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)

Lipopolysaccharide endotoxin and interferon-gamma induced inducible nitric oxide synthase (iNOS) protein expression and nitrite/nitrate formation in microvascular endothelial cell cultures (ECs) derived from rat skeletal muscle. Pretreatment of ECs with ascorbate accumulated a large amount of ascorbate inside the cells and consequently decreased both intracellular oxidant level and iNOS induction. These effects of ascorbate were abolished in the presence of exogenous superoxide generated by xanthine oxidase/xanthine plus catalase but were not altered when N-nitro-L-arginine methyl ester was applied to inhibit nitric oxide synthesis. Ascorbate also attenuated the activation of transcription factor IRF-1 but not NF kappa B. These results indicate that ascorbate inhibits iNOS expression in ECs by an antioxidant mechanism independent of both NF kappa B activation and the reported negative feedback effect of nitric oxide.
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PMID:Ascorbate inhibits iNOS expression in endotoxin- and IFN gamma-stimulated rat skeletal muscle endothelial cells. 1204 83

This study investigated the effects of the natural polyphenol mangiferin (MA) on superoxide anion (O(2)(-)) production, xanthine oxidase (XO) activity, vascular contractility, inducible nitric oxide synthase (iNOS) mRNA levels, tumour necrosis factor-alpha (TNF-alpha) mRNA levels, and tumour growth factor-beta (TGF-beta) mRNA levels. O(2)(-) was generated by the hypoxanthine-xanthine oxidase (HX-XO) and phenazine methosulphate (PMS)-NADH systems. XO activity was determined by measurement of uric acid production with xanthine as substrate. Vascular contraction experiments were performed with intact rat aortic rings. iNOS, TNF-alpha and TGF-beta gene expression in rat macrophages stimulated in vivo with 3% thioglycollate and in vitro with 100 ng/mL lipopolysaccharide and 10U/mL of interferon-gamma were evaluated semiquantitatively by the retrotranscriptase-polymerase chain reaction. MA at 10-100 microM, like the known O(2)(-) scavenger superoxide dismutase (1U/mL), scavenged O(2)(-) produced by the HX/XO and PMS-NADH systems. By contrast MA at 1-100 microM, unlike allopurinol (10 microM), was unable to inhibit XO activity. MA at 1-100 microM did not modify resting tone or the contractile responses elicited by 1 microM phenylephrine or 1 microM phorbol 12-myristate 13-acetate in rat aorta. MA at 1-100 microM, like dexamethasone (100 microM), decreased iNOS mRNA levels in activated macrophages. At 100 microM, MA also reduced TNF-alpha mRNA levels, but increased TGF-beta mRNA levels. These results thus indicate that MA is an O(2)(-) scavenger and that it inhibits expression of the iNOS and TNF-alpha genes, suggesting that it may be of potential value in the treatment of inflammatory and/or neurodegenerative disorders. In addition, the finding that MA enhances TGF-beta gene expression suggests that this polyphenol might also be of value in the prevention of cancer, autoimmune disorders, atherosclerosis and coronary heart disease.
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PMID:In vitro effects of mangiferin on superoxide concentrations and expression of the inducible nitric oxide synthase, tumour necrosis factor-alpha and transforming growth factor-beta genes. 1269 77

