Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A striking similarity exists between the pathogenetic properties of group A streptococci and those of activated mammalian professional phagocytes (neutrophils, macrophages). Both types of cells are endowed by the ability to adhere to target cells; to elaborate oxidants, hydrolases, and membrane-active agents (hemolysins, phospholipases); and to freely invade tissues and destroy cells. From the evolutionary point of view, streptococci might justifiably be considered the forefathers of "modern" leukocytes. Our earlier findings that synergy between a streptococcal hemolysin (streptolysin S, SLS) and a streptococcal thiol-dependent proteinase and between cytotoxic antibodies+complement and streptokinase-activated plasmin readily killed tumor cells, led us to hypothesize that by analogy to the pathogenetic mechanisms of streptococci, the mechanisms of tissue destruction initiated by activated leukocytes in inflammatory sites, as well as in tissues undergoing episodes of ischemia and reperfusion, might also be the result of the synergistic effects among leukocyte-derived oxidants, phospholipases, proteinases, cytokines, and cationic proteins. The current report extends our previous synergy studies with endothelial cells to two additional cell types--monkey kidney epithelial cells and rat beating heart cells. Monolayers of 51Cr-labeled cells that had been treated by combinations of sublytic amounts of hydrogen peroxide (generated either by glucose oxidase, xanthine-xanthine oxidase, or by paraquat) and with sublytic amounts of a variety of membrane-active agents (streptolysin S, phospholipases A2 and C, lysophosphatides, histone, chlorhexidine) were killed in a synergistic manner (double synergy). Crystalline trypsin markedly enhanced cell killing by combinations of oxidant and the membrane-active agents (triple synergy). Injury to the cells was characterized by the appearance of large membrane blebs that detached from the cells and floated freely in the media, looking like lipid droplets. Cytotoxicity induced by the various combinations of agonists was depressed, to a large extent, by scavengers of hydrogen peroxide (catalase, dimethyl thiourea, and by Mn2+) but not by SOD or by deferoxamine. When cationic agents were employed together with hydrogen peroxide, polyanions (heparin, polyanethole sulfonate) were also found to inhibit cell killing. It is proposed that in order to effectively combat the deleterious toxic effects of leukocyte-derived agonists on cells and tissues, antagonistic "cocktails" comprised of cationized catalase, cationized SOD, dimethylthiourea, Mn(2+)+glycine, proteinase inhibitors, putative inhibitors of phospholipases, and polyanions might be concocted. The current literature on synergistic phenomena pertaining to mechanisms of cell and tissue injury in inflammation is selectively reviewed.
 ...
PMID:Synergism among oxidants, proteinases, phospholipases, microbial hemolysins, cationic proteins, and cytokines. 142 26

Intravenous administration of xanthine (X: 0.225 mg/kg, i.v.) plus xanthine oxidase (XO: 3.0 units/kg, i.v.) to anesthetized rats resulted in a rapid fall in the arterial pressure and a mortality rate of over 80% during 120 min observation period. Pretreatment of the rats with superoxide dismutase (SOD) or SOD plus catalase significantly enhanced survival rate to 60% confirming that the toxicity after [X + XO] administration is due to the generation of oxygen free radicals. Pretreatment of the rats with either felodipine, a dihydropyridine calcium antagonist or verapamil, a structurally different Ca(2+)-channel blocker was most effective in promoting survival rate to 90%; in contrast, hydralazine, an arteriolar dilator but not a calcium antagonist, was ineffective in significantly enhancing survival. In the vehicle treated groups, mortality of the rats after [X + XO] administration was associated with significant increases in serum creatine phosphokinase (CPK) levels; both the calcium antagonists as well as hydralazine prevented any significant changes in CPK levels. Since only the calcium antagonists but not hydralazine were effective in providing significant protection against mortality, the data suggests that CPK may not be a reliable indicator to predict prevention of lethal toxicity induced by free radicals. Hence, the observation that calcium antagonists can promote survival would suggest that calcium overload may be the ultimate mediator of tissue toxicity. These observations can account for the remarkable efficacy of various calcium antagonists in preventing ischemia-reperfusion induced damage to organs, such as heart and kidneys, in which a role for free radicals has been postulated.
 ...
PMID:Evaluation of the effects of felodipine, verapamil and hydralazine on the survival rate of rats subjected to lethal effects of oxygen free radicals. 143 30

