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 activation of microsomal glutathione (GSH) S-transferase in isolated rat liver by oxidative stress was investigated using both ischemia/reperfusion and perfusion with hydrogen peroxide. When the isolated liver was reperfused for 30 min and 60 min after 90 min ischemia, microsomal GSH S-transferase activity, but not cytosolic transferase activity, was increased 1.2-fold and 1.3-fold, respectively. In addition, microsomal GSH peroxidase activity was also significantly increased after 60 min reperfusion following ischemia. The increase in microsomal GSH S-transferase activity by ischemia/reperfusion was reversed by dithiothreitol. When N-ethylmaleimide, which activates microsomal GSH S-transferase by covalent binding to the cysteine residue of the enzyme, was incubated with microsomes, transferase activity was increased to 526% in control microsomes and to 399% in liver that underwent ischemia/reperfusion liver. These data indicate that microsomal GSH S-transferase is activated by ischemia/reperfusion of the liver by means of disulfide bond formation. When rats were pretreated with a catalase inhibitor 3-amino-1,2,4-triazole for 6 weeks, microsomal GSH S-transferase activity was increased 1.4-fold by ischemia/reperfusion, corresponding to a 1.8-fold increase as compared to the non-perfused liver of untreated rats. Perfusion of the isolated liver with hydrogen peroxide (1 mM, 15 min) also caused a significant increase in microsomal GSH S-transferase activity with a concomitant decrease in GSH content, confirming that liver microsomal GSH S-transferase in rats was activated in vivo by oxidative stress.
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PMID:Oxidative stress-induced activation of microsomal glutathione S-transferase in isolated rat liver. 842 21

The relationship between lipid peroxidation and alterations in hepatic secretory function and microsomal function during hepatic ischemia/reperfusion was studied. Rats pretreated with free radical scavengers were subjected to 60 min of hepatic ischemia and to 1 and 5 h of reperfusion thereafter. Serum aminotransferase level and microsomal lipid peroxidation were markedly increased by ischemia/reperfusion. These increases were significantly attenuated by rebamipide, alpha-tocopherol or allopurinol. Bile flow and cholate output were markedly decreased by ischemia/reperfusion and free radical scavengers, especially rebamipide, restored their secretion. NADPH-cytochrome P450 reductase activity and cytochrome P450 content were decreased by ischemia/reperfusion. Rebamipide prevented the decrease of the NADPH-cytochrome P450 reductase activity but had little effect on the cytochrome P450 content. Aminopyrine N-demethylase activity was decreased and aniline p-hydroxylase was increased by ischemia/reperfusion, which were prevented by alpha-tocopherol and allopurinol, but not by rebamipide. Our findings suggest that ischemia/reperfusion diminishes hepatic secretory function and microsomal function by increasing lipid peroxidation, and rebamipide significantly ameliorates these changes through its free radical scavenging activity.
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PMID:Rebamipide ameliorates hepatic dysfunction induced by ischemia/reperfusion in rats. 878 14

The primary cause of neurologic impairment in newborn infants is hypoxic-ischemic injury. Studies of the mechanisms involved in the damaging effects of hypoxia-ischemia and reperfusion in brain tissue indicate significant contributions from reactive oxygen species, with the loss of homeostatic control of intracellular iron an important determinant of oxidant-mediated damage. We investigated the effects of cerebral hypoxia-ischemia and reperfusion on the redistribution of nonheme iron in newborn piglets. Anesthetized newborn piglets were subjected to reductions in cerebral blood flow by phlebotomy and cervical cuff compression. Control animals were sham-operated. Subcellular fractions were isolated from brain tissue homogenates by differential centrifugation, and nonheme iron contents of these fractions were measured with ferene-S. Iron contents in the homogenates were not altered. However, iron contents of the microsomal fractions of animals subjected to 30 minutes of hypoxia-ischemia increased from 0.517 +/- 0.053 to 0.930 +/- 0.061 nmol/mg protein (p < 0.01); 120 minutes of reperfusion caused no further changes. This translocation of iron may be linked to oxidative alterations of brain proteins, which we investigated by detection of dinitrophenylhydrazine-derivitized protein carbonyls, which are characteristic of iron-catalyzed oxidation reactions.
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PMID:Cerebral hypoxia-ischemia increases microsomal iron in newborn piglets. 897 54

