Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although it is considered that L-Glutamine (L-Gln) supplementation improves gut morphology and survival in animal models such as radiation and drug-induced enterocolitis, the mechanisms underlying are far from being established. Recently, Gln has been reported to give protection against stress in in vitro intestinal epithelial cell lines through the induction of heat shock proteins (HSPs). This study is designed to examine whether L-Gln may induce cytoprotective molecules such as heme oxygenase-1/HSP32 (HO-1) and reduced glutathione (GSH) in in vivo intestinal tissues, and to clarify whether these molecules may play a role in warm ischemia and reperfusion (I/R) injury. We measured the releases of serotonin and tumor necrosis factor-alpha (TNF-alpha), and graft survival as viability assays following reperfusion of warm ischemically injured intestinal grafts. The substantial expression of HO-1 after L-Gln administration was observed in villous epithelial cells, crypts and muscular layers, and peaked at 6 h, while that of the control group pretreated with lactated Ringer (LR) solution was observed throughout tissues to be slightly similar to those of fresh untreated tissues. Tissue GSH contents slightly increased 24 h after administration and were less reduced through the periods of I/R than those of the LR group. Releases of serotonin and TNF-alpha in L-Gln group were attenuated during the brief periods of warm ischemia, compared with those in the LR group. A significant graft survival rate was also observed between both groups (6/6 of L-Gln group vs. 1/6 of LR group; p < 0.05). In conclusion, the protective effects of L-Gln in small intestines against warm I/R injury were considered to be in part mediated by up-regulation of molecules such as HO-1 and GSH via cellular antioxidant activity. Thus, L-Gln pretreatment may represent an innovative approach to the prevention of complex I/R injury.
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PMID:[L-glutamine-induced heme oxygenase-1 protects small intestine from warm ischemia and reperfusion injury in the rat]. 1123 9

The lipid products derived from the cyclooxygenase pathway can have diverse and often contrasting effects on vascular cell function. Cyclopentenone prostaglandins (cyPGs), such as 15-deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)), a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, have been reported to cause endothelial cell apoptosis, yet in other cell types, cyPGs induce cytoprotective mediators, such as heat shock proteins, heme oxygenase-1, and glutathione (GSH). Herein, we show in human endothelial cells that low micromolar concentrations of 15d-PGJ(2) enhance GSH-dependent cytoprotection through the upregulation of glutamate-cysteine ligase, the rate-limiting enzyme of GSH synthesis, as well as GSH reductase. The effect of 15d-PGJ(2) on GSH synthesis is attributable to the cyPG structure but is independent of PPAR, inasmuch as the other cyPGs, but not PPARgamma or PPARalpha agonists, are able to increase GSH. The increase in cellular GSH is accompanied by abrogation of the proapoptotic effects of 4-hydroxynonenal, a product of lipid peroxidation present in atherosclerotic lesions. However, higher concentrations of 15d-PGJ(2) (10 micromol/L) cause endothelial cell apoptosis, which is further enhanced by depletion of cellular GSH by buthionine sulfoximine. We propose that the GSH-dependent cytoprotective pathways induced by 15d-PGJ(2) contribute to its antiatherogenic effects and that these pathways are distinct from those leading to apoptosis.
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PMID:Biphasic effects of 15-deoxy-delta(12,14)-prostaglandin J(2) on glutathione induction and apoptosis in human endothelial cells. 1170 76

