Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00369 (ROS)
 19,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The short-term metabolic fate of labeled nitrogen derived from [13N]ammonia or from L-[amide-13N]glutamine was determined in murine tumors known to be resistant (Ridgeway Osteogenic Sarcoma (ROS] or sensitive (Sarcoma-180 (S-180)) to glutaminase therapy. At 5 min after intraperitoneal injection of [13N]ammonia or of L-[amide-13N]glutamine, only about 0.7% of the label recovered in both tumors was in protein and nucleic acid. After [13N]ammonia administration, most of the label (over 80%) was in a metabolized form; a large portion of this metabolized label (50-57%) was in the urea fraction with a smaller amount in glutamine (37-42%). The major short-term fate of label derived from L-[amide-13N]glutamine was incorporation into components of the urea cycle with smaller amounts in the acidic metabolites and in acidic amino acids. No labeled urea was found during in vitro studies in which S-180 tumor slices were incubated with [13N]ammonia, suggesting that the [13N]urea formed in the tumor in the in vivo experiments was not due to de novo synthesis through carbamyl phosphate in the tumor. Both tumors exhibited very low glutamine synthetase activity. Following glutaminase treatment, glutamine synthetase and gamma-glutamyltransferase activities, while remaining low, increased in the resistant tumor but not in the sensitive tumor; this increase may be related to the insensitivity of the ROS tumor toward glutaminase treatment.
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PMID:[13N]Ammonia and L-[amide-13N]glutamine metabolism in glutaminase-sensitive and glutaminase-resistant murine tumors. 286 80

Reactive oxygen species (ROS: superoxide radical, O2.-; hydrogen peroxide, H2O2; hydroxyl radical, OH.), which arise from the univalent reduction of dioxygen are formed in mitochondria. We summarize here results which indicate that ROS, and also the radical nitrogen monoxide ('nitric oxide', NO), act as physiological modulators of some mitochondrial functions, but may also damage mitochondria. Hydrogen peroxide, which originates in mitochondria predominantly from the dismutation of superoxide, causes oxidation of mitochondrial pyridine nucleotides and thereby stimulates a specific Ca2+ release from intact mitochondria. This release is prevented by cyclosporin A (CSA). Hydrogen peroxide thus contributes to the maintenance of cellular Ca2+ homeostasis. A stimulation of mitochondrial ROS production followed by an enhanced Ca2+ release and re uptake (Ca2+ 'cycling') by mitochondria causes apoptosis and necrosis, and contributes to hypoxia/reperfusion injury. These kinds of cell injury can be attenuated at the mitochondrial level by CSA. When ROS are produced in excessive amounts in mitochondria nucleic acids, proteins, and lipids are extensively modified by oxidation. Physiological (sub-micromolar) concentrations of NO potently and reversibly deenergize mitochondria at oxygen tensions that prevail in cells by transiently binding to cytochrome oxidase. This is paralleled by mitochondrial Ca2+ release and uptake. Higher NO concentrations or prolonged exposure of cells to NO causes their death. It is concluded that ROS and NO are important physiological reactants in mitochondria and become toxic only when present in excessive amounts.
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PMID:Oxidants in mitochondria: from physiology to diseases. 759 28

Nitric oxide (NO) is a free radical produced enzymatically in biological systems from the guanidino group of L-arginine. Its large spectrum of biological effects is achieved through chemical interactions with different targets including oxygen (O2), superoxide (O2o-) and other oxygen reactive species (ROS), transition metals and thiols. Superoxide anions and other ROS have been reported to react with NO to produce peroxynitrite anions that can decompose to form nitrogen dioxide (NO2) and hydroxyl radial (OHo). Thus, NO has been reported to have a dual effect on lipid peroxidation (prooxidant via the peroxynitrite or antioxydant via the chelation of ROS). In the present study we have investigated in different models the in vitro and in vivo action of NO on lipid peroxidation. Copper-induced LDL oxidation were used as an in vitro model. Human LDL (100 micrograms ApoB/ml) were incubated in oxygene-saturated PBS buffer in presence or absence of Cu2+ (2.5 microM) with increasing concentrations of NO donnors (sodium nitroprussiate or nitroso-glutathione). LDL oxidation was monitored continuously for conjugated diene formation (234 nm) and 4-hydroxynonenal (HNE) accumulation. Exogenous NO prevents in a dose dependent manner the progress of copper-induced oxidation. Ischaemia-reperfusion injury (I/R), characterized by an overproduction of ROS, is used as an in vivo model. Anaesthetized rats were submitted to 1 hour renal ischaemia following by 2 hours of reperfusion. Sham-operated rats (SOP) were used as control. Lipid peroxidation was evaluated by measuring the HNE accumulated in rats kidneys in presence or absence of L-arginine or D-arginine infusion. L-arginine, but not D-arginine, enhances HNE accumulation in I/R but not in SOP (< 0.050 pmol/g tissue in SOP versus 0.6 nmol/g tissue in I/R), showing that, in this experimental conditions, NO produced from L-arginine, enhances the toxicity of ROS. This study shows that the pro- or antioxydant effects of NO are different in vivo and in vitro and could be driven by environmental conditions such as pH, relative concentrations of NO and ROS, ferryl species.
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PMID:[Nitric oxide and lipid peroxidation]. 867 27

