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)

Substantial evidence suggests the involvement of oxidative stress in the pathophysiology of congestive heart failure and its antecedent conditions such as cardiac hypertrophy and adverse remodelling after MI. Oxidative stress describes an imbalance between antioxidant defences and the production of reactive oxygen species (ROS), which at high levels cause cell damage but at lower levels induce subtle changes in intracellular signalling pathways (termed redox signalling). ROS are derived from many sources including mitochondria, xanthine oxidase, uncoupled nitric oxide synthases and NADPH oxidases. The latter enzymes are especially important in redox signalling, being implicated in the pathophysiology of hypertension and atherosclerosis, and activated by diverse pathologically relevant stimuli. We review the contribution of ROS to heart failure pathophysiology and discuss potential therapies that may specifically target detrimental redox signalling. Indeed, drugs such as ACE inhibitors and statins may act in part through such mechanisms. A better understanding of redox signalling mechanisms may enable the development of new targeted therapeutic strategies rather than the non-specific antioxidant approaches that have to date been disappointing in clinical trials.
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PMID:Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. 1667 Jan

Inflammation and oxidative stress are associated with cancer, atherosclerosis, and other chronic diseases. Dietary flavonoids have been reported to possess antiinflammatory and antioxidant properties, but their mechanisms of action and structure-activity relations have not been fully investigated. We hypothesized that differences in antioxidant activity between the structurally similar flavones, luteolin and chrysin (differing only in B-ring hydroxylation patterns), would differentially affect inflammation-associated Cox-2 expression and PGE2 formation. Pretreatment of RAW 264.7 macrophage-like cells with 25, 50, or 100 micromol/L concentrations of luteolin inhibited lipopolysaccharide (LPS)-induced Cox-2 protein expression (P < 0.0001). Chrysin pretreatment did not reduce LPS-induced Cox-2 protein expression at any level tested. Conversely, both luteolin and chrysin completely suppressed LPS-induced PGE2 formation (P < 0.001). Luteolin, but not chrysin, inhibited xanthine/xanthine oxidase-generated superoxide formation at 100 micromol/L in a cell-free system (P < 0.001). Although both luteolin and chrysin reduced LPS-induced hydroxyl radical formation relative to the positive control (P < 0.001), luteolin was superior to chrysin (P = 0.003). In summary, luteolin and chrysin suppressed PGE2 formation equally well, despite differential effects on Cox-2 protein expression and on superoxide and hydroxyl radical scavenging. These data indicate that flavones may display similar antiinflammatory activity via different mechanisms.
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PMID:Luteolin and chrysin differentially inhibit cyclooxygenase-2 expression and scavenge reactive oxygen species but similarly inhibit prostaglandin-E2 formation in RAW 264.7 cells. 1670 14

Reactive oxygen species (ROS) contribute to the pathogenesis of cardiovascular diseases including hypertension, atherosclerosis, cardiac hypertrophy, heart failure and diabetes mellitus. Oxidative stress is resulted from excessive generation of ROS that outstrips the antioxidant system. Various agonists, pathological conditions and therapeutic interventions lead to modulated expression and function of oxidant and antioxidant enzymes, including NAD(P)H oxidase, endothelial nitric oxide synthase, xanthine oxidase, myeloperoxidase, superoxide dismutases, catalase and glutathione peroxidase. ROS formed in vascular wall target a wide range of signaling molecules and cellular pathways in both endothelium and vascular smooth muscle, such as transcription factors, protein tyrosine phosphatase, protein tyrosine kinase, mitogen-activated protein kinase, Ca(2+)-transporting system and protein modification. ROS also have distinct physiological and pathophysiological impacts on vascular cells. ROS contribute to vascular dysfunction and remodeling through oxidative damage by (1) reducing the bioavailability of NO, (2) impairing endothelium-dependent vasodilatation and endothelial cell growth, (3) causing apoptosis or anoikis, (4) stimulating endothelial cell migration, and (5) activating adhesion molecules and inflammatory reaction, leading to endothelial dysfunction, an initial episode progressing toward hypertension and atherosclerosis. Cellular events underlying these processes involve changes in vascular smooth muscle cell growth, apoptosis/anoikis, cell migration, inflammation, and vasoconstriction. The present communication focuses on the biology of ROS signaling in vascular cells, discusses how oxidative stress contributes to vascular damage, and the therapeutic strategies/biotic factors that can prevent or treat ROS-associated cardiovascular disorders.
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PMID:Reactive oxygen species in vascular wall. 1672 32

