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)

Oxidized irwN has been proposed as a mediator of the free radical-induced damage that occurs during cerebral ischemia. Dihydroriboflavin, a compound produced from riboflavin (B2) by NADPH-dependent flavin reductase, rapidly reduces oxidized iron. Since treatment with riboflavin offers protection from ischemic injury in other tissues, we tested the effect of pretreatment with B2 on brain edema formation during focal ischemia. Two different models of middle cerebral artery occlusion (MCAO) in rats were tested: transcranial electrocautery and intracarotid occlusion with a nylon thread. Groups of 6-8 animals were treated with 7.5 mg of B2/kg or saline vehicle 1 h before MCAO and brain water content was determined after 4 h of ischemia. Pretreatment with B2 reduced total hemisphere edema formation from 0.37 +/- 0.05 to 0.19 +/- 0.05 mg/g dry wt. (48% protection, p < 0.01) following transcranial MCAO. Edema was greater following MCAO with the intra-carotid thread (0.54 +/- 0.05 ml/g) but protection by B2 was less (21%). We conclude that pretreatment with B2 reduces ischemic brain injury, perhaps by reacting with oxidized iron. However, the larger stroke produced by the thread MCAO method makes it more difficult to observe protection following brief ischemia in this model.
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PMID:Riboflavin reduces edema in focal cerebral ischemia. 797 77

The present study investigated the effects of diclofenac sodium (Dic Na) on lipid peroxidation (LPO) and liver injury in ischemia-reperfused rat. LPO was estimated from the levels of phosphatidylcholine hydroperoxide (PCOOH), a primary peroxidative product of phosphatidylcholine. Hepatic ischemia-reperfusion induced significant elevation of plasma PCOOH and caused liver injury in rats. Rats were treated daily with Dic Na or alpha-tocopherol (alpha-toc.), p.o., for 5 days and once at 1 hr prior to induction of ischemia. Both substances prevented LPO from decreasing the plasma PCOOH level, and they significantly suppressed the elevation of serum GOT and LDH, in a dose-dependent manner. Dic Na was able to scavenge the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH), but did not show radical-trapping ability for superoxide anion (O2-) or hydroxyl radicals (.OH), nor a suppressive ability for the NADPH-dependent LPO of microsomes. In contrast, alpha-toc. trapped both DPPH and O2-, but not .OH, and it inhibited the NADPH dependent LPO in vitro. These results suggest that Dic Na may suppress liver injury caused by ischemia-reperfusion through stable radical scavenging and the inhibition of superoxide production in activated phagocytes, both of which may restrain the induction and progression of oxidative stress.
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PMID:Effect of diclofenac, a non-steroidal anti-inflammatory drug, on lipid peroxidation caused by ischemia-reperfusion in rat liver. 802 32

Metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, blood flow, and (Na+,K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. NADPH is an obligate cofactor for both aldose reductase and nitric oxide synthase such that activation of aldose reductase by hyperglycemia could limit nitric oxide synthesis by cofactor competition, producing vasoconstriction, ischemia, and slowing of nerve conduction. In accordance with this construct, N-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase reversed the increased nerve conduction velocity afforded by aldose reductase inhibitor treatment in the acutely diabetic rat without affecting the attendant correction of nerve sorbitol and myo-inositol. With prolonged administration, N-nitro-L-arginine methyl ester fully reproduced the nerve conduction slowing and (Na+,K+)-ATPase impairment characteristic of diabetes. Thus the aldose reductase-inhibitor-sensitive component of conduction slowing and the reduced (Na+,K+)-ATPase activity in the diabetic rat may reflect in part impaired nitric oxide activity, thus comprising a dual metabolic-ischemic pathogenesis.
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PMID:The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. 804 Mar 41

