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: UNIPROT:P47989 (xanthine oxidase)
8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The signalling mechanisms in oxidative stress mediated by cytokines in the perinatal alveolar epithelium are not well known. In an in vitro model of fetal alveolar type II epithelial cells, we investigated the profile of cytokines in response to ascending Deltap O(2)regimen (oxyexcitation). The peak of TNF-alpha (4 h) preceded IL-1beta and IL-6 (6-9 h), indicating a positive feedback autocrine loop confirmed by exogenous rmTNF-alpha. Reactive oxygen species (ROS) induced a dose-dependent release of cytokines, an effect specifically obliterated by selective antioxidants of the hydroxyl radical (*OH) and superoxide anion (O(2)-). Actinomycin and cycloheximide blocked the induced production of cytokines, implicating transcriptional and translational control. Whilst the dismutating enzymes superoxide dismutase (SOD) and catalase were ineffective in reducing ROS-induced cytokines, MnP, a cell-permeating SOD mimetic, abrogated xanthine/xanthine oxidase-dependent cytokine release. Desferrioxamine mesylate, which inhibits the iron-catalysed generation of *OH via the Fenton reaction, exhibited a mild effect on the release of cytokines. Dynamic variation in alveolar p O(2)constitutes a potential signalling mechanism within the perinatal lung allowing upregulation of cytokines in an ROS-dependent manner.
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PMID:Chemioxyexcitation (delta pO2/ROS)-dependent release of IL-1 beta, IL-6 and TNF-alpha: evidence of cytokines as oxygen-sensitive mediators in the alveolar epithelium. 1116 56

During sepsis the host's system-wide response to microbial invasion seems dysregulated. Here we explore the diverse multiorgan transcriptional programs activated during systemic inflammation in a cecal ligation/puncture model of sepsis in rats. Using DNA microarrays representing 7398 genes, we examined the temporal sequence of sepsis-induced gene expression patterns in major organ systems including lung, liver, kidney, thymus, spleen, and brain. Although genes known to be associated with systemic inflammation were identified by our global transcript analysis, many genes and expressed sequence tags not previously linked to the septic response were also elucidated. Taken together, our results suggest activation of a highly complex transcriptional response in individual organs of the septic animal. Several overlying themes emerged from our genome-scale analysis that includes 1) the sepsis response elicited gene expression profiles that were either organ-specific, common to more than one organ, or distinctly opposite in some organs; 2) the brain is protected from sepsis-induced gene activation relative to other organs; 3) the thymus and spleen have an interesting cohort of genes with opposing gene expression patterns; 4) genes with proinflammatory effects were often balanced by genes with anti-inflammatory effects (eg, interleukin-1beta/decoy receptor, xanthine oxidase/superoxide dismutase, Ca2+-dependent PLA2/Ca2+-independent PLA2); and 5) differential gene expression was observed in proteins responsible for preventing tissue injury and promoting homeostasis including anti-proteases (TIMP-1, Cpi-26), oxidant neutralizing enzymes (metallothionein), cytokine decoy receptors (interleukin-1RII), and tissue/vascular permeability factors (aquaporin 5, vascular endothelial growth factor). This global perspective of the sepsis response should provide a molecular framework for future research into the pathophysiology of systemic inflammation. Understanding, on a genome scale, how an organism responds to infection, may facilitate the development of enhanced detection and treatment modalities for sepsis.
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PMID:Molecular signatures of sepsis: multiorgan gene expression profiles of systemic inflammation. 1158 46

Reactive oxygen species are considered important regulators in the pathogenesis and in the development of pancreatitis. The transcription factor nuclear factor kappaB (NF-kappaB) is activated by reactive oxygen species and regulates the gene expressions of inflammatory cytokines. The present study investigates (1) the susceptibility of isolated rat pancreatic acinar cells to oxidant attacks produced by adenosine diphosphate/ferrous iron, hypoxanthine/xanthine oxidase, and neutrophils primed with 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA) and (2) the potential of small-molecule antioxidants (N-acetylcysteine, beta-carotene, rebamipide, allopurinol) and superoxide dismutase (SOD) to prevent such injury and oxidant-mediated NF-kappaB activation and inflammatory cytokine production in the cells. As a result, oxidative stress resulted in a time-dependent increase in lipid peroxide production in pancreatic acinar cells which was inhibited by small-molecule antioxidants and SOD. PMA-primed neutrophils induced NF-kappaB activation and increased the production of cytokines (IL-6, TNF-alpha) in the cells. This was in parallel with lipid peroxide production. Small-molecule antioxidants and SOD inhibited NF-kappaB activation and cytokine production in acinar cells caused by PMA-primed neutrophils. In conclusion, oxidative stress activates NF-kappaB, resulting in upregulation of inflammatory cytokines in pancreatic acinar cells. Small-molecule antioxidants might be clinically useful anti-inflammatory agents by inhibiting oxidant-induced cytokine production.
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PMID:Oxidative stress induced cytokine production in isolated rat pancreatic acinar cells: effects of small-molecule antioxidants. 1180 45

