Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Shichimotsu-koka-to (SKT) has been prescribed to treat patients with essential and renal hypertension. We investigated the effects of SKT on renal lesions in stroke-prone spontaneously hypertensive rats (SHRSPs). SHRSPs were given an extract of SKT by mixing it with drinking water, from 8 through 29 weeks of age, so that the average intake of SKT extract was about 1.5 g/kg/d. At 29 weeks of age, the kidneys of SHRSPs exhibited proliferative arteritis characterized by the proliferation of smooth muscle cells in the interlobular arteries, dilation and degeneration of renal tubules, infiltration of inflammatory cells and hemorrhage, with partial swelling or necrotizing of glomeruli. In particular, arteritis and periarteritis were noted. The treatment of SHRSPs with SKT ameliorated this morphological damage in the kidney and significantly decreased urea nitrogen in the serum. Treatment with SKT also strongly decreased the xanthine oxidase (XOD) activity and significantly increased the superoxide dismutase (SOD) activity in the kidney of SHRSPs; consequently, these values became close to those in normotensive Wistar Kyoto rats (WKYs). These results indicate that treatment with SKT ameliorated the histopathological damage and change in activity of enzymes related to free radicals in the kidney of SHRSPs, which may be important mechanisms for SKT for protecting SHRSPs from renal dysfunction.
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PMID:Preventive effects of Shichimotsu-koka-to on renal lesions in stroke-prone spontaneously hypertensive rats. 978 38

Oxidation by rat liver microsomes of 13 compounds involving a C=N(OH) function (including N-hydroxyguanidines, amidoximes, ketoximes, and aldoximes) was found to occur with the release of nitrogen oxides such as NO, NO2-, and NO3-. The greatest activities were observed with liver microsomes from dexamethasone-treated rats (up to 8 nmol of NO2- nmol of P450(-)1 min-1). A detailed study of the microsomal oxidation of some of these compounds was performed. Oxidation of N-(4-chlorophenyl)-N'-hydroxy-guanidine led to the formation of the corresponding urea and cyanamide in addition to NO, NO2-, and NO3-. Formation of all these products was dependent on NADPH, O2, and cytochromes P450. Oxidation of two arylamidoximes was found to occur with formation of the corresponding amides and nitriles in addition to nitrogen oxides. Oxidation of 4-(chlorophenyl)methyl ketone oxime gave the corresponding ketone and nitroalkane as well as NO, NO2-, and NO3-. These reactions were also dependent on cytochromes P450 and required NADPH and O2. Mechanistic experiments showed that microsomal oxidations of amidoximes to the corresponding nitriles and of ketoximes to the corresponding nitroalkanes are not inhibited by superoxide dismutase (SOD) and are performed by a cytochrome P450 active species, presumably the high-valent P450-iron-oxo complex. On the contrary, microsomal oxidation of N-hydroxyguanidines to the corresponding cyanamides was greatly inhibited by SOD and appeared to be mainly due to O2*- derived from the oxidase function of cytochromes P450. Similarly, microsomal oxidations of N-hydroxyguanidines and amidoximes to the corresponding ureas and amides were also found to be mainly performed by O2*-, as shown by the great inhibitory effect of SOD (70-100%) and the ability of the xanthine-xanthine oxidase system to give similar oxidation products. However, it is noteworthy that other species, such as the P450 Fe(II)-O2 complex, are also involved, to a minor extent, in the SOD-insensitive microsomal oxidative cleavages of compounds containing a C=N(OH) bond. Our results suggest a general mechanism for such oxidative cleavages of C=N(OH) bonds with formation of nitrogen oxides by cytochromes P450 and NO-synthases, with the involvement of O2*- and its Fe(III) complex [(FeIII-O2-) or (FeII-O2)] as main active species.
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PMID:Microsomal cytochrome P450 dependent oxidation of N-hydroxyguanidines, amidoximes, and ketoximes: mechanism of the oxidative cleavage of their C=N(OH) bond with formation of nitrogen oxides. 986 Aug 31