The effect of an inhibitor of protein kinase, HA1077 [1-(5-isoquinolinesulfonyl)-homopiperazine HCl], and its hydroxylated metabolite, HA1100, on the activation of NADPH oxidase in human neutrophils were studied. Cells were preincubated with each drug for 10 min and then activated by treatment with phorbol myristate acetate (PMA) or formylmethionyl leucyl phenylalanine (FMLP). After activation, the rate of superoxide dismutase-inhibitable reduction of cytochrome c was estimated. HA1077 and HA1100 inhibited the PMA-induced production of O2- by neutrophil NADPH oxidase in a concentration-dependent manner (IC50 = 15 and 24 microM, respectively). The sensitivity of the FMLP-induced production of O2- to these drugs was similar. The production of O2- in 1,25-dihydroxyvitamin D3-treated HL-60 cells, which differentiated to macrophage-like cells, was also inhibited by the drugs. The extent of inhibition by HA1077 was almost the same as that by a calmodulin inhibitor (W-7) and by inhibitors of protein kinase (H-7 and H-8). In a cell-free lysate of neutrophils, the NADPH-dependent production of O2- can be induced by sodium dodecyl sulfate (SDS). HA1077 at 100 microM had only a weak inhibitory effect on the cell-free, SDS-induced production of O2-, an indication that HA1077 inhibits the activation of NADPH oxidase, not the actual activity. The effects of H-7 and H-8 were similar to that of HA1077, whereas W-7 inhibited the production of O2- by the cell-free extract of HL-60 cells. This action of HA1077 could explain, in part, its ability to protect neuronal cells from death after ischemia.
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PMID:Inhibition by the protein kinase inhibitor HA1077 of the activation of NADPH oxidase in human neutrophils. 824 Apr

NADPH-dependent methemoglobin reductase, first detected in erythrocytes sixty years ago, has subsequently been purified and characterized as a methylene blue reductase and a flavin reductase. The reductase plays no role in methemoglobin reduction under normal conditions, but its activity serves as the basis for the treatment of methemoglobinemia with methylene blue or flavin. On-going studies demonstrate that this cytosolic protein is also present in liver and that its primary structure distinguishes it from other known proteins. The bovine erythrocyte reductase tightly binds hemes, porphyrins, and fatty acids with resulting loss of activity. Pyrroloquinoline quinone serves as a high-affinity substrate of the reductase, suggesting that this naturally-occurring compound may be a physiological substrate. The ability of the reductase to catalyze the intracellular reduction of administered riboflavin to dihydroriboflavin suggested that this system might be exploited to protect tissues from oxidative damage. This hypothesis was supported by our finding that dihydroriboflavin reacts rapidly with Fe(IV)O and Fe(V)O oxidation states of hemeproteins, states that have been implicated in tissue damage associated with ischemia and reperfusion. Preliminary studies demonstrate that, as predicted, administration of low concentrations of riboflavin protects isolated rabbit heart from reoxygenation injury, rat lung from injury resulting from systemic activation of complement, and rat brain from damage caused by four hours of ischemia. Data from these animal studies suggest that flavin therapy holds promise in protecting tissue from the oxidative injuries of myocardial infarction, acute lung injury, stroke, and a number of other clinical conditions.
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PMID:Evidence that NADPH-dependent methemoglobin reductase and administered riboflavin protect tissues from oxidative injury. 841 88

Ischemia-reperfusion of organs such as the kidney produces reactive oxygen and free radical species in tissues and leads to injury of intracellular molecules critical to cell homeostasis. Ischemia-reperfusion affects the NADPH-dependent monooxygenase system including P450 system, which is also a source of reactive oxygen species. In this study, the effects of ischemia-reperfusion on monooxygenase activity and levels of individual P450 isoforms including CYP2C23, 4A2, and 4A8 in the rat kidney were investigated. Ischemia of the rat kidney for 30 min had little effect on lauric acid hydroxylation activity and levels of P450 isoforms but ischemia for 60 min significantly decreased lauric acid omega- and (omega-1)-hydroxylation activities and also decreased the levels of CYP2C23, 4A2, and 4A8. Reperfusion for 60 min after 30-min ischemia decreased the levels of CYP2C23 and 4A2 in the rat kidney although 30-min ischemia did not. Reperfusion for 240 min after 30-min or 60-min ischemia recovered the decreased levels of lauric acid hydroxylation activity and the levels of CYP2C23 and 4A2. Changes in the levels of monooxygenase activity and the levels of P450 isoforms in kidneys by ischemia-reperfusion are faster than those in the liver; it takes several hours for ischemia-reperfusion to affect the levels of monooxygenase activity and the levels of P450 in the rat liver. Our findings suggest that damage of P450 isoforms in the kidney by ischemia-reperfusion occurs by a mechanism different from that in the liver and that active oxygen or free radical species directly attack proteins.
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PMID:Effects of ischemia-reperfusion on individual cytochrome P450 isoforms in the rat kidney. 900 Jan 20

