of this study was to investigate how GbE protects vascular endothelial cells against the proatherosclerotic stressor oxidized low-density lipoprotein (oxLDL) in vitro. Human umbilical vein endothelial cells (HUVECs) were incubated with GbE (12.5-100 microg/ml) for 2 h and then incubated with oxLDL (150 microg/ml) for an additional 24 h. Subsequently, reactive oxygen species (ROS) generation, antioxidant enzyme activities, adhesion to monocytes, cell morphology, viability, and several apoptotic indexes were assessed. Our data show that ROS generation is an upstream signal in oxLDL-treated HUVECs. Cu,Zn-SOD, but not Mn-SOD, was inactivated by oxLDL. In addition, oxLDL diminished expression of endothelial NO synthase and enhanced expression of adhesion molecules (ICAM, VCAM, and E-selectin) and the adherence of monocytic THP-1 cells to HUVECs. Furthermore, oxLDL increased intracellular calcium, disturbed the balance of Bcl-2 family proteins, destabilized mitochondrial membrane potential, and triggered subsequent cytochrome c release into the cytosol and activation of caspase-3. These detrimental effects were ameliorated dose dependently by GbE (P < 0.05). Results from this study may provide insight into a possible molecular mechanism underlying GbE suppression of the oxLDL-mediated vascular endothelial dysfunction.
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PMID:Ginkgo biloba extract attenuates oxLDL-induced oxidative functional damages in endothelial cells. 1922 86

We have previously reported that addition of prefibrillar aggregates (PFAs) derived from W7FW14F apomyoglobin mutant to NIH-3T3 cells affects their viability. In this article, we have found that cytotoxicity induced by PFAs in NIH 3T3 and SH-SY5Y human neuroblastoma cells was due to early activation of apoptotic cell death dependent from a caspase-3- and -9-mediated mitochondrial pathway. A time-dependent increase of intracellular ROS and an about twofold decrease of mitochondrial localization of scavenger protein MnSOD was found. The use of the anti-oxidant agent N-acetyl-cysteine (NAC) antagonized both the increase of intracellular ROS and apoptosis induced by PFAs. PFAs caused an about 60% increase of the activity of both Ras and Erk-1/2 at 30 and 45 min while they were restored to basal levels at later time points. This effect was paralleled by a time-dependent decrease of the activity of the survival enzyme Akt. Effects similar to those on Ras activity were also recorded on the activity of the stress involved small GTP binding protein Rac that was about 75% increased after 30 min but resumed to basal levels at later time points. This effect was paralleled by a time-dependent activation of p38 kinase activity and HSP-70 expression. The use of both the ras farnesyltransferase inhibitor tipifarnib and the Rac geranyl-geranyltransferase GGTI-298, but not of the MEK-1 inhibitor U0126 partially antagonized the effects of PFAs on apoptosis occurrence. On the other hand, the PI3K/Akt inhibitor LY 294002 potentiated apoptosis induced by PFAs. Our results indicate a role for Ras and Rac in the induction of both intracellular ROS increased levels and apoptosis mediated by PFAs and disclose a new scenario of intervention in neurodegenerative diseases.
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PMID:W7FW14F apomyoglobin amyloid aggregates-mediated apoptosis is due to oxidative stress and AKT inactivation caused by Ras and Rac. 1958 24

The aim of this study was to determine whether heat-shock pretreatment exerted a protective effect against sorbitol-induced apoptotic cell death in K562, U937 and HeLa cell lines and whether such protection was associated with a decreased cytochrome c release from mithocondria and a decreased activation of caspase-9 and -3. Following heat-shock pretreatment (42 +/- 0.3 degrees C for 1 hr), these cell lines were exposed to sorbitol for 1 hr. Apoptosis was evaluated by DNA fragmentation, whereas caspase-9,-3 activation, cytochrome c release and heat-shock protein70 (HSP70) were assayed by Western Blot. Sorbitol exposure-induced apoptosis in these different cell lines with a marked activation of caspase-9 and caspase-3, whereas heat-shock pretreatment before sorbitol exposure, induced expression of HSP70 and inhibited sorbitol-mediated cytochrome c release and subsequent activation of caspase-9 and caspase-3. Similarly, overexpression of HSP70 in the three cell lines studied prevented caspase-9 cleavage and activation as well as cell death. Furthermore, we showed that the mRNA expression of iNOS decreased during both the heat-shock treatment and heat-shock pretreatment before sorbitol exposure. By contrast, the expression of Cu-Zn superoxide dismutase (SOD) and Mn-SOD proteins increased during heat-shock pretreatment before sorbitol exposure. We conclude that, heat-shock pretreatment protects different cell lines against sorbitol-induced apoptosis through a mechanism that is likely to involve SOD family members.
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PMID:Heat-shock pretreatment inhibits sorbitol-induced apoptosis in K562, U937 and HeLa cells. 3121 30


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