In the present study, we investigated the effects and mechanisms of a novel potent antioxidant, octyl caffeate, on the induction of iNOS expression by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) in cultured primary rat aortic smooth muscle cells (RASMCs) in vitro and LPS-induced hypotension in vivo. Octyl caffeate (0.1-1.0 microM) exerted a concentration-dependent inhibition of iron-catalyzed lipid peroxidation in rat brain homogenates. Furthermore, octyl caffeate (20, 50, and 100 microM) concentration-dependently diminished the initial rate of superoxide-induced NBT reduction and the enzymatic activity of xanthine oxidase. It also concentration-dependently (1-50 microM) inhibited the NO production, iNOS protein and messenger RNA expressions upon stimulation by LPS (100 microg/mL)/IFN-gamma (100U/mL) in RASMCs. In addition, we found that octyl caffeate did not significantly affect IkappaBalpha degradation stimulated by LPS/IFN-gamma in RASMCs. On the other hand, octyl caffeate (10 and 50 microM) significantly suppressed activation of c-Jun-N-terminal kinase and extracellular signal-regulated kinase. Moreover, octyl caffeate (10mg/kg, i.v.) significantly inhibited the fall in mean arterial pressure stimulated by LPS (7.5mg/kg) in rats. In conclusion, we demonstrate that a novel potent antioxidant, octyl caffeate, significantly ameliorates circulatory failure of endotoxemia in vivo by a mechanism involving suppression of iNOS expression through inactivation of mitogen-activated protein kinases in RASMCs.
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PMID:A novel antioxidant, octyl caffeate, suppression of LPS/IFN-gamma-induced inducible nitric oxide synthase gene expression in rat aortic smooth muscle cells. 1269 79

We have shown that nitric oxide treatment for 30-90 min causes inhibition of insulin secretion, DNA damage and disturbs sub-cellular organization in rat and human islets of Langerhans and HIT-T15 cells. Here rat islets and beta-cell lines were treated with various free radical generating systems S-nitrosoglutathione (nitric oxide), xanthine oxidase plus hypoxanthine (reactive oxygen species), 3-morpholinosydnonimine (nitric oxide, super-oxide, peroxynitrite, hydrogen peroxide) and peroxynitrite and their effects over 4 h to 3 days compared with those of the cytokine combination interleukin-1beta, tumour necrosis factor-alpha and interferon-gamma. End points examined were de novo protein synthesis, cellular reducing capacity, morphological changes and apoptosis by acridine orange cytochemistry, DNA gel electrophoresis and electron microscopy. Treatment (24-72 h) with nitric oxide, superoxide, peroxynitrite or combined cytokines differentially decreased redox function and inhibited protein synthesis in rat islets of Langerhans and in insulin-containing cell lines; cytokine effects were arginine and nitric oxide dependent. Peroxynitrite gave rare apoptosis in HIT-T15 cells and superoxide gave none in any cell type, but caused the most beta cell-specific damage in islets. S-nitroso-glutathione was the most effective agent at causing DNA laddering or chromatin margination characteristic of apoptotic cell death in insulin-containing cells. Cytokine-induced apoptosis was observed specifically in islet beta cells, combined cytokine effects on islet function and death most resembled those of the mixed radical donor SIN-1.
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PMID:Superoxide, nitric oxide, peroxynitrite and cytokine combinations all cause functional impairment and morphological changes in rat islets of Langerhans and insulin secreting cell lines, but dictate cell death by different mechanisms. 1464 51

Quantitation of superoxide radical (O2.-) production at the site of radical generation remains challenging. Microdialysis sampling is an advantageous tool for sampling from localized environments. It is difficult to combine electron spin resonance (ESR) spin traps with microdialysis because O2.- adducts with common nitrone spin traps have shorter half-lives than typical microdialysis collection times. Furthermore, typical dialysate samples (5-15 microL) suffer significant sensitivity loss when diluted for detection in a conventional ESR flat cell (200 microL). To overcome these difficulties, a cyclic hydroxylamine, 1-hydroxy-4-phosphonooxy-2,2,6,6-tetramethylpiperidine (PP-H), which produces a stable nitroxide radical (PP.) product upon reaction with O2.- was employed. Capillary cells (1.4 microL effective volume) coupled with a loop-gap resonator were utilized to measure PP. in microliter microdialysis samples (LOD 0.36 pmol). A xanthine/xanthine oxidase (X/XO) model system provided sustained O2.- production. When PP-H was included in the X/XO medium external to the microdialysis probe, a relative recovery of 22.1 +/- 1.1 and 57.2 +/- 5.7% for PP. was achieved at perfusion fluid flow rates of 0.5 and 1.0 microL/min, respectively. The respiratory burst in interferon-gamma and zymosan-stimulated RAW 264.7 macrophages was also investigated.
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PMID:Microdialysis sampling combined with electron spin resonance for superoxide radical detection in microliter samples. 1530 84

