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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upon reperfusion of ischemic tissues, reactive oxygen metabolites are generated and are responsible for much of the organ damage. Experimental studies have revealed two main sources of these metabolites: 1) the oxidation of hypoxanthine to xanthine and on to uric acid by the oxidase form of xanthine oxidoreductase and 2) neutrophils accumulating in ischemic and reperfused tissue. Blocking either source will reduce reperfusion damage in a number of experimental situations. Although xanthine oxidoreductase activity may be unmeasurably low in organs other than liver and intestine, it may be involved in reperfusion injury elsewhere because of its localization in capillary endothelial cells. Time course considerations suggest that substrate accumulation and NADH inhibition of dehydrogenase activity may be more important in the pathogenesis than conversion of xanthine dehydrogenase into the oxidase form. Neutrophil accumulation may be partly due to oxidants in the first place, suggesting a link between the two sources of reactive oxygen metabolites. In the clinical context, many of the sequelae of perinatal asphyxia may be accounted for by reperfusion damage to organs such as brain, kidney, heart, liver, and lungs. During asphyxia, substrates of xanthine oxidase accumulate, upon resuscitation the cosubstrate oxygen is introduced, and evidence for oxidant production and effects has been obtained. In the pathogenesis of brain damage after asphyxia, both microvascular injury and parenchymal cell damage are important. Oxygen metabolites are involved in the former, but in the latter process their role is less clear because ischemia-reperfusion triggers not only oxidant production but many other phenomena, including gene activation, ATP depletion, glutamate accumulation, and increase of intracellular calcium. A severe insult results in cell necrosis, but more moderate asphyxia may cause delayed neuronal death through apoptosis. The time course of the changes in high energy phosphates as well as of selective neuronal death suggest that in the first hours of life there is a "therapeutic window," with future possibilities for prevention of permanent damage.
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PMID:Reperfusion injury as the mechanism of brain damage after perinatal asphyxia. 912 79

Measure of oxidative stress were studied in blood samples from 10 patients undergoing bloodless lower limb surgery. Ischaemia induced a significant increase in plasma hypoxanthine concentration and xanthine oxidase activity both in the operated leg and in the systemic circulation. Five minutes after reperfusion, ratio of xanthine oxidase/total xanthine oxidase and dehydrogenase activities rose moderately, whereas at 20 min xanthine oxidase accounted for all xanthine oxidoreductase activity in the systemic circulation. A significant increase in blood glutathione redox ratio, enhanced oxidation of haemoglobin to methaemoglobin and rise in plasma haemoglobin concentration were present only in the operated limb. Thus, although the level of the potential free radical generators rose significantly both locally and in the systemic circulation, oxidative stress, as indicated by blood glutathione and erythrocyte injuries, remained limited to the reperfused leg.
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PMID:Oxidative stress induced by bloodless limb surgery on humans. 946 25

Xanthine oxidoreductase (XOR) has been implicated in tissue injury following ischemia-reperfusion because of its ability to generate reactive oxygen species under these conditions. In order to elucidate its role in various organs, we quantified the levels of XOR mRNA expression and activity in developing human tissues. XOR gene expression was highest in the intestine and in the liver, which also showed the highest enzyme activities. By a sensitive RNA-PCR assay, low levels of the transcript were detected in the kidney, lung, cardiac muscle, and brain of all subjects studied. XOR activities followed the mRNA distribution, being low or undetectable in tissues other than the liver and the intestine.
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PMID:Xanthine oxidoreductase gene expression and enzyme activity in developing human tissues. 970 49

Xanthine oxidoreductase is an important cytoplasmic source of reactive oxygen species, and has been implicated in the pathogenesis of ischemia-reperfusion damage. Because the cellular localization of this protein remains unclear, our aim was to study its distribution in fresh normal human tissue obtained at surgery. For immunohistochemical studies we purified the protein from human milk and raised a polyclonal antibody in rabbits. In the liver the protein was preferentially localized to the periportal hepatocytes and it was absent from the perivenous region. In the proximal intestine, the protein was expressed in epithelial cells and goblet cells. Lactating mammary gland acinar cells showed intense staining. Small vessel vascular endothelial cells of the intestine, mammary gland, and skeletal muscle showed immunoreactivity, but in the kidney, glomerular endothelial cells were negative. No cells in the heart, brain, or lung expressed the enzyme protein. The observed localization of the xanthine oxidoreductase protein is consistent with previously observed enzyme activities in the organs studied. The widely assumed exclusive localization to capillary endothelium obviously does not apply to humans.
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PMID:Cellular expression of xanthine oxidoreductase protein in normal human tissues. 1046 34