Endothelial cells increase their secretion of the cytokine interleukin-6 (IL-6) during hypoxia, which then acts in an autocrine fashion to increase the permeability of cell monolayers. These responses are attenuated by antioxidants, suggesting that reactive oxygen species (ROS) participate in signaling in hypoxic endothelium. We tested whether mitochondria are responsible for these ROS in human umbilical vein endothelial cells exposed to hypoxia. Oxidation of the probe 2', 7'-dichlorodihydrofluorescein to fluorescent dichlorofluorescein or the probe dihydroethidium was used to assess oxidant signaling, whereas permeability was assessed by using transendothelial electrical resistance. Hypoxia elicited increases in dichlorofluorescein and dihydroethidium fluorescence that were abrogated by the mitochondrial electron transport (ET) inhibitors rotenone (2 micromol/L) and diphenyleneiodonium (5 micromol/L). The same ET inhibitors also attenuated hypoxia-induced increases in nuclear factor-kappaB (NF-kappaB) activation, although they did not abrogate NF-kappaB activation in response to endotoxin (lipopolysaccharide). ET inhibition also abolished the hypoxia-induced increases in IL-6 mRNA expression, hypoxia-stimulated IL-6 secretion into the media, and the hypoxia-induced increases in transendothelial electrical resistance of human umbilical vein endothelial cell monolayers. By contrast, the above responses to hypoxia were not significantly affected by treatment with the NAD(P)H oxidase inhibitor apocynin (30 micromol/L), the xanthine oxidase inhibitor allopurinol (100 micromol/L), or the NO synthase inhibitor N-nitro-L-arginine (100 micromol/L). We conclude that ROS signals originating from the mitochondrial ET chain trigger the increase in NF-kappaB activation, the transcriptional activation of IL-6, the secretion of IL-6 into the cell culture media, and the increases in endothelial permeability observed during hypoxia.
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PMID:Role of mitochondrial oxidant generation in endothelial cell responses to hypoxia. 1195 Jun 85

Interleukin (IL)-10, an anti-inflammatory cytokine, preserves endothelial function during acute inflammation. We tested the hypotheses that IL-10 plays a protective role in blood vessels during diabetes by suppressing impairment of endothelium-dependent relaxation and that protection by IL-10 is mediated by effects on superoxide (O(2-)). Streptozotocin (150 mg/kg i.p.) or citrate buffer was injected into IL-10-deficient (IL-10(-/-)) mice and wild-type controls (IL-10(+/+)). In IL-10(+/+) and IL-10(-/-) mice, blood glucose levels were approximately 120 mg/dl after citrate administration and approximately 400 mg/dl after streptozotocin administration. Vasorelaxation was examined in arteries in vitro 12-16 weeks later. Maximum relaxation to acetylcholine (30 micromol/l) was 88 +/- 3% (means +/- SE) in nondiabetic mice and 84 +/- 3% in diabetic IL-10(+ /+) mice (P > 0.05). Thus, at this time point, diabetes did not impair endothelium-dependent relaxation in vessels in wild-type mice. In contrast, maximum relaxation in vessels from diabetic IL-10(-/-) mice was significantly decreased (74 +/- 5%) compared with nondiabetic IL-10(-/-) mice (93 +/- 2%, P < 0.05). Superoxide dismutase with polyethylene glycol (PEG-SOD) restored impaired responses to acetylcholine to levels seen in controls. Responses to acetylcholine also were improved by allopurinol (an inhibitor of xanthine oxidase) in vessels from diabetic IL-10(- /-) mice. Thus, diabetes produces greater impairment of relaxation to acetylcholine in IL-10(-/-) mice than in IL-10(+/ +) mice. These findings provide direct evidence that IL-10 impedes mechanisms of endothelial dysfunction during diabetes. Restoration of vasorelaxation with PEG-SOD or allopurinol suggests that the mechanism(s) by which IL-10 preserves endothelium-dependent vasorelaxation involves O(2-), perhaps by reducing production of O(2-) by xanthine oxidase.
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PMID:Interleukin-10 protects nitric oxide-dependent relaxation during diabetes: role of superoxide. 1203 83