Hypercholesterolemia, an independent risk factor for increased oxidative renal injury, is associated with the formation of oxidized low-density lipoprotein. Production of reactive oxygen species and nitrogen species have been implicated in diet-induced hypercholesterolemia, principally as means of oxidising low-density lipoproteins. This in turn initiates the accumulation of cholesterol in macrophages, which sets key event in the initiation of atherosclerosis. The aim of the present work is to evaluate the effects of eicosapentaenoic acid (EPA), DL alpha-lipoic acid (LA) and eicosapentaenoate-lipoate derivative (EPA-LA) in controlling the atherogenic disturbances. Four groups of male Wistar rats were fed with a high cholesterol diet (rat chow supplemented with 4% cholesterol and 1% cholic acid; HCD) for 30 days. Among them, 3 groups of rats were treated with either EPA (35 mg/kg body weight/day, oral gavage), LA (20 mg/kg body weight/day, oral gavage) or EPA-LA derivative (50 mg/kg body weight/day, oral gavage) from 16th day to 30th day of the experimental period. Abnormal increase in the levels of reactive oxygen species, 3-nitrotyrosine, malondialdehyde and protein carbonyl as well as an elevation in the activities of xanthine oxidase, lactate dehydrogenase, alkaline phosphatase and acid phosphatase was observed in renal tissue of HCD fed rats. HCD fed rats also showed an increased susceptibility of the apo B-containing lipoproteins to in vitro oxidation. These changes were restored partially in the EPA and LA administered groups. However, the combined derivative EPA-LA almost ameliorated the hypercholesterolemic-oxidative changes in the HCD fed rats.
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PMID:Oxidative renal injury and lipoprotein oxidation in hypercholesterolemic atherogenesis: Role of eicosapentaenoate-lipoate (EPA-LA) derivative. 1673 4

Hyperlipidemia enhances xanthine oxidase (XO) activity. XO is an important source of reactive oxygen species (ROS). Since ROS are thought to promote atherosclerosis, we hypothesized that XO is involved in the development of atherosclerosis. ApoE(-/-) mice were fed a Western-type (WD) or control diet. In subgroups, tungsten (700 mg/L) was administered to inhibit XO. XO is a secreted enzyme which is formed in the liver as xanthine dehydrogenase (XDH) and binds to the vascular endothelium. High expression of XDH was found in the liver and WD increased liver XDH mRNA and XDH protein expression. WD induced the conversion of XDH to the radical-forming XO. Moreover, WD increased the hepatic expression of CD40, demonstrating activation of hepatic cells. Aortic tissue of ApoE(-/-) mice fed a WD for 6 months exhibited marked atherosclerosis, attenuated endothelium-dependent relaxation to acetylcholine, increased vascular oxidative stress, and mRNA expression of the chemokine KC. Tungsten treatment had no effect on plasma lipids but lowered the plasma XO activity. In animals fed a control diet, tungsten had no effect on radical formation, endothelial function, or atherosclerosis development. In mice fed a WD, however tungsten attenuated the vascular superoxide anion formation, prevented endothelial dysfunction, and attenuated KC mRNA expression. Most importantly, tungsten treatment largely prevented the development of atherosclerosis in the aorta of ApoE(-/-) mice on WD. Therefore, tungsten, potentially via the inhibition of XO, prevents the development of endothelial dysfunction and atherosclerosis in ApoE(-/-) mice on WD.
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PMID:Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet. 1702 62

This study was carried out on carotid artery plaque and plasma of 50 patients. We analyzed uric acid, hypoxanthine, xanthine, and allantoin levels to verify if enzymatic purine degradation occurs in advanced carotid plaque; we also determined free radicals and sulphydryl groups to check if there is a correlation between oxidant status and purine catabolism. Comparing plaque and plasma we found higher levels of free radicals, hypoxanthine, xanthine, and a decrease of some oxidant protectors, such as sulphydryl groups and uric acid, in plaque. We also observed a very important phenomenon in plaque, the presence of allantoin due to chemical oxidation of uric acid, since humans do not have the enzyme uricase. The hypothetical elevated activity of xanthine oxidase in atherosclerosis could be reduced by specific therapies using its inhibitors, such as oxypurinol or allopurinol.
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PMID:Purine catabolism in advanced carotid artery plaque. 1706 9

Reactive oxygen species (ROS) are by-products of oxygen metabolism, normally present in low levels inside cells, where they participate in signaling processes. The delicate balance in the continuous cycle of ROS generation and inactivation is maintained by enzymatic and nonenzymatic endogenous systems. Overwhelming production of ROS (by such sources as the mitochondrial electron transport chain, NADPH oxidase, xanthine oxidase, or uncoupled nitric oxide synthase), when inadequately counteracted by destruction through antioxidant systems (such as superoxide dismutase or catalase), leads to a prooxidant state also known as oxidative stress. Increased levels of ROS and markers of oxidative stress have been consistently found in such cardiovascular diseases as atherosclerosis or hypertension, although controversy still exists over the pathophysiological role of oxidative stress in these conditions. ROS can modulate vascular function either by direct oxidative damage or by activating cellular signaling pathways that lead to abnormal contractile, inflammatory, proliferative, or remodeling properties of the blood vessel. Most current research focuses on these processes in arteries, leaving veins, "the other side" of vascular biology, in obscurity. Veins are different structurally and functionally from arteries. Equipped with a smaller smooth muscle layer compared to arteries, but being able to accommodate 70% of the circulating blood volume, veins can modulate cardiovascular homeostasis and contribute significantly to hypertension pathogenesis. Although the reports on the quantitative differences in ROS production in veins compared to arteries had conflicting results, there is a clear qualitative difference in ROS metabolism and utilization between the two vessel types. This review will compare and contrast the current knowledge of ROS metabolism in arteries versus veins in both physiological and pathophysiological conditions. Our understanding of the mechanisms underlying vascular diseases would greatly benefit from a more thorough exploration of the role of veins and venous oxidative stress.
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PMID:A comparison of arteries and veins in oxidative stress: producers, destroyers, function, and disease. 1720 83

