Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated whether maternal obstructive cholestasis during pregnancy (OCP) causes oxidative stress and apoptosis in rat placenta and whether treatment with ursodeoxycholic acid (UDCA, i.g., 60 microg/100 g b.wt./day, following complete biliary obstruction on day 14 of pregnancy) has protective effects on this organ. In rats with OCP, increased (15-fold) serum bile acid concentrations (BAs) together with signs of placental oxidative stress (lipid peroxidation and protein carbonylation) were found. The latter were partly prevented by UDCA, even though hypercholanemia was not corrected. Some elements of the antioxidant system (total glutathione content, GSH/GSSG ratio and catalase, glutathione peroxidase, and glutathione-S-transferase--but not glutathione reductase--activities) were impaired in placentas from the OCP group. UDCA treatment partly prevented changes in the antioxidant system. OCP induced an increase in Bax-alpha/Bcl-2 mRNA ratio, as determined by real-time quantitative PCR, suggesting enhanced susceptibility to apoptosis activation through the mitochondria-mediated pathway. Accordingly, the activity of caspase-3, but not caspase-8, was increased in OCP placentas, in which DNA-ladder analysis and TUNEL confirmed the existence of apoptosis. UDCA prevented changes in the Bax-alpha/Bcl-2 mRNA ratio and caspase-3 activity. In conclusion, OCP causes oxidative stress and apoptosis in rat placenta, which can be prevented by treatment with UDCA.
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PMID:Maternal cholestasis induces placental oxidative stress and apoptosis. Protective effect of ursodeoxycholic acid. 1631 35

Ethanol is able to cross the placenta, which may cause teratogenicity. Here we investigated whether ethanol consumption during pregnancy (ECDP), even at doses unable to cause malformation, might increase the susceptibility of fetal rat liver to oxidative insults. Since cholestasis is a common condition in alcoholic liver disease and pregnancy, exposure to glycochenodeoxycholic acid (GCDCA) has been used here as the oxidative insult. The mothers received drinking water without or with ethanol from 4 weeks before mating until term, when placenta, maternal liver, and fetal liver were used. Ethanol induced a decreased GSH/GSSG ratio in these organs, together with enhanced gamma-glutamylcysteine synthetase and glutathione reductase activities in both placenta and fetal liver. Lipid peroxidation in placenta and fetal liver was enhanced by ethanol, although it had no effect on caspase-3 activity. Although the basal production of reactive oxygen species (ROS) was higher by fetal (FHs) than by maternal (AHs) hepatocytes in short-term cultures, the production of ROS in response to the presence of varying GCDCA concentrations was higher in AHs and was further increased by ECDP, which was associated to a more marked impairment in mitochondrial function. Moreover, GCDCA-induced apoptosis was increased by ECDP, as revealed by enhanced Bax-alpha/Bcl-2 ratio (both in AHs and FHs) and the activity of caspase-8 (only in AHs) and caspase-3. In sum, our results indicate that although AHs are more prone than FHs to producing ROS, at doses unable to cause maternal liver damage ethanol consumption causes oxidative stress and apoptosis in fetal liver.
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PMID:Maternal ethanol consumption during pregnancy enhances bile acid-induced oxidative stress and apoptosis in fetal rat liver. 1682 60

Inherited defects of copper metabolism resulting in hepatic copper accumulation and oxidative-stress might cause breed-associated forms of hepatitis. Biliary excretion is the major elimination route of copper, therefore increased hepatic copper concentrations could also be caused by cholestasis. The aim of this study was to find criteria to determine whether copper-accumulation is primary or occurs secondary to hepatitis. Liver samples of Bedlington Terriers with copper toxicosis (CT), breeds with non-copper-associated chronic extrahepatic cholestasis (EC) or chronic hepatitis (CH), and healthy dogs were used. Copper metabolism was analyzed by means of histochemical staining (copper concentration) and quantitative reverse transcriptase polymerase chain reaction (Q-PCR) on copper excretion/storage (ATOX1, COX17, ATP7A, ATP7B, CP, MT1A, MURR1, XIAP). Oxidative stress was measured by determining GSH/GSSG ratios and gene-expression (SOD1, CAT, GSHS, GPX1, CCS, p27KIP, Bcl-2). Results revealed 5+ copper in CT, but no or 1-2+ copper in EC and CH. Most gene products for copper metabolism remained at concentrations similar to healthy dogs. Three clear exceptions were observed in CT: 3-fold mRNA increase of ATP7A and XIAP and complete absence of MURRI. The only quantitative differences between the diseased and the control groups were in oxidative stress, evidenced by reductions in all GSH/GSSG ratios. We conclude that 3+ or higher histochemical detection of copper indicates a primary copper storage disease. The expression profile of copper-associated genes can be used as a reference for future studies on copper-associated diseases. All 3 diseases have reduced protection against oxidative stress, opening a rationale to use antioxidants as possible therapy.
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PMID:Copper metabolism and oxidative stress in chronic inflammatory and cholestatic liver diseases in dogs. 1706

