Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8IXL6 (RNS)
 1,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Large doses of acetaminophen (APAP) could cause oxidative stress and tissue damage through production of reactive oxygen/nitrogen (ROS/RNS) species and quinone metabolites of APAP. Although ROS/RNS are known to modify DNA, the effect of APAP on DNA modifications has not been studied systematically. In this study, we investigate whether large doses of APAP can modify the nuclear DNA in C6 glioma cells used as a model system, because these cells contain cytochrome p450-related enzymes responsible for APAP metabolism and subsequent toxicity (Geng and Strobel, 1995). Our results revealed that APAP produced ROS and significantly elevated the 8-oxo- deoxyguanosine (8-oxodG) levels in the nucleus of C6 glioma cells in a time and concentration dependent manner. APAP significantly reduced the 8- oxodG incision activity in the nucleus by decreasing the activity and content of a DNA repair enzyme, Ogg1. These results indicate that APAP in large doses can increase the 8-oxodG level partly through significant reduction of Ogg1 DNA repair enzyme.
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PMID:Acetoaminophen-induced accumulation of 8-oxodeoxyguanosine through reduction of Ogg1 DNA repair enzyme in C6 glioma cells. 1503 74

NO is considered to be an ubiquitous endogenous system which takes part in body's homeostatic regulations and in pathological events. NO derives from a) the actions of enzymes, the NO Synthases (NOS), which are constitutives (endothelial NOS (eNOS) and nervous NOS (nNOS)) and generate small amounts of NO and have homeostatic functions: and b) from the actions of inducible NOS (iNOS), which generate large amounts of NO and exert protective actions against noxious agents but also toxic effects (e.g. inhibition of enzymes) through the production of peroxynitrite (ONOO-). Modulation of the L-Arg/NO system may be used to obtain favourable therapeutic results, either by promoting (e.g. with NO donors) or by reducing (e.g. with NOS inhibitors) the production of NO. The present chapter will consider two approaches and four groups of potential therapeutic agents: 1) The stimulation of NO production with; a) agents which improve the efficiency of the Kallikrein-Kinin System; b) NO donors. 2) The reduction of excessive NO production with: a) inhibitors of NO Synthases; b) agents that reduce the formation of reactive nitrogen/ oxygen species (RNS / ROS).
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PMID:Pharmacology of nitric oxide: molecular mechanisms and therapeutic strategies. 1513 64

Hyperhomocysteinemia is a risk factor for cardiovascular diseases that induces endothelial dysfunction. Here, we examine the participation of endothelial NO synthase (eNOS) in the homocysteine-induced alterations of NO/O(2)(-) balance in endothelial cells from human umbilical cord vein. When cells were treated for 24 h, homocysteine dose-dependently inhibited thrombin-activated NO release without altering eNOS phosphorylation and independently of the endogenous NOS inhibitor, asymmetric dimethylarginine. The inhibitory effect of homocysteine on NO release was associated with increased production of reactive nitrogen and oxygen species (RNS/ROS) independent of extracellular superoxide anion (O(2)(-)) and was suppressed by the NOS inhibitor L-NAME. In unstimulated cells, L-NAME markedly decreased RNS/ROS formation and the ethidium red fluorescence induced by homocysteine. This eNOS-dependent O(2)(-) synthesis was associated with reduced intracellular levels of both total biopterins (-45%) and tetrahydrobiopterin (-80%) and increased release of 7,8-dihydrobiopterin and biopterin in the extracellular medium (+40%). In addition, homocysteine suppressed the activating effect of sepiapterin on NO release, but not that of ascorbate. The results show that the oxidative stress and inhibition of NO release induced by homocysteine depend on eNOS uncoupling due to reduction of intracellular tetrahydrobiopterin availability.
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PMID:Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. 1518 55