Reactions of linoleate (and presumably other unsaturated fatty acids) with reactive nitrogen species that form in biological systems from secondary reactions of .NO yield two main nitration product groups, LNO2 (formed by ONOO-, .NO2, or NO2+ reaction with linoleate), and LONO2 (formed by HONO reaction with 13(S)-HPODE, or .NO termination with LOO.). Comparison of HPLC retention times and m/z for lipid nitration products indicate that the mechanisms of nitrated product formation converge at several points: (i) The initial product of HONO attack on LOOH will be LOONO, which is identical to the initial termination product of LOO. reaction with .NO. (ii) Dissociation of LOONO to give LO. and .NO2 via caged radicals, which recombine to give LONO2 (m/z 340) will occur, regardless of how LOONO is formed (Fig. 7). (iii) In some experiments, the reaction of O2- (where oxidation is initiated by xanthine oxidase-derived O2- production and metal-dependent decomposition of H2O2) with .NO will result in generation of ONOO-. Nitration of unsaturated lipid by this species will yield a species demonstrated herein to be LNO2. Lipid oxidation leads to formation of bioactive products, including hydroxides, hydroperoxides, and isoprostanes. In vivo, nitrated lipids (LNO2, LONO2) may also possess bioactivity, for example through eicosanoid receptor binding activity, or by acting as antagonists/competitive inhibitors of eicosanoid receptor-ligand interactions. In addition, nitrated lipids could mediate signal transduction via direct .NO donation, transnitrosation, or following reductive metabolism. Similar bioactive products are formed following ONOO- reaction with glucose, glycerol, and other biomolecules.
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PMID:Nitration of unsaturated fatty acids by nitric oxide-derived reactive species. 991 94

Brain ischemia initiates a complex cascade of metabolic events, several of which involve the generation of nitrogen and oxygen free radicals. These free radicals and related reactive chemical species mediate much of damage that occurs after transient brain ischemia, and in the penumbral region of infarcts caused by permanent ischemia. Nitric oxide, a water- and lipid-soluble free radical, is generated by the action of nitric oxide synthases. Ischemia causes a surge in nitric oxide synthase 1 (NOS 1) activity in neurons and, possibly, glia, increased NOS 3 activity in vascular endothelium, and later an increase in NOS 2 activity in a range of cells including infiltrating neutrophils and macrophages, activated microglia and astrocytes. The effects of ischemia on the activity of NOS 1, a Ca2+-dependent enzyme, are thought to be secondary to reversal of glutamate reuptake at synapses, activation of NMDA receptors, and resulting elevation of intracellular Ca2+. The up-regulation of NOS 2 activity is mediated by transcriptional inducers. In the context of brain ischemia, the activity of NOS 1 and NOS 2 is broadly deleterious, and their inhibition or inactivation is neuroprotective. However, the production of nitric oxide in blood vessels by NOS 3, which, like NOS 1, is Ca2+-dependent, causes vasodilatation and improves blood flow in the penumbral region of brain infarcts. In addition to causing the synthesis of nitric oxide, brain ischemia leads to the generation of superoxide, through the action of nitric oxide synthases, xanthine oxidase, leakage from the mitochondrial electron transport chain, and other mechanisms. Nitric oxide and superoxide are themselves highly reactive but can also combine to form a highly toxic anion, peroxynitrite. The toxicity of the free radicals and peroxynitrite results from their modification of macromolecules, especially DNA, and from the resulting induction of apoptotic and necrotic pathways. The mode of cell death that prevails probably depends on the severity and precise nature of the ischemic injury. Recent studies have emphasized the role of peroxynitrite in causing single-strand breaks in DNA, which activate the DNA repair protein poly(ADP-ribose) polymerase (PARP). This catalyzes the cleavage and thereby the consumption of NAD+, the source of energy for many vital cellular processes. Over-activation of PARP, with resulting depletion of NAD+, has been shown to make a major contribution to brain damage after transient focal ischemia in experimental animals. Neuronal accumulation of poly(ADP-ribose), the end-product of PARP activity has been demonstrated after brain ischemia in man. Several therapeutic strategies have been used to try to prevent oxidative damage and its consequences after brain ischemia in man. Although some of the drugs used in early studies were ineffective or had unacceptable side effects, other trials with antioxidant drugs have proven highly encouraging. The findings in recent animal studies are likely to lead to a range of further pharmacological strategies to limit brain injury in stroke patients.
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PMID:Oxidative stress in brain ischemia. 998 55

