Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular dysfunction is a hallmark of many diseases, including coronary heart disease, stroke, and diabetes. The underlying mechanisms of these disorders are intimately associated with an increase in oxidative stress and excess generation of reactive oxygen species. Here, we report that the anionic free radical, superoxide (O2*- ), directly affects the function of ion channels in vascular endothelial cells. Vascular endothelial cells were exposed to O2*- under physiological, symmetrical chloride and chloride-free conditions. Superoxide was generated from the reaction of xanthine (0.2 mM) and xanthine oxidase (0.1, 1, and 10 mU/ml) while its effects were determined with the whole cell mode of the patch-clamp technique. Inhibitors of K+ and Cl- channels were used to determine the role of these ion channels in mediating the electrophysiological effects of superoxide. The addition of O2*- caused a dose-dependent depolarization of endothelial cells and activation of the whole cell current. Activation of superoxide-dependent current was observed in the presence of inhibitors of K+ channels, Ba2+ (100 microM) or iberiotoxin (100 nM), and was not affected by inhibitors of nonselective cation channels, La3+, or by inhibition of the Cl-/HCO3- transporter by bumetanide. The inhibitors of the Cl- channel, NPPB (0.1 mM) or DIDS (100 microM), partially prevented activation of superoxide-dependent current but were unable to reverse it. The effects of superoxide on the amplitude of whole cell current were prevented and reversed by superoxide dismutase. Taken together, these results suggest that superoxide directly affects the function of ion channels in vascular endothelium but the mechanisms of its modulatory effects remain unresolved.
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PMID:Electrophysiological effects of O2*- on the plasma membrane in vascular endothelial cells. 1596 27

The levels of oxidants xanthine oxidase (XO), nitric oxide (NO), and malondialdehyde (MDA) and of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione reductase (GRD) were determined in plasma within 24 h after onset of hemorrhagic stroke in 17 patients (9 men and 8 women, aged 60.7+/-11.5 yr) and in 20 healthy controls (12 men and 8 women, aged 62.5+/-8.3 yr). Compared to controls, the plasma SOD and total superoxide scavenger activities (TSSA) were significantly lower and the NO levels were significantly higher among the stroke patients. XO showed a slight, nonsignificant increase in the patients, but the levels of MDA, NSSA, GRD, and GSH-Px did not show any significant differences between the two groups. The hemorrhage volume was negatively correlated with the initial score of the Glasgow Coma Scale and a positive correlation with lethal outcome, but it did not correlate significantly with any of the measured parameters. The results suggest that free radicals might play a role in the development of brain injury following brain hemorrhage.
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PMID:Plasma values of oxidants and antioxidants in acute brain hemorrhage: role of free radicals in the development of brain injury. 1632 58

Ischemic stroke is caused by obstruction of blood flow to the brain, resulting in energy failure that initiates a complex series of metabolic events, ultimately causing neuronal death. One such critical metabolic event is the activation of phospholipase A2 (PLA2), resulting in hydrolysis of membrane phospholipids and release of free fatty acids including arachidonic acid, a metabolic precursor for important cell-signaling eicosanoids. PLA2 enzymes have been classified as calcium-dependent cytosolic (cPLA2) and secretory (sPLA2) and calcium-independent (iPLA2) forms. Cardiolipin hydrolysis by mitochondrial sPLA2 disrupts the mitochondrial respiratory chain and increases production of reactive oxygen species (ROS). Oxidative metabolism of arachidonic acid also generates ROS. These two processes contribute to formation of lipid peroxides, which degrade to reactive aldehyde products (malondialdehyde, 4-hydroxynonenal, and acrolein) that covalently bind to proteins/nucleic acids, altering their function and causing cellular damage. Activation of PLA2 in cerebral ischemia has been shown while other studies have separately demonstrated increased lipid peroxidation. To the best of our knowledge no study has directly shown the role of PLA2 in lipid peroxidation in cerebral ischemia. To date, there are very limited data on PLA2 protein by Western blotting after cerebral ischemia, though some immunohistochemical studies (for cPLA2 and sPLA2) have been reported. Dissecting the contribution of PLA2 to lipid peroxidation in cerebral ischemia is challenging due to multiple forms of PLA2, cardiolipin hydrolysis, diverse sources of ROS arising from arachidonic acid metabolism, catecholamine autoxidation, xanthine oxidase activity, mitochondrial dysfunction, activated neutrophils coupled with NADPH oxidase activity, and lack of specific inhibitors. Although increased activity and expression of various PLA2 isoforms have been demonstrated in stroke, more studies are needed to clarify the cellular origin and localization of these isoforms in the brain, their responses in cerebral ischemic injury, and their role in oxidative stress.
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PMID:Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. 1644 52