Changes in the activities of rat liver heme oxygenase (HO), superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione reductase (GR), as well as changes in lipid peroxidation and reduced glutathione (GSH) levels were measured after acute loading and chronic administration of cobalt chloride (CoCl2). Acute loading was achieved by a single subcutaneous injection of 60 mg CoCl2/kg body weight for 24 h. Chronic administration was performed by giving the same total amount of CoCl2 in small doses over longer periods of time: 30 mg CoCl2/kg daily for 2 days, 15 mg CoCl2/kg daily for 4 days, or 10 mg CoCl2/kg daily for 6 days. The results showed that HO activity was increased both after acute loading (7-fold increase) and upon 6-day administration of CoCl2 (5-fold increase). The GSH level, 24 h after a single injection of CoCl2, was lower than that of the control animals. However, upon chronic administration of small doses CoCl2, the level of GSH increased and was accompanied by an increase in GR activity. Chronic administration of CoCl2 produced persistent oxidative stress, which was illustrated with a continuous increase in lipid peroxidation. At the same time, under these conditions, the activities of oxidative-stress-protective enzymes were either inhibited (SOD, catalase) or not significantly changed (GPx). Collectively, these findings suggest that the sustained up-regulation of HO activity in rat liver upon 6 day administration of CoCl2 would be beneficial by providing the cells with antioxidants, biliverdin and bilirubin, and together with the increased levels of GSH would act as a part of the defence mechanisms against the cobalt-induced oxidative stress.
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PMID:Heme oxygenase is the main protective enzyme in rat liver upon 6-day administration of cobalt chloride. 1175 67

The amounts of superoxide and hydrogen peroxide generated by mitochondria under physiological conditions can be enhanced by cellular stress. This study tested the hypothesis that the response to hemin-induced stress, which includes heme oxygenase-1 (HO-1) induction, predisposes to oxidative damage of mitochondrial DNA (mtDNA). Hepatic mitochondria from control, hemin-, and CO-exposed rats were incubated with tert-butyl hydroperoxide (tert-BH) or the NO donor 1,2,3,4-oxatriazolium, 5-amino-3- (3,4-dichlorophenyl)-chloride (GEA 3162). Mitochondrial total and oxidized glutathione (GSH and GSSG), total and free iron, and 8-oxo-7, 8-dihydro-2' deoxyguanosine (8-OHdG) were determined with and without oxidants. As expected, oxidation by tert-BH induced significant GSH depletion and increased amounts of free iron and 8-OhdG. Oxidant exposure rapidly produced a large mtDNA deletion involving the coding regions for cytochrome c oxidase (COX 1) and NADH dehydrogenase (ND1 and ND2). Hemin and CO greatly exacerbated susceptibility to the deletion of mtDNA by tert-BH, and this was attenuated by preincubation with GSH methyl ester. Analysis of mitochondria-associated proteins Bax and Bcl-xl in hemin- and CO-exposed rats showed significant responses, revealing interactions with apoptotic pathways. Thus, hemin-induced mitochondrial events sensitize a specific region of the mitochondrial genome to deletion, which is related to depletion of GSH and is not explained by effects of CO. This mtDNA damage is associated with altered expression of mitochondrial cell death proteins, thereby suggesting a novel mechanism for systemic or environmental pro-oxidants to influence apoptosis.
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PMID:Rapid mtDNA deletion by oxidants in rat liver mitochondria after hemin exposure. 1182 50

It is generally recognized that lipid peroxides play an important role in the pathogenesis of several diseases and that sulfhydryl groups are critically involved in cellular defense against endogenous or exogenous oxidants. Recent evidence indicates that lipid peroxides directly participate in induction of cytoprotective proteins, such as heat shock proteins (Hsps), which play a central role in the cellular mechanisms of stress tolerance. Heme oxygenase (HO) is a stress protein that has been implicated in defense mechanisms against agents that may induce oxidative injury, such as endotoxins, cytokines and heme and its induction represents a common feature in a number of neurodegenerative diseases. In the present report we studied regional distribution of heme oxygenase (HO) activity and protein expression, together with that of Hps70, in brain of C57BL6 mice. Endogenous lipid peroxidation was investigated on the basis of the analysis of ultra weak chemiluminescence, hydro peroxides and lipid soluble fluorescent products, and compared to the regional distribution of thiols, antioxidant enzymes and trace metals. Our results show that levels of HO activity and expression of inducible Hsp70 and the ratio of GSH/GSSG in the different brain regions examined were positively correlated with the content of peroxides. Substantia Nigra was the brain area exhibiting the highest levels of HO-2, constitutive and inducible Hsp70, GSSG, peroxides, iron, and calcium, in contrast with the lowest content in GSH, GSH/GSSG ratio and glutathione reductase activity, compared to the other cerebral regions examined. Among these, cortex showed the lowest levels of HO-2, Hsp70, GSSG and peroxides that were associated with the highest levels of GSH and GSH/GSSG ratio. These data support the hypothesis that the glutathione redox state and basal peroxides can directly participate in the signaling pathways of heat shock protein expression and hence of stress tolerance.
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PMID:Regional distribution of heme oxygenase, HSP70, and glutathione in brain: relevance for endogenous oxidant/antioxidant balance and stress tolerance. 1193 50