The therapeutic potential of alpha-lipoic acid (thioctic acid) was evaluated with respect to its influence on cellular reducing equivalent homeostasis. The requirement of NADH and NADPH as cofactors in the cellular reduction of alpha-lipoic acid to dihydrolipoate has been reported in various cells and tissues. However, there is no direct evidence describing the influence of such reduction of alpha-lipoate on the levels of cellular reducing equivalents and homeostasis of the NAD(P)H/NAD(P) ratio. Treatment of the human Wurzburg T-cell line with 0.5 mM alpha-lipoate for 24 hr resulted in a 30% decrease in cellular NADH levels. alpha-Lipoate treatment also decreased cellular NADPH, but this effect was relatively less and slower compared with that of NADH. A concentration-dependent increase in glucose uptake was observed in Wurzburg cells treated with alpha-lipoate. Parallel decreases (30%) in cellular NADH/NAD+ and in lactate/pyruvate ratios were observed in alpha-lipoate-treated cells. Such a decrease in the NADH/NAD+ ratio following treatment with alpha-lipoate may have direct implications in diabetes, ischemia-reperfusion injury, and other pathologies where reductive (high NADH/NAD+ ratio) and oxidant (excess reactive oxygen species) imbalances are considered as major factors contributing to metabolic disorders. Under conditions of reductive stress, alpha-lipoate decreases high NADH levels in the cell by utilizing it as a co-factor for its own reduction process, whereas in oxidative stress both alpha-lipoate and its reduced form, dihydrolipoate, may protect by direct scavenging of free radicals and recycling other antioxidants from their oxidized forms.
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PMID:Modulation of cellular reducing equivalent homeostasis by alpha-lipoic acid. Mechanisms and implications for diabetes and ischemic injury. 906 43

A cDNA encoding a P450 monooxygenase was amplified from reverse transcribed rat heart and liver total RNA by polymerase chain reaction using primers based on the 5'- and 3'-end sequences of two rat pseudogenes, CYP2J3P1 and CYP2J3P2. Sequence analysis revealed that this 1,778-base pair cDNA contained an open reading frame and encoded a new 502 amino acid protein designated CYP2J3. Based on the deduced amino acid sequence, CYP2J3 was approximately 70% homologous to both human CYP2J2 and rabbit CYP2J1. Recombinant CYP2J3 protein was co-expressed with NADPH-cytochrome P450 oxidoreductase in Sf9 insect cells using a baculovirus expression system. Microsomal fractions of CYP2J3/NADPH-cytochrome P450 oxidoreductase-transfected cells metabolized arachidonic acid to 14,15-, 11,12-, and 8, 9-epoxyeicosatrienoic acids and 19-hydroxyeicosatetraenoic acid as the principal reaction products (catalytic turnover, 0.2 nmol of product/nmol of cytochrome P450/min at 37 degrees C). Immunoblotting of microsomal fractions prepared from rat tissues using a polyclonal antibody raised against recombinant CYP2J2 that cross-reacted with CYP2J3 but not with other known rat P450s demonstrated abundant expression of CYP2J3 protein in heart and liver. Immunohistochemical staining of formalin-fixed paraffin-embedded rat heart tissue sections using the anti-CYP2J2 IgG and avidin-biotin-peroxidase detection localized expression of CYP2J3 primarily to atrial and ventricular myocytes. In an isolated-perfused rat heart model, 20 min of global ischemia followed by 40 min of reflow resulted in recovery of only 44 +/- 6% of base-line contractile function. The addition of 5 microM 11, 12-epoxyeicosatrienoic acid to the perfusate prior to global ischemia resulted in a significant 1.6-fold improvement in recovery of cardiac contractility (69 +/- 5% of base line, p = 0.01 versus vehicle alone). Importantly, neither 14,15-epoxyeicosatrienoic acid nor 19-hydroxyeicosatetraenoic acid significantly improved functional recovery following global ischemia, demonstrating the specificity of the biological effect for the 11, 12-epoxyeicosatrienoic acid regioisomer. Based on these data, we conclude that (a) CYP2J3 is one of the predominant enzymes responsible for the oxidation of endogenous arachidonic acid pools in rat heart myocytes and (b) 11,12-epoxyeicosatrienoic acid may play an important functional role in the response of the heart to ischemia.
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PMID:Molecular cloning, expression, and functional significance of a cytochrome P450 highly expressed in rat heart myocytes. 913 7