Thirty years ago, Kurt Oster promulgated the avant-garde theory that bovine xanthine oxidase, absorbed intact from homogenized milk, promoted atherogenesis by oxidatively damaging membrane plasmalogens. Under the mistaken impression that folic acid is a xanthine oxidase inhibitor, he administered high-dose folate (80 mg daily) to hundreds of patients afflicted with symptomatic atherosclerosis, and reported marked improvements in angina, intermittent claudication, and wound healing; he also suspected that this regimen was decreasing heart attack risk. The xanthine oxidase theory has since fallen by the wayside, but there is now evidence that folic acid can lessen endothelial oxidative stress by improving the function of "uncoupled" nitric oxide synthase deficient in tetrahydrobiopterin. In light of these new findings, a properly controlled assessment of Oster's mega-dose folate therapy is warranted.
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PMID:Oster rediscovered--mega-dose folate for symptomatic atherosclerosis. 1722 45

Uric acid and oxidative stress promote cardiovascular diseases, including atherosclerosis and hypertension. Xanthine oxidase, through which uric acid is generated, is a free-radical generating enzyme. The aim of the current study was to investigate whether allopurinol, an inhibitor of xanthine oxidase activity, affects vascular remodeling and vascular smooth muscle cell (VSMC) proliferation. In the carotid artery ligation model using spontaneously hypertensive rats (SHR), treatment with allopurinol induced a reduction in the neointima/media ratio by 27% (38.5+/-34.3% in the control group and 28.1 20.8% in the allopurinol-treated group, respectively, p<0.01) without alterations in vascular circumference at 3 weeks after ligation when compared to the control. Allopurinol lowered the serum uric acid concentration (147.0+/-3.6 micromol/l in the control group and 16.1+/-3.6 micromol/l in the allopurinol-treated group, respectively p<0.01) and xanthine oxidase activity, but not the blood pressure. In an in vitro study, high concentrations of uric acid (100 and 200 micromol/l) stimulated VSMC growth, but there was no stimulation of these cells by a low concentration of uric acid (50 micromol/I) or by any of three concentrations of xanthine (50, 100 and 200 micromol/l). In addition, allopurinol (5 micromol/I) had no effect on the cell growth. In conclusion, uric acid is a potent stimulator of VSMC proliferation, and allopurinol prevented vascular remodeling in SHR at least in part by inhibiting uric acid concentration.
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PMID:Allopurinol reduces neointimal hyperplasia in the carotid artery ligation model in spontaneously hypertensive rats. 1734 92

Pomegranate (Punica granatum L.) juice (PJ) is being increasingly proposed as a nutritional supplement to prevent atherosclerosis in humans. This therapeutically valuable potential has been attributed to PJ antioxidant capacity which has been mostly tested by means of cell-free assays: indeed, to the best of our knowledge, no study has focused on the direct antioxidant capacity of PJ in cultured cells. Here, the antioxidant capacity in cell free-systems of preparations from various parts of pomegranate has been compared with their cytoprotective -bona fide antioxidant--activity in cultured human cells (U937 promonocytes and HUVEC endothelial cells) exposed to an array of oxidizing agents. Pomegranate derivatives were PJ, arils only juice (AJ) and aqueous rinds extract (RE). In cell-free assays--1,1-diphenyl-2-picrylhydrazyl (DPPH), chemiluminescence luminol/xanthine/xanthine oxidase and lipoxygenase assays--all the preparations displayed good antioxidant capacity, the relative potency order being RE>PJ>AJ. On the contrary, only RE was capable of preventing the deleterious effects--cytotoxicity, DNA damage and depletion of non-protein sulphydrils (NPSH) pool--caused by treatment of cells with H(2)O(2), tert-butylhydroperoxide (tB-OOH) or oxidized lipoproteins (Ox-LDL) via a mechanism which is likely to involve both direct scavenging of radical species and iron chelation. Surprisingly, AJ and PJ slightly sensitized cells to the cytotoxic effects of the three agents. Then it would appear that AJ, the major and tasty part of PJ, does not contain ellagic acid and punicalagin (i.e. the polyphenols highly represented in RE which are reputed to be responsible for the antioxidant capacity) in amounts sufficient to exert cytoprotection in oxidatively injured, living cells. Based on these results, the development and evaluation of rinds-only based derivatives for antiatherogenic preventive purposes in humans should be encouraged.
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PMID:Cytoprotective effect of preparations from various parts of Punica granatum L. fruits in oxidatively injured mammalian cells in comparison with their antioxidant capacity in cell free systems. 1737 99


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