In dogs, it has been reported that acute ischemia or severe and terminal heart failure results in a selective reduction of myocardial alpha 3 isoform of Na, K-ATPase activity. The aim of this study was to evaluate if a similar change in the two canine digitalis receptor isoforms occurs following 4 weeks of rapid ventricular pacing-induced heart failure without profound necrosis. Heart failure was induced in dogs by rapid ventricular pacing (240 beats x min-1). Digitalis receptors were quantitated by [3H]-ouabain binding with isolated microsomal membranes from sham-operated (n = 3) and heart failure dogs (n = 4) and by Western blot analysis using specific alpha 1 and alpha 3 polyclonal antibodies. In kinetic studies, similar dissociation rates of 19 to 22 x 10(-4) s-1 and 1.3 to 2.4 x 10(-4) s-1 corresponding to high and low affinity sites respectively, were found in sham-operated and CHF dogs. Immunoblotting showed similar abundance of alpha 1 isoform in the two groups; however, levels of alpha 3 were increased by at least 50% in pacing-induced heart failure animals. In conclusion, heart failure selectively modulates the expression of cardiac alpha 3 isoform in dogs.
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PMID:Canine cardiac digitalis receptors are preserved in congestive heart failure induced by rapid ventricular pacing. 902 7

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

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

Cytochrome P-450 containing enzymes, known to be present in the endoplasmic reticulum and mitochondria, catalyze the oxidation of various compounds. In this study we have used highly purified peroxisomes (> 95%) to provide evidence by analytical cell fractionation, enzyme activity, Western blot, and immunocytochemical analysis that cytochrome P-450 2E1 (Cyp 2E1) is present in peroxisomes. Similar specific activities of aniline hydroxylase, a Cyp 2E1-dependent enzyme, in purified peroxisomes (0.72 +/- 0.03 nmol/min/mg protein) and microsomes (0.58 +/- 0.03 nmol/min/mg protein) supports the conclusion that peroxisomes contain significant amount of Cyp 2E1. This peroxisomal Cyp 2E1 was also induced in acetone-treated rat liver. The status of microsomal and peroxisomal Cyp 2E1 was also examined following ischemia/reperfusion-induced oxidative stress. Ischemia alone had no effect; however, reperfusion following ischemia resulted in decrease in Cyp 2E1 both in microsomes and peroxisomes. This demonstration of cytochrome P-450 2E1 in peroxisomes and its downregulation during ischemia/reperfusion describes a new role for this organelle in cytochrome P-450 related cellular metabolism and in oxidative stress induced disease conditions.
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PMID:Cytochrome P-450 2E1 in rat liver peroxisomes: downregulation by ischemia/reperfusion-induced oxidative stress. 935 38

Neonatal rats were subjected to transient cerebral hypoxic-ischemia (HI, unilateral occlusion of the common carotid artery +7.70% O2 for 100 min) and allowed to recover for up to 14 days. Calpain caseinolytic activity was found to increase in both hemispheres for at least 20 hr. Hypoxic exposure per se increased the activity of calpains, more pronounced in a membrane-associated fraction, probably through interaction with cellular components, whereas HI introduced a loss of activity, most likely through consumption and loss of proteases. Consecutive tissue sections were stained with antibodies against calpastatin, alpha-fodrin, the 150-kDa breakdown product of alpha-fodrin (FBDP, marker of calpain proteolysis) or microtubule-associated protein 2 (MAP-2, marker of dendrosomatic neuronal injury). Areas with brain injury displayed a distinct loss of MAP-2, which clearly delineated the infarct. FBDP accumulated in injured and borderline regions ipsilaterally, and a less conspicuous, transient increase in FBDP also occurred in the contralateral hemisphere, especially in the white matter. The cytosolic fraction (CF) and the membrane and microsomal fraction (MMF) of cortical tissue were subjected to Western blotting and stained with antibodies against calpain, calpastatin and the 150-kDa breakdown product of alpha-fodrin (FBDP). Calpain immunoreactivity decreased bilaterally in the CF during the insult (62-68% of controls) and remained significantly lower during early recovery, whereas the MMF showed no significant changes. This translocation of calpains coincided with the appearance of FBDP in the ipsilateral, HI hemisphere, displaying a significantly higher level of FBDP from immediately after the insult until at least 1 day of recovery (204-292% of controls). No significant changes in FBDP were found in the contralateral, undamaged hemisphere, despite translocation of calpains in both hemispheres, a prerequisite for calpain activation. This discrepancy may be related to changes in the endogenous inhibitor, calpastatin. Calpastatin protein was found to decrease during and shortly after HI in the ipsilateral, but not the contralateral, hemisphere. The inhibitory activity of calpastatin also tended to decrease after HI, indicating that a reduction of calpastatin may be necessary for extensive calpain activation to occur. The mRNA of m-calpain increased in the HI hemisphere 48 hr after the insult (167%, p < 0.001), a time point when the protein was also increased. In summary, our findings indicate that calpains are activated during HI and in the early phase of reperfusion after HI, preceding neuronal death.
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PMID:The calpain proteolytic system in neonatal hypoxic-ischemia. 936 79