The present study was designed to evaluate the apoptotic efficacy of selenium (Se) under glutathione-deprived conditions. Testicular cells were used as a model to assess the above. For the study, cells were maintained for 4 h under various treatments; control (media only), selenium (0.5 microM and 1.5 microM), BSO (20 nM), selenium + BSO (0.5 microM Se + 20 nM BSO and 1.5 microM Se + 20 nM BSO). The treated cells were harvested for various estimations viz. viability, GSH, GSSG, redox ratio, ROS generation and integrity of DNA. mRNA was extracted for RT-PCR analysis of JNK, p38, caspase 3 and Bcl-2. It was observed that the cell viability decreased concomitant with the decrease in GSH levels, increase in GSSG levels and increase in the generation of ROS in the combined treatment group in comparison to control and individual treatments. Also, there was an increase in the mRNA expression of JNK and p38 MAPK along with an increase in caspase 3 expression and decrease in Bcl-2 expression. The integrity of DNA was also found to be altered in the combined treatment. Thus, the results presented in this work agree with those earlier reports in a notion that sodium selenite causes apoptosis and the toxicity of selenite is mediated by increase of intracellular ROS. Also, reduction in endogenous GSH along with selenite treatment is associated with increased apoptosis, increased expression of p38 and JNK MAPK, decreased Bcl-2 expression, and increase in caspase-3 expression. Our data indicates that GSH participates in apoptosis in testicular cells and that depletion of this molecule may be critical in predisposing these cells to apoptotic cell death.
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PMID:Decreased glutathione levels potentiate the apoptotic efficacy of selenium: possible involvement of p38 and JNK MAPKs--in vitro studies. 1798 39

In this study, we determined the changes in the intracellular redox environment of the heart during ischemia and reperfusion and the effects of resveratrol on such changes. Because redox regulation by thioredoxin (Trx) plays a crucial role in signal transduction and cytoprotection against ROS, the effects of resveratrol on the changes in the amounts of thioredoxin were monitored in an attempt to determine the role of intracellular thioredoxin in resveratrol-mediated changes in intracellular redox environment and its role in resveratrol-mediated cardioprotection. Rats were randomly divided into four groups: group I, control (rats were gavaged with vehicle only); group II, rats were gavaged with 2.5 mg/kg body wt resveratrol per day for 10 days; group III, rats were given resveratrol for 10 days, but on the 7th day, they were treated with shRNA against Trx-1; group IV, rats were given resveratrol for 10 days, but were injected (iv) with cisplatin (1 mg/kg body wt) on days 1, 3, 5, 7, and 9. In concert, two groups of mice (Dn-Trx-1) and a corresponding wild-type group were also gavaged with 2.5 mg/kg body wt resveratrol for 10 days. After 10 days, isolated rat and mouse hearts perfused via working mode were made globally ischemic for 30 min followed by 2 h of reperfusion. Ischemia/reperfusion developed an infarct size of about 40% and resulted in about 25% apoptotic cardiomyocytes, which were reduced by resveratrol. Cisplatin, but not shRNA-Trx-1, abolished the cardioprotective abilities of resveratrol. In the experiments with mouse hearts, similar to rat hearts, resveratrol significantly reduced the ischemia/reperfusion-mediated increase in infarct size and apoptosis in both groups. MDA formation, a presumptive marker for lipid peroxidation, was increased in the I/R group and reduced in the resveratrol group, and resveratrol-mediated reduction in MDA formation was abolished with cisplatin, but not with shRNA-Trx-1. I/R-induced reduction in GSH/GSSH ratio was prevented by resveratrol, and resveratrol-mediated preservation of GSH/GSSG ratio was reduced by cisplatin, but not by sh-RNA-Trx-1. RT-PCR revealed an increase in both Trx-1 and Trx-2 transcripts; but only Trx-2 protein, not Trx-1 protein, was enhanced with resveratrol by Western blot analysis. Electron paramagnetic resonance spectroscopic study revealed that resveratrol treatment significantly increased the decay rates of nitroxide radicals compared to control hearts, suggesting that resveratrol can switch into the reduction state more compared to control heart. Finally, resveratrol generated a survival signal by phosphorylation of Akt and increase in induction of Bcl-2 expression, which was inhibited by cisplatin, but not by shRNA-Trx-1. Taken together, the results of this study indicate that resveratrol provides cardioprotection by maintaining intracellular redox environments, and Trx-2 is likely to play a role in switching I/R-induced death signal into survival signal.
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PMID:Redox regulation of resveratrol-mediated switching of death signal into survival signal. 2301 55

