Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.19 (NOS)
 7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We identify water-soluble (23 degrees C) crude oil NSO nonvolatile acidic, basic, and neutral crude oil hydrocarbons by negative-ion ESI and continuous flow FD FT-ICR MS at an average mass resolving power, m/deltam50% = 550,000. Of the 7000+ singly charged acidic species identified in South American crude oil, surprisingly, many are water-soluble, and much more so in pure water than in seawater. The truncated m/z distributions for water-soluble components exhibit preferential molecular weight, size, and heteroatom class influences on hydrocarbon solubility. Acidic water-soluble heteroatomic classes detected at >1% relative abundance include O, O2, O3, O4, OS, O2S, O3S, O4S, NO2, NO3, and NO4. Parent oil class abundance does not directly relate to abundance in the water-soluble fraction. Acidic oxygen-containing classes are most prevalent in the water-solubles, whereas acidic nitrogen-containing species are least soluble. In contrast to acidic nitrogen-containing heteroatomic classes, basic nitrogen classes are water-soluble. Water-soluble heteroatomic basic classes detected at >1% relative abundance include N, NO, NO2, NS, NS2, NOS, NO2S, N2, N2O, N2O2, OS, O2S, and O2S2.
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PMID:Identification of water-soluble heavy crude oil organic-acids, bases, and neutrals by electrospray ionization and field desorption ionization fourier transform ion cyclotron resonance mass spectrometry. 1753 26

A variety of gene mutations can cause familial forms of Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). Mutations in the synaptic protein alpha-synuclein (alpha-Syn) cause PD. Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) cause ALS. The mechanisms of human mutant a-Syn and SOD1 toxicity to neurons are not known. Transgenic (tg) mice expressing human mutant alpha-Syn or SOD1 develop profound fatal neurologic disease characterized by progressive motor deficits, paralysis, and neurodegeneration. Ala-53-->Thr (A53T)-mutant alpha-Syn and Gly-93-->Ala (G93A)-mutant SOD1 tg mice develop prominent mitochondrial abnormalities. Interestingly, although nigral neurons in A53T mice are relatively preserved, spinal motor neurons (MNs) undergo profound degeneration. In A53T mice, mitochondria degenerate in neurons, and complex IV activity is reduced. Furthermore, mitochondria in neurons develop DNA breaks and have p53 targeted to the outer membrane. Nitrated a-Syn accumulates in degenerating MNs in A53T mice. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of reactive oxygen/nitrogen species than MNs in control mice. mSOD1 mouse MNs accumulate DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. Nitrated and aggregated cytochrome c oxidase subunit-I and nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible NOS (iNOS)-like immunoreactivity, and iNOS gene deletion significantly extends the lifespan of G93A-mSOD1 mice. Mitochondrial changes develop long before symptoms emerge. These experiments reveal that mitochondrial nitrative stress and perturbations in mitochondrial trafficking may be antecedents of neuronal cell death in animal models of PD and ALS.
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PMID:Transgenic mice with human mutant genes causing Parkinson's disease and amyotrophic lateral sclerosis provide common insight into mechanisms of motor neuron selective vulnerability to degeneration. 1759 75

