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

The excessive generation of free radicals is thought to be one of the major mechanisms leading to tissue injury in various pathological conditions, including ischemia, inflammation, and trauma. Conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO) contributes to the formation of superoxide, an oxygen radical. We measured XDH and XO activity using a newly developed fluorometric assay in an experimental spinal cord injury model in rats. XO activity increased by more than 100% 4 h after spinal cord trauma. Total (XDH + XO) activity also increased by 96% during the same period. Allopurinol, an inhibitor of XO (100 mg/kg/day x 2 days, i.p.), completely inhibited plasma and spinal cord XO activity but did not affect posttraumatic edema determined by water content or polymorphonuclear (PMN) cell infiltration reflected by myeloperoxidase (MPO) activity in traumatized spinal cord. These results indicate that XDH conversion to XO may not be the major mechanism of oxygen radical formation in the pathogenesis of vasogenic edema or inflammatory response in this experimental spinal cord injury model in rats.
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PMID:Xanthine oxidase in experimental spinal cord injury. 164 10

Tissue oxidases, especially xanthine oxidase, have been proposed as primary sources of toxic oxygen radicals in many experimental models of disease states. Among these, ischemia-reperfusion injury may be of the greatest clinical interest. In this paper we propose the use of methylene blue as a means of suppressing the production of superoxide radicals O2- by acting as an alternative electron acceptor for xanthine oxidase. Previous work has indicated that methylene blue accepts electrons from xanthine oxidase at the iron-sulfur center. Initial experiments in our laboratory demonstrated that (1) pairs of electrons from each enzymatic oxidation are transferred to methylene blue, (2) the reduction of methylene blue can be achieved by model iron-sulfur centers, similar to the iron-sulfur center of xanthine oxidase, (3) reduced methylene blue auto-oxidizes to produce H2O2 directly, rather than O2-, and (4) methylene blue is effective at non-toxic levels (2-5 mg/kg) in preventing free radical damage to liver and kidney tissues in an in vitro model of ischemia and reoxygenation. Accordingly, we propose that methylene blue may represent a new class of antioxidant drugs that competitively inhibit reduction of molecular oxygen to superoxide by acting as alternative electron acceptors for tissue oxidases. We have termed these agents "parasitic" electron acceptors.
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PMID:Methylene blue as an inhibitor of superoxide generation by xanthine oxidase. A potential new drug for the attenuation of ischemia/reperfusion injury. 165 Feb 13

The role of tissue-type plasminogen activator (t-PA) was investigated in the gastric ulcer formation induced by microvascular derangement. The rat stomach was exposed and repeated electrical stimuli (irritation) were applied on the small arterial wall close to the lesser curvature to induce mucosal ischemia followed by hyperemia. The t-PA activity in the regional blood of the stomach was significantly elevated as early as 5 min after the irritation. Immunohistochemical study using anti-t-PA monoclonal antibody revealed that t-PA was detectable in the endothelial cells of capillaries and collecting venules, suggesting the involvement of endothelium-mediated fibrinolytic activity in the irritation-induced ulcer formation. Pretreatment of SOD or allopurinol significantly attenuated the irritation-induced t-PA activation, suggesting that the t-PA activity was modulated by xanthine oxidase-associated superoxide anions. CV-6209, a selective antagonist of platelet-activating factor (PAF), also prevented the activation of t-PA as well as ulcer formation, providing a concept that PAF may be associated with the local fibrinolytic activation which may cause hemorrhagic changes in the gastric mucosal microvasculature. The present study supports the hypothesis that increased t-PA activity may reflect the microvascular endothelial damages caused by vasomotor derangement and suggests that oxygen-derived free radicals may participate in the regulation of endothelium-derived fibrinolytic activities in the mucosal microvasculature.
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PMID:Involvement of superoxide anion and platelet-activating factor in increased tissue-type plasminogen activator during rat gastric microvascular damages. 165 Sep 66

Ischemia induced oxygen free radical damage was formerly attributed only to xanthine oxidase in intestine, liver, kidney and heart. A reevaluation indicated neutrophils as one of the major sources of postischemic oxidative tissue damage, chiefly in the intestine. Our data, obtained from the same occlusion time period for intestine, liver and kidney, showed a certain oxidative damage in intestine and kidney already during ischemia, expressed by an increase of thiobarbituric acid reactive substances (TBARS), whereas the liver sustained damage of this kind only during reperfusion. Oxidative stress was expressed by a comparison of the increase of TBARS, though this test is not a measure of a specific product of lipid peroxidation, but rather comprises several breakdown products of free radical damage. Myeloperoxidase as measure of neutrophil stimulation increased in the intestine and liver. The kidney sustained damage without an increase of myeloperoxidase activity, but showed a similar pattern of increase of TBARS as in the intestine. Our data suggest a major role of neutrophils in intestinal ischemia induced damage, where neutrophils can effect initiation and propagation. In the liver neutrophils may play a minor role concerning propagation, but they may act as an important initiating mechanism. Hepatic tissue shows a high ischemic tolerance, which is demonstrated by a missing increase of TBARS in spite of a certain increase of myeloperoxidase activity during ischemia. This can be interpreted by the high capacity of antioxidative mechanisms of liver tissue and the ability of a higher oxygen extraction ratio under nearly ischemic conditions. In the kidney there appears a smaller contribution of neutrophils. The similar pattern of increase of TBARS in kidney and intestine demonstrates a comparable low ischemic tolerance of these two tissues, whereas different initiating and propagating systems may occur.
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PMID:Intestinal, hepatic and renal production of thiobarbituric acid reactive substances and myeloperoxidase activity after temporary aortic occlusion and reperfusion. 165 85