Reactive oxygen species have been reported to be involved in the airway inflammatory process of chronic obstructive pulmonary disease (COPD). The aim of this study was to quantify the activity of xanthine oxidase (XO), which generates a potent radical superoxide anion in COPD airways. Thirteen stable COPD patients and 10 healthy subjects participated in this study. We collected the epithelial lining fluid using a newly developed microsampling technique, and quantified of cytokines responsible for the XO gene upregulation. The XO activity was significantly increased in COPD patients compared with that in healthy subjects. A significant negative correlation was found between the XO activity and the %FEV1 values. The level of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma in COPD patients was significantly higher than that in healthy subjects. Both the amount of tumor necrosis factor-alpha and interleukin-1beta were significantly correlated with the degree of XO activity. These results suggest that the XO activity is increased in COPD airways, possibly due to its gene upregulation by proinflammatory cytokines. Because the XO activity was significantly correlated with the degree of airway obstruction, these cytokine-XO production pathways may play a key role in the inflammation of COPD.
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PMID:Cytokine-mediated xanthine oxidase upregulation in chronic obstructive pulmonary disease's airways. 1577 13

We previously conducted screening tests of the chloroform extracts from a total of 89 species of Japanese plant food items for their suppressive effects on superoxide (O(2) ()) generation through both NADPH oxidase and xanthine oxidase, and reported that mioga ginger (Zingiber mioga Roscoe) indicated the strongest suppressive activities. In this study, the suppressive effects of mioga ginger constituents, aframodial, and galanal B, together with [6]-gingerol and galanolactone occurring in ginger, on free radical generation and inducible proinflammatory gene expressions were investigated. Of these constituents, aframodial (20 microM) exhibited marked suppressive effects on 12-O-tetradecanoylphorbol-13-acetate-induced O(2) () generation in HL-60 cells and lipopolysaccharide (LPS)/interferon-gamma-induced nitric oxide (NO) generation in RAW264.7 cells (inhibition rates [IRs]=84.6% and 95.9%, respectively). Aframodial also strongly suppressed the stimulated HL-60 cell-induced mutagenicity in AS52 cells (IR=95.9%). The LPS-induced expression of inducible proinflammatory genes such as inducible NO synthase, interleukin (IL)-1beta, IL-6, and granulocyte-macrophage colony-stimulating factor was significantly abolished (IRs=99.1%, 74.6%, 74.0%, and 64.4%, respectively) by aframodial. In addition, degradation of the inhibitor of nuclear factor kappaB was suppressed by this compound (IR=100%), suggesting that the suppression of nuclear factor kappaB activation, at least in part, is involved. Taken together, these results suggest that aframodial has potent antioxidative and anti-inflammatory potentials, and may be a promising candidate in prevention and/or therapy for chronic inflammationassociated carcinogenesis.
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PMID:Suppressive effects of mioga ginger and ginger constituents on reactive oxygen and nitrogen species generation, and the expression of inducible pro-inflammatory genes in macrophages. 1635 25