Free radical generation, including reactive nitrogen and reactive oxygen species, is known to participate in cell physiology in both a positive and negative manner. Moreover, alterations in their concentrations are implicated in a number of renal diseases. However, there is evidence that high concentration of nitric oxide (NO) occurring as a result of iNOS induction and peroxynitrite formation, is capable of causing lipid peroxidation and protein oxidation in cyclosporine A (CsA) induced cellular damage. The present study was conducted to investigate the possible protective role of Lipoic acid (LA) in nitric oxide mediated cellular abnormalities induced by CsA in rat kidney. Adult male albino rats of Wistar strain were given CsA at a dose of 25 mg/kg body weight, orally for 21 days. An extensive elevation in the activities of xanthine oxidase was noted in the renal tissue of the CsA administered rats. These changes were associated with significant increase in the levels of plasma lipid peroxidation with high protein carbonyl contents and 3-nitrotyrosine formation coupled with diminished protein thiols. In addition, plasma nitrite/nitrate (NO(x)), RT-PCR for inducible NOS (iNOS) mRNA, and immunohistochemically demonstrable iNOS protein were evaluated to assess peroxidative damage. Concomitant treatment with LA (20 mg/kg body weight, orally for 21 days showed that the oxidative stress alteration were significantly decreased in CsA treated renal tissue. While the expression of iNOS and the amounts of NO(x) were decreased simultaneously. These results indicate that the antioxidant LA might have a protective effect against CsA-induced peroxidative changes and cellular damage of the renal tissue of the rat.
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PMID:Protective effect of lipoic acid on oxidative and peroxidative damage in cyclosporine A-induced renal toxicity. 1776 48

Increased expression of inducible nitric oxide synthase (NOS-2) in inflammatory diseases like uveitis suggests that it contributes to the observed pathological state. The aim of this study was to evaluate corneal expression of NOS-2 and corneal protein nitration in a rat model of uveitis. A single injection of intravitreal lipopolysaccharide was used to induce uveitis. Corneal proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and visualized by Coomassie blue staining. Expression of NOS-2 and nitrotyrosine (NO(2)Tyr) formation were determined via immunohistochemistry and Western blot analysis. Total nitrate/nitrite levels in the vitreous were measured by spectral analysis via the Griess reagent. Immunohistochemical analysis revealed increased corneal NOS-2 and NO(2)Tyr immunoreactivity in rats with uveitis compared with controls. NOS-2 and NO(2)Tyr immunoreactivity was observed in and around basal cells in the corneal epithelium. Western blot analysis of corneal lysates showed multiple nitrated protein bands in uveitic rats. Spectrophotometric measurement of total nitrate/nitrite levels in the vitreous affirmed significantly increased levels of nitric oxide generation in uveitis (126 +/-2.63 microM/mg protein) compared with controls (65 +/-6.57 microM/mg protein). The presented data suggests that extensive formation of protein nitration and reactive nitrogen species in the cornea contributes to tissue destruction in uveitis. Hence, selective inhibition of NOS-2 may prevent long-term complications and lead to an improvement in the management of uveitis.
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PMID:Corneal protein nitration in experimental uveitis. 1795 43

Insulin Resistance along with endothelial dysfunction give rise to a constellation of syndromes designated as IRS/MBS metabolic syndrome. Endothelial dysfunction starts early in life much before the development of structural atherosclerosis. Recent insights into vascular biology enable us to understand the molecular mechanisms underlying endothelial dysfunction, and the scope and need for prevention of "pre-clinical" coronary atherosclerosis through lifestyle modification; diet, exercise and stress management. Diminished production of nitric oxide (NO) and/or increased inactivation of NO through oxidative stress (reactive oxygen species ROS and reactive nitrogen species (RNS) are the basis of endothelial dysfunction hence increasing the bioavailability of NO and decreasing its inactivation is the aim of prevention and reversal of endothelial dysfunction. Insulin regulates constitutive NOS gene expression in endothelial cells in vivo; vasodilation is an important component of Insulin-stimulated whole body glucose uptake. Successful strategies are: PPAR alpha and gamma agonists which increase NO production in endothelium; anti-oxidants such as vit. E and C; supplementation with L-arginine, tetrahydrobiopterin-BH4 or sepiapterin (precursor of BH4), SOD mimetic tempol, statins which apart from lowering cholesterol improve NO production, selective beta1 adrenoreceptor antagonists such as nebivolol; suppression of angiotensin-mediated endothelin production by ACE inhibitors and ATR blockers; CB1 receptor blockers, PKCb inhibitors, nitric oxide donors (glyceryl trinitrate and isosorbide dinitrate), dietary supplements of EPA/DHA and regular physical exercise and control of mental stress.
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PMID:Causation, prevention and reversal of vascular endothelial dysfunction. 1805 38