1. Nilvadipine (FK 235, FR 34235) suppressed ischemia (20 min)-reflow (20 min)-induced paw edema of mice (ED30:0.4 mg/kg i.v. and 2 mg/kg p.o.). Other calcium entry blockers of dihydropyridine-type also suppressed the edema, but 30-fold higher doses were required. 2. Oral dosing of nilvadipine suppressed carrageenan-induced paw edema (ED30:15 mg/kg in rats and 20 mg/kg in mice) at a potency corresponding to that of an anti-inflammatory drug, ibuprofen. Nifedipine, nicardipine and nimodipine resulted in a suppression of 30% only with 100 mg/kg oral dosing in rats. Nitrendipine, diltiazem and verapamil were without effect. 3. Nilvadipine inhibited superoxide radical (O-2production from xanthine oxidase (XOD) both with lactate dehydrogenase + NADH method and cytochrome c method (IC50:90 and 100 micrograms/ml, respectively). Nifedipine and nicardipine showed some inhibition, but the other calcium entry blockers failed to inhibit significantly even at 320 micrograms/ml. As uric acid formation was not reduced by the tested drugs, the inhibitory action might be due to their O-2scavenging effects. 4. Superoxide production of neutrophils from casein-induced peritoneal fluid in rats was most strongly inhibited by nilvadipine when the cells were stimulated by a calcium ionophore, A23187 (IC50:4 micrograms/ml). Inhibition by this drug when stimulated by f-methonyl-leucyl-phenylalanine and phorbol myristate acetate was less effective (IC50:20 and 30 micrograms/ml, respectively). Nifedipine and nicardipine inhibited neutrophil O-2production at higher concentrations (30-200 micrograms/ml) with all stimulants. Inhibitory actions by other drugs were weak. 5. Triggering of atherosclerosis depends largely on the oxidative stress on blood vessels after recently established concept.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition by nilvadipine of ischemic and carrageenan paw edema as well as of superoxide radical production from neutrophils and xanthine oxidase. 165 7

Simulated ischemic conditions or a source of oxygen-derived free radicals, such as xanthine plus xanthine oxidase, released a significant amount of the excitotoxic amino acids Asp and Glu from adult rat hippocampal slices incubated in vitro. The concentrations of Asp and Glu in the incubation medium increased by 20 and 30 times respectively when such slices were exposed to simulated ischemia for a 10-min period. However, preparations obtained from 4- to 9-day-old rats did not release Asp or Glu either when exposed to ischemia or after K+ depolarization. This release appeared 10-15 days after birth and progressively increased up to 13 months of age. No further increase was observed in 25-month-old animals. The exposure of the slices to a source of oxygen-derived free radicals induced a release of excitotoxic amino acids independently from the age of the rats. The massive excitotoxic amino acid release from adult hippocampal slices and the formation of free radicals induced by ischemic insults has been previously associated with degeneration of hippocampal neurons. The lack of ischemia-induced excitotoxic amino acid release from the newborn hippocampus may help to explain why the newborn hippocampus is more resistant than the adult to hypoxic/ischemic insults.
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PMID:Ischemia does not induce the release of excitotoxic amino acids from the hippocampus of newborn rats. 168 34

Xanthine oxidase (XO)-derived oxygen radicals are thought to play an important role in the intestinal injury resulting from ischemia and reperfusion. In vitro data shows enhanced XO activity in the presence of histamine. Histamine is known to be released during intestinal ischemia and reperfusion. The purpose of this study was to evaluate the relationship between histamine and XO in vivo in intestinal ischemia/reperfusion injury. Using an established model of gut ischemia and reperfusion, portal venous plasma was obtained and assayed for histamine levels, XO activity, and xanthine dehydrogenase (XD) activity following injury. Intestinal ischemia for 120 minutes resulted in a 200% increase in plasma histamine levels (263.4 +/- 36.9 nmol/mL control, v 548.7 +/- 35.1 nmol/mL experimental, P less than .05). Reperfusion for 15 minutes resulted in a further increase in plasma histamine (to 658.3 +/- 33.9 nmol/mL), compared with 120 minutes of ischemia alone. No significant change in plasma XO activity resulted after simple ischemia for 120 minutes. However, XO activity doubled within 15 minutes of reperfusion of the ischemic intestine (6.37 +/- 0.53 nmol O2- per milliliter per minute v 3.12 +/- 0.25 nmol O2- per milliliter per minute, P less than .05). Reperfusion for 60 minutes resulted in the maximal observed increase in plasma XO activity (9.49 +/- 0.67 nmol O2- per milliliter per minute). Analysis of XD activity demonstrated no significant decrease compared with controls until 120 minutes of ischemia and 60 minutes of reperfusion (1.62 +/- 0.49 nmol uric acid per milliliter per minute at 60 minutes of reperfusion, versus 5.02 +/- 0.52 nmol uric acid per milliliter per minute control, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Histamine: a promoter of xanthine oxidase activity in intestinal ischemia/reperfusion. 168 83

