UMLS:C0406810 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In guinea-pig myocardial mitochondria preparation, lowering the Ca2+ concentration or pH level in the perfusate rapidly elevated the fura-2 Ca2+ signal ([Ca2+]m). Pretreatment with 10(-4) M L-Arg inhibited the rapid [Ca2+]m influx, whereas administration of 10(-4) M L-NAME did not, suggesting some association between nitric oxide (NO*) synthase (NOS) activation and Ca2+ kinetics in mitochondria. Immunoblotting analysis showed that endothelial (e)-NOS was present in mitochondria, but not inducible (i)-NOS or brain (b)-NOS. Electron microscopy observations revealed that the e-NOS antibody-reactive site in the mitochondria was the inner cristae. The production of reactive oxygen species and NO* in isolated mitochondria was detected by the spin trapping technique with electron paramagnetic resonance (EPR) spectrometry. Pretreatment with 10(-5) M S-nitroso-N-acetyl-DL-penicillamine (SNAP) and 10(-5) M 3-[2-Hydroxy-1-(1-methylethyl)-2-nitrosohydrazino]-1-propananin e (NOC 5), which spontaneously generate NO*, completely inhibited the [Ca2+]m uptake. In addition, N-morpholino sydnonimine hydrochloride (SIN-1) (10(-5) M), which simultaneously generates NO* as well as *O2- and peroxynitrite anion (ONOO-), inhibited the increase in [Ca2+]m. ONOO- (3 x 10(-4) M) itself also inhibited this increase. Pretreatment with the *O2(-)-scavenger manganese superoxide dismutase or catalase (200 units/ml) completely inhibited the increase in [Ca2+]m caused by lowering of either the Ca2+ concentration or the pH in the perfusate. These results suggested that the formation of reactive oxygen species promoted the [Ca2+]m influx. The agents that inhibited the [Ca2+]m influx improved contractility even in Langendorff preparations after ischemia. Based on these findings, we concluded that e-NOS exists in mitochondria and that NO* may play an important protective role in reperfusion cardiac injury after ischemia, by inhibiting the Ca2+ influx into mitochondria which are otherwise damaged by *O2-.
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PMID:Protective role of nitric oxide synthase against ischemia-reperfusion injury in guinea pig myocardial mitochondria. 1051 58

It has been shown that independent sources of nitric oxide (NO) and the inflammatory cytokine tumor necrosis factor alpha (TNFalpha) contribute to the breakdown of the blood-brain barrier (BBB) in the pathogenesis of a number of brain disorders. However, the interaction of NO and TNFalpha has not been elucidated. The present study was designed to determine whether the toxicity induced by NO is altered by TNFalpha in brain capillary endothelial cells (BCECs), and if so, whether it is related to the generation of superoxide. TNFalpha (50-400 U/ml) did not produce toxicity until at a concentration of 800 U/ml. This toxic effect was completely blocked by copper-zinc superoxide dismutase (SOD)/catalase or N(omega)-nitro-L-arginine methyl ester (L-NAME) or oxyhemoglobin (HbO2). Sodium nitroprusside (SNP) reduced with 0.4 mM ascorbate (SNP/Vc) significantly increased Lactate dehydrogenase (LDH) efflux in a concentration-dependent manner. This cytotoxicity of SNP/Vc was also completely inhibited by SOD/catalase or HbO2. When SNP/Vc used in combination with 400 U/ml TNFalpha, a more remarkable LDH efflux was induced than SNP/Vc alone, even as little as 0.01 mM SNP/Vc was toxic, although a dose of 400 U/ml TNFalpha alone had no effect on LDH efflux. In addition, either 0.4 mM SNP/Vc and 800 U/ml TNFalpha alone or 0.4 mM SNP/Vc and 400 U/ml TNFalpha in combination significantly increased malondialdehyde (MDA) content, but nitric oxide synthase (NOS) activity was inhibited only by SNP/Vc and TNF in combination. These results suggest that TNFalpha enhances the toxicity of NO in BCECs and that at least part of this enhancement involves the generation of superoxide.
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PMID:Tumor necrosis factor alpha enhances the cytotoxicity induced by nitric oxide in cultured cerebral endothelial cells. 1075 68