Xanthine oxidoreductase (XD: xanthine dehydrogenase + xanthine oxidase) is a complex enzyme that catalyzes oxidation of hypoxathine to xanthine, subsequently producing uric acid. The enzyme complex exists in separate but interconvertible forms, xanthine dehydrogenase (XDH) and xanthine oxidase (XOD). XOD is one of the major cellular sources of superoxide production and is well known as a causative factor in ischemia/reperfusion damage. At present, almost no information on the conversion status is available with respect to aging. In the present study, we investigated the effect of age on the XOD/XDH status and gene expression in the kidney. In addition, we assessed XOD-induced reactive oxygen species (ROS) using the dichlorofluoroscein (DCF) method. Our results show that XD activity gradually up to 18 months of age and then a slight decrease at 24 months of age. XDH activity showed increases up to 18 months of age, then decreased at 24 months of age. The conversion of XDH to XOD, assessed by changes in the ratios of XOD/(XOD+XDH), showed an age-related increase, which peaked at 24 months. Levels of XD protein and its mRNA paralleled to overall XD activity. ROS generation has tendency to increase with age. Our results suggest that the increased conversion of XDH to XOD observed with age may be an important contributing factor to the increased renal oxidative stress during aging.
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PMID:Modulation of renal xanthine oxidoreductase in aging: gene expression and reactive oxygen species generation. 1088 79

We have shown previously that rats subjected to tourniquet shock develop an acute form of remote organ injury of the liver that is both Kupffer cell (KC) and polymorphonuclear (PMN) leukocyte dependent. Circulating plasma xanthine oxidase (XO) has been shown to be responsible for the development of endothelial dysfunction and for remote organ injury of the lung and intestine after ischemia-reperfusion protocols. We now hypothesize that XO is released from rat hind limbs upon reperfusion and that it is responsible for KC and PMN leukocyte activation in this shock model. Our results show that about 30% of rat gastrocnemius muscle xanthine dehydrogenase (XD) is converted to XO during the 5-h tourniquet period and that it is released into the femoral vein within 10 min of reperfusion. Total muscle xanthine oxidoreductase activity (XO + XD) decreases within 30 min of reperfusion and is paralleled by a corresponding increase in femoral vein lactic dehydrogenase. In addition, liver tissue XO increases significantly within 30 min of reperfusion without a corresponding conversion of endogenous XD. Conversion of hepatic XD becomes evident 60 min after reperfusion is initiated, as does XO, and alanine aminotransferase (ALT) release into the hepatic vein, presumably from damaged hepatocytes as a consequence of oxidative stress. Tissue myeloperoxidase activity also increases significantly after the 60-min reperfusion period. That XO mediates KC and PMN activation is supported by the following observations: a) the close relationships between plasma XO and the time courses of tumor necrosis factor-alpha TNFalpha release into the hepatic vein and colloidal carbon clearance by KCs; b) that colloidal carbon clearance, TNFalpha and ALT release, loss of tissue free thiols, lipid peroxidation (TBARS), and liver infiltration by PMN neutrophils can also be induced by the administration of exogenous XO to normal rats; and c) pretreatment of rats with allopurinol inhibits KC activation and liver leukocyte infiltration. These results suggest that XO, released from the ischemic limb on reperfusion, is taken up by the liver were it mediates KC and PMN neutrophil activation and thus contributes to the development of multiple system organ failure after hind limb reperfusion.
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PMID:Xanthine oxidase released from reperfused hind limbs mediate kupffer cell activation, neutrophil sequestration, and hepatic oxidative stress in rats subjected to tourniquet shock. 1109 91

Xanthine oxidase (EC 1.1.3.22) and xanthine dehydrogenase (EC 1.1.1. 204) are both members of the molybdenum hydroxylase flavoprotein family and represent different forms of the same gene product. The two enzyme forms and their reactions are often referred to as xanthine oxidoreductase (XOR) activity. Physiologically, XOR is known as the rate-limiting enzyme in purine catabolism but has also been shown to be able to metabolize a number of other physiological compounds. Recent studies have also demonstrated its ability to metabolize xenobiotics, including a number of anticancer compounds, to their active metabolites. During the past 10 years, evidence has mounted to support a role for XOR in the pathophysiology of inflammatory diseases and atherosclerosis as well as its previously determined role in ischemia-reperfusion injury. While significant progress has recently been made in our understanding of the physiological and biochemical nature of this enzyme system, considerable work still needs to be done. This paper will review some of the more recent work characterizing the interactions and the factors that influence the interactions of XOR with various physiological and xenobiotic compounds.
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PMID:Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system. 1115 41