Nitric oxide synthase is inhibited by NG-methylated derivatives of arginine whose cellular levels are controlled by dimethylarginine dimethylamino-hydrolase (DDAH). DDAH-1 is a Zn(II)-containing enzyme that through hydrolysis of methylated l-arginines regulates the activity of NOS. Herein, we report the kinetic properties of hDDAH-1 and its redox-dependent regulation. Kinetic studies using recombinant enzyme demonstrated Km values of 68.7 and 53.6 microM and Vmax values of 356 and 154 nmols/mg/min for ADMA and L-NMMA, respectively. This enzymatic activity was selective for free ADMA and L-NMMA and was incapable of hydrolyzing peptide incorporated methylarginines. Subsequent studies performed to determine the effects of reactive oxygen and reactive nitrogen species on DDAH activity demonstrated that low level oxidant exposure had little effect on enzyme activity and that concentrations approaching >or=100 microM were needed to confer significant inhibition of DDAH activity. However, exposure of DDAH to the lipid oxidation product, 4-HNE, dose-dependently inhibited DDAH activity with 15% inhibition observed at 10 microM, 50% inhibition at 50 microM, and complete inhibition at 500 microM. Mass spectrometry analysis demonstrated that the mechanism of inhibition resulted from the formation of Michael adducts on His 173, which lies within the active site catalytic triad of hDDAH-1. These studies were performed with pathophysiologicaly relevant concentrations of this lipid peroxidation product and suggest that DDAH activity can be impaired under conditions of increased oxidative stress. Because DDAH is the primary enzyme involved in methylarginine metabolism, the loss of activity of this enzyme would result in impaired NOS activity and reduced NO bioavailability.
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PMID:Mechanism of 4-HNE mediated inhibition of hDDAH-1: implications in no regulation. 1817 Oct 27

We earlier demonstrated that nitric oxide (NO) is a fungicidal molecule against Sporothrix schenckii in vitro. In the present study we used mice deficient in inducible nitric oxide synthase (iNOS-/-) and C57BL/6 wild-type (WT) mice treated with Nomega-nitro-arginine (Nitro-Arg-treated mice), an NOS inhibitor, both defective in the production of reactive nitrogen intermediates, to investigate the role of endogenous NO during systemic sporotrichosis. When inoculated with yeast cells of S. schenckii, WT mice presented T-cell suppression and high tissue fungal dissemination, succumbing to infection. Furthermore, susceptibility of mice seems to be related to apoptosis and high interleukin-10 and tumour necrosis factor-alpha production by spleen cells. In addition, fungicidal activity and NO production by interferon-gamma (IFN-gamma) and lipopolysaccharide-activated macrophages from WT mice were abolished after fungal infection. Strikingly, iNOS-/- and Nitro-Arg-treated mice presented fungal resistance, controlling fungal load in tissues and restoring T-cell activity, as well as producing high amounts of IFN-gamma Interestingly, macrophages from these groups of mice presented fungicidal activity after in vitro stimulation with higher doses of IFN-gamma. Herein, these results suggest that although NO was an essential mediator to the in vitro killing of S. schenckii by macrophages, the activation of NO system in vivo contributes to the immunosuppression and cytokine balance during early phases of infection with S. schenckii.
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PMID:Detrimental role of endogenous nitric oxide in host defence against Sporothrix schenckii. 1819 65

