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)

There is increasing evidence that endogenously generated reactive oxygen (ROS) and reactive nitrogen (RNS) species at sites of inflammation and in tumors may be genotoxic. We have developed a murine tumor model (MN-11) in which mutations at the hypoxanthine phosphoribosyltransferase (HPRT) locus, arising both in vitro and in vivo, can be detected. In the present report, we describe an in vitro study of the ability of ROS and RNS to induce mutations in our model system. 137Cs radiation and radiomimetic drugs caused a dose-dependent increase in mutant frequency. At D0, radiation induced about 170 mutants per 10(5) viable cells, compared to 50 and 95 for streptonigrin and bleomycin, respectively. H2O2 induced a lower frequency of mutants, 20-30 per 10(5), for enzymatically generated or bolus, respectively. For the following treatments, mutant frequency at 50% survival is shown. Incubation with human granulocytes induced a low frequency of mutants (about 15 per 10(5)). RNS was tested using a series of NO-donating drugs. Spermine/NO. induced cytotoxicity but no mutants while S-nitroso-N-acetylpenicillamine induced a low level, 10 per 10(5). Both release nitrogen monoxide spontaneously, with a t1/2 < 3 h. Glyceryl trinitrate and sodium nitroprusside are two drugs that were slowly metabolized by MN-11 cells (> 12 h). Glyceryl trinitrate induced about 20 per 10(5) while nitroprusside induced 50 per 10(5). Our results indicate that RNS can readily induce mutations detectable in MN-11 cells. At equicytotoxic doses, the induced mutant frequency varied considerably for different drugs, suggesting that different states of nitrogen monoxide (such as NO+ or NO.) may be generated and these may vary in their mutagenic/cytotoxic potential.
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PMID:Mutagenicity and cytotoxicity of reactive oxygen and nitrogen species in the MN-11 murine tumor cell line. 935 53

Reactive oxygen (ROS) or nitrogen (RNS) species can affect epithelial cells to cause acute damage and an array of pulmonary diseases. The goal of this study was to determine patterns of early response gene expression and functional end points of exposure to nitric oxide (NO.), H2O2, or peroxynitrite (ONOO-) in a line of rat lung epithelial (RLE) cells. Our focus was on c-fos and c-jun protooncogenes, as these genes play an important role in proliferation or apoptosis, possible end points of exposure to reactive metabolites in lung. Our data demonstrate that NO. generated by spermine 1,3-propanediamine N-14-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]-butyl] or S-nitroso-N-acetylpenicillamine as well as H2O2 cause increased c-fos and c-jun mRNA levels, nuclear proteins, and complexes binding the activator protein-1 recognition sequence in RLE cells. These agents also lead to apoptosis and increased membrane permeability. In contrast, exogenously administered ONOO- or 3-morpholinosydnonimine do not induce protooncogenes or apoptosis in RLE cells despite nitration oftyrosines. We conclude that ROS and RNS can elicit distinct molecular and phenotypic responses in a target cell of pulmonary disease.
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PMID:Differential induction of c-fos, c-jun, and apoptosis in lung epithelial cells exposed to ROS or RNS. 935 54

Oxidative injury has been implicated in the pathogenesis of numerous neurodegenerative diseases. Recently, it has been found that with the existence of hydrogen peroxide and nitrite, hemin catalyzes protein nitration. We hypothesize under certain pathological conditions, hemin catalyzed protein nitration may happen in the brain. In this paper, the effects of three flavonoids, i.e. quercetin, catachin and baicalein on hemin/nitrite/H2O2 induced brain homogenate oxidation and nitration were studied. The results showed that hemin/nitrite/H2O2 system could effectively induce brain homogenate protein oxidation and nitration. Quercetin, catachin and baicalein dose-dependently inhibited hemin/nitrite/H2O2 system-induced protein nitration in a dose-dependent manner, the inhibition of protein nitration was in the order of quercetin>catachin>baicalein. These compounds also inhibited hemin/H2O2 system-induced lipid peroxidation, the inhibition order was baicalein >quercetin>catachin. However, these flavonoids showed marginal effect on hemin/nitrite/H2O2 system caused protein oxidation and thiol oxidation. The inhibition activities of flavonoids on hemin/nitrite/H2O2 system-induced protein nitration may closely relate to their radical scavenging activities, since the inhibition order of protein nitration is the same as the radical scavenging order. These results indicate hemin/nitrite/H2O2 system induces different types of oxidative assault on bio-molecules. Flavonoids could act as antioxidants inhibiting ROS and RNS caused brain damage.
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PMID:Hemin/nitrite/H2O2 induces brain homogenate oxidation and nitration: effects of some flavonoids. 1553 73