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) have been implicated as mediators of osteoclastic bone resorption. Xanthine oxidase (XO) a ubiquitous enzyme is widely known for its production of these ROS. We therefore evaluated the potential of XO as a source of ROS in cytokine-and hormone-induced bone resorption. XO activity in rat calvarial osteoblasts was found to be significantly elevated upon stimulation by the cytokines, TNFalpha and IL-1beta. These cytokines also caused a dose related increase in bone resorption of mouse calvariae, which was significantly inhibited by catalase (10 IU/ml). Allopurinol, the competitive inhibitor of XO, also caused a dose related (1-50 microM) inhibition of TNFalpha (20 ng/ml) and (0.01-10 microM) IL-1beta (50 IU/ml)-induced bone resorption, respectively. PTH- and 1,25-(OH)2 Vitamin D3-induced bone resorption could also be inhibited by catalase (100 IU/ml) but was unaffected by allopurinol, indicating that another mediator, other than XO, is required for hormone-induced bone resorption. These results demonstrate, that modulation of the redox balance in the bone microenvironment, which contains XO, can affect the bone resorbing process. Therefore, XO may play a pivotal role in cytokine-induced bone resorption and, if manipulated appropriately, could show a therapeutic benefit in inflammatory bone disorders such as RA.
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PMID:Xanthine oxidase mediates cytokine-induced, but not hormone-induced bone resorption. 1265 6

Many harmful effects of nitric oxide are caused by the reaction of NO with superoxide anion. The present study was carried out to find out the concomitant production of superoxide and to investigate a suitable inhibitor of NO, which is produced by iNOS. THP-1 cells were differentiated into macrophages by PMA and cytokine. Addition of L-NAME showed decrement in superoxide production. Addition of apocynin, aminoguanidine or ONO 1714 brought about a significant reduction in superoxide production. The expressions of p67 and p47(phox) were reduced by the addition of apocynin, aminoguanidine or ONO 1714 whereas xanthine oxidase and cyclooxygenase did not have a major role in superoxide production. The results of the present study show that iNOS and NADPH oxidase play an important role in superoxide release. It suggests that addition of iNOS inhibitor together with apocynin may be more effective in case of therapeutic application in disease conditions like atherosclerosis.
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PMID:Concomitant production of nitric oxide and superoxide in human macrophages. 1452 19

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

In order to develop new anti-photoaging agents, we examined the antioxidative activity and the inhibition effect of matrix metalloproteinase-1 (MMP-1) on the extracts of a marine product, Zostera marina L., which is known for its potent activity. Three compounds (compounds 1, 2, and 3) were isolated from an ethyl acetate (EtOAc) soluble fraction of the product; they were identified as apigenin-7-O-beta-D-glucoside (1), chrysoeriol (2), and luteolin (3). These compounds were found to scavenge radicals and reactive oxygen species (ROS) and were measured to have SC50 values of 0.18 mM, 0.68 mM, and 0.01 mM against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and 0.04 mM, 0.03 mM, and 0.01 mM against the superoxide radical in the xanthine/xanthine oxidase system, respectively. Compound 3 suppressed the expression of MMP-1 by up to 44% at 4.0 microM and inhibited the production of interleukin 6 (IL-6), which is known as a cytokine that induces MMP-1 expression. From these results, compound 3 and the other compounds were determined to have antioxidative activity and to inhibit MMP-1 expression. Thus, the three compounds are expected to be useful for preventing the photoaging of skin.
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PMID:Antioxidants and inhibitor of matrix metalloproteinase-1 expression from leaves of Zostera marina L. 1502 19

Transactivation of the DNA-binding proteins nuclear factor-kappa B (NF-kappa B) and activator protein (AP)-1 by de novo oxyradical generation is a stereotypic redox-sensitive process during hypoxic stress of the liver. Systemic trauma is associated with splanchnic hypoxia-reoxygenation (H/R) followed by intraportal gram-negative bacteremia, which collectively have been implicated in posttraumatic liver dysfunction and multiple organ damage. We hypothesized that hypoxic stress of the liver before stimulation by Escherichia coli serotype O55:B5 (EC) amplifies oxyradical-mediated transactivation of NF-kappa B and AP-1 as well as cytokine production compared with noninfectious H/R or gram-negative sepsis without prior hypoxia. Livers from Sprague-Dawley rats underwent perfusion for 180 min with or without 0.5 h of hypoxia (perfusate PO(2), 40 +/- 5 mmHg) followed by reoxygenation and infection with 10(9) EC or 0.9% NaCl infusion. In H/R + EC livers, nuclear translocation of NF-kappa B and AP-1 was unexpectedly reduced in gel shift assays vs. normoxic EC controls, as were perfusate TNF-alpha and IL-1 beta levels. Preceding hypoxic stress paradoxically increased postbacteremic reduced-to-oxidized glutathione ratios plus nuclear localization of I kappa B alpha and phospho-I kappa B alpha, but not JunB/FosB profiles. Notably, xanthine oxidase inhibition increased transactivation as well as cytokine production in H/R + EC livers. Thus brief hypoxic stress of the liver before intraportal gram-negative bacteremia potently suppresses activation of canonical redox-sensitive transcription factors and production of inflammatory cytokines by mechanisms including xanthine oxidase-induced oxyradicals functioning in an anti-inflammatory signaling role. These results suggest a novel multifunctionality of oxyradicals in decoupling hepatic transcriptional activity and cytokine biosynthesis early in the posttraumatic milieu.
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PMID:Hypoxic suppression of E. coli-induced NF-kappa B and AP-1 transactivation by oxyradical signaling. 1505 91


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