Although several epidemiological studies have shown a positive relationship between exposure to ambient air particulate matter (PM) and adverse health effects in humans, there is still a fundamental lack of understanding of the most toxic particle components and the biological mechanisms through which they act. Since our studies on the biological effects of diesel exhaust particles (DEP) have highlighted the role of reactive oxygen species (ROS), catalyzed by organic chemical compounds, we set out to establish whether this constitutes an oxidative stress model that can be used to study the biological effects of ambient coarse and fine PM. We demonstrate that organic DEP extracts induce a stratified oxidative stress response, leading to heme oxygenase 1 (HO-1) expression at normal GSH/ GSSG ratios, proceed to Jun kinase activation and interleukin 8 (IL-8) production at intermediary oxidative stress levels, and culminate in cellular apoptosis in parallel with a sharp decline in GSH/GSSG ratios. We demonstrate that ambient concentrated air particulates, collected with a particle concentrator and a liquid impinger, mimic the effects of organic DEP extracts at lower oxidative stress levels. While fine PM consistently induced HO-1 expression in all most of the samples collected over a 9-mo survey period, coarse particulates were effective at inducing that effect during fall and winter. Moreover, HO-1 expression was positively correlated to the higher organic carbon (OC) and polyaromatic hydrocarbons (PAHs) content of fine versus coarse PM, as well as the rise in PAH content that occurs in coarse PM during the winter months. Although coarse and fine PM lead to a decrease in cellular glutathione (GSH)/GSSG ratios, oxidative stress did not increase to cytotoxic levels. Taken together, these data demonstrate that it is possible to use the stratified oxidative stress model developed for DEP to interpret the biological effects of coarse and fine PM. This work has important implications for the selection of relevant biological endpoints for in vivo studies.
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PMID:Use of a stratified oxidative stress model to study the biological effects of ambient concentrated and diesel exhaust particulate matter. 1202 3

Although they are known to be effective antidiabetic agents, little is published about the toxic effects of carnitine palmitoyltransferase-1 (CPT-1) inhibitors, such as etomoxir (ET). These compounds inhibit mitochondrial fatty acid beta-oxidation by irreversibly binding to CPT-1 and preventing entry of long chain fatty acids into the mitochondrial matrix. Treatment of HepG2 cells with 1 mM etomoxir for 6 h caused significant modulations in the expression of several redox-related and cell cycle mRNAs as measured by microarray analysis. Upregulated mRNAs included heme oxygenase 1 (HO1), 8-oxoguanine DNA glycosylase 1 (OGG1), glutathione reductase (GSR), cyclin-dependent kinase inhibitor 1A (CDKN1 [p21(waf1)]) and Mn+ superoxide dismutase precursor (SOD2); while cytochrome P450 1A1 (CYP1A1) and heat shock 70kD protein 1 (HSPA1A) were downregulated. Real time quantitative PCR (RT-PCR) confirmed the significant changes in 4 of 4 mRNAs assayed (CYP1A1, HO1, GSR, CDKN1), and identified 3 additional mRNA changes; 2 redox-related genes, gamma-glutamate-cysteine ligase modifier subunit (GCLM) and thioredoxin reductase (TXNRD1) and 1 DNA replication gene, topoisomerase IIalpha (TOP2A). Temporal changes in selected mRNA levels were examined by RT-PCR over 11 time points from 15 min to 24 h postdosing. CYP1A1 exhibited a 38-fold decrease by 4 h, which rebounded to a 39-fold increase by 20 h. GCLM and TXNRD1 exhibited 13- and 9-fold increases, respectively at 24 h. Etomoxir-induced oxidative stress and impaired mitochondrial energy metabolism were confirmed by a significant decrease in reduced glutathione (GSH), reduced/oxidized glutathione ratio (GSH/GSSG), mitochondrial membrane potential (MMP), and ATP levels, and by concurrent increase in oxidized glutathione (GSSG) and superoxide generation. This is the first report of oxidative stress caused by etomoxir.
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PMID:Etomoxir-induced oxidative stress in HepG2 cells detected by differential gene expression is confirmed biochemically. 1207 14