In Klebsiella pneumoniae, NifL modulates the activity of the transcriptional activator NifA in response to combined nitrogen or external molecular oxygen. We recently showed that K. pneumoniae NifL is a flavoprotein which apparently senses oxygen through a redox-sensitive, conformational change. In order to study whether the nitrogen signal might be transmitted to NifA through a stable modification of NifL we characterized the redox properties of NifL synthesized in Escherichia coli in the presence of different nitrogen sources. FAD analyses showed that purified NifL carried FAD as cofactor independent of nitrogen and oxygen availability. The redox potential of NifL synthesized in the presence of ammonium was -277+/-5 mV at pH 8.0 and 25 degrees C, as determined by reduction with dithionite or with enzymatic reduction by xanthine oxidase in the presence of methyl viologen as redox mediator. When synthesized under nitrogen-limiting conditions, NifL showed a redox potential of -274+/-6 mV at pH 8.0 and 25 degrees C. Fully reduced NifL fractions, synthesized under either condition listed above, reoxidized rapidly in the presence of molecular oxygen. These results indicate that for NifL synthesized in E. coli, the redox potential of the NifL-bound FAD is not influenced by the nitrogen source. The two NifL fractions differed, however, in that a non-flavin specific absorbance at 420 nm was found only in NifL synthesized in the presence of ammonium.
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PMID:NifL of Klebsiella pneumoniae: redox characterization in relation to the nitrogen source. 1035 Jun 21

Transforming growth factor (TGF)-beta1 is a growth factor involved in the mechanisms of lung repair and fibrosis that follow inflammatory processes. We sought to examine the link between the generation of reactive oxygen intermediates (ROI) or reactive nitrogen intermediates (RNI) by inflammatory cells and the expression of TGF-beta1 by alveolar epithelial cells. Exposure of the A549 lung epithelial cell line to either an ROI generating system (xanthine and xanthine oxidase) or an RNI donor (S-nitroso-N-acetyl-penicillamine [SNAP]) promoted a time- and dose-dependent increase in TGF-beta1 release, as measured by a specific enzyme-linked immunosorbent assay. At the peak, the levels of TGF-beta1 were twice the control values. The induction of TGF-beta1 release by ROI was blunted by catalase and unaffected by superoxide dismutase, indicating the involvement of hydrogen peroxide. The response was also blunted by 5, 6-dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB), a specific RNA polymerase II inhibitor, and accompanied by a corresponding increase in TGF-beta1 messenger RNA, as measured by quantitative/competitive reverse transcription polymerase chain reaction, suggesting the involvement of transcriptional mechanisms and possibly other downstream mechanisms. In contrast, RNI-induced TGF-beta1 release was unaffected by DRB and blunted by the protein synthesis inhibitor cycloheximide, suggesting the involvement of translational and post-translational mechanisms. This response required cyclic guanosine monophosphate (cGMP)- mediated processes because (1) immunoreactive cGMP accumulated in the culture medium of SNAP-treated cells; (2) SNAP-induced TGF-beta1 release was blunted by KT 5823, an inhibitor of cGMP-dependent protein kinase; and (3) similar increase in TGF-beta1 release was obtained by cell exposure to membrane-permeable dibutyryl-cGMP or to atrial natriuretic factor, a known agonist of particulate guanylate cyclase. These data suggest that in vitro exposure of human alveolar epithelial cells to ROI and RNI enhances TGF-beta1 release through different mechanisms. In vivo, this control may constitute a molecular link between inflammatory and fibrotic processes.
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PMID:Reactive oxygen and nitrogen intermediates increase transforming growth factor-beta1 release from human epithelial alveolar cells through two different mechanisms. 1038 1