After 60 min of reperfusion following 60 min of ischemia, the ischemia-induced decrease in liver tissue adenosine triphosphate (ATP) concentration had recovered by 66%, and full recovery of mitochondrial function--that is, the respiratory control index (RCI) and the rate of oxygen consumption in state-III respiration (ST III O2)--was observed. In contrast, liver tissue ATP concentration had recovered by only 13%, and marked low RCI and ST III O2 were observed after 60 min of reperfusion following 180 min of ischemia. Intermediate results were observed in rats after 60 min of reperfusion following 120 min of ischemia. Liver tissue hypoxanthine and xanthine, substrates of xanthine oxidase, increased ischemic time dependently. Liver tissue concentrations of the reduced form of glutathione (GSH) and the oxidized form of glutathione (GSSG) and activities of glutathione peroxidase and glutathione reductase did not change after 60 min of reperfusion following 60 min of ischemia. In contrast, GSH concentration and glutathione peroxidase activity decreased significantly after 60 min of reperfusion following 180 min of ischemia. Since the glutathione redox system is an important contributor to the scavenging of free radicals after reperfusion following a long time of ischemia, the free radical scavenging ability might decrease in spite of enhancement of free radical generation, which might play an important role in the inhibition of the recovery of tissue ATP concentrations and mitochondrial function.
 ...
PMID:Changes in the glutathione redox system during ischemia and reperfusion in rat liver. 143 57

The protective effect of a new potent protease inhibitor, ONO 3307, in combination with a xanthine oxidase inhibitor, allopurinol, was tested in pancreatico-biliary duct obstruction (PBDO) with temporary pancreatic ischemia in rats. After PBDO with ischemia, we observed hyperamylasemia, pancreatic edema, congestion of amylase and lysosomal enzyme cathepsin B as well as impaired output of amylase and cathepsin B into the pancreatic juice and a redistribution of lysosomal enzyme from the lysosomal fraction to the zymogen fraction. The administration of ONO 3307 plus allopurinol almost completely prevented the pancreatic injuries induced by PBDO with ischemia. These results indicate the important roles of temporary pancreatic ischemia in the pathogenesis of pancreatic damage and the usefulness of combination therapy with a new potent protease inhibitor and xanthine oxidase inhibitor in the protection against clinical acute pancreatitis.
 ...
PMID:Protective effects of combined therapy with a protease inhibitor, ONO 3307, and a xanthine oxidase inhibitor, allopurinol on temporary ischaemic model of pancreatitis in rats. 144 2

The aim of this work was to assess the catalytic activity of xanthine oxidase, the level of lipid peroxides and enzymic antioxidant systems in isolated rat heart muscle subjected to a globally partial ischemia followed by varying durations of reperfusion. After 40 min of globally partial ischemia (residual perfusion flow rate: 0.1 ml/min), four different durations of reperfusion were investigated (0, 20, 40, and 60 min). After each experimental ischemia/reperfusion sequence, the heart was frozen in liquid nitrogen. Lipid peroxides were assayed in the cardiac homogenate and the catalytic activity of xanthine oxidase and enzymic antioxidant systems (glutathione peroxidase, superoxide dismutase and catalase) were determined in the centrifuged supernatant. In the different experimental protocols studied in this work, there was no significant increase in the activity of cardiac xanthine oxidase or in the level of lipid peroxides when compared to the non reperfused or to the continuously perfused hearts. Indeed, enzymic antioxidant systems were also not significantly modified in the different periods of reperfusion when compared to control hearts (continuously perfused hearts). These results suggest that xanthine oxidase is apparently not a major source of free radicals in the course of an ischemia-reperfusion sequence in heart muscle, in particular, if we consider the early phases of reperfusion. The process of lipid peroxidation, assessed by assaying thiobarbituric acid reactants, is not a predominant phenomenon of reperfusion-induced injury, at least in the experimental model used here. However, enzymic antioxidant systems investigated in this study do not seem modified. This could mean that the small quantity of oxygen free radicals produced does not overwhelm the enzymic antioxidant systems of myocardium which is in agreement with peroxidatized lipid results.
 ...
PMID:Ischemia and reperfusion injury in isolated rat heart: effect of reperfusion duration on xanthine oxidase, lipid peroxidation, and enzyme antioxidant systems in myocardium. 146 31

