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)

It is anticipated that further understanding of the protective mechanism induced by ischemic preconditioning will improve prognosis for patients of ischemic injury. It is not known whether preconditioning exerts beneficial actions in neurodegenerative diseases, in which ischemic injury plays a causative role. Here we show that transient activation of ATP-sensitive potassium channels, a trigger in ischemic preconditioning signaling, confers protection in PC12 cells and SH-SY5Y cells against neurotoxic effect of rotenone and MPTP, mitochondrial complex I inhibitors that have been implicated in the pathogenesis of Parkinson's disease. The degree of protection is in proportion to the bouts of exposure to an ATP-sensitive potassium channel opener, a feature reminiscent of ischemic tolerance in vivo. Protection is sensitive to a protein synthesis inhibitor, indicating the involvement of de novo protein synthesis in the protective processes. Pretreatment of PC12 cells with preconditioning stimuli FeSO(4) or xanthine/xanthine oxidase also confers protection against rotenone-induced cell death. Our results demonstrate for the first time the protective role of ATP-sensitive potassium channels in a dopaminergic neuronal cell line against rotenone-induced neurotoxicity and conceptually support the view that ischemic preconditioning-derived therapeutic strategies may have potential and feasibility in therapy for Parkinson's disease.
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PMID:Activation of adenosine triphosphate-sensitive potassium channels confers protection against rotenone-induced cell death: therapeutic implications for Parkinson's disease. 1221 Aug 49

Hydroethidine (HE) or dihydroethidium (DHE), a redox-sensitive probe, has been widely used to detect intracellular superoxide anion. It is a common assumption that the reaction between superoxide and HE results in the formation of a two-electron oxidized product, ethidium (E+), which binds to DNA and leads to the enhancement of fluorescence (excitation, 500-530 nm; emission, 590-620 nm). However, the mechanism of oxidation of HE by the superoxide anion still remains unclear. In the present study, we show that superoxide generated in several enzymatic or chemical systems (e.g., xanthine/xanthine oxidase, endothelial nitric oxide synthase, or potassium superoxide) oxidizes HE to a fluorescent product (excitation, 480 nm; emission, 567 nm) that is totally different from E+. HPLC measurements revealed that the HE/superoxide reaction product elutes differently from E+. This new product exhibited an increase in fluorescence in the presence of DNA. Mass spectral data indicated that the molecular weight of the HE/superoxide reaction product is 330, while ethidium has a molecular weight of 314. We conclude that the reaction between superoxide and HE forms a fluorescent marker product that is different from ethidium. Potential implications of this finding in intracellular detection and imaging of superoxide are discussed.
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PMID:Superoxide reacts with hydroethidine but forms a fluorescent product that is distinctly different from ethidium: potential implications in intracellular fluorescence detection of superoxide. 1275 45

Arsenic compounds with a +3 oxidation state are more toxic than analogous compounds with a +5 oxidation state, for example, arsenite versus arsenate, monomethylarsonous acid (MMA(III)) versus monomethylarsonic acid (MMA(V)), and dimethylarsinous acid (DMA(III)) versus dimethylarsinic acid (DMA(V)). It is no longer believed that the methylation of arsenite is the beginning of a methylation-mediated detoxication pathway. The oxidation of these +3 compounds to their less toxic +5 analogs by hydrogen peroxide needs investigation and consideration as a potential mechanism for detoxification. Xanthine oxidase uses oxygen to oxidize hypoxanthine to xanthine to uric acid. Hydrogen peroxide and reactive oxygen are also products. The oxidation of +3 arsenicals by the hydrogen peroxide produced in the xanthine oxidase reaction was blocked by catalase or allopurinol but not by scavengers of the hydroxy radical, e.g., mannitol or potassium iodide. Melatonin, the singlet oxygen radical scavenger, did not inhibit the oxidation. The production of H2O2 by xanthine oxidase may be an important route for decreasing the toxicity of trivalent arsenic species by oxidizing them to their less toxic pentavalent analogs. In addition, there are many other reactions that produce hydrogen peroxide in the cell. Although chemists have used hydrogen peroxide for the oxidation of arsenite to arsenate to purify water, we are not aware of any published account of its potential importance in the detoxification of trivalent arsenicals in biological systems. At present, this oxidation of the +3 oxidation state arsenicals is based on evidence from in vitro experiments. In vivo experiments are needed to substantiate the role and importance of H2O2 in arsenic detoxication in mammals.
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PMID:Oxidation and detoxification of trivalent arsenic species. 1461 11