Methylglyoxal (MG) is a metabolite of glucose. Our previous study demonstrated an elevated MG level with an increased oxidative stress in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. Whether MG causes the generation of nitric oxide (NO) and superoxide anion (O2*-), leading to peroxynitrite (ONOO-) formation in VSMCs, was investigated in the present study. Cultured rat thoracic aortic SMCs (A-10) were treated with MG or other different agents. Oxidized DCF, reflecting H2O2 and ONOO- production, was significantly increased in a concentration- and time-dependent manner after the treatment of SMCs with MG (3-300 microM) for 45 min-18 h (n = 12). MG-increased oxidized DCF was effectively blocked by reduced glutathione or N-acetyl-l-cysteine, as well as L-NAME (p < 0.05, n = 12). Both O2*- scavenger SOD and NAD(P)H oxidase inhibitor DPI significantly decreased MG-induced oxidized DCF formation. MG significantly and concentration-dependently increased NO and O2*- generation in A-10 cells, which was significantly inhibited by L-NAME and SOD or DPI, respectively. In conclusion, MG induces significant generation of NO and O2*- in rat VSMCs, which in turn causes ONOO- formation. An elevated MG level and the consequential ROS/RNS generation would alter cellular signaling pathways, contributing to the development of different insulin resistance states such as diabetes or hypertension.
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PMID:Methylglyoxal-induced nitric oxide and peroxynitrite production in vascular smooth muscle cells. 1560 12

Previously, we reported that mitogenicity in L6 muscle cells was stimulated by insulin but inhibited by reactive oxygen/nitrogen species (ROS/RNS; []) and that preincubation with sodium ascorbate (ASC) protected from either the impaired DNA synthesis and/or loss of cell viability. Now, we addressed the question how ascorbate (AA) rescued DNA synthesis in L6 muscle cells being challenged with ROS/RNS. We assumed that AA might be able to influence insulin signaling. We found that insulin elevated the protein levels of both PKB/Akt kinase phosphorylated at Serine(473) (pS473-Akt), and c-Jun phosphorylated at Serine63, Serine73 (pS63, pS73-c-Jun) residues, respectively. A short-term treatment experiment (0 - 45 min) revealed that either insulin (0.1 muM) or hydrogen peroxide (0.1, 0.5 mM; H2O2) increased the pS473-Akt and pS63, pS73-c-Jun protein levels, although the effect of ROS/RNS peaked earlier (5 min) than that of insulin (45 min). Astonishingly, the elevated levels of both pS473-Akt and pS63, pS73-c-Jun in response to insulin were reduced by the concomitant treatment with H2O2 in a dose-dependent fashion. In contrast, a 4-hour preincubation with ASC (1 mM) augmented the signal from pS473-Akt and pS63, pS73-c-Jun, when both insulin and H2O2 were added. Moreover, a 24 h preincubation with ASC also elevated the pS473-Akt and pS63, pS73-c-Jun levels in response to insulin irrespective to ROS/RNS co-treatment. During chronic treatment studies, ROS/RNS stimulated neither phosphorylation of Akt nor c-Jun, indicating that ROS/RNS-dependent activation of the above-mentioned proteins was short-term and transient. Furthermore, higher levels of pS473 Akt and pS63, pS73-c-Jun after preincubation with ASC suggest that by this route AA could protect insulin-induced mitogenicity. Basal levels of Akt and its target p70(S6K) remained constant regardless of treatment. These results suggest that AA defends the insulin-stimulated mitogenicity hampered by ROS/RNS most likely by the amplification of insulin signal at the level of pS473-Akt and pS63, pS73-c-Jun, respectively.
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PMID:Preincubation with sodium ascorbate potentiates insulin-dependent PKB/Akt and c-Jun phosphorylation in L6 rat myoblasts challenged with reactive oxygen/nitrogen species. 1590 68