If a coronary occlusion long enough to produce a myocardial infarction is preceded by one or more brief periods of occlusion, the infarct size is reduced with respect to the area at risk. Also the ischaemia reperfusion injury is remarkably reduced. Such effects form the ischaemic preconditioning. Ischaemia-reperfusion injury is attributed to a Ca2+ overload of the myocardial fibres together with an inadequate resynthesis of ATP, a loss of membrane phospholipids and a release of free oxygen radicals. The inadequate resynthesis of ATP is responsible for an increased concentration of nucleosides and purinic bases with swelling of the myocardial fibres. The cell Ca2+ overload depends on a reduced activity of the ionic pumps caused by the oxygen lack during ischaemia. During reperfusion the vascular endothelial cells of the previously ischaemic area release free oxygen radicals in response to the activity of the xanthine-oxidase on hypoxanthine produced by the ischaemic myocardium. This initial release of oxygen radicals is responsible for the adhesion of neutrophils to the endothelium. After adhesion also the neutrophils release free radicals due to the activity of NADPH-oxidase on molecular oxygen. Myocardial, neural and endothelial mechanisms account for the protective effect of preconditioning. Myocardial mechanisms include the release of adenosine as well as of antioxidant enzymes. Adenosine, which activates protein-kinase C, favours the phosphorylation of a protective protein, whereas the antioxidant enzymes impair the activity of the free oxygen radicals. Preconditioning may also involve the synthesis of a heat shock protein. Neural mechanisms are represented by a reduced release of noradrenaline from the sympathetic nerve endings and a reduced sensitivity of myocardium to noradrenaline. Finally, vascular endothelial cells take part in preconditioning by means of an increased production of nitric oxide which seems to exert a protection against arrhythmias.
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PMID:[Mechanisms of ischemic preconditioning: relation with ischemia-reperfusion injury]. 924 32

Policosanol, a defined mixture of high molecular weight aliphatic alcohol isolated and purified from sugar cane (Saccharum officinarum, L) wax is a new cholesterol-lowering agent effective in experimental models, healthy volunteers, and patients with type II hypercholesterolemia. Also, policosanol prevents the onset of spontaneously- and experimentally-induced atherosclerotic lesions and cerebral ischemia in Mongolian gerbils. Free radicals are linked to many diseases including atherosclerosis and ischemia/ reoxidation cellular injury. Therefore, in this study the authors evaluate the antioxidant activity of policosanol on rat liver microsomes. The extent of lipid peroxidation was measured by thiobarbituric acid reactive substances (TBARS). When policosanol was administered orally (100 and 250 mg/kg) for up to 4 weeks, a partial prevention of rat in vitro microsomal lipid peroxidation was noted. The formation of TBARS in microsomes isolated from treated rats was significantly decreased by about 50%, when peroxidation was initiated by Fe3+/ADP/ NADPH, Fe2+/ascorbate and CCl4/NADPH-generating system. Also, oral administration of policosanol in rats provides a partial inhibition of lipid peroxidation, but the mechanism supporting such effect remains to be elucidated. This beneficial effect of policosanol on membrane lipid peroxidation may be useful in protecting to some extent against free radical-associated diseases.
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PMID:Effect of policosanol on in vitro and in vivo rat liver microsomal lipid peroxidation. 929 30


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