The enzyme xanthine oxidase has been implicated in the tissue oxidative injury after ischemia-reperfusion. This enzyme, which is a source of oxygen free radicals, is formed from a dehydrogenase form during ischemia. The ratio dehydrogenase/oxidase of rat kidney homogenates decreases during the ischemia and the reperfusion. Two flavonoids, quercetin and silybin, characterized as free radical scavengers, exert a protective effect preventing the decrease in the dehydrogenase/oxidase ratio observed during ischemia-reperfusion. The mechanism of this effect and the role of flavonoids in the ischemia-reperfusion tissue damage is discussed.
 ...
PMID:Changes in the xanthine dehydrogenase/xanthine oxidase ratio in the rat kidney subjected to ischemia-reperfusion stress: preventive effect of some flavonoids. 147 27

To investigate the pathophysiology of warm ischemia (WI) of the liver, the changes in hemodynamics and energy metabolism were studied during and after 60-min complete WI induced by total hepatic vascular exclusion (HVE) in the canine model. Hepatic arterial blood flow after WI was maintained at 76% of the pre-ischemic level, while portal blood flow was only 27% of the pre-ischemic level associated with increased portal vein pressure, which was twice the pre-ischemic level, resulting in a decrease of total hepatic blood flow to 46% of the pre-ischemic level. Concentration of tissue lipid peroxide increased after WI. Arterial blood ketone body ratio (AKBR), which reflects the hepatic mitochondrial redox state, could not recover to the pre-ischemic level after termination of WI. However, when 100 mg/kg of allopurinol (xanthine oxidase inhibitor) was administered intravenously 10 min prior to initiating WI, AKBR was restored to the pre-ischemic level at 30 min after WI in spite of the fact that allopurinol administration to one group produced no remarkable changes in the hepatic hemodynamics compared with the group without allopurinol treatment. Concentration of adenine nucleotides was significantly higher for the treated group at the end of and after WI than for the group without allopurinol treatment and was maintained at a higher level even after WI. Lipid peroxide production was suppressed. Electron microscopic examination revealed that allopurinol treatment could not prevent mitochondrial swelling. It is suggested that WI causes injury primarily to the portal sinusoidal circulation, resulting in portal congestion concomitant with high portal pressure after the release of WI. Allopurinol could prevent the deterioration of mitochondrial ATP metabolism, and was able to inhibit lipid peroxide production, resulting in the rapid recovery of mitochondrial redox state in spite of the fact that it produced no amelioration of hepatic hemodynamics and morphological alterations.
 ...
PMID:Preserved mitochondrial function by allopurinol despite deteriorated hemodynamics in warm ischemia-damaged canine liver. 148 Aug 16

