Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The release of zinc (Zn) from glutamatergic synapses contributes to the neuropathology of ischemia, traumatic brain injury, and stroke. Astrocytes surround glutamatergic synapses and are vulnerable to the toxicity of Zn, which impairs their antioxidative glutathione (GSH) system and elevates the production of reactive oxygen species (ROS). It is not known whether one or both of these actions are the primary cause of Zn-induced cell death in astrocytes. Using primary rat astrocyte cultures we have examined whether Zn-mediated impairment of GSH redox cycling is the main source of its toxicity. Zn acetate at concentrations of 100 microM or greater were found to inactivate glutathione reductase (GR) via an NADPH-dependent mechanism, while concentrations of 150 microM and above caused substantial cell death. Furthermore, Zn increased the ratio of GSSG:GSH in astrocytes, increased their export of GSSG, slowed their clearance of exogenous H2O2, and promoted the intracellular production of ROS. In contrast, the GR inhibitor, carmustine, did not induce cell death, cause the production of ROS, or alter the GSH thiol redox balance. Taken together these results indicate that Zn toxicity in astrocytes is primarily associated with the generation of intracellular ROS, rather than the inhibition of GR.
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PMID:Zinc stimulates the production of toxic reactive oxygen species (ROS) and inhibits glutathione reductase in astrocytes. 1738 3

Recent observations point to the role played by Zn2+ as an inducer of neuronal death. Two Zn2+ targets have been identified that result in inhibition of mitochondrial respiration: the bc1 center and, more recently, alpha-ketoglutarate dehydrogenase. Zn2+ is also a mediator of oxidative stress, leading to mitochondrial failure, release of apoptotic peptides, and neuronal death. We now present evidence, by means of direct biochemical assays, that Zn2+ is imported through the Ca2+ uniporter and directly targets major enzymes of energy production (lipoamide dehydrogenase) and antioxidant defense (thioredoxin reductase and glutathione reductase). We demonstrate the following. (a) These matrix enzymes are rapidly inhibited by application of Zn2+ to intact mitochondria. (b) Delayed treatment with membrane-impermeable chelators has no effect, indicating rapid transport of biologically relevant quantities of Zn2+ into the matrix. (c) Membrane-permeable chelators stop but do not reverse enzyme inactivation. (d) Enzyme inhibition is rapid and irreversible and precedes the major changes associated with the mitochondrial permeability transition (MPT). (e) The extent and rate of enzyme inactivation linearly correlates with the MPT onset and propagation. (f) The Ca2+ uniporter blocker, Ruthenium Red, protects enzyme activities and delays pore opening up to 2 microm Zn2+. An additional, unidentified import route functions at higher Zn2+ concentrations. (g) No enzyme inactivation is observed for Ca2+-induced MPT. These observations strongly suggest that, unlike Ca2+, exogenous Zn2+ interferes with mitochondrial NADH production and directly alters redox protection in the matrix, contributing to mitochondrial dysfunction. Inactivation of these enzymes by Zn2+ is irreversible, and thus only their de novo synthesis can restore function, which may underlie persistent loss of oxidative carbohydrate metabolism following transient ischemia.
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PMID:Zinc irreversibly damages major enzymes of energy production and antioxidant defense prior to mitochondrial permeability transition. 1756 98

Heat shock protein (Hsp) 70 has been reported to protect various cells and tissues from ischemic damage. However, the molecular mechanisms of the protection are incompletely understood. Ischemia induces significant alterations in cellular redox status that plays a critical role in cell survival/death pathways. We investigated the effects of Hsp70 overexpression on cellular redox status in Madin-Darby canine kidney (MDCK) cells under both hypoxic and ischemic conditions with 3 different approaches: reactive oxygen species (ROS) measurement by a fluorescence probe, redox environment evaluation by a hydroxylamine spin probe, and redox status assessment by the glutathione/glutathione disulfide (GSH/GSSG) ratio. Results from each of these approaches showed that the redox status in Hsp70 cells was more reducing than that in control cells under either hypoxic or oxygen and glucose deprivation (OGD) conditions. In order to determine the mechanisms that mediated the alterations in redox state in Hsp70 cells, we measured the activities of glutathione peroxidase (GPx) and glutathione reductase (GR), two GSH-related antioxidant enzymes. We found that OGD exposure increased GPx and GR activities 47% and 55% from their basal levels (no stress) in Hsp70 cells, compared to only 18% and 0% increase in control cells, respectively. These data, for the first time, indicate that Hsp70 modulates the activities of GPx and GR that regulate cellular redox status in response to ischemic stress, which may be important in Hsp70's cytoprotective effects.
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PMID:Heat shock protein 70 regulates cellular redox status by modulating glutathione-related enzyme activities. 1791 57