This study investigated the effect of nitric oxide on lipid peroxide formation during endotoxaemia. Nitric oxide synthase inhibitors N(G)-monomethyl-L-arginine acetate (L-NMMA, 20 mg/kg, intravenously), N(G)-nitro-L-arginine-methyl ester (L-NAME, 10 mg/kg, intravenously), and N(G)-nitro-L-arginine (L-NA, 10 mg/kg, intravenously), and a relatively selective inducible nitric oxide synthase inhibitor aminoguanidine (10 mg/kg, intravenously), did not protect against endotoxin-induced death of mice. Superoxide dismutase activity in liver 18 hr after administration of endotoxin (6 mg/kg, intraperitoneally) to L-arginine analogues (L-NMMA, L-NAME, L-NA)-treated mice was lower than in mice treated with endotoxin alone, whereas the administration of L-arginine analogues increased xanthine oxidase activity in the livers of endotoxin-injected mice compared with mice treated with endotoxin alone. In mice treated with L-arginine analogues and aminoguanidine, the levels of non-protein sulfhydryl and lipid peroxide in liver 18 hr after endotoxin injection did not show significant differences from mice treated with endotoxin alone. L-Arginine analogues and aminoguanidine had little effect on lipid peroxide formation in liver caused by endotoxin. Treatment with aminoguanidine (300 microM) significantly inhibited endotoxin-induced intracellular peroxide in J774A.1 cells, however, aminoguanidine did not affect endotoxin-induced cytotoxicity in J774A.1 cells. Our results clearly demonstrate that treatment with catalase (10 microg/ml), D-mannitol (10 mM), or superoxide dismutase (100 U/ml), has little or no effect on nitric oxide production by endotoxin (1 microg/ml)-activated J774A.1 cells. These findings suggest that nitric oxide is not crucial for lipid peroxide formation during endotoxaemia. Therefore, it is unlikely that nitric oxide plays a significant role in liver injury caused by free radical generation in endotoxaemia.
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PMID:Effect of nitric oxide synthase inhibitors on lipid peroxide formation in liver caused by endotoxin challenge. 1081 49

In order to study effects of cigarette smoking and smoking cessation on plasma constituents and enzyme activities related to oxidative stress, 1255 smokers and 524 healthy non-smokers were investigated in terms of plasma levels of lipoperoxides (LPO), nitric oxide (NO), vitamin C (VC), vitamin E (VE) and beta-carotene (beta-CAR). Additionally, erythrocytes were examined to determine the level of LPO, the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). The results showed that, when compared with the average values of the non-smoker group, the average plasma values of LPO, NO and the average erythrocyte value of LPO in the smoker group were significantly increased (P < 0. 001), while the average plasma values of VC, VE, beta-CAR, and the average erythrocyte activities of SOD, CAT, GSH-Px were significantly decreased (P < 0.001). A linear regression and correlation analysis for 65 male smokers who were all 40 years old showed that with longer smoking duration and greater daily smoking quantity, the plasma values of LPO, NO and the erythrocyte value of LPO were elevated, while the plasma values of VC, VE, beta-CAR and erythrocyte values of SOD, CAT, GSH-Px were decreased. In a group of 73 smokers who stopped smoking completely for six months, the average plasma values of LPO, NO and the average erythrocyte value of LPO decreased, although they were still significantly higher than those in the matched non-smoker group (P < 0.05). Additionally, the average plasma values of VC, VE, beta-CAR and the average erythrocyte values of SOD, CAT, GSH-Px increased, although they were still significantly lower than those in the matched non-smoker group (P < 0.05). However, after smoking cessation for one year the above average values were not significantly different from those in the matched non-smoker group (P > 0.05). This finding indicates that the markedly increased oxidative stress in smokers might gradually return to normal but only after a long period of smoking cessation. In conclusion, in the bodies of smokers a series of free radical chain reactions were gravely aggravated, the dynamic balance between oxidation and antioxidation was seriously disrupted, and oxidative stress was clearly exacerbated, which is closely related to many disorders or diseases in smokers. The present study underscored the need, urgency and importance of complete smoking cessation.
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PMID:Effects of cigarette smoking and smoking cessation on plasma constituents and enzyme activities related to oxidative stress. 1085 40

Mitomycin C (MC) requires bioreduction prior to the generation of alkylating moieties. NADPH-cytochrome P450 reductase is predominant in metabolic activation of MC in hypoxic cancer cells. In this study, neuronal nitric oxide synthase (nNOS), whose reductase domain is structurally similar to that of NADPH-cytochrome P450 reductase, was assessed for its ability to activate MC. nNOS under anaerobic conditions catalyzed the reduction of MC, which was measured as the decrease in absorbance at 375 nm. Neither the heme blocker potassium cyanide (1 mM) nor the nNOS competitive inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 1 mM) affected the bioreduction of MC, whereas 0.1 mM diphenyleneiodonium chloride, which binds to the reductase domain of nNOS, inhibited MC reduction completely. The reduction of MC by nNOS was influenced by Ca(2+)/calmodulin. In the absence of Ca(2+)/calmodulin, the rate of MC reduction decreased by 28% at pH 6.6. The formation of an alkylated complex of 4-(p-nitrobenzyl)pyridine occurred in a manner analogous to that observed in MC metabolic experiments. The rate of MC reduction and the formation of the alkylated complex of 4-(p-nitrobenzyl)pyridine at pH 6.6 were increased by 43 and 54%, respectively, as compared with that at pH 7.6. nNOS-activated MC resulted in the consumption of oxygen in air. The rate of oxygen consumption decreased by 50% in the presence of 2000 U/mL of catalase. MC inhibited nNOS activity in a noncompetitive manner. These findings demonstrate that nNOS is capable of catalyzing the bioreduction of MC.
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PMID:Reductive activation of mitomycin C by neuronal nitric oxide synthase. 1087 32