Albendazole (ABZ) and mebendazole (MBZ) are two benzimidazole-derived drugs that show remarkable antihelmintic activity and are widely used in the treatment and control of helminths. Some antihelmintic drugs seem to act through the deleterious generation of reactive oxygen and nitrogen species (ROS and RNS, respectively) to which helminths have no, or relatively low, antioxidant defences (AD), when compared to aerobic organisms. The main objective of the present study consisted of the evaluation of the effect of both drugs on the AD and on some oxidative stress indicators in the host liver. Adult, male, Wistar rats were treated with ABZ or MBZ at doses of 40 mg/kg for different periods of time (2, 4, 8 and 10 days). After treatment, the activities of superoxide dismutase, catalase, glutathione reductase, and glutathione S-transferase, as well as the concentrations of TBARS, reduced glutathione, oxidized glutathione and total glutathione, were evaluated in rat hepatocytes. The serum nitrogen monoxide, usually known as nitric oxide (NO) levels, was also measured. The results showed that both drugs provoked an oxidative stress condition, demonstrated through the elevation of TBARS contents and through the decrease of some AD. Moreover, ABZ showed to be a strong ROS and RNS generator while MBZ showed a low and transient effect on ROS generation. It is suggested that MBZ could be the first-choice drug in the treatment of helminthiasis because it shares a similar therapeutic indication with ABZ, and because it causes only a mild oxidative stress to the host.
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PMID:A comparative study of albendazole and mebendazole-induced, time-dependent oxidative stress. 1523 Oct 63

N-nitrosomorpholine (NMOR) is a well-known hepatocarcinogen. Since this compound is representative of the group of indirect-acting N-nitrosamines, its metabolic activation should be essential. However, the mechanism of NMOR-induced carcinogenesis is still not completely clear. In this paper we tried to further our understanding of the genotoxic effects of NMOR. The central aim of this study was to elucidate to what extent NMOR requires metabolic activation. For evaluation of the mutagenicity of NMOR, V79 cells were used either in the presence or absence of the microsomal S9 fraction in the mutation assay and formation of reactive oxygen/nitrogen species (ROS/RNS) in Caco-2 cells treated with NMOR was measured by a fluorescent assay. A very weak rise of 6-thioguanine resistant mutations was observed in both NMOR-treated model cells, V79/-S9 and V79/+S9. A significant difference between the level of mutations in V79/-S9 and V79/+S9 cells was recorded on the 7th day of expression only. Data obtained by the fluorescent assay confirmed that NMOR caused generation of ROS/RNS. In summary, the presented results showed that NMOR might induce DNA damage not only indirectly by its activation by drug-metabolizing enzymes but also via direct formation of ROS/RNS.
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PMID:An investigation of the genotoxic effects of N-nitrosomorpholine in mammalian cells. 1527 72

NO or its derivatives (reactive nitrogen species, RNS) inhibit mitochondrial complex I by several different mechanisms that are not well characterised. There is an inactivation by NO, peroxynitrite and S-nitrosothiols that is reversible by light or reduced thiols, and therefore may be due to S-nitrosation or Fe-nitrosylation of the complex. There is also an irreversible inhibition by peroxynitrite, other oxidants and high levels of NO, which may be due to tyrosine nitration, oxidation of residues or damage of iron sulfur centres. Inactivation of complex I by NO or RNS is seen in cells or tissues expressing iNOS, and may be relevant to inflammatory pathologies, such as septic shock and Parkinson's disease.
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PMID:Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. 1528 73

Inhaled fibres with certain physico-chemical properties are known to induce mesothelioma in humans. The induction of reactive oxygen (ROS) or nitrogen species (RNS) have been suggested as molecular mechanism of fibre induced carcinogenesis. In earlier studies we were able to demonstrate that crocidolite asbestos in vivo induces mutations in transgenic rats with a specific molecular spectrum that indicates the involvement of 8-hydroxydeoxyguanosine (8-OHdG) as pre-mutagenic adduct. 8-OHdG may be induced by primary (direct) and/or secondary (cellular mediated) mechanisms. Therefore, the induction of 8-OHdG as well as the inflammatory response of animals treated with fibre samples significantly differing in their physico-chemical characteristics was investigated. As appropriate system to study mesothelioma carcinogenesis, intraperitoneal injection in rats was used with samples of UICC crocidolite, crocidolite with reduced iron content, and a vitreous fibre (MMVF 11). Equal numbers of carcinogenic fibres from each sample revealed significant comparable increases in 8-OHdG induction. Parameters of inflammation (percentage of macrophages and TNF-alpha secretion) correlated significantly with the induction of 8-OHdG, 10 weeks after treatment.
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PMID:Induction of 8-hydroxydeoxyguanosine by man made vitreous fibres and crocidolite asbestos administered intraperitoneally in rats. 1528 33

