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)

Hearts from rats treated with interleukin-1 (IL-1) intraperitoneally developed a rapid (6 h after IL-1), transient increase in neutrophils, tissue hydrogen peroxide (H2O2), and oxidized glutathione (GSSG) levels, and a subsequent (36 h after IL-1) increase in myocardial glucose-6-phosphate dehydrogenase (G6PD) activity and tolerance to ischemia-reperfusion. In the present investigation, we found that rats treated similarly with IL-1 had increased numbers of neutrophils in their kidneys, which were comparable to myocardial neutrophil increases, but did not develop increased renal tissue H2O2 or GSSG levels acutely (6 h after IL-1) or increased G6PD activity or resistance to ischemia-reperfusion injury later (36 h after IL-1). Our findings indicate that IL-1 treatment increased neutrophil accumulation in rat kidneys but did not increase oxidative stress, antioxidant enzyme activity, or resistance to ischemia-reperfusion injury. We conclude that organ-to-organ differences exist with respect to IL-1-induced tolerance.
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PMID:Interleukin-1 treatment increases neutrophils but not antioxidant enzyme activity or resistance to ischemia-reperfusion injury in rat kidneys. 784 98

Melatonin, the chief secretory product of the pineal gland, was recently found to be a free radical scavenger and antioxidant. This review briefly summarizes the published reports supporting this conclusion. Melatonin is believed to work via electron donation to directly detoxify free radicals such as the highly toxic hydroxyl radical. Additionally, in both in vitro and in vivo experiments, melatonin has been found to protect cells, tissues and organs against oxidative damage induced by a variety of free radical generating agents and processes, e.g., the carcinogen safrole, lipopolysaccharide, kainic acid, Fenton reagents, potassium cyanide, L-cysteine, excessive exercise, glutathione depletion, carbon tetrachloride, ischemia-reperfusion, MPTP, amyloid beta (25-35 amino acid residue) protein, and ionizing radiation. Melatonin as an antioxidant is effective in protecting nuclear DNA, membrane lipids and possibly cytosolic proteins from oxidative damage. Also, melatonin has been reported to alter the activities of enzymes which improve the total antioxidative defense capacity of the organism, i.e., superoxide dimutase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and nitric oxide synthase. Most studies have used pharmacological concentrations or doses of melatonin to protect against free radical damage; in a few studies physiological levels of the indole have been shown to be beneficial against oxidative stress. Melatonin's function as a free radical scavenger and antioxidant is likely assisted by the ease with which it crosses morphophysiological barriers, e.g., the blood-brain barrier, and enters cells and subcellular compartments. Whether the quantity of melatonin produced in vertebrate species is sufficient to significantly influence the total antioxidative defense capacity of the organism remains unknown, but its pharmacological benefits seem assured considering the low toxicity of the molecule.
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PMID:Pharmacological actions of melatonin in oxygen radical pathophysiology. 919 81

We studied the effect of 2-week treatment with estradiol 17beta on myocardial glutathione concentration in dogs and isolated perfused rat heart subjected to brief coronary ischemia and reperfusion. Estradiol protected against ischemia/reperfusion-induced myocardial systolic shortening and malonylaldehyde production and increased myocardial glutathione concentration and glucose-6-phosphate dehydrogenase enzyme activity. Reduction of myocardial glutathione with buthionine sulfoximine to levels seen in the absence of estrogen reversed the protective effect of estradiol against myocardial dysfunction and lipid peroxidation associated with ischemia/reperfusion. These results suggest that the antioxidant effect of estradiol in ischemia/reperfusion may be mediated by regulation of myocardial glutathione metabolism.
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PMID:17-Beta estradiol regulation of myocardial glutathione and its role in protection against myocardial stunning in dogs. 973 60

Melatonin was recently reported to be an effective free radical scavenger and antioxidant. Melatonin is believed to scavenge the highly toxic hydroxyl radical, the peroxynitrite anion, and possibly the peroxyl radical. Also, secondarily, it reportedly scavenges the superoxide anion radical and it quenches singlet oxygen. Additionally, it stimulates mRNA levels for superoxide dismutase and the activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase (all of which are antioxidative enzymes), thereby increasing its antioxidative capacity. Also, melatonin, at least at some sites, inhibits nitric oxide synthase, a pro-oxidative enzyme. In both in vivo and in vitro experiments melatonin has been shown to reduce lipid peroxidation and oxidative damage to nuclear DNA. While these effects have been observed primarily using pharmacological doses of melatonin, in a small number of experiments melatonin has been found to be physiologically relevant as an antioxidant as well. The efficacy of melatonin in inhibiting oxidative damage has been tested in a variety of neurological disease models where free radicals have been implicated as being in part causative of the condition. Thus, melatonin has been shown prophylactically to reduce amyloid beta protein toxicity of Alzheimer's disease, to reduce oxidative damage in several models of Parkinson's disease (dopamine auto-oxidation, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine), to protect against glutamate excitotoxicity, to reduce ischemia-reperfusion injury, to lower neural damage due to gamma-aminolevulinic acid (phorphyria), hyperbaric hyperoxia and a variety of neural toxins. Since endogenous melatonin levels fal 1 markedly in advanced age, the implication of these findings is that the loss of this antioxidant may contribute to the incidence or severity of some age-associated neurodegenerative diseases.
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PMID:Oxidative damage in the central nervous system: protection by melatonin. 977 Feb 44

Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger and indirect antioxidant. In terms of its scavenging activity, melatonin has been shown to quench the hydroxyl radical, superoxide anion radical, singlet oxygen, peroxyl radical, and the peroxynitrite anion. Additionally, melatonin's antioxidant actions probably derive from its stimulatory effect on superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase and its inhibitory action on nitric oxide synthase. Finally, melatonin acts to stabilize cell membranes, thereby making them more resistant to oxidative attack. Melatonin is devoid of prooxidant actions. In models of oxidative stress, melatonin has been shown to resist lipid peroxidation induced by paraquat, lipopolysaccharide, ischemia-reperfusion, L-cysteine, potassium cyanide, cadmium chloride, glutathione depletion, alloxan, and alcohol ingestion. Likewise, free radical damage to DNA induced by ionizing radiation, the chemical carcinogen safrole, lipopolysaccharide, and kainic acid are inhibited by melatonin. These findings illustrate that melatonin, due to its high lipid solubility and modest aqueous solubility, is able to protect macromolecules in all parts of the cell from oxidative damage. Melatonin also prevents the inhibitory action of ruthenium red at the level of the mitochondria, thereby promoting ATP production. In humans, the total antioxidative capacity of serum is related to melatonin levels. Thus, the reduction in melatonin with age may be a factor in increased oxidative damage in the elderly.
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PMID:Reactive oxygen intermediates, molecular damage, and aging. Relation to melatonin. 992 48

Oxidative stress is implicated in the pathogenesis of neurodegenerative disorders and brain ischemia, and hydrogen peroxide (H(2)O(2)) plays a central role in the stress. In this study, we have examined the kinetics of H(2)O(2) elimination by PC12 cells as a neuronal model in connection with the enzyme activities supporting the reaction. Similarly to other cell lines previously studied, H(2)O(2) removal kinetics could be divided into two reactions: one apparently following the Michaelis-Menten kinetics (GSH-dependent reaction) and the other following the first-order kinetics (mainly catalyzed by catalase). Based on the enzyme activities in the cell homogenate, it was inferred that glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the GSH- and NADPH-dependent H(2)O(2) elimination by PC12 cells. This is in contrast with fibroblasts and endothelial cells previously examined, in which glutathione reductase (GR) is rate-limiting in the reaction sequence. Treatment of PC12 cells with nerve growth factor increased G6PD activity in the cell homogenate and H(2)O(2) removal activity of the whole cells, with a concomitant increase in the resistance against H(2)O(2) toxicity. These results suggest the importance of G6PD in the antioxidant function of brain and pathogenesis of the oxidative stress-related diseases.
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PMID:Kinetic studies on the hydrogen peroxide elimination by cultured PC12 cells: rate limitation by glucose-6-phosphate dehydrogenase. 1220 36

In this brief review the antioxidative actions of melatonin are summarized and they are discussed relative to several models of oxidative neurotoxicity. Melatonin is a ubiquitously acting antioxidant. It has been shown to scavenge the hydroxyl radical, peroxyl radical, singlet oxygen and the peroxynitrite anion; secondarily, it also scavenges the superoxide anion radical. In addition, melatonin reportedly stimulates a number of antioxidative enzymes including glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase. On the other hand, melatonin inhibits the pro-oxidative enzyme nitric oxide synthase. Besides these actions which help to resist oxidative damage, melatonin prevents membrane rigidity, reduces polymorphonuclear cell infiltration into damaged tissue, limits the adhesion of leucocytes to endothelial cells, thereby increasing blood flow and reducing edema. Some or all of these actions may have been operative in the experimental models of oxidative neurotoxicity that were improved by melatonin treatment. In brief, melatonin has been found to protect the CNS from beta-amyloid toxicity, experimental models of Parkinsonism, excitotoxicity, nitric oxide toxicity, aminolevulinic acid, lipopolysaccharide, hyperbaric hyperoxia, L-cysteine, cyanide and ischemia/reperfusion injury.
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PMID:Oxidative toxicity in models of neurodegeneration: responses to melatonin. 1267 8