In continuing studies of limb effects resulting from fetal exposure to N(G)-nitro-(L)-arginine methyl ester (L-NAME), we examined the early time course of vascular changes and the effectiveness of fetal intraamniotic injection. Vascular engorgement and hemorrhage occurred within 4 hr of L-NAME treatment on gestational day (gd) 17, and direct injection appeared to be as effective as maternal intraperitoneal injection in inducing limb hemorrhage. Further studies examined protein nitration and electron transport inhibition in tissues of exposed fetuses. L-NAME caused significant increases in nitrotyrosine (NT) formation in limb but not in heart or brain, and reduced electron transport rates in limb. Three agents, alpha-phenyl-N-t-butylnitrone (PBN), a radical trap and inhibitor of inducible nitric oxide synthase (iNOS), allopurinol, an inhibitor of xanthine oxidase, and aminoguanidine, a relatively specific inhibitor of iNOS, significantly moderated limb hemorrhage and protein nitration in distal limb. These results suggest that L-NAME works directly on the fetal limb vasculature and indicate a cytotoxic role for peroxynitrite, a potent oxidant and nitrating agent that is the reaction product of nitric oxide and superoxide anion radical. We propose that L-NAME and other vasoactive toxicants disrupt the fetal limb in a sequential process. Initially, nitric oxide (NO) is depleted, causing hemorrhage and edema in the limb. Within hours, iNOS is induced, resulting in cytotoxic tissue concentrations of NO and reactive nitrogen species that induce apoptosis and/or necrosis in the limb. We suggest that L-NAME exposure may serve as a model of vascular disruptive limb malformations.
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PMID:Role of free radicals in the limb teratogenicity of L-NAME (N(G)-nitro-(L)-arginine methyl ester): a new mechanistic model of vascular disruption. 1047

The radical scavenging activity and the antioxidant content of fresh and air-dried tomatoes were investigated. Tomato halves were dried in a pilot-scale dryer under the following conditions: air temperature, 80 degrees C; air flow rate, 1.5 m/s; drying time, 400 min; final moisture, 25%. Carotenoid (lycopene, beta-carotene, lutein) and ascorbic acid were analyzed by HPLC with a spectrophotometric and an electrochemical detector, respectively. Total phenolics were determined by using the Folin-Ciocalteu reagent. The radical scavenging activity was studied in three model systems: (a) the xanthine oxidase and xanthine system, which generates superoxide radical and hydrogen peroxide; (b) the 3-morpholinosydnonimine system, which releases spontaneously superoxide radical and nitrogen monoxide, forming peroxynitrite; (c) the linoleic acid and CuSO(4) system, which promotes lipid peroxidation. These model systems allow the simulation of key reactions involved in the pathogenesis of certain chronic diseases and may be related to the in vivo activity of tomato antioxidants. Hence, these measurements can be used for optimizing tomato processing and storage. The drying process resulted in a decrease of ascorbic acid content, whereas phenol reagent reducing compounds increased. Carotenoid levels were substantially unchanged upon drying. Fresh and air-dried tomato extracts could act as radical scavengers both in the reactive oxygen species-mediated reactions and in lipid peroxidation. Drying affected the antioxidant effectiveness as measured in the xanthine/xanthine oxidase system, which was found to be the most sensitive method for the measurement of tomato antioxidant activity (lower I(50)) but retained the antioxidant effectiveness in the other two systems.
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PMID:Evaluation of radical scavenging activity of fresh and air-dried tomatoes by three model reactions. 1055 29