Xanthine oxidoreductase (XOR) is a ubiquitous metalloflavoprotein that appears in two interconvertible yet functionally distinct forms: xanthine dehydrogenase (XD), which is constitutively expressed in vivo; and xanthine oxidase (XO), which is generated by the posttranslational modification of XD, either through the reversible, incremental thiol oxidation of sulfhydryl residues on XD or the irreversible proteolytic cleavage of a segment of XD, which occurs at low oxygen tension and in the presence of several proinflammatory mediators. Functionally, both XD and XO catalyze the oxidation of purines to urate. However, whereas XD requires NAD+ as an electron acceptor for these redox reactions, thereby generating the stable product NADH, XO is unable to use NAD+ as an electron acceptor, requiring instead the reduction of molecular oxygen for this purine oxidation and generating the highly reactive superoxide free radical. Nearly 100 years of study has documented the physiologic role of XD in urate catabolism. However, the rapid, posttranslational conversion of XD to the oxidant-generating form XO provides a possible physiologic mechanism for rapid, posttranslational, oxidant-mediated signaling. XO-generated reactive oxygen species (ROS) have been implicated in various clinicopathologic entities, including ischemia/reperfusion injury and multisystem organ failure. More recently, the concept of physiologic signal transduction mediated by ROS has been proposed, and the possibility of XD to XO conversion, with subsequent ROS generation, serving as the trigger of the microvascular inflammatory response in vivo has been hypothesized. This review presents the evidence and basis for this hypothesis.
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PMID:The physiology of endothelial xanthine oxidase: from urate catabolism to reperfusion injury to inflammatory signal transduction. 1208 Apr 14

Xanthine oxidoreductase (xanthine dehydrogenase + xanthine oxidase) is a complex enzyme that catalyzes the oxidation of hypoxanthine to xanthine, subsequently producing uric acid. The enzyme complex exists in separate but interconvertible forms, xanthine dehydrogenase and xanthine oxidase, which generate reactive oxygen species (ROS), a well known causative factor in ischemia/reperfusion injury and also in some other pathological states and diseases. Because the enzymes had not been localized in human corneas until now, the aim of this study was to detect xanthine oxidoreductase and xanthine oxidase in the corneas of normal post-mortem human eyes using histochemical and immunohistochemical methods. Xanthine oxidoreductase activity was demonstrated by the tetrazolium salt reduction method and xanthine oxidase activity was detected by methods based on cerium ion capture of hydrogen peroxide. For immunohistochemical studies. we used rabbit antibovine xanthine oxidase antibody, rabbit antihuman xanthine oxidase antibody and monoclonal mouse antihuman xanthine oxidase/xanthine dehydrogenase/aldehyde oxidase antibody. The results show that the enzymes are present in the corneal epithelium and endothelium. The activity of xanthine oxidoreductase is higher than that of xanthine oxidase, as clearly seen in the epithelium. Further studies are necessary to elucidate the role of these enzymes in the diseased human cornea. Based on the findings obtained in this study (xanthine oxidoreductase/xanthine oxidase activities are present in normal human corneas), we hypothesize that during various pathological states, xanthine oxidase-generated ROS might be involved in oxidative eye injury.
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PMID:Xanthine oxidoreductase and xanthine oxidase in human cornea. 1216 84

Xanthine oxidoreductase (XOR) is a complex molybdoflavoenzyme, present in milk and many other tissues, which has been studied for over 100 years. While it is generally recognized as a key enzyme in purine catabolism, its structural complexity and specialized tissue distribution suggest other functions that have never been fully identified. The publication, just over 20 years ago, of a hypothesis implicating XOR in ischemia-reperfusion injury focused research attention on the enzyme and its ability to generate reactive oxygen species (ROS). Since that time a great deal more information has been obtained concerning the tissue distribution, structure, and enzymology of XOR, particularly the human enzyme. XOR is subject to both pre- and post-translational control by a range of mechanisms in response to hormones, cytokines, and oxygen tension. Of special interest has been the finding that XOR can catalyze the reduction of nitrates and nitrites to nitric oxide (NO), acting as a source of both NO and peroxynitrite. The concept of a widely distributed and highly regulated enzyme capable of generating both ROS and NO is intriguing in both physiological and pathological contexts. The details of these recent findings, their pathophysiological implications, and the requirements for future research are addressed in this review.
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PMID:Structure and function of xanthine oxidoreductase: where are we now? 1220 66


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