Differences in lung heme oxygenase-1 (HO-1) regulation have been demonstrated in newborn (<12 h old) and adult (>2 month old) rats after exposure to hyperoxia. Contrary to adults, neonates do not demonstrate increased lung HO-1 induction nor transcription factor activator protein-1 (AP-1) binding in hyperoxia. Because AP-1 activation can be posttranslationally modified by oxidants or reductants, we investigated whether differences in lung glutathione (GSH) content account for the maturational differences in AP-1 activation and subsequent HO-1 gene regulation after hyperoxia. Neonatal rats were injected with either 1-buthionine-[S,R] sulfoximine (BSO), diamide, or selenite during the 72-h hyperoxic exposure. Lung GSH content, glutathione disulfide (GSSG) content, AP-1 binding, and HO-1 mRNA were evaluated. The ratios of GSSG to GSH were used to reflect the GSH redox state in the lungs. Changes in lung GSSG/GSH ratio did not alter AP-1 binding but did increase HO-1 mRNA in neonates. These data suggest that the neonatal lung is relatively resistant to AP-1 activation and HO-1 induction by GSH perturbation.
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PMID:Effect of glutathione on lung activator protein-1 activation and heme oxygenase-1 induction in the immature rat. 1208 44

The in vivo effect of the known herbicide, paraquat, on both hepatic oxidative stress and heme metabolism was studied. A marked increase in lipid peroxidation and a decrease in reduced glutathione (GSH) content were observed 1 h after paraquat administration. The activity of liver antioxidant enzymes, superoxide dismutase, catalase and glutathione peroxidase was decreased 3 h after paraquat injection. Heme oxygenase-1 induction started 9 h after treatment, peaking at 15 h. delta-aminolevulinic acid synthase induction occurred once heme oxygenase had been enhanced, reaching its maximum (1.5-fold of control) at 16 h. delta-aminolevulinic acid dehydratase activity was 40% inhibited at 3 h showing a profile similar to that of GSH, while porphobilinogenase activity was not modified along the whole period of the assay. Administration of alpha-tocopherol (35 mmol/kg body weight) 2 h before paraquat treatment entirely prevented the increase in thiobarbituric acid reactive substances (TBARS) content, the decrease in GSH levels as well as heme oxygenase-1 and delta-aminolevulinic acid synthase induction. This study shows that oxidative stress produced by paraquat leads to an increase in delta-aminolevulinic acid synthase and heme oxygenase-1 activities, indicating that the herbicide affects both heme biosynthesis and degradation.
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PMID:Paraquat-generated oxidative stress in rat liver induces heme oxygenase-1 and aminolevulinic acid synthase. 1218 Jan 88

The in vivo effect of hemin on both brain oxidative stress and heme oxygenase-1 (HO-1) induction was studied. A marked increase in lipid peroxidation was observed 1 h after hemin administration and antioxidant enzymes significantly decreased 3 h after hemin injection. HO-1 activity appeared 6 h after treatment, peaking 9 h after hemin administration. Such induction was preceded by a decrease in GSH pool and an increase in hydrogen peroxide concentration. Iron ferritin levels and ferritin content began to increase 6 h after HO-1 induction, and these increases remained high for at least 24 h after hemin injection. Administration of bilirubin entirely prevented HO-1 induction as well as the generation of oxidative stress parameters. These results indicate that the induction of heme oxygenase by hemin may be a general response to oxidant stress, by increasing bilirubin and ferritin levels and could therefore provide a major cellular defense mechanism against oxidative damage.
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PMID:Heme oxygenase-1 induction and dependent increase in ferritin. A protective antioxidant stratagem in hemin-treated rat brain. 1240 54


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