Modulation of the biosynthesis of the vasoconstrictor peptide endothelin-1 by oxygen-derived free radicals generated by xanthine oxidase or hydrogen peroxide was studied in cultured endothelial cells. Endothelin-1 metabolism was investigated at the level of endothelin-1 promoter, preproendothelin-1 mRNA and intracellular big endothelin-1. Endothelin-1 mRNA, as characterized by Northern blotting, was increased both time- and dose-dependently by xanthine oxidase to up to 500% above baseline. Analysis of endothelin-1 promoter activity using a construct containing 1329 bp of the endothelin-1 promoter revealed that promoter activity was increased up to eight-fold by incubation with xanthine oxidase. Specificity was ascertained by co-incubation with superoxide dismutase and catalase leading to inhibition of the effect of xanthine oxidase. A significant contribution of nitric oxide was ruled out, since NOS III-mRNA transcription remained unchanged and l -NAME did not significantly alter endothelin-1 promoter activity. Synthesis of intracellular big endothelin-1 protein was increased dose-dependently by xanthine oxidase. Our results indicate that oxidative stress leads to increased endothelial synthesis of big endothelin-1, which is a previously unknown mechanism and may help to understand the detrimental association of increased oxidative stress and elevated endothelin-1 levels in pathophysiological conditions promoting atherosclerosis.
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PMID:Oxidative stress increases synthesis of big endothelin-1 by activation of the endothelin-1 promoter. 1090 Jan 69

Protective effects of NOS inhibitors and free radical scavengers in cerebral ischemia are well documented. The present study was undertaken to determine the possible effects of NOS inhibition on brain antioxidants. Levels of both enzymatic [glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD)] and non-enzymatic [reduced glutathione (GSH)] antioxidants following nitric oxide synthase (NOS) inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME), D-NAME or 7-nitroindazole (7-NI) have been investigated. NOS activity and antioxidant levels in the rat cerebellum and medulla were estimated 1 h after treatment with L-NAME (10, 30 and 100 mg/kg, i.p.), D-NAME (100 mg/kg, i.p.) or 7-NI (25 mg/kg, i.p.). L-NAME and 7-NI inhibited NOS activity in a dose-dependent manner. D-NAME also exhibited significant NOS inhibition. The activity of SOD and the GSH level remained unaltered following NOS inhibition. However, L-NAME and D-NAME at 100 mg/kg attenuated GPx activity in the cerebellum, though 7-NI had no effect. L-NAME inhibited catalase activity in medulla only at 30 mg/kg, but had no effect in cerebellum. However, 7-NI (25 mg/kg), D-NAME and L-NAME at 100 mg/kg did not affect catalase activity in the rat brain. Thus, NOS inhibition by the three agents did not have major effects on brain antioxidant levels.
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PMID:Antioxidant levels in the rat brain after nitric oxide synthase inhibition: a preliminary report. 1093 75

Objective: to determine the role of nitric oxide (NO) in rat liver ischemia reperfusion we examined the effects of competitive NO synthesis inhibitor L-nitro-arginine-methyl-ester (L-NAME) and NO precursor L-arginin. Methods: 46 Sprague-Dawley rats were divided into five groups. Group 1, sham operated; group 2, 30-min ischemia administered; group 3, 60-min reperfusion administered after ischemia; group 4, 50 mg/kg L-NAME was given i.v. immediately before reperfusion; group 5, 50 mg/kg L-NAME+250 mg/kg L-arginin was given i.v. immediately before reperfusion. At the end of the experiment, liver was removed and superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) were measured, transaminases SGOT and SGPT were measured in sera. Liver was also evaluated histopathologically. Results: transaminase levels were the highest in ischemia reperfusion group. Transaminases in this group were high compared with sham, ischemia, L-NAME and L-arginin groups (***P<0.001, ***P<0.001, *P<0.05, *P<0.05, respectively). SOD activity was 29.8+4 U/mg protein in L-arginin group. This level was the lowest level in all groups. SOD activity in L-arginin group was lower than that of sham and ischemia reperfusion groups (**P<0.01, *P<0.05, respectively). There were no significant differences in catalase activity and MDA levels among groups. Tissue damage was significant in ischemia and ischemia reperfusion groups. Tissue damages in these groups were greater than that of sham group (***P<0.001). In L-NAME treated group, tissue damage was similar to sham group, and significantly less than ischemia reperfusion group and L-arginin group (**P<0.01). Conclusion: even though there was significant tissue damage, we have not observed oxidative stress in the length of ischemia reperfusion period that we have performed. Mechanism of this damage seems to be independent from lipid peroxidation. NO supplementation decreased SOD, but did not cause further tissue damage. NO may dispose O(2)(-) by formation of peroxynitrite. L-NAME did not change lipid peroxidation, but clearly reduced reperfusion injury.
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PMID:Effect of nitric oxide inhibition on rat liver ischemia reperfusion injury. 1099 12