Reactive oxygen and reactive nitrogen species (ROS, RNS) formed in the inner ear in response to high-intensity noise are thought to play an important role in noise-induced hearing loss (NIHL). ROS appear rapidly and transiently in the inner ear during and following noise exposure, while hair cell loss progresses over time stabilizing two or more weeks after insult. Although the delayed loss may, in part, reflect slowly progressing apoptotic or necrosis pathways, an alternate hypothesis is that a continued formation of free radicals contributes to cell death. To evaluate this hypothesis, we measured auditory brain stem responses (ABRs), hair cell loss, and free radical activity in the guinea pig following noise exposure (5 h, 120 dB SPL, 1 OCB). Nitrotyrosine (NT) and 4-hydroxy-2-noneal (4-HNE) were used as histochemical markers of RNS and ROS formation, respectively. Assessments were performed prior to and on Days 1, 3, 7, 10, 14 and 21 after exposure. Immunoreactivity to NT and 4-HNE was low initially, reached a maximum at 7 to 10 days, and then declined. ABR thresholds increased maximally immediately after exposure, with partial recovery stabilizing at 7 to 10 days. Correlating with the delayed formation of ROS/RNS, there was a progressive hair cell loss, stabilizing at approximately 2 weeks. Based on these findings, we suggest that initial hair cell damage after noise may primarily reflect mechanical events plus transient intense ROS formation, while continued formation of ROS/RNS contributes to the long-term hair cell loss. The late formation of free radicals may provide a window of opportunity for pharmacological rescue immediately following exposure, requiring both ROS and RNS scavengers.
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PMID:Delayed production of free radicals following noise exposure. 1530 54

When a spontaneous autoxidation of arachidonic acid to prostaglandin-like products was first described almost 40 years ago, it was thought to be an artifact that interfered with the detection of enzymatically generated prostaglandins. It has now been generally accepted that the autoxidation of arachidonic acid occurs in vivo and leads to formation of isoprostanes and other products. Sensitive methods can detect the isoprostanes as useful biological markers, which help to estimate, non-invasively, the burden of free radicals formed in pathologies resulting from oxidative stress. After the discovery of NO, it has been hypothesized that NO and its active congeners (reactive nitrogen species, RNS), such as nitrogen dioxide radical (NO2), nitrous acid, peroxynitrite, can also participate in lipid peroxidation, either as initiators or modulators of processes initiated by the hydroxyl radical. In biological systems these RNS not only originate from the biosynthesis of NO but also from exogenous sources such as polluted air and dietary nitrite. While the ability of NO2 to induce lipid peroxidation has been long known, more recent studies have discovered novel processes that have been termed lipid nitration. Polyunsaturated fatty acids appear to be readily targeted by RNS. Among the products of arachidonic acid nitration by NO2, interesting lipids have been detected, such as nitroeicosatetraenoic acids, alpha,beta-nitrohydroxyeicosatrienoic acids, and trans-arachidonic acids. The products of fatty acid nitration have the potential to function as biomarkers and/or lipid mediators of mechanisms distinct from fatty acid peroxidation but offering insight into the contribution of specific RNS such as NO2 to the damage of biological membrane resulting from nitrooxidative stress.
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PMID:Biological nitration of arachidonic acid. 1532 Aug 36

The immature and adult brain display clear differences in the way they respond to insults. The effects of prenatal irradiation on the developing brain are well known. Both epidemiological and experimental data indicate that ionizing radiation may disrupt developmental processes leading to deleterious effects on post-natal brain functions. A central role of reactive oxygen and nitrogen species (ROS/RNS) as important mediators in both neurotoxicity and neuroprotection has been demonstrated. However, data concerning the role of ROS/RNS in radiation-induced damage in the developing brain are scarce. The goal of this review was to summarize the current studies concerning the role of nitric oxide and its reactive intermediates in activation of signal transduction pathways involved in cellular radiation response, with particular focus on radiation-induced effects in the developing brain.
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PMID:The role of nitric oxide in the radiation-induced effects in the developing brain. 1534 Nov 84


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