Mitochondrial glutaredoxin-2 (Glrx2) has been recognized as an important redox regulator in mammalian organs including heart. To date no investigations have addressed the potential role of Glrx2 in cardiac disorders. The present study examined if myocardial overexpression of Glrx2 in the heart could rescue the cardiac cells from apoptosis and necrosis induced by ischemia and reperfusion. The human Glrx2 transgene was created by placing a full-length cDNA fragment encoding human mitochondrial Glrx2 downstream to the 5' flanking sequence and promoter of the mouse alpha-myosin heavy chain gene. The isolated hearts from Glrx2 transgenic mice and non-transgenic (wild type) littermates [on c57BL/6xC3H hybrid background] were subjected to 30 min of global ischemia followed by 2 h of reperfusion via working mode. The hearts from Glrx2 transgenic mice displayed significantly improved contractile performance and reduced myocardial infarct size and cardiomyocyte apoptosis. There was a reduction in cytochrome c release and activation of caspase 3 and caspase 9. Glrx2 overexpression also reduced the ischemia/reperfusion-mediated loss of mitochondrial cardiolipin, decreased the activities of reactive oxygen species (ROS) and preserved GSH/GSSG ratio. Glrx2 mediated survival signal appeared to be stemmed from PI-3-kinase-Akt survival signaling pathway and involved the activation of redox sensitive transcription factor NFkappaB and antiapoptotic protein Bcl-2. The results indicated a crucial role of mitochondrial Glrx2 in cardioprotection.
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PMID:Overexpression of glutaredoxin-2 reduces myocardial cell death by preventing both apoptosis and necrosis. 2323 Jun 5

Chronic exposure to arsenic causes health problems, including peripheral neuropathy. Oxidative stress is one of the mechanisms underlying arsenic-induced neurotoxicity. For this report, we studied the protective effect of N-acetylcysteine (NAC) on arsenic-induced oxidative injury in dorsal root ganglion (DRG) explants. After 24-h incubation, NAC concentration-dependently attenuated arsenite-induced depletion in glutathione (GSH) content and increases in the ratio of oxidized GSH/reduced GSH (GSSG/GSH ratio) in DRG explants. Furthermore, NAC inhibited arsenite-induced elevation in the expression of stress proteins, such as heat shock protein 70 and heme oxygenase 1, as well as arsenite-induced phosphorylation of p38 mitogen-activated protein kinase. Incubation with NAC ameliorated arsenite-induced apoptosis by abolishing both mitochondrial and endoplasmic reticulum (ER) pathways. In the mitochondrial pathway, NAC attenuated arsenite-induced elevation in Bcl-2 level and cytosolic cytochrome c, as well as arsenite-induced reduction in procaspase-3 levels. In the ER pathway, NAC suppressed arsenite-induced increases in activating transcription factor 6 and C/EBP homologous protein in the nuclear fraction. Furthermore, arsenite-induced reductions in procaspase-12 and elevation in BIP and caspase-12, an ER-specific enzyme, were prevented after NAC incubation. Taken together, our results demonstrate that NAC is neuroprotective against arsenite-induced oxidative injury in DRG explants. Furthermore, NAC inhibits arsenite-induced toxicity by inhibiting ER and mitochondrion activation. Our data indicate that NAC is potentially therapeutic for arsenite-induced peripheral neuropathy.
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PMID:N-acetylcysteine attenuates arsenite-induced oxidative injury in dorsal root ganglion explants. 1807 80