Free radicals, such as superoxide, hydroxyl and nitric oxide, and other "reactive species", such as hydrogen peroxide, hypochlorous acid and peroxynitrite, are formed in vivo. Some of these molecules, e.g. superoxide and nitric oxide, can be physiologically useful, but they can also cause damage under certain circumstances. Excess production of reactive oxygen or nitrogen species (ROS, RNS), their production in inappropriate relative amounts (especially superoxide and NO) or deficiencies in antioxidant defences may result in pathological stress to cells and tissues. This oxidative stress can have multiple effects. It can induce defence systems, and render tissues more resistant to subsequent insult. If oxidative stress is excessive or if defence and repair responses are inadequate, cell injury can be caused by such mechanisms as oxidative damage to essential proteins, lipid peroxidation, DNA strand breakage and base modification, and rises in the concentration of intracellular "free" Ca(2+). Considerable evidence supports the view that oxidative damage involving both ROS and RNS is an important contributor to the development of atherosclerosis. Peroxynitrite (derived by reaction of superoxide with nitric oxide) and transition metal ions (perhaps released by injury to the vessel wall) may contribute to lipid peroxidation in atherosclerotic lesions.
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PMID:Blood radicals: reactive nitrogen species, reactive oxygen species, transition metal ions, and the vascular system. 886 Apr 19

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

Epidemiologic and occupational studies indicate adverse health effects due to inhalation of particulate air pollutants, but precise biologic mechanisms responsible have yet to be fully established. The tracheobronchial epithelium forms the body's first physiologic barrier to such airborne pollutants, where ciliary movement functions to remove the offending substances caught in the overlying mucus layer. Resident and infiltrating phagocytic cells also function in this removal process. In this paper, we examine the role of reactive oxygen and nitrogen species (ROS/RNS) in the response of airway epithelium to particulates. Some particulates themselves can generate ROS, as can the epithelial cells, in response to appropriate stimulation. In addition, resident macrophages in the airways and the alveolar spaces can release ROS/RNS after phagocytosis of inhaled particles. These macrophages also release large amounts of tumor necrosis factor alpha (TNF-alpha), a cytokine that can generate responses within the airway epithelium dependent upon intracellular generation of ROS/RNS. As a result, signal transduction pathways are set in motion that may contribute to inflammation and other pathobiology in the airway. Such effects include increased expression of intercellular adhesion molecule 1, interleukin-6, cytosolic and inducible nitric oxide synthase, manganese superoxide dismutase, cytosolic phospholipase A2, and hypersecretion of mucus. Ultimately, ROS/RNS may play a role in the global response of the airway epithelium to particulate pollutants via activation of kinases and transcription factors common to many response genes. Thus, defense mechanisms involved in responding to offending particulates may result in a complex cascade of events that can contribute to airway pathology.
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PMID:The role of reactive oxygen and nitrogen species in the response of airway epithelium to particulates. 940 Jul 42