The activities of rat hepatic subcellular antioxidant enzymes were studied during hepatic ischemia/reperfusion. Ischemia was induced for 30 min (reversible ischemia) or 60 min (irreversible ischemia). Ischemia was followed by 2 or 24 h of reperfusion. Hepatocyte peroxisomal catalase enzyme activity decreased during 60 min of ischemia and declined further during reperfusion. Peroxisomes of normal density (d = 1.225 gram/ml) were observed in control tissues. However, 60 min of ischemia also produced a second peak of catalase specific activity in subcellular fractions corresponding to newly formed low density immature peroxisomes (d = 1.12 gram/ml). The second peak was also detectable after 30 min of ischemia followed by reperfusion for 2 or 24 h. Mitochondrial and microsomal fractions responded differently. MnSOD activity in mitochondria and microsomal fractions increased significantly (p < 0.05) after 30 min of ischemia, but decreased below control values following 60 min of ischemia and remained lower during reperfusion at 2 and 24 h in both organelle fractions. Conversely, mitochondrial and microsomal glutathione peroxidase (GPx) activity increased significantly (p < 0.001) after 60 min of ischemia and was sustained during 24 h of reperfusion. In the cytosolic fraction, a significant increase in CuZnSOD activity was noted following reperfusion in animals subjected to 30 min of ischemia, but 60 min of ischemia and 24 h of reperfusion resulted in decreased CuZnSOD activity. These studies suggest that the antioxidant enzymes of various subcellular compartments respond to ischemia/reperfusion in an organelle or compartment specific manner and that the regulation of antioxidant enzyme activity in peroxisomes may differ from that in mitochondria and microsomes. The compartmentalized changes in hepatic antioxidant enzyme activity may be crucial determinant of cell survival and function during ischemia/reperfusion. Finally, a progressive decline in the level of hepatic reduced glutathione (GSH) and concomitant increase in serum glutamate pyruvate transaminase (SGPT) activity also suggest that greater tissue damage and impairment of intracellular antioxidant activity occur with longer ischemia periods, and during reperfusion.
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PMID:Studies on hepatic injury and antioxidant enzyme activities in rat subcellular organelles following in vivo ischemia and reperfusion. 940 79

The author studied the effects of 30-min heat ischemia of rat kidneys on the level of malonic dialdehyde (MDA) and Ca-dependent ATPase activity of microsomal fraction isolated from the cortical substance in the presence and absence of antibiotic alameticine and ortovandate in the incubation medium and protective action on Ca-ATPase activity of rat pretreatment with alpha-tocopherol (TP). It has been demonstrated that thermal ischemia induces inhibition of Ca-ATPase activity of microsomes resistant to vanadate. Administration of TP reduced MDA level, enhanced Ca-ATPase microsomal activity in the presence of alameticine against inhibition of enzymic activity in the absence of alameticine. This indicates a rise in the true enzyme activity under decreasing membrane permeability in conditions of diminishing activity of lipid peroxidation in response to TP effects.
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PMID:[The membrane phospholipid peroxidation and Ca-dependent ATPase activity of the microsomal fractions isolated from rat renal tissue in thermal ischemia with and without alpha-tocopherol protection]. 941 18


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