We designed a randomized controlled study to identify and compare the liver tissue responses in systemic hypoxia and resuscitation with 21% and 100% oxygen using an animal model of neonatal hypoxia and reoxygenation. Twenty-seven piglets (1-3 days old, weight 1.5-2.0 kg) were acutely instrumented and mechanically ventilated. The animals underwent 2 h of normocapnic alveolar hypoxia (10-15% oxygen) then reoxygenation with 21% or 100% oxygen for 1 h, then 1 h with 21% oxygen. Controls were sham-operated without hypoxia-reoxygenation. After 2 h of reoxygenation liver tissue samples were immediately processed for histological and biochemical analyses of markers of oxidative stress and tissue injury. Two hours of hypoxia caused a significant reduction in mean arterial pressure with cardiogenic shock and metabolic acidemia, with similar recovery upon resuscitation with 21% and 100% oxygen. After 2 h of reoxygenation, the hepatic GSSG:total glutathione ratio and matrix metalloproteninase-9 activity, which correlated with the portal venous oxygenation at 15 min of reoxygenation, were greater in the 100% group and hepatic lactate level was higher in the 21% group than the controls (all P<0.05). Both hypoxic-reoxygenated groups had similarly elevated hepatic Bcl-2 levels. Apart from more non-distinct mitochondria identified in the 100% group, hepatic tissue adenylate energy charge and plasma transaminases levels did not differ among groups. We concluded that in this acute model of neonatal hypoxia and reoxygenation, resuscitation using 21% oxygen avoids the excess oxidative stress and elevated matrix metalloproteninase-9 activity in the liver when 100% oxygen was used. The study supports the conservative use of oxygen in optimizing post-hypoxic hepatic recovery.
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PMID:Oxidative stress and matrix metalloproteinase-9 activity in the liver after hypoxia and reoxygenation with 21% or 100% oxygen in newborn piglets. 1815 50

The aim of the present study was to investigate the mechanism of hyperoside protecting ECV-304 cells against tertbutyl hydroperoxide (TBHP)-induced injury. ECV-304 cell viability was measured by MTT assay. Cellular morphologic changes were observed using phase contrast microscopy. The genotoxic effects of TBHP and the protective ability of hyperoside were assessed by the Comet test. Lipid peroxidation was measured by HPLC method. The cellular redox status was determined from GSH/GSSG ratios. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. Western blot analysis was used to evaluate the levels of cytochrome c, p53, SIRT1, Bax and Bcl-2 expression. The results showed that 128 mumol/l hyperoside could effectively protect TBHP-treated ECV-304 cells from death, increase superoxide dismutase activity and significantly decrease malondialdehyde production. Hyperoside was effective in protecting against the induction of oxidized DNA bases and redox state alterations induced by TBHP. Furthermore, the release of proapoptotic cytochrome c from mitochondria was reduced by hyperoside, which increased the expression of antiapoptotic SIRT1 and inhibited the translocation of Bax from cytoplasm to mitochondria. Taken together, these results indicate that hyperoside is effective in protecting against the oxidative damage induced by TBHP. The mechanism of hyperoside protecting against ECV-304 cell apoptosis by TBHP is related with resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members.
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PMID:The mechanism of hyperoside protection of ECV-304 cells against tert-butyl hydroperoxide-induced injury. 1855 16

Hydrogen sulfide (H(2)S) is an endogenously produced gaseous signaling molecule with diverse physiological activity. The potential protective effects of H(2)S have not been evaluated in the liver. The purpose of the current study was to investigate if H(2)S could afford hepatoprotection in a murine model of hepatic ischemia-reperfusion (I/R) injury. Hepatic injury was achieved by subjecting mice to 60 min of ischemia followed by 5 h of reperfusion. H(2)S donor (IK1001) or vehicle were administered 5 min before reperfusion. H(2)S attenuated the elevation in serum alanine aminotransferase (ALT) by 68.6% and aspartate aminotransferase (AST) by 70.8% compared with vehicle group. H(2)S-mediated cytoprotection was associated with an improved balance between reduced glutathione (GSH) vs. oxidized glutathione (GSSG), an attenuated formation of lipid hydroperoxides, and an increased expression of thioredoxin-1 (Trx-1). Furthermore, H(2)S inhibited the progression of apoptosis after I/R injury by increasing the protein expression of heat shock protein (HSP-90) and Bcl-2. These results indicate that H(2)S protects the murine liver against I/R injury through an upregulation of intracellular antioxidant and antiapoptotic signaling pathways.
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PMID:Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling. 1856 6


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