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)

Accumulating evidence suggests that changes in both 5-hydroxytryptamine (5-HT) receptor activity and in the levels of reactive oxygen species (ROS) play an important role in regulating pulmonary artery (PA) vascular responsiveness, particularly in the setting of pulmonary hypertension. Therefore, we hypothesized that increased levels of superoxide enhance 5-HT-induced PA constriction. With the use of a small-vessel bioassay, 5-HT (0.01-10 microM) induced a concentration-dependent vasoconstriction in isolated wild-type murine intrapulmonary arteries (100-150 microm diameter) that was enhanced by both removal of the endothelium and by treatment with either N(G)-nitro-L-arginine methyl ester (30 microM) or xanthine (10 microM) + xanthine oxidase (0.005 U/ml). PA isolated from extracellular superoxide dismutase (EC-SOD) knockout mice also showed enhanced constriction. On the other hand, PA constriction to 5-HT was attenuated by either the addition of GR-127935 (0.1 microM, a selective inhibitor of 5-HT(1B/1D) receptor) or copper/zinc-containing superoxide dismutase (Cu/Zn SOD, 150 U/ml) and in PA isolated from transgenic mice overexpressing human EC-SOD. With the use of both oxidative fluorescent confocal microscopy and lucigenin-enhanced chemiluminescence, superoxide levels were increased significantly after 5-HT-induced PA vasoconstriction. This increase in superoxide levels could be blocked by the exogenous addition of Cu/Zn SOD (150 U/ml) or by apocynin (30 microM, an inhibitor of NADPH oxidase) but was not affected by gp91(phox) knockout mice. Overall, our results are consistent with 5-HT increasing vascular smooth muscle superoxide production via an NADPH oxidase pathway that is independent of gp91(phox), which leads to increases in extracellular superoxide levels, which in turn enhances 5-HT-induced murine pulmonary vasoconstriction.
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PMID:Extracellular superoxide enhances 5-HT-induced murine pulmonary artery vasoconstriction. 1502 Feb 94

Carboplatin, a second-generation platinum-containing anti-cancer drug, is currently being used against human cancers. High-dose carboplatin chemotherapy can cause renal tubular injury in cancer patients. We have shown a dose-dependent nephrotoxicity of carboplatin in a rat model. However, the time response of carboplatin-induced renal injury has not been explored. This study investigated the time response of carboplatin-induced nephrotoxicity in rat. Male Wistar rats (250-300 g) were divided into two groups of 30 animals each and treated as follows: (1) control (saline, intraperitoneally) and (2) carboplatin (256 mg kg(-1), intraperitoneally). The animals (n = 6) from each group were sacrificed 1-5 days after treatment. The blood and kidneys were isolated and analyzed. Plasma creatinine, blood urea nitrogen (BUN), and blood urea levels were increased significantly in response to carboplatin in a time-dependent manner, indicating potential nephrotoxicity. Carboplatin time-dependently increased the renal platinum concentration, renal xanthine oxidase activity, increased membrane lipid peroxidation (MDA) concentration, while ratio of reduced-to-oxidized glutathione (GSH/GSSG) depleted significantly, indicating oxidative renal injury. Renal anti-oxidant enzymes, such as cytosolic copper/zinc-superoxide dismutase (CuZn-SOD) and mitochondrial manganese (Mn)-SOD, catalase (CAT), and glutathione peroxidase (GSH-Px) activities were decreased significantly due to carboplatin 3-5 days post-treatment. The protein expressions of renal CuZn-SOD and Mn-SOD significantly depleted 3-5 days after carboplatin administration, indicating decline in de novo synthesis of enzyme proteins. The data suggested that carboplatin caused time-dependent oxidative renal injury, as evidenced by renal anti-oxidant depletion, enhanced lipid peroxidation, platinum content, plasma creatinine BUN, and blood urea levels in rats.
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PMID:Time response of carboplatin-induced nephrotoxicity in rats. 1522 73

Curcumin (diferuloylmethane) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animal models. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase; and an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF(Epidermal growth factor)-receptor tyrosine kinase and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF(nucleor factor)kappaB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs and iNOS. It is proposed that curcumin may suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, while the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin and that these compounds subsequently were converted to monoglucuronide conjugates. These results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are the major metabolites of curcumin in mice, rats and humans.
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PMID:Suppression of protein kinase C and nuclear oncogene expression as possible action mechanisms of cancer chemoprevention by Curcumin. 1535 94