To further reveal the risks of heroin abuse to human body, and to determine the injuries of oxidation, peroxidation and lipoperoxidation induced by nitric oxide and other free radicals to heroin abusers, we determined and compared plasma values of lipoperoxides (LPO), nitric oxide (NO), vitamin C (VC), vitamin E (VE), beta-carotene (beta-CAR) and erythrocyte values of LPO, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in 114 heroin abusers and 100 healthy volunteers. Using linear regression and correlation as well as stepwise regression and correlation, we also analyzed the effect of the abusing duration, and daily abusing quantity on the above-mentioned biochemical parameters in the heroin abusers. The results showed that, compared with the healthy volunteer groups, the average plasma values of LPO, and NO, and the average erythrocyte value of LPO in the heroin abuser group were significantly increased (P < 0.0001), and the average plasma values of VC, VE, and beta-CAR and the average erythrocyte values of SOD, CAT, and GSH-Px were significantly decreased (P < 0.0001). Analysis of linear regression and correlation showed that with prolonged heroin abusing and with increased daily quantity in the heroin abusers, the plasma values of LPO, and NO, and the erythrocyte value of LPO were gradually increased (P < 0.001), whereas the plasma values of VC, VE, and beta-CAR and the erythrocyte values of SOD, CAT, and GSH-Px were gradually decreased (P < 0.001). Analysis of stepwise regression and correlation indicated that the plasma values of NO, VC and VE were closely correlated with the abusing duration and daily abusing quantity. These results indicate that the balance between oxidation and antioxidation in the heroin abusers was seriously disturbed, and the injuries induced by nitric oxide and other free radicals, through oxidation, peroxidation and lipoperoxidation to the bodies of heroin abusers exacerbated. It is therefore necessary that in abstaining from heroin dependence, the heroin abusers should acquire sufficient quantities of antioxidants such as VC, VE and beta-CAR.
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PMID:Heroin abuse and nitric oxide, oxidation, peroxidation, lipoperoxidation. 1105 15

Diesel exhaust particles (DEP) have been proved to induce serious pulmonary injury, among which lethal pulmonary edema has been assumed to be mediated by vascular endothelial cell damage. In the present study, we investigated the cytotoxic mechanism of DEP on human pulmonary artery endothelial cells focusing on the role of active oxygen species. Endothelial cell viability was assessed by WST-8, a novel tetrazolium salt. Nitric oxide (NO) production was measured by using a new fluorescence indicator, diaminofluorescein-2 (DAF-2). Organic compounds in DEP were extracted by dichloromethane and methanol. DEP-extracts damaged endothelial cells under both subconfluent and confluent conditions. The DEP-extract-induced cytotoxicity was markedly reduced by treatment with SOD, catalase, N-(2-mercaptopropionyl)-glycine (MPG), or ebselen (a selenium-containing compound with glutathione peroxidase-like activity). Thus superoxide, hydrogen peroxide, and other oxygen-derived free radicals are likely to be implicated in DEP-extract-induced endothelial cell damage. Moreover, L-NAME and L-NMA, inhibitors of NO synthase, also attenuated DEP-extract-induced cytotoxicity, while sepiapterin, the precursor of tetrahydrobiopterin (BH(4), a NO synthase cofactor) interestingly enhanced DEP-extract-induced cell damage. These findings suggest that NO is also involved in DEP-extract-mediated cytotoxicity, which was confirmed by direct measurement of NO production. These active oxygen species, including peroxynitrite, may explain the mechanism of endothelial cell damage upon DEP exposure during the early stage.
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PMID:The cytotoxic effects of diesel exhaust particles on human pulmonary artery endothelial cells in vitro: role of active oxygen species. 1118 26

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