Much attention has been paid in initial biochemical studies on the ability of indoleamine 2,3-dioxygenase to use superoxide as substrate to cleave tryptophan to N-formyl kynurenine. This ability, however, is limited to the ferric form of the enzyme only, whereas the ferrous form requires oxygen rather than superoxide as substrate. As long as the enzyme is held in the ferrous form, high yield formation of product proceeds from the ferrous oxygen tryptophan ternary complex without the participation of superoxide. Enzyme assays in homogenates are carried out in presence of Methylene Blue, ascorbate and catalase. Ascorbate can be replaced by other reductants like e.g. tetrahydrobiopterin. Experiments with alteration of intracellular tetrahydrobiopterin concentrations in intact interferon-gamma treated cells clearly showed that tetrahydrobiopterin is not required for the indoleamine 2,3-dioxygenase reaction. In homogenates of interferon-gamma treated T-24 cells, substrates of xanthine oxidase did not stimulate the indoleamine 2,3-dioxygenase reaction, nor did allopurinol inhibit the reaction, nor did superoxide dismutase alter indoleamine 2,3-dioxygenase activity irrespective of the reductant used. From these experiments we concluded that molecular oxygen rather than superoxide is used in cell homogenates by indoleamine 2,3-dioxygenase to cleave L-tryptophan. A detailed analysis of available reports on oxygen and superoxide utilization by indoleamine 2,3-dioxygenase gives a comprehensive picture that the enzyme uses oxygen bound to the ferrous enzyme for cleavage of tryptophan, that the enzyme needs to be held by reductants in the ferrous state in enzyme incubations, and that superoxide is one of the reductants capable performing this reduction.
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PMID:Substrate and cofactor requirements of indoleamine 2,3-dioxygenase in interferon-gamma-treated cells: utilization of oxygen rather than superoxide. 1743 Jan 7

The present study aimed to examine the antioxidant properties of Houttuynia cordata (HC) and its protective effect on bleomycin-induced pulmonary fibrosis in rats. Results showed that aqueous extract of HC exhibited a different magnitude of antioxidant activities in all model systems tested. Although HC showed weaker free radical scavenging and xanthine oxidase inhibitory activity than vitamin E, its anti-lipid peroxidation activity in rat liver homogenate was close to that of vitamin E. In animal studies, HC significantly decreased the levels of superoxide dismutase, malondialdehyde, hydroxyproline, interferon-gamma, and tumor necrosis factor-alpha. However, an increase in the concentration of catalase was noted in the bronchoalveolar lavage fluid. HC also remarkably improved the morphological appearance of the lung of bleomycin-treated rats. These results suggest that HC possesses a protective effect against bleomycin-induced pulmonary fibrosis. Interestingly, this protective effect was more pronounced than that of vitamin E. In conclusion, the protective effect of HC on pulmonary fibrosis could be partly associated with the reduction of oxidative damage caused by bleomycin.
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PMID:Protective effect of Houttuynia cordata extract on bleomycin-induced pulmonary fibrosis in rats. 1759 5

The heme protein indoleamine 2,3-dioxygenase (IDO) initiates oxidative metabolism of tryptophan along the kynurenine pathway, and this requires reductive activation of Fe(3+)-IDO. The current dogma is that superoxide anion radical (O(2)(*-)) is responsible for this activation, based largely on previous work employing purified rabbit IDO and rabbit enterocytes. We have re-investigated this role of O(2)(*-) using purified recombinant human IDO (rhIDO), rabbit enterocytes that constitutively express IDO, human endothelial cells, and monocyte-derived macrophages treated with interferon-gamma to induce IDO expression, and two cell lines transfected with the human IDO gene. Both potassium superoxide and O(2)(*-) generated by xanthine oxidase modestly activated rhIDO, in reactions that were prevented completely by superoxide dismutase (SOD). In contrast, SOD mimetics had no effect on IDO activity in enterocytes and interferon-gamma-treated human cells, despite significantly decreasing cellular O(2)(*-) Similarly, cellular IDO activity was unaffected by increasing SOD activity via co-expression of Cu,Zn-SOD or by increasing cellular O(2)(*-) via treatment of cells with menadione. Other reductants, such as tetrahydrobiopterin, ascorbate, and cytochrome P450 reductase, were ineffective in activating cellular IDO. However, recombinant human cytochrome b(5) plus cytochrome P450 reductase and NADPH reduced Fe(3+)-IDO to Fe(2+)-IDO and activated rhIDO in a reconstituted system, a reaction inhibited marginally by SOD. Additionally, short interfering RNA-mediated knockdown of microsomal cytochrome b(5) significantly decreased IDO activity in IDO-transfected cells. Together, our data show that cytochrome b(5) rather than O(2)(*-) plays a major role in the activation of IDO in human cells.
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PMID:Cytochrome b5, not superoxide anion radical, is a major reductant of indoleamine 2,3-dioxygenase in human cells. 1829 24


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