Two new compounds, sodium N-(6, '8-dimercaptooctanoyl)-2-amino ethanesulfonate- and sodium N-(6, 8-dimercaptooctanoyl)-L-aspartate - zinc complex were synthesized from alpha-lipoyl-2-aminoethanesulfonate and alpha-lipoyl-L- aspartate by reduction of zinc/acetic acid respectively. These alpha-lipoyl-amino acids were obtained by a coupling of alpha-lipoic acid and 2-aminoethanesulfonate or L-aspartate, using a mixed anhydride method. Scavenging activities of these derivatives against hydroxyl radicals (*OH) was demonstrated directly using electron spin resonance (ESR) spectrometry with spin trapping. Otherwise an apparent superoxide anion radical (O2*-) scavenging effect of these derivatives may be due to the inhibition of 02*- generation system, i.e., xanthine oxidase. Scavenging activities of these compounds against nitric oxide radicals (NO*), and peroxynitrite (ONOO-) were estimated by the flow injection analysis using the Griess reagent and by a fluorescence spectrometry using dihydrorhodamine 123 respectively. Meanwhile, these derivatives showed protective effects against lipid peroxidation and protein carbonyl formation. Scavenging activities against NO* and ONOO-, and inhibitory effects on protein carbonyl formation of these derivatives were much stronger than these of alpha-lipoic acid itself.
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PMID:Antioxidant activities of novel alpha-lipoic acid derivatives: N-(6, 8-dimercaptooctanoyl)-2-aminoethanesulfonate- and N-(6, 8-dimercaptooctanoyl)-L-aspartate-zinc complex. 1568 13

Physiological medium constitutes a crowded environment that serves as the field of action for protein-protein interaction in vivo. Measuring protein-protein interaction in crowded solutions can mimic this environment. Here we report the application of fluorescence spectroscopy and resonant mirror biosensor to investigate the interactions of bovine milk xanthine oxidase and bovine erythrocyte copper, zinc-superoxide dismutase in crowded solutions. Four nonspecific high molecular mass crowding agents, poly(ethylene glycol) 2000 and 20,000, Ficoll 70, and dextran 70, and one low molecular mass compound, glycerol, are used. Superoxide dismutase shows a strong and macromolecular crowding agent concentration-dependent binding affinity to xanthine oxidase. Addition of high concentrations of such high molecular mass crowding agents increases the binding constant remarkably and thus stabilizes superoxide dismutase activity, compared to those in the absence of crowding agents. In contrast, glycerol has little effect on the binding constant and decreases superoxide dismutase activity over the same concentration range. Such a pattern suggests that the enhancing effects of polymers and polysaccharides on the binding are due to macromolecular crowding. Taken together, these results indicate that macromolecular crowding enhances the binding of superoxide dismutase to xanthine oxidase and is favorable to the function of superoxide dismutase.
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PMID:Macromolecular crowding enhances the binding of superoxide dismutase to xanthine oxidase: implications for protein-protein interactions in intracellular environments. 1685 7

Cyclooxygenase-2 (COX-2) expression is induced in the neurons of the pathologic brain and elevated COX-2 expressions can lead to neuronal death. Here, we report that COX-2 induction in cortical neurons induced by LPS pretreatment for more than 12 h increased the neurotoxic effects of low doses of Fe2+ by more than 2.5-fold. Moreover, the neurotoxicity induced by 30 muM Fe2+ in LPS-pretreated cells exceeded that induced by 100 microM Fe2+ in LPS-untreated cells. LPS pretreatment also similarly aggravated the neurotoxic effects of low doses of H2O2, Zn2+, and sodium nitroprusside. This LPS-induced Fe2+ -toxicity enhancement was blocked by trolox, vitamin C, the SOD mimetic MnTBAP, and by the COX-2-specific inhibitor NS398, but not by inhibitors of xanthine oxidase, NADPH oxidase, NOS, and monoamine oxidase. Cortical neurons with enhanced COX-2 expression showed superoxide generation, GSH depletion, and lipid peroxidation in response to low doses of Fe2+, and all of these changes were repressed by MnTBAP or NS398. Consistent with this pharmacological data, cortical neurons prepared from COX-2 knockout mice showed marked reductions in LPS-induced Fe2+ -toxicity enhancement and superoxide generation. These results suggest that COX-2 functions as a cellular factor which induces superoxide-mediated cell death in primary cortical neurons.
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PMID:Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation. 1693 79

Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive-oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase, and inducible nitric oxide synthase (iNOS); it is an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF-receptor tyrosine kinase, and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF-KB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs, and iNOS. It is considered that PKC, mTOR, and EGFR tyrosine kinase are the major upstream molecular targest for curcumin intervention, whereas the nuclear oncogenes such as c-jun, c-fos, c-myc, CDKs, FAS, and iNOS might act as downstream molecular targets for curcumin actions. It is proposed that curcumin might suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, whereas the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes, including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of the ubiquitin-proteasome pathway.
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PMID:Molecular targets of curcumin. 1756 14