We studied the effect of inhibition of oxyradical formation and of endogenous glutathione (GSH) depletion on lesion formation in the gastrointestinal tract in a modified rat hemorrhagic shock model (1 h hypotension and 1 h reperfusion). Allopurinol, an inhibitor of xanthine oxidase, did not protect against lesion formation. This suggests that oxygen radicals generated from xanthine oxidase may not be the major cause of injury under these conditions of prolonged 'ischemia'-reperfusion. Phorone (diisopropylideneacetone), a GSH depletor, decreased mucosal GSH levels in the corpus, duodenum and small intestine, and also significantly reduced lesion formation histologically in the corpus, antrum, duodenum and small intestine. However, there was no significant differences in mucosal blood flow (as estimated by changes in mucosal hemoglobin concentrations and oxygen saturation of mucosal hemoglobin) in the corpus, antrum, duodenum and small intestine between phorone-pretreated and control rats. We conclude that phorone decreased mucosal GSH concentrations and exerted a protective effect against hemorrhagic shock-induced gastrointestinal mucosal lesions. The protective effect appears to be independent of mucosal blood flow.
 ...
PMID:Effect of phorone and allopurinol on ischemia-reperfusion injury in gastrointestinal mucosa of the rat. 150 63

Isolated working rat hearts were subjected to aerobic perfusion (25 min), cardioplegic infusion (3 min), global ischemia (30 min at 37 degrees C) and reperfusion (35 min). Measurements of myocardial xanthine oxidase and dehydrogenase activity, together with various adenine nucleotides and metabolites, were made at defined stages of the protocol (n = 6/group). Allopurinol pretreatment (20 mg/kg body wt/day for 3 days) improved the postischemic recovery of cardiac function; thus, aortic flow (a representative index) recovered to 68.8 +/- 4.2% compared with 53.2 +/- 2.3% in untreated controls (p less than 0.05). In fresh tissue, allopurinol pretreatment inhibited xanthine dehydrogenase activity by 73.1% (from 11.9 +/- 0.5 to 3.2 +/- 0.8 mIU/g wet wt: p less than 0.05) and xanthine oxidase activity by 95.2% (from 8.3 +/- 1.2 to 0.4 +/- 0.2 mIU/g wet wt: p less than 0.05); however, this inhibition was not maintained during perfusion. During reperfusion, myocardial xanthine dehydrogenase and oxidase activity was reduced by 40-60% (p less than 0.05) in both allopurinol pretreated and control hearts. Tissue content of creatine phosphate, adenosine triphosphate and catabolites, NAD and inorganic phosphate were not different in allopurinol pretreated or control hearts during either ischemia or reperfusion. This study does not support the concept that allopurinol protects the rat heart during ischemia and reperfusion by inhibition of xanthine oxidase activity or by conservation of purines. It appears that allopurinol achieves its protective effects by some, as yet undefined, mechanism.
 ...
PMID:Allopurinol-enhanced myocardial protection does not involve xanthine oxidase inhibition or purine salvage. 152 Feb 48

In this study rat epigastric island flaps were used as a model to investigate selected tissue biochemical changes occurring during secondary ischemia. It was hypothesized that free radical damage, depletion of free radical scavengers, depletion of ATP, and increased edema might explain differences in flap survival between partial (venous obstruction) and total (arteriovenous obstruction) ischemia and decreased flap survival with increasing ischemia time. Flaps were given 2 hr or primary ischemia, 8 hr of normal perfusion, then secondary ischemia of 0, 2, 4, 8, or 12 hr with either arteriovenous obstruction or venous obstruction. Biochemical analysis of the skin was performed after 0, 24, or 96 hr reperfusion. Only minor differences were found between arteriovenous and venous ischemia for any of five biochemical parameters, despite a previous finding that venous ischemic flaps are more susceptible to necrosis. Levels of xanthine oxidase and malonyldialdehyde (both indices of free radical generation) increased with ischemia time. Levels of superoxide dismutase (a free radical scavenger) correspondingly decreased. Tissue levels of ATP decreased after ischemia and recovered to normal for shorter but not for longer ischemia times after 96 hr of reperfusion in parallel with flap survival. Edema increased immediately after the ischemic insult but decreased once the tissue became necrotic. These results imply roles for free radicals, ATP, and edema in secondary ischemia, but do not distinguish between arteriovenous and venous secondary ischemia.
 ...
PMID:The biochemical basis of secondary ischemia. 153 98


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>