The search for the causative factors in Dupuytren's disease has historically progressed form gross anatomical dissection, through microscopical tissue studies, to the biochemistry of the collagen produced. But these elements are merely the end products of cellular activity - not revealing the factors responsible for the changes in cellular activity. Recent biochemical investigations suggest that a number of conditions including localized microvascular ischemia and high alcohol concentrations transform the "benign" xanthine dehydrogenase of endothelial cells to the oxygen-free radical-releasing xanthine oxidase. Oxygen-free radicals are highly reactive species with half-lives in the order of milliseconds capable of both damaging the surrounding peri-microvasculature and stimulating fibroblast proliferation. It is this stimulation of fibroblast proliferation in the palmar fascia that is the key event in the pathogenesis of Dupuytren's contracture.
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PMID:Cell-controlling factors in Dupuytren's contracture. 169 16

Hydrogen peroxide produces marked antigonadotropic and lytic actions in luteal cells, but the effects of superoxide, the archetypal oxygen radical, are unknown. Xanthine oxidase generates superoxide, and the activity of this enzyme, and purine substrate, are increased under ischemia, such as that seen at luteal regression. We therefore examined the actions of xanthine oxidase on luteal cells to assess the effects of this enzyme and the superoxide anion on luteal function. Xanthine oxidase, in the presence of hypoxanthine (50 microM), produced marked inhibition of LH-sensitive cAMP and progesterone production with complete inhibition at 25 mU/ml and half-maximal inhibition at about 5 mU/ml. These antigonadotropic actions of xanthine oxidase were rapid with maximal effects within 5 min, followed several minutes later by substantial depletion of ATP. Heat, superoxide dismutase, and catalase or catalase alone abolished the actions of xanthine oxidase. While depletion of ATP by xanthine oxidase was prevented by 3-amino-benzamide, an inhibitor of DNA repair, inhibition of cAMP and progesterone production was still evident. Xanthine oxidase also inhibited progesterone synthesis stimulated by 8-bromo-cAMP. Isobutylmethylxanthine, a cAMP phosphodiesterase inhibitor, did not reverse the inhibition of cAMP accumulation by xanthine oxidase, and the enzyme had no effect on LH receptor binding activity. Since catalase reversed the effects of xanthine oxidase, we conclude that superoxide was rapidly dismuted to hydrogen peroxide and mediated the antigonadotropic and antisteroidogenic actions of xanthine oxidase in luteal cells. The sensitivity of luteal cells to xanthine oxidase raises the possibility that this enzyme may serve as a significant source of hydrogen peroxide in the corpus luteum.
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PMID:Inhibition of gonadotropin action and progesterone synthesis by xanthine oxidase in rat luteal cells. 170 32

Postischemic myocardial dysfunction in canine myocardium has been reported to be reduced by scavengers of oxygen-derived free radicals. One potential source of oxygen-derived free radicals in canine myocardium is xanthine oxidase, but human and rabbit myocardium either lack or possess very low levels of this enzyme. Therefore, the effects of scavengers of oxygen-derived free radicals on postischemic myocardial dysfunction produced by 15 min of ischemia and 3 h of reperfusion were evaluated in vivo in the rabbit. Superoxide dismutase (SOD) (45,000 U/kg) and catalase (55,000 U/kg) were given into the left atrium 10 min before ischemia, and followed by an additional 45,000 U/kg of SOD and 55,000 U/kg of catalase given over 85 min. This treatment reduced postischemic myocardial dysfunction, as did sulfhydryl-containing free radical scavengers N-2-mercaptopropionyl glycine (4 mg/kg, i.v.) and captopril (3 mg/kg, i.v.) given 5 min before and 60 min after reperfusion. SOD given alone at the same dose was ineffective, as was enalaprilat (0.3 mg/kg, i.v.), an angiotensin-converting enzyme inhibitor that does not scavenge oxygen-derived free radicals. Thus, postischemic myocardial dysfunction was reduced by scavengers of oxygen-derived free radicals in vivo in a species that is deficient in myocardial xanthine oxidase. This suggests that oxygen-derived free radicals derived from a source other than xanthine oxidase play a role in postischemic myocardial dysfunction.
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PMID:Protection against postischemic myocardial dysfunction in anesthetized rabbits with scavengers of oxygen-derived free radicals: superoxide dismutase plus catalase, N-2-mercaptopropionyl glycine and captopril. 170 21


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