In the vasculature, nitrosothiols derived from the nitric oxide (NO)-mediated S-nitrosation of thiols play an important role in the transport, storage, and metabolism of NO. The present study was designed to examine the reactions that promote the decomposition, formation, and distribution of extracellular nitrosothiols in the circulation. The disappearance of these species in plasma and whole blood was examined using a high-performance liquid chromatography method to separate low- and high-molecular weight nitrosothiols. We found that incubation of S-nitrosocysteine (CySNO) or S-nitrosoglutathione (GSNO) with human plasma resulted in a rapid decomposition of these nitrosothiols such that <10% of the initial concentration was recovered after 10-15 min. Neither metal chelators (DTPA, neocuproine), nor zinc chloride (glutathione peroxidase inhibitor), acivicin (gamma-glutamyl transpeptidase inhibitor), or allopurinol (xanthine oxidase inhibitor) inhibited the decomposition of GSNO. With both CySNO and GSNO virtually all NO was recovered as S-nitrosoalbumin (AlbSNO), suggesting the involvement of a direct transnitrosation reaction. Electrophilic attack of the albumin-associated thiols by reactive nitrogen oxides formed from the interaction of NO with O(2) was ruled out because one would have expected 50% yield of AlbSNO. Similar results were obtained in whole blood. The amount of S-nitrosohemoglobin recovered in the presence of 10 microM GSNO or CySNO was less than 100 nM taking into consideration the detection limit of the assay used. Our results suggest that serum albumin may act as a sink for low-molecular-weight nitrosothiols and as a modulator of NO(+) transfer between the vascular wall and intraerythrocytic hemoglobin.
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PMID:Dynamic state of S-nitrosothiols in human plasma and whole blood. 1069 53

Reactive nitrogen species, including nitrogen oxides (N(2)O(3) and N(2)O(4)), peroxynitrite (ONOO(-)), and nitryl chloride (NO(2)Cl), have been implicated as causes of inflammation and cancer. We studied reactions of secondary amines with peroxynitrite and found that both N-nitrosamines and N-nitramines were formed. Morpholine was more easily nitrosated by peroxynitrite at alkaline pH than at neutral pH, whereas its nitration by peroxynitrite was optimal at pH 8.5. The yield of nitrosomorpholine in this reaction was 3 times higher than that of nitromorpholine at alkaline pH, whereas 2 times more nitromorpholine than nitrosomorpholine was formed at pH <7.5. For the morpholine-peroxynitrite reaction, nitration was enhanced by low concentrations of bicarbonate, but was inhibited by excess bicarbonate. Nitrosation was inhibited by excess bicarbonate. On this basis, we propose a free radical mechanism, involving one-electron oxidation by peroxynitrite of secondary amines to form amino radicals (R(2)N(*)), which react with nitric oxide ((*)NO) or nitrogen dioxide ((*)NO(2)) to yield nitroso and nitro secondary amines, respectively. Reaction of morpholine with NO(*) and superoxide anion (O(2)(*)(-)), which were concomitantly produced from spermine NONOate and by the xanthine oxidase systems, respectively, also yielded nitromorpholine, but its yield was <1% of that of nitrosomorpholine. NO(*) alone increased the extent of nitrosomorpholine formation in a dose-dependent manner, and concomitant production of O(2)(*)(-) inhibited its formation. Reactions of morpholine with nitrite plus HOCl or nitrite plus H(2)O(2), with or without addition of myeloperoxidase or horseradish peroxidase, also yielded nitration and nitrosation products, in yields that depended on the reactants. Tyrosine was nitrated easily by synthetic peroxynitrite, by NaNO(2) plus H(2)O(2) with myeloperoxidase, and by NaNO(2) plus H(2)O(2) under acidic conditions. Nitrated secondary amines, e.g., N-nitroproline, could be identified as specific markers for endogenous nitration mediated by reactive nitrogen species.
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PMID:Formation of N-nitrosamines and N-nitramines by the reaction of secondary amines with peroxynitrite and other reactive nitrogen species: comparison with nitrotyrosine formation. 1077 31


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