We report the modulatory effect of coumarin (1,2-benzopyrone) on potassium bromate (KBrO(3)) mediated nephrotoxicity in Wistar rats. KBrO(3) (125 mg/kg body weight, i.p.) enhances gamma-glutamyl transpeptidase, renal lipid peroxidation, xanthine oxidase and hydrogen peroxide (H(2)O(2)) generation with reduction in renal glutathione content and antioxidant enzymes. It also enhances blood urea nitrogen, serum creatinine, ornithine decarboxylase (ODC) activity and [(3)H]-thymidine incorporation into renal DNA. Treatment of rats orally with coumarin (10 mg/kg body weight and 20 mg/kg body weight) resulted in a significant decrease in gamma-glutamyl transpeptidase, lipid peroxidation, xanthine oxidase, H(2)O(2) generation, blood urea nitrogen, serum creatinine, renal ODC activity and DNA synthesis (P < 0.001). Renal glutathione content (P < 0.01) and antioxidant enzymes were also recovered to significant level (P < 0.001). These results show that coumarin may be used as an effective chemopreventive agent against KBrO(3)-mediated renal oxidative stress, toxicity and tumor promotion response in Wistar rats.
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PMID:Attenuation of potassium bromate-induced nephrotoxicity by coumarin (1,2-benzopyrone) in Wistar rats: chemoprevention against free radical-mediated renal oxidative stress and tumor promotion response. 1503 24

Experiments using purified recombinant human NAD(P)H:quinone oxidoreductase 1 (NQO1) revealed that the auto-oxidation of fully reduced protein resulted in a 1:1 stoichiometry of oxygen consumption to NADH oxidation with the production of hydrogen peroxide. The rate of auto-oxidation of fully reduced NQO1 was markedly accelerated in the presence of superoxide (O(2)(*)(-)), whereas the addition of superoxide dismutase greatly inhibited the rate of auto-oxidation. The ability of reduced NQO1 to react with O(2)(*)(-) suggested a role for NQO1 in scavenging O(2)(*)(-), and this hypothesis was tested using established methods for O(2)(*)(-) production and detection. The addition of NQO1 in combination with NAD(P)H resulted in inhibition of dihydroethidium oxidation, pyrogallol auto-oxidation, and elimination of a potassium superoxide-generated ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide:O(2)(*)(-) adduct signal (electron spin resonance). Kinetic parameters for the reduction of O(2)(*)(-) by NQO1 were estimated using xanthine/xanthine oxidase as the source of O(2)(*)(-) and after NQO1-dependent NADH oxidation at 340 nm. The ability of NQO1 to scavenge O(2)(*)(-) was also examined using cell sonicates prepared from isogenic cell lines containing no NQO1 activity (NQO1(-)) or very high levels of NQO1 activity (NQO1(+)). We demonstrated that addition of NAD(P)H and cell sonicate from NQO1(+) but not NQO1(-) cells resulted in an increased level of O(2)(*)(-) scavenging could be inhibited by 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a mechanism-based inhibitor of NQO1. NQO1 can generate hydroquinones that are redox active, and the O(2)(*)(-) scavenging activity of NQO1 may allow protection against O(2)(*)(-) at the site of hydroquinone generation. In addition, the O(2)(*)(-) scavenging activity of NQO1 may provide an additional level of protection against O(2)(*)(-) induced toxicity.
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PMID:NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. 1510 52

Recently, it was demonstrated that superoxide oxidizes dihydroethidium to a specific fluorescent product (oxyethidium) that differs from ethidium by the presence of an additional oxygen atom in its molecular structure. We have adapted this new HPLC-based assay to quantify this product as a tool to estimate intracellular superoxide in intact tissues. Ethidium and oxyethidium were separated using a C-18 column and quantified using fluorescence detection. Initial cell-free experiments with potassium superoxide and xanthine oxidase confirmed the formation of oxyethidium from dihydroethidium. The formation of oxyethidium was inhibited by superoxide dismutase but not catalase and did not occur upon the addition of H(2)O(2), peroxynitrite, or hypochlorous acid. In bovine aortic endothelial cells (BAEC) and murine aortas, the redox cycling drug menadione increased the formation of oxyethidium from dihydroethidium ninefold (0.4 nmol/mg in control vs. 3.6 nmol/mg with 20 microM menadione), and polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) significantly inhibited this effect. Treatment of BAEC with angiotensin II caused a twofold increase in oxyethidium formation, and this effect also was reduced by PEG-SOD (0.5 nmol/mg). In addition, in the aortas of mice with angiotensin II-induced hypertension and DOCA-salt hypertension, the formation of oxyethidium was increased in a manner corresponding to superoxide production estimated on the basis of cytochrome c reduction. Detection of oxyethidium using HPLC represents a new, convenient, quantitative method for the detection of superoxide in intact cells and tissues.
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PMID:Detection of intracellular superoxide formation in endothelial cells and intact tissues using dihydroethidium and an HPLC-based assay. 1530 39