The purpose of this study is to examine the antiarrhythmic and antioxidant effects of tamoxifen, one of the selective estrogen modulators, in ovariectomized rats subjected to myocardial ischemia-reperfusion (I/R) injury. A month after ovariectomy, rats were divided into four groups: (I) ovariectomized controls without any treatment, (II) ovariectomized rats treated with vehicle dimethylsulfoxide (DMSO), (III)-(IV) ovariectomized rats treated with tamoxifen 1 or 10 mg/kg,sc daily for 14 days. To produce arrhythmia, the left main coronary artery was occluded for 7 min, followed by 7 min of reperfusion. The blood pressure (BP), heart rate (HR), electrocardiography (ECG) was recorded before and during the ischemia-reperfusion period. The blood levels of malondialdehyde (MDA), creatine kinase (CK), glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione reductase (GR), and catalase (CAT) were measured after the rats were killed. Tamoxifen reduced the incidence of ventricular tachycardia (VT) on ischemia and reperfusion as well as the incidence and duration of reversible ventricular fibrillation (VF) on reperfusion. I/R injury caused a significant fall in GSH, GSH-Px as well as an increase in MDA and CK levels in the control group when compared to tamoxifen treated groups. The changes in levels of CAT and GR were however, not significant. In conclusion, our findings suggest that tamoxifen has cardioprotective effects against I/R injury in rats, likely its antioxidant properties.
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PMID:Effects of tamoxifen on myocardial ischemia-reperfusion injury model in ovariectomized rats. 1797 64

Ischaemia and reperfusion result in mitochondrial dysfunction, with decreased oxidative capacity, loss of cytochrome c and generation of reactive oxygen species. The aim of this study was to evaluate the effect of a methanol extract of Desmodium gangeticum (L) DC (Fabaceae) (DG) on lipid peroxidation and antioxidants in mitochondria and tissue homogenates of normal, ischaemic and ischaemia-reperfused rats. Myocardial lipid peroxidation products (thiobarbituric acid reactive substances; TBARS) in cardiac tissue homogenates and mitochondrial fractions were significantly increased during ischaemia reperfusion. Antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase (GPx) and glutathione reductase) in the myocardial tissue homogenate and mitochondria decreased significantly during ischaemia reperfusion, accompanied by a decreased activity of mitochondrial respiratory enzymes. Daily pretreatment of rats with DG (50 or 100 mgkg(-1)) orally for 30 days had a significant effect on the activity of mitochondrial and antioxidant enzymes. In-vitro studies showed that DG inhibited lipid peroxidation, and also scavenged hydroxyl and superoxide radicals. The concentrations required to scavenge 50% of the superoxide and hydroxyl radicals were 21 and 50.5 microgmL(-1), respectively. Administration of DG to normal rats did not have any significant effect on any of the parameters studied. The results of our study showed that DG possesses the ability to scavenge the free radicals generated during ischaemia and ischaemia reperfusion and thereby preserves the mitochondrial respiratory enzymes that eventually lead to cardioprotection.
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PMID:Methanol extract of Desmodium gangeticum roots preserves mitochondrial respiratory enzymes, protecting rat heart against oxidative stress induced by reperfusion injury. 1838 Sep 26