This study examined the effects of estrogen supplementation on markers of neutrophil infiltration and damage in skeletal muscle of rats following ischemia. Male and female gonad-intact rats, with or without 14 days of estrogen supplementation were subjected to two hours of hind-limb ischemia and sacrificed at 24, 48 or 72 hours post-ischemia. Control animals were sacrificed without ischemia. Plantaris and red and white gastrocneimus muscles were removed and assayed for myeloperoxidase (MPO), a marker of neutrophil infiltration, and glucose-6-phosphate dehydrogenase (G6PD) and beta-glucuronidase (betaGLU), as markers of muscle damage. Significant elevations of MPO, G6PD and betaGLU activities were observed at various time points post-ischemia. No systematic differences between genders were noted in any of the measures. Estrogen supplementation in both male and female animals failed to significantly attenuate post-ischemia increases in MPO, G6PD and betaGLU activities in any of the muscles studied and in some cases accentuated activities of some of these measures. Unlike previous findings following exercise in skeletal muscle, this study failed to demonstrate estrogen-induced attenuation of indices of neutrophil infiltration or damage in skeletal muscles of rats up to 72 hours following ischemia. This demonstrates that estrogen may not consistently attenuate neutrophil infiltration and that a number of variables including damage modality, tissue or estrogen level may influence this.
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PMID:Estrogen supplementation failed to attenuate biochemical indices of neutrophil infiltration or damage in rat skeletal muscles following ischemia. 1623

Hypoxia inducible factor 1 (HIF-1) has been suggested to play a critical role in the fate of cells exposed to hypoxic stress. However, the mechanism of HIF-1-regulated cell survival is still not fully understood in ischemic conditions. Redox status is critical for decisions of cell survival, death and differentiation. We investigated the effects of inhibiting HIF-1 on cellular redox status in SH-SY5Y cells exposed to hypoxia or oxygen and glucose deprivation (OGD), coupled with cell death analyses. Our results demonstrated that inhibiting HIF-1alpha expression by HIF-1alpha specific small interfering RNA (siRNA) transfection increased reactive oxygen species generation, and transformed the cells to more oxidizing environments (low GSH/GSSG ratio, low NADPH level) under either hypoxic or OGD exposure. Cell death increased dramatically in the siRNA transfected cells, compared to non-transfected cells after hypoxic/OGD exposures. In contrast, increasing HIF-1alpha expression by desferrioxamine, a metal chelator and hydroxylase inhibitor, induced a more reducing environment (high GSH/GSSG ratio, high NADPH level) and reduced cell death. Further studies showed that HIF-1 regulated not only glucose transporter-1 expression, but also the key enzymes of the pentose phosphate pathway such as glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. These enzymes are important in maintaining cellular redox homeostasis by generating NADPH, the primary reducing agent in cells. Moreover, catalase significantly decreased cell death in the siRNA-transfected cells induced by hypoxia and OGD. These results suggest that maintenance of cellular redox status by HIF-1 protects cells from hypoxia and ischemia mediated injuries.
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PMID:Specific inhibition of hypoxia inducible factor 1 exaggerates cell injury induced by in vitro ischemia through deteriorating cellular redox environment. 1918 69

The Ca(2+)-independent phospholipase A(2) VI (iPLA(2)-VI) and the Na(+)/H(+) exchanger isoform 1 (NHE1) are highly pH-sensitive proteins that exert both protective and detrimental effects in cardiac ischemia-reperfusion. Here, we investigated the role of extracellular pH (pH(o)) in ischemia-reperfusion injury and death and in regulation and function of iPLA(2)-VI and NHE1 under these conditions. HL-1 cardiomyocytes were exposed to simulated ischemia (SI; 0.5% O(2), 8 mM K(+), and 20 mM lactate) at pH(o) 6.0 and 7.4, with or without 4 or 8 h of reperfusion (SI/R). Cytochrome c release and caspase-3 activation were reduced after acidic compared with neutral SI, whereas necrotic death, estimated as glucose-6-phosphate dehydrogenase release, was similar in the two conditions. Inhibition of iPLA(2)-VI activity by bromoenol lactone (BEL) elicited cardiomyocyte necrosis during normoxia and after acidic, yet not after neutral, SI. The isoform-selective enantiomers R- and S-BEL both mimicked the effect of racemic BEL after acidic SI. In contrast, inhibition of NHE activity by EIPA had no significant effect on necrosis after SI. Both neutral and acidic SI were associated with a reversible loss of F-actin and cortactin integrity. Inhibition of iPLA(2)-VI disrupted F-actin, cortactin, and mitochondrial integrity, whereas inhibition of NHE slightly reduced stress fiber content. iPLA(2)-VIA and NHE1 mRNA levels were reduced during SI and upregulated in a pH(o)-dependent manner during SI/R. This also affected the subcellular localization of iPLA(2)-VIA. Thus, the mode of cell death and the roles and regulation of iPLA(2)-VI and NHE1 are at least in part determined by the pH(o) during SI. In addition to having clinically relevant implications, these findings can in part explain the contradictory results obtained from previous studies of iPLA(2)-VIA and NHE1 during cardiac I/R.
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PMID:HL-1 mouse cardiomyocyte injury and death after simulated ischemia and reperfusion: roles of pH, Ca2+-independent phospholipase A2, and Na+/H+ exchange. 1926 8


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