Intracellularly generated reactive species of both oxygen (ROS) and nitrogen (RNS) have been implicated in signaling responses in airway epithelial cells, but these radicals have not been measured directly in such cells. In this study, intracellular production of both ROS and RNS were measured in the same cell lysates of guinea pig tracheal epithelial (GPTE) cells maintained in primary culture. ROS and RNS were quantified under basal (constitutive) conditions and in response to different stimuli: LPS and TNFalpha [activators of inducible nitric oxide synthase (iNOS)]; several activators of calcium-dependent cNOS (ATP, bradykinin, ionophore A23187, and thapsigargin); and exogenous oxidant stress generated by addition of xanthine oxidase to purine (p + XO). Studies with LPS and TNFalpha also were performed using the murine macrophage cell line, RAW 264.7, as a positive control. Intracellular oxidant production was detected from oxidation of dihydrorhodamine to rhodamine. NOx was quantified by either chemiluminescent or fluorescent detection. NOS activity was measured as citrulline production from arginine. Basal production of oxidants by GPTE cells (0.08 + 0.00 nmol rhodamine) was less than 10% that of RAW.267 cells (0.91 + 0.03 nmol rhodamine). TNFalpha and LPS significantly increased intracellular oxidant production in GPTE cells, as did p + XO, but none of the cNOS activators affected production of oxidants in these cells. Concentrations of NO2 after 4 h in unstimulated RAW 264.7 and GPTE cells were similar and comprised 63% of total NOx in GPTE and 62% in RAW cells. TNFalpha and LPS both increased NO2 in GPTE cells, but none of the Ca++-mobilizing agents nor p + XO significantly affected intracellular RNS. The results suggest both ROS and RNS can be measured in the same lysates from airway epithelial cells, and that both ROS and RNS are produced in these cells in response to different stimuli.
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PMID:Concurrent production of reactive oxygen and nitrogen species by airway epithelial cells in vitro. 958 18

Nitrogen monoxide (NO) has diverse physiological roles and also contributes to the immune defense against viruses, bacteria, and other parasites. However, excess production of NO is associated with various diseases such arthritis, diabetes, stroke, septic shock, autoimmune, chronic inflammatory diseases, and atheriosclerosis. Cells respond to activating or depressing stimuli by enhancing or inhibiting the expression of the enzymatic machinery that produce NO. Thus, maintenance of a tight regulation of NO production is important for human health. Phytochemicals have been traditionally utilized in ways to treat a family of pathologies that have in common the disregulation of NO production. Here we report the scavenging activity of Pycnogenol (the polyphenols containing extract of the bark from Pinus maritima) against reactive oxygen and nitrogen species, and its effects on NO metabolism in the murine macrophages cell line RAW 264.7. Macrophages were activated by the bacterial wall components lipopolysaccharide (LPS) and interferon (IFN-gamma), which induces the expression of large amounts of the enzyme nitric oxide synthase (iNOS). Preincubation of cells with physiological concentrations of Pycnogenol significantly decreased NO generation. It was found that this effect was due to the combination of several different biological activities, i.e., its ROS and NO scavenging activity, inhibition of iNOS activity, and inhibition of iNOS-mRNA expression. These data begin to provide the basis for the conceptual understanding of the biological activity of Pycnogenol and possibly other polyphenolic compounds as therapeutic agents in various human disorders.
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PMID:Procyanidins extracted from Pinus maritima (Pycnogenol): scavengers of free radical species and modulators of nitrogen monoxide metabolism in activated murine RAW 264.7 macrophages. 962 66

Peroxynitrite (ONOO-) is a strong oxidant derived from nitric oxide ('NO) and superoxide (O2.-), reactive nitrogen (RNS) and oxygen species (ROS) present in inflamed tissue. Other oxidant stresses, e.g., TNF-alpha and hyperoxia, induce mitochondrial, manganese-containing superoxide dismutase (MnSOD) gene expression. These experiments tested whether ONOO regulated MnSOD gene expression in human lung epithelial (A549) cells. 3-morpholinosydnonimine HCI (SIN-1) (10 or 1000 microM) increased MnSOD mRNA, but did not change hypoxanthine guanine phosphoribosyl transferase (HPRT) mRNA. Authentic peroxynitrite (ONOO ) (100-500 microM) also increased MnSOD mRNA but did not change constitutive HPRT mRNA expression. ONOO stimulated luciferase gene expression driven by a 2.5 kb fragment of the rat MnSOD gene 5' promoter region. MnSOD gene induction due to ONOO- was inhibited effectively by L-cysteine (10 mM) and partially inhibited by N-acetyl cysteine (50 mM) or pyrrole dithiocarbamate (10 mM). .NO from 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazine) (PAPA NONOate) (100 or 1000 microM) did not change MnSOD or HPRT mRNA. Neither H202 nor NO2-, breakdown products of SIN-1 and ONOO , had any effect on MnSOD mRNA expression; however, ONOO- and SIN-1 did not increase MnSOD protein content detectable by western blots, nor did they increase MnSOD enzymatic activity. Increased steady state [O2.-] in the presence of .NO yields ONOO , and ONOO has direct, stimulatory effects on MnSOD transcript expression.
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PMID:Peroxynitrite modulates MnSOD gene expression in lung epithelial cells. 974 82


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