Liver ischemia-reperfusion (I/R) injury occurs in many clinical conditions, including liver surgery and transplantation. Oxygen free radicals generated during I/R reduce endogenous antioxidant systems and contribute to hepatic injury. trans-Resveratrol (trans-3,5,4'-trihydroxystilbene) is reported to have antioxidant properties. We investigated the effect of trans-resveratrol on liver injury induced by I/R. After 1 hour of ischemia, administered 5 minutes before 3 hours of reperfusion, trans-resveratrol was hepatoprotective at a low dose (0.02 mg/kg). It significantly decreased aminotransferase levels by about 40% and improved sinusoidal dilatation. trans-Resveratrol preserved antioxidant defense by preventing total and reduced glutathione depletion caused by I/R. At 0.2 mg/kg, trans-resveratrol significantly increased glutathione reductase, Cu/Zn-superoxide dismutase, and catalase activities. However, at a high dose (20 mg/kg), trans-resveratrol became prooxidant with an aggravation of liver injury evaluated by aminotransferase release and histological analysis and associated with a depletion of total and reduced glutathione levels and a decrease of antioxidant enzyme activities. In conclusion, a prereperfusion treatment by trans-resveratrol only at low doses decreases liver injury induced by I/R by protecting against antioxidant defense failure. This administration protocol could reduce liver damage during surgery or transplantation.
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PMID:Postischemic treatment by trans-resveratrol in rat liver ischemia-reperfusion: a possible strategy in liver surgery. 1838 89

Reactive oxygen species are important mediators that exert a toxic effect during ischemia-reperfusion injury of various organs. Sulforaphane, which is a naturally occurring isothiocyanate that is present in cruciferous vegetables such as broccoli, is known to be an indirect antioxidant that acts by inducing Nrf2-dependent phase 2 enzymes. Phase 2 enzymes such as heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, glutathione reductase, and glutathione peroxidase participate in adaptive and protective responses to oxidative stress and various inflammatory stimuli. Therefore, we evaluated the preactivation of Nrf2 by sulforaphane to determine if it could inhibit ischemia-reperfusion-induced kidney damage. Treatment of HK2 renal tubular epithelial cells with sulforaphane effectively protected cells against cytotoxicity induced by hypoxia-reoxygenation, and sulforaphane dramatically induced phase 2 enzymes by decreasing the Keap1 protein levels and increasing Nrf2 nuclear translocation. Additionally, a second set of experiments using a renal ischemia-reperfusion model produced results that were essentially the same as those observed when HK2 cells were used; namely, that sulforaphane induced Nrf2-dependent phase 2 enzymes and thereby improved ischemia-reperfusion-induced changes in the lipid hydroperoxides, glutathione, creatinine clearance, kidney weight, and histologic abnormalities. Collectively, these results suggest that sulforaphane can be used as an effective adjunct for the prevention of renal oxidative insults during ischemia-reperfusion injury.
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PMID:Sulforaphane protects kidneys against ischemia-reperfusion injury through induction of the Nrf2-dependent phase 2 enzyme. 1840 46

Antioxidants have been the focus of studies for developing neuroprotective agents to be used in the therapy for stroke, which is an acute and progressive neurodegenerative disorder and is the second leading cause of death throughout the world. In fact, many herbal antioxidants have been developed in in vitro and in vivo experiments and some of these have been tested in clinical studies of stroke. Embelia ribes have been reported to have antioxidant and antidiabetic effects. In addition to these effects, this study was designed to investigate the neuroprotective effect of ethanolic extract of E. ribes Burm fruits on middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia in rats. Male Wistar albino rats were fed ethanolic E. ribes extract (100 and 200 mg/kg body weight; p.o.) for 30 days. After 30 days of feeding, all animals were anaesthetized with chloral hydrate (400 mg/kg, i.p.). The right middle cerebral artery was occluded with a 4-0 suture for 2 h. The suture was removed after 2 h to allow reperfusion injury. Ischemia followed by reperfusion in ischemic group rats significantly (P < 0.001) reduced the grip strength activity and non-enzymatic (reduced glutathione, GSH) and enzymatic [glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST)] antioxidant levels in hippocampus and frontal cortex compared to sham-operated rats. Further, serum lactate dehydrogenase (LDH) and thiobarbituric acid reactive substance (TBARS) levels in hippocampus and frontal cortex were significantly increased in ischemic group compared to sham-operated rats. Furthermore, ethanolic E. ribes extracts pretreatment significantly (P < 0.001) increased the grip strength activity, and GSH, GPx, GR and GST levels in hippocampus and frontal cortex with significant decrease in LDH levels in serum and TBARS levels in hippocampus and frontal cortex compared to MCAO + vehicle group rats. The data from this study suggest that chronic treatment with ethanolic E. ribes extract enhances the antioxidant defense against MCAO- induced focal cerebral ischemia in rats and exhibits neuroprotective activity.
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PMID:Evaluation of antioxidant and neuroprotective effect of ethanolic extract of Embelia ribes Burm in focal cerebral ischemia/reperfusion-induced oxidative stress in rats. 1848 49