The controlled formation of ROS (reactive oxygen species) and RNS (reactive nitrogen species) is now known to be critical in cellular redox signalling. As with the more familiar phosphorylation-dependent signal transduction pathways, control of protein function is mediated by the post-translational modification at specific amino acid residues, notably thiols. Two important classes of oxidant-derived signalling molecules are the lipid oxidation products, including those with electrophilic reactive centres, and decomposition products such as lysoPC (lysophosphatidylcholine). The mechanisms can be direct in the case of electrophiles, as they can modify signalling proteins by post-translational modification of thiols. In the case of lysoPC, it appears that secondary generation of ROS/RNS, dependent on intracellular calcium fluxes, can cause the secondary induction of H2O2 in the cell. In either case, the intracellular source of ROS/RNS has not been defined. In this respect, the mitochondrion is particularly interesting since it is now becoming apparent that the formation of superoxide from the respiratory chain can play an important role in cell signalling, and oxidized lipids can stimulate ROS formation from an undefined source. In this short overview, we describe recent experiments that suggest that the cell signalling mediated by lipid oxidation products involves their interaction with mitochondria. The implications of these results for our understanding of adaptation and the response to stress in cardiovascular disease are discussed.
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PMID:Cell signalling by oxidized lipids and the role of reactive oxygen species in the endothelium. 1624 25

Persistent inflammation and associated excessive oxidative stress have been crucially implicated in quartz-induced pulmonary diseases, including fibrosis and cancer. We have investigated the significance of the particle surface reactivity of respirable quartz dust in relation to the in vivo generation of reactive oxygen and nitrogen species (ROS/RNS) and the associated induction of oxidative stress responses in the lung. Therefore, rats were intratracheally instilled with 2 mg quartz (DQ12) or quartz whose surface was modified by either polyvinylpyridine-N-oxide (PVNO) or aluminium lactate (AL). Seven days after instillation, the bronchoalveolar lavage fluid (BALF) was analysed for markers of inflammation (total/differential cell counts), levels of pulmonary oxidants (H2O2, nitrite), antioxidant status (trolox equivalent antioxidant capacity), as well as for markers of lung tissue damage, e.g. total protein, lactate dehydrogenase and alkaline phosphatase. Lung homogenates as well as sections were investigated regarding the induction of the oxidative DNA-lesion/oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) using HPLC/ECD analysis and immunohistochemistry, respectively. Homogenates and sections were also investigated for the expression of the bifunctional apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1) by Western blotting and immunohistochemistry. Significantly increased levels of H2O2 and nitrite were observed in rats treated with non-coated quartz, when compared to rats that were treated with either saline or the surface-modified quartz preparations. In the BALF, there was a strong correlation between the number of macrophages and ROS, as well as total cells and RNS. Although enhanced oxidant generation in non-coated DQ12-treated rats was paralleled with an increased total antioxidant capacity in the BALF, these animals also showed significantly enhanced lung tissue damage. Remarkably however, elevated ROS levels were not associated with an increase in 8-OHdG, whereas the lung tissue expression of APE/Ref-1 protein was clearly up-regulated. The present data provide further in vivo evidence for the crucial role of particle surface properties in quartz dust-induced ROS/RNS generation by recruited inflammatory phagocytes. Our results also demonstrate that quartz dust can fail to show steady-state enhanced oxidative DNA damage in the respiratory tract, in conditions were it elicits a marked and persistent inflammation with associated generation of ROS/RNS, and indicate that this may relate to compensatory induction of APE/Ref-1 mediated base excision repair.
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PMID:The crucial role of particle surface reactivity in respirable quartz-induced reactive oxygen/nitrogen species formation and APE/Ref-1 induction in rat lung. 1626 28