The radical scavenging activity of oxidized and reduced idebenone (ID-O and ID-H, respectively) against superoxide radical (O2(-*) was studied in vitro using two methods: (1) O2(-*) radicals were generated enzymatically in a hypoxanthine (HPX)-xanthine oxidase (XOD) system and detected by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) spin trapping. Superoxide dismutase and other scavengers added to this system competed to various extents with DMPO to trap O2(-*) radicals, resulting in a decrease of the ESR signal intensity of the DMPO-OOH spin adduct. ID-O reacted about 12-fold quicker (k = 4.48 x 10(4) M(-1)s(-1)) with the O2(-*) radicals than ID-H (k = 3.62 x 10(3) M(-1)s(-1)) x (2) O2(-*) radicals were generated chemically in potassium superoxide (KO2)-crown ether system. Quinoid compounds reacted with the O2(-*)radicals to form semiquinone radicals that could be observed by ESR. At liquid nitrogen temperature (-196 degrees C), the ESR signal of O2(-*) radicals could be observed directly, thus allowing us to estimate the scavenging activity of ID-O and ID-H. These experiments also revealed that ID-O possesses an O2(-*) radical scavenging activity, whereas ID-H reacts quantitatively much slower. Analyzing various quinone compounds, it has been established that the O2(-*) radical scavenging process is a reversible, most probably oscillating, monovalent electron transfer from superoxide to the quinone, and that the O2(-*) radical scavenging activity depends on the redox potential, i.e., on the actual state of oxidation of the quinones.
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PMID:Superoxide radical scavenging activity of idebenone in vitro studied by ESR spin trapping method and direct ESR measurement at liquid nitrogen temperature. 1537 69

Ethanol-water (70:30 v/v) extracts from rice brans removed from seeds of two blackish-purple pigmented (Sanhaehyanghyulla and Suwon 415) and one nonpigmented (Chuchung) brown rice cultivars were evaluated for antioxidative, anti-tumor-promoting, and anticarcinogenic activities in chemical assays and in mammalian cells (human leukemia HL-60, marmoset B lymphoblastoid B95-8, and Chinese hamster V79 lung cells) by the following tests: inhibition of xanthine oxidase activity; chelation of ferrous ions; reduction of potassium ferricyanide; scavenging of superoxide anions, hydroxyl radicals, and intracellular peroxides; inhibition of 4-nitroquinoline N-oxide-induced mutagenesis; and inhibition of phorbol ester-induced tumor promotion. The extracts from the pigmented rice seeds had generally higher activities in all tests than did the extract from the nonpigmented variety. The results suggest that brans from pigmented rice varieties may provide a source of new natural antioxidants and anticarcinogens and that such rice cultivars with high antioxidative potential also provide a genetic resource for the development of new, improved rice cultivars that may make it possible to enhance both the nutritional and medical value of rice-based diets.
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PMID:Antioxidative, antimutagenic, and anticarcinogenic activities of rice bran extracts in chemical and cell assays. 1568 39

Scopoletin exhibited an immediate and dose-dependent hypouricemic effect after intraperitoneal administration (50, 100, 200 mg/kg) in hyperuricemic mice induced by potassium oxonate; however, it did not affect the serum uric acid level in normal mice at the tested doses. For exploring the involved mechanisms of action of scopoletin, potential inhibitory effects on xanthine oxidase and possible uricosuric effects were investigated. Scopoletin (50, 100, 200 mg/kg) significantly inhibited the activity of xanthine oxidase in liver homogenates of hyperuricemic mice although it only showed a relatively weak, albeit competitive-type, inhibition of xanthine oxidase in a commercial assay. Furthermore, a potent uricosuric effect of scopoletin (100, 200 mg/kg) was ascertained. These results demonstrated for the first time that scopoletin exhibits, hypouricemic activities through decreasing uric acid production and as well as a uricosuric mechanism.
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PMID:Hypouricemic action of scopoletin arising from xanthine oxidase inhibition and uricosuric activity. 1572 30

It is well established that the central cardiovascular effects of angiotensin II (Ang II) involve superoxide production. However, the intracellular mechanism by which reactive oxygen species (ROS) signaling regulates neuronal Ang II actions remains to be elucidated. In the present study, we have used neuronal cells in primary cultures from the hypothalamus and brain stem areas to study the role of ROS on the cellular actions of Ang II. Ang II increases neuronal firing rate, an effect mediated by the AT(1) receptor subtype and involving inhibition of the delayed rectifier potassium current (I(Kv)). This increase in neuronal activity was associated with increases in NADPH oxidase activity and ROS levels within neurons, the latter evidenced by an increase in ethidium fluorescence. The increases in NADPH oxidase activity and ethidium fluorescence were blocked by either the AT(1) receptor antagonist losartan or by the selective NAD(P)H oxidase inhibitor gp91ds-tat. Extracellular application of the ROS scavenger, Tempol, attenuated the Ang II-induced increase in neuronal firing rate by 70%. In addition, gp91ds-tat treatment resulted in a 50% inhibition of Ang II-induced increase in firing rate. In contrast, the ROS generator Xanthine-Xanthine oxidase significantly increased neuronal firing rate. Finally, Ang II inhibited neuronal I(Kv,) and this inhibition was abolished by gp91ds-tat treatment. These observations demonstrate, for the first time, that Ang II regulates neuronal activity via a series of events that includes ROS generation and inhibition of I(Kv). This signaling seems to be a critical cellular event in central Ang II regulation of cardiovascular function.
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PMID:NAD(P)H oxidase inhibition attenuates neuronal chronotropic actions of angiotensin II. 1574 42


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