Hibernating mammals exhibit oxidative stress resistance in brain, liver and other tissues. In many animals, cellular oxidative stress resistance is associated with enhanced expression of intracellular antioxidant enzymes. Intracellular antioxidant capacity may be upregulated during hibernation to protect against oxidative damage associated with the ischemia-reperfusion that occurs during transitions between torpor and arousal. We tested the hypothesis that the 13-lined ground squirrel (Spermophilus tridecemlineatus), upregulates intracellular antioxidant enzymes in major oxidative tissues during hibernation. The two major intracellular isoforms of superoxide dismutase (MnSOD and CuZnSOD), which catalyze the first step in superoxide detoxification, were quantified in heart, brain and liver tissue using immunodetection and an in-gel activity assay. However, no differences in SOD protein expression or activity were found between active and hibernating squirrels. Measurements of glutathione peroxidase and glutathione reductase, which catalyze hydrogen peroxide removal, were not broadly upregulated during hibernation. The activity of catalase, which catalyzes an alternative hydrogen peroxide detoxification pathway, was higher in heart and brain of torpid squirrels, but lower in liver. Taken together, these data do not support the hypothesis that hibernation is associated with enhanced oxidative stress resistance due to an upregulation of intracellular antioxidant enzymes in the major oxidative tissues.
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PMID:Intracellular antioxidant enzymes are not globally upregulated during hibernation in the major oxidative tissues of the 13-lined ground squirrel Spermophilus tridecemlineatus. 1894 23

The primary cause of morbidity and mortality in renal transplantation is cardiovascular disease. Increased oxidative stress implies a greater degree of atherogenesis in these patients. N-acetylcysteine (NAC) which has a thiol group that is the source of l-cysteine and reduced glutathione, acts against atherosclerosis via a decrease in apoptosis, vasoconstriction, and endothelial dysfunction. Experimental models have examined the antioxidant effects of NAC during and after ischemia-reperfusion, but few studies have shown an effect in renal transplantation in human beings. In 8 months, we studied the effect of NAC treatment on oxidative stress, lipids, and renal function in 25 patients with stable renal function and no diabetes after transplantation. Data were collected on oxidative parameters: malondialdehyde, glutathione peroxidase, catalase, superoxide dismutase, glutathione reductase, lipid profile, and renal function (creatinine concentration, Cockroft-Gault formula, and Modified Diet in Renal Disease study). There were no significant differences in oxidative profile before and after treatment with NAC. The mean serum high-density lipoprotein cholesterol fraction increased after treatment and showed a significant positive correlation with glutathione peroxidase (r = 0.495). Serum creatinine concentration decreased, and Cockroft-Gault and Modified Diet in Renal Disease study estimates of renal function increased in the treatment period. In conclusion, NAC treatment in patients with stable renal function after transplantation increased high-density lipoprotein cholesterol and antioxidant molecules in relation to glutathione peroxidase, with a positive influence on renal function.
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PMID:Treatment with N-acetylcysteine in stable renal transplantation. 1901 Jan 40


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