Plasma levels of the oxidants xanthine oxidase, nitric oxide and malondialdehyde and the antioxidants superoxide dismutase, glutathione peroxidase and glutathione reductase, together with total superoxide scavenger activity and non-enzymatic superoxide scavenger activity, were determined in 19 patients with acute ischaemic stroke and 20 controls. Compared with controls, superoxide dismutase, total superoxide scavenger activity, glutathione peroxidase and glutathione reductase activities were significantly lower, and nitric oxide and malondialdehyde levels significantly higher, in acute stroke patients. Xanthine oxidase showed a slight but non-significant increase in stroke patients compared with controls. There was no significant difference in non-enzymatic superoxide scavenger activity between the two groups. There was a positive correlation between glutathione reductase levels and Glasgow Coma Scale scores, and a negative correlation between malondialdehyde levels and non-enzymatic superoxide scavenger activity. These findings suggest that oxidative stress in patients with acute ischaemic stroke may be the result of an imbalance in oxidant/antioxidant homeostasis.
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PMID:Plasma oxidants and antioxidants in acute ischaemic stroke. 1698 98

Oxidative stress is involved in the pathogenesis of cocaine-induced cardiomyopathy. In the present study, we aimed to determine the enzymatic sources of reactive oxygen species (ROS) production, namely NADPH oxidase and xanthine oxidoreductase (XOR) in male Wistar rats treated for 7 days with cocaine (2x7.5 mg/kg/day, ip) or cocaine with a NADPH oxidase inhibitor (apocynin, 50 mg/kg/day, po) or a XOR inhibitor (allopurinol, 50 mg/kg/day, po). Cocaine-induced cardiac dysfunction is associated with an increase in NADPH oxidase and XOR activities (59% and 29%, respectively) and a decrease in catalase activity. Apocynin or allopurinol treatment prevents the cocaine-induced cardiac alteration by restoration of cardiac output, stroke volume and fractional shortening. This is associated with a reduction of the myocardial production of superoxide anions and an enhancement of catalase activity. Surprisingly, apocynin treatment prevents XOR up-regulation supporting the hypothesis that NADPH oxidase-derived ROS play a role in modulating ROS production by XOR. These data suggest that NADPH and xanthine oxidase act synergically to form myocardial ROS and clearly demonstrate that their inhibition may be critical in preventing the initiation and progression of cocaine-induced LV dysfunction.
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PMID:NADPH oxidase inhibition prevents cocaine-induced up-regulation of xanthine oxidoreductase and cardiac dysfunction. 1721 56

The free radical-generating system of xanthine and xanthine oxidase is commonly used experimentally as a source of superoxide anion, which can produce oxidative stress, leading to cellular damage and death. Models of oxidative stress are important in elucidating pathologies associated with increased levels of reactive oxygen species, including stroke and neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We therefore, examined the effect of the xanthine/xanthine oxidase system on the viability of postnatal cerebellar granule neurones obtained from 8-day old Sprague-Dawley rat pups. Xanthine (100 microM) and xanthine oxidase (0.02 U/ml) applied for 1 or 6h reduced the viability of cells at 8 div assessed using the alamar blue assay, and induced morphological changes, such as shrinkage of the cell bodies and neurites. Heat-inactivation of xanthine oxidase resulted in complete loss of its activity. Superoxide dismutase (250 U/ml) failed to modify the damage by xanthine and xanthine oxidase, while catalase (250 U/ml) completely prevented it. When applied alone, xanthine oxidase significantly lowered cell viability, an effect that was blocked by allopurinol and catalase, but not by superoxide dismutase. The results indicate that xanthine and xanthine oxidase can produce predominantly hydrogen peroxide instead of the superoxide anion. Cerebellar granule cells in culture may also possess significant levels of endogenous xanthine.
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PMID:Hydrogen peroxide mediates damage by xanthine and xanthine oxidase in cerebellar granule neuronal cultures. 1736 Jan 18