Sphingolipids including ceramide and its derivatives such as ceramide-1-phosphate, glycosyl-ceramide, and sphinogosine (-1-phosphate) are now recognized as novel intracellular signal mediators for regulation of inflammation, apoptosis, proliferation, and differentiation. One of the important and regulated steps in these events is the generation of these sphingolipids via hydrolysis of sphingomyelin through the action of sphingomyelinases (SMase). Several lines of evidence suggest that reactive oxygen species (ROS; O2-, H2O2, and OH-,) and reactive nitrogen species (RNS; NO, and ONOO-) and cellular redox potential, which is mainly regulated by cellular glutathione (GSH), are tightly linked to the regulation of SMase activation. On the other hand, sphingolipids are also known to play an important role in maintaining cellular redox homeostasis through regulation of NADPH oxidase, mitochondrial integrity, and antioxidant enzymes. Therefore, this paper reviews the relationship between cellular redox and sphingolipid metabolism and its biological significance.
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PMID:Sphingolipid signaling and redox regulation. 1671 89

Reactive oxygen or nitrogen species (ROS/RNS) generated endogenously or in response to environmental stress have long been implicated in tissue injury in the context of a variety of disease states. ROS/RNS can cause cell death by nonphysiological (necrotic) or regulated pathways (apoptotic). The mechanisms by which ROS/RNS cause or regulate apoptosis typically include receptor activation, caspase activation, Bcl-2 family proteins, and mitochondrial dysfunction. Various protein kinase activities, including mitogen-activated protein kinases, protein kinases-B/C, inhibitor-of-I-kappaB kinases, and their corresponding phosphatases modulate the apoptotic program depending on cellular context. Recently, lipid-derived mediators have emerged as potential intermediates in the apoptosis pathway triggered by oxidants. Cell death mechanisms have been studied across a broad spectrum of models of oxidative stress, including H2O2, nitric oxide and derivatives, endotoxin-induced inflammation, photodynamic therapy, ultraviolet-A and ionizing radiations, and cigarette smoke. Additionally ROS generated in the lung and other organs as the result of high oxygen therapy or ischemia/reperfusion can stimulate cell death pathways associated with tissue damage. Cells have evolved numerous survival pathways to counter proapoptotic stimuli, which include activation of stress-related protein responses. Among these, the heme oxygenase-1/carbon monoxide system has emerged as a major intracellular antiapoptotic mechanism.
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PMID:Mechanisms of cell death in oxidative stress. 1711 87

A fluorophotometric method for the determination of hydrogen peroxide (H2O2) using fluorescin was developed. This method was based on the oxidative reaction of fluorescin, a colorless, non-fluorescent lactoid fluorescein, by H2O2 to give highly fluorescein fluorescence emission. In the determination of H2O2, the calibration curve exhibited linearity over the H2O2 concentration range of 1.5-310 ng mL(-1) at an emission wavelength of 525 nm with an excitation of 500 nm and with relative standard deviations (n = 6) of 2.51%, 2.48%, and 1.31% for 3.1 ng mL(-1), 30.8 ng mL(-1), and for 308 ng mL(-1) of H2O2, respectively. The detection limit for H2O2 was 1.9 ng mL(-1) six blank determinations was performed (rho = 6). This proposed method was applied to detection of other reactive oxygen species and nitrogen species (ROS/RNS) such as singlet oxygen (1O2), hydroxyl radical (*OH), peroxynitrite (ONOO-) etc., and it was possible to detect them with a high sensitivity. In addition, this proposed method was applied to the recovery tests of H2O2 in calf serum, human saliva, rain water, and wheat noodles; the results were satisfactory.
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PMID:Fluorophotometric determination of hydrogen peroxide with fluorescin in the presence of cobalt (II) and reaction against other reactive oxygen species. 1925 31


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