Reactive oxygen species (ROS), such as superoxide anion radicals (O.-2) and hydrogen peroxide (H2O2) are potentially harmful by-products of normal cellular metabolism that directly affect cellular functions. ROS is generated by all aerobic organisms and it seems to be indispensable for signal transduction pathways that regulate cell growth and reduction-oxidation (redox) status. However, overproduction of these highly reactive oxygen metabolites can initiate lethal chain reactions, which involve oxidation and damage to structures that are crucial for cellular integrity and survival. In fact, many antitumor agents, such as vinblastine, cisplatin, mitomycin C, doxorubicin, camptothecin, inostamycin, neocarzinostatin and many others exhibit antitumor activity via ROS-dependent activation of apoptotic cell death, suggesting potential use of ROS as an antitumor principle. Thus, a unique anticancer strategy named "oxidation therapy" has been developed by inducing cytotoxic oxystress for cancer treatment. This goal could be achieved mainly by two methods, namely, (i) inducing the generation of ROS directly to solid tumors and (ii) inhibiting the antioxidative enzyme (defense) system of tumor cells. Since 1950s, many strategies have been employed based on the first method, namely, administration of ROS per se (e.g. H2O2) or ROS generating enzyme to tumor bearing animals. However no successful and practical results were obtained probably because of the lack of tumor selective ROS delivery and hence resulting in subsequent induction of severe side effects. To overcome these obstacles, we developed polyethylene glycol (PEG) conjugated O.-2 or H2O2-generating enzymes, xanthine oxidase (XO) and D-amino acid oxidase (DAO) (PEG-DAO) respectively. More recently, a pegylated (PEG) zinc protoporphyrin (PEG-ZnPP) and a highly water soluble micellar formulation of ZnPP based on amphiphilic styrene maleic acid (SMA) copolymer, SMA-ZnPP, are prepared, which are potent inhibitors of heme oxygenase-1 (HO-1). HO-1 is a major antioxidative enzyme of tumors, that is different in mechanism of catalase or superoxide dismutase (SOD). Consequently, both PEG-enzymes and PEG-ZnPP exhibited superior in vivo pharmacokinetics than their parental molecules, particularly in tumor delivery by taking advantage of the EPR effect of macromolecular nature, and thus showed remarkable antitumor effects suggesting the potentials of this anticancer therapeutic for clinical application. Furthermore, it has been well known that many antioxidative enzymes such as catalase, SOD are down-regulated in most solid tumors in vivo. On the contrary, HO-1 is highly upregulated and it plays a very important role of antioxidation, because HO-1 generates biliverdin, which being converted to bilirubin exhibits a very potent antioxidative effect, and hence antiapoptosis in tumors. Thus this oxidation therapy, by inhibiting this HO-1 dependent antioxidant (bilirubin) formation by ZnPP, and by enhancing ROS generation, is expected to offer a powerful therapeutic modality for future anticancer therapy.
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PMID:Tumor-targeted induction of oxystress for cancer therapy. 1767 94

In this study, we have used the PC12 cell model to elucidate the mechanisms by which sublethal doses of oxidants induce neuritogenesis. The xanthine/xanthine oxidase (X/XO) system was used for the steady state generation of superoxide, and CoCl(2) was used as a representative transition metal redox catalyst. Upon treatment of purified protein kinase C (PKC) with these oxidants, there was an increase in its cofactor-independent activation. Redox-active cobalt competed with the redoxinert zinc present in the zinc-thiolates of the PKC regulatory domain and induced the oxidation of these cysteine-rich regions. Both CoCl(2) and X/XO induced neurite outgrowth in PC12 cells, as determined by an overexpression of neuronal marker genes. Furthermore, these oxidants induced a translocation of PKC from cytosol to membrane and subsequent conversion of PKC to a cofactor-independent form. Isoenzyme-specific PKC inhibitors demonstrated that PKCepsilon plays a crucial role in neuritogenesis. Moreover, oxidant-induced neurite outgrowth was increased with a conditional overexpression of PKCepsilon and decreased with its knock-out by small interfering RNA. Parallel with PKC activation, an increase in phosphorylation of the growth-associated neuronal protein GAP-43 at Ser(41) was observed. Additionally, there was a sustained activation of extracellular signal-regulated kinases 1 and 2, which was correlated with activating phosphorylation (Ser(133)) of cAMP-responsive element-binding protein. All of these signaling events that are causally linked to neuritogenesis were blocked by antioxidant N-acetylcysteine (both L and D-forms) and by a variety of PKC-specific inhibitors. Taken together, these results strongly suggest that sublethal doses of oxidants induce neuritogenesis via a direct redox activation of PKCepsilon.
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PMID:A direct redox regulation of protein kinase C isoenzymes mediates oxidant-induced neuritogenesis in PC12 cells. 1837 50

To synthesize aristolochic acid (AA)-2'-deoxyguanosine 5'-monophosphate (dGp) adducts in vitro and develop a novel method for the characterization of the adducts using multiple mass spectrometric techniques. AA was incubated with dGp in vitro using either enzymatic activation (by xanthine oxidase) or chemical activation (by zinc) to synthesize AA-dGp adducts, and the reaction conditions were optimized. Crude extracts were analyzed by techniques of liquid chromatography-electrospray ionization/tandem mass spectrometry (LC-MS/MS) and high accuracy mass data and isotope pattern of super high resolution Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICRMS). The quasi-molecular ion peaks of the AA-dGp adducts were obtained in the negative ion mode. Analysis by electrospray ionization/tandem mass spectrometry (ESI-MS/MS) provided useful structural information about AA-dGp adducts. AA can bind covalently to the exocyclic amino group of deoxyguanosine to form AA-dGp adducts. MS analysis is a powerful tool to detect and identify AA-dGp adducts simply, rapidly and accurately.
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PMID:[Synthesis and mass spectrometric analysis of aristolochic acid-deoxyguanosine adducts]. 1863 Feb 67


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