So far, several treatment modalities have been attempted to brain protection in cases such as brain trauma, stroke or brain hemorrhage. However, a treatment method that the effect begins immediately and definitely helpful has not been discovered yet. In this study, we aimed to compare the effects of propofol and erythropoietin (Epo) on brain injury caused by oxidative stress and antioxidant properties of these agents after closed head injury (CHI) in rats. For this study, female Wistar Albino rats were divided into five groups: non-traumatic control group, trauma performed group CHI, trauma with propofol (100 mg/kg) intraperitoneally (i.p.), trauma with Epo (5000 U/kg) i.p. and trauma with propofol and Epo performed study groups. Twenty-four hours after CHI, rats were sacrificed and the brains were removed. Superoxide dismutase (SOD), catalase (CAT), xanthine oxidase (XO), nitric oxide (NO), and malondialdehyde (MDA) levels were measured in brain tissue. MDA and NO levels were decreased significantly in Groups Epo, Propofol and Epo+Propofol than Group CHI (p<0.01). XO activity was significantly lower in Group Epo than Group CHI (p<0.05). Epo and propofol decreased oxidative stress by decreasing MDA and NO level in brain tissue after CHI. However, combination of Epo and propofol has no significant beneficial advantage than Epo or propofol alone.
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PMID:Propofol and erythropoietin antioxidant properties in rat brain injured tissue. 1776 98

This review focuses on the morphological features of atherosclerosis and the involvement of oxidative stress in the initiation and progression of this disease. There is now consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein in the vascular wall. Reactive oxygen species (ROS) are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis, starting from the initiation of fatty streak development, through lesion progression, to ultimate plaque rupture. Plaque rupture and thrombosis result in the acute clinical complications of myocardial infarction and stroke. Many data support the notion that ROS released from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, myeloperoxidase (MPO), xanthine oxidase (XO), lipoxygenase (LO), nitric oxide synthase (NOS) and enhanced ROS production from dysfunctional mitochondrial respiratory chain, indeed, have a causatory role in atherosclerosis and other vascular diseases. Moreover, oxidative modifications in the arterial wall can contribute to the arteriosclerosis when the balance between oxidants and antioxidants shifts in favour of the former. Therefore, it is important to consider sources of oxidants in the context of available antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase and transferases thiol-disulfide oxidoreductases and peroxiredoxins. Here, we review also the mechanisms in which they are involved in order to accelerate the pace of the discovery and facilitate development of novel therapeutic approaches.
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PMID:Atherosclerosis and oxidative stress. 1807 94

Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by microvascular vaso-occlusion with erythrocytes containing polymerized sickle (S) hemoglobin, erythrocyte hemolysis, vasculopathy, and both acute and chronic multiorgan injury. It is associated with steady state increases in plasma cell-free hemoglobin and overproduction of reactive oxygen species (ROS). Hereditary and acquired hemolytic conditions release into plasma hemoglobin and other erythrocyte components that scavenge endothelium-derived NO and metabolize its precursor arginine, impairing NO homeostasis. Overproduction of ROS, such as superoxide, by enzymatic (xanthine oxidase, NADPH oxidase, uncoupled eNOS) and nonenzymatic pathways (Fenton chemistry), promotes intravascular oxidant stress that can likewise disrupt NO homeostasis. The synergistic bioinactivation of NO by dioxygenation and oxidation reactions with cell-free plasma hemoglobin and ROS, respectively, is discussed as a mechanism for NO resistance in SCD vasculopathy. Human physiological and transgenic animal studies provide experimental evidence of cardiovascular and pulmonary resistance to NO donors and reduced NO bioavailability that is associated with vasoconstriction, decreased blood flow, platelet activation, increased endothelin-1 expression, and end-organ injury. Emerging epidemiological data now suggest that chronic intravascular hemolysis is associated with certain clinical complications: pulmonary hypertension, cutaneous leg ulcerations, priapism, and possibly stroke. New therapeutic strategies to limit intravascular hemolysis and ROS generation and increase NO bioavailability are discussed.
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PMID:Sickle cell disease vasculopathy: a state of nitric oxide resistance. 1826 70

The importance of xanthine oxidase and its products is being increasingly recognized in cardiovascular medicine. Patients who have had a stroke are at high risk of future cardiovascular events and this risk is higher in those with high urate levels. The aim of this pilot study was to see if inhibiting xanthine oxidase altered arterial wave reflection, determined from the augmentation index (AIx). In a double-blind study, 30 patients with high urate (> or = 0.38 mmol/L) were randomized to 300 mg allopurinol or placebo for 8 weeks. AIx measurements were made before and after treatment using the validated SphygmoCor pulse waveform analysis system. For patients treated with allopurinol, there was a reduction in AIx from 26.08 +/- 3.31% to 20.15 +/- 2.23% compared with an increase in the placebo group from 23.57 +/- 3.13% to 27.64 +/- 3.44% (P = 0.031, ANOVA). The vascular benefits of allopurinol are rapidly emerging. We have demonstrated that allopurinol has beneficial effects on AIx, a validated measure of vascular function. A further larger study is warranted to look at whether a therapeutic intervention with allopurinol will impact positively on mortality and morbidity in stroke survivors.
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PMID:Allopurinol treatment reduces arterial wave reflection in stroke survivors. 1903 75


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