There is growing evidence indicating that reactive nitrogen species (RNS) and reactive oxygen species (ROS) are a major contributor to the pathogenesis and progression of Parkinson's disease. Here we investigated whether edaravone (free radical scavenger), minocycline (inducible nitric oxide synthase, iNOS inhibitor), 7-nitroindazole (neuronal NOS, nNOS inhibitor), fluvastatin (endothelial NOS, eNOS activator) and pitavastatin (eNOS activator) can protect against MPTP neurotoxicity in mice under the same condition. The present study showed that 7-nitroindazole could protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletion. Our immunohistochemical study showed that TH (tyrosine hydroxylase) and DAT (dopamine transporter) immunoreactivity was decreased significantly in the striatum and substantia nigra 5 days after MPTP treatment. The administration of 7-nitroindazole showed a protective effect against the severe reductions in levels of TH and DAT immunoreactivity in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the remarkable loss of TH protein levels in the striatum 5 days after MPTP treatment. In contrast, 7-nitroindazole prevented a significant loss in TH protein levels in the striatum 5 days after MPTP treatment. On the other hand, GFAP (glial fibrillary acidic protein) immunoreactivity increased significantly in the striatum and substantia nigra, 5 days after MPTP treatment. 7-Nitroindazole ameliorated severe increases in number of GFAP immunoreactive astrocytes in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the increase of GFAP protein levels in the striatum 5 days after MPTP treatment. 7-Nitroindazole prevented a significant increase in the GFAP protein levels in the striatum 5 days after MPTP treatment. The present results indicate that 7-nitroindazole can protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletions. These findings demonstrate that the overexpression of nNOS may play a major role in the neurotoxic processes of MPTP, as compared to the production of ROS, the overexpression of iNOS and the modulation of eNOS. Thus, our findings provide strong evidence for neuroprotective properties of nNOS inhibitor in this animal model of Parkinson's disease.
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PMID:Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice. 1823 88

Previous studies have shown that in situ exposure to arsenic induced increased vascular leakage. However, the underlying mechanism remains unclear. Reactive nitrogen and oxygen species such as nitric oxide (NO) and hydroxyl radical (OH(-)) are known to affect vascular permeability. Therefore, the goal of our present studies is to investigate the functional impact of the generation of NO or OH(-) on arsenic-induced vascular leakage. Vascular permeability changes were evaluated by means of Evans blue (EB) assay. Rats were anesthetized and intravenously injected with EB. Permeability changes were induced in back skin by intradermal injections of sodium arsenite mixed with NOS inhibitor: N(omega)-Nitro-L-arginine methyl ester (L-NAME) or aminoguanidine (AG) and OH(-) scavenger: 1,3 Dimethyl-2 thiourea (DMTU). Experiments were also performed to determine whether DMTU mixed with L-NAME would further inhibit arsenic-induced vascular leakage as compared with attenuation effects by either DMTU or L-NAME. One hour after administration, EB accumulated in the skin was extracted and quantified. Both L-NAME (0.02, 0.1 and 0.5 micromol/site) and DMTU (0.05, 0.2 and 1.2 micromol/site) inhibited the increase in vascular leakage induced by arsenite. However, only high dose (1 micromol/site) of AG significantly attenuated arsenite-induced vascular leakage. In contrast, neither D-NAME (0.02, 0.1 and 0.5 micromol/site) nor AG (0.04 and 0.2 micromol/site) attenuated increased vascular leakage by arsenic. DMTU mixed with L-NAME caused no further inhibition of arsenic-induced vascular leakage by either DMTU or L-NAME. The techniques of India ink and immunostaining were used to demonstrate both vascular labeling and nitrotyrosine staining in tissue treated with arsenic. L-NAME apparently reduced the density of leaky vessels and the levels of peroxynitrite staining induced by arsenite. These results suggest that NO, OH(-) and peroxynitrite play a role in increased vascular permeability induced by arsenic exposure.
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PMID:Vascular leakage induced by exposure to arsenic via increased production of NO, hydroxyl radical and peroxynitrite. 1824 49

7-Nitroindazole (NI) is a widely used inhibitor of neuronal nitricoxide synthase (nNOS) used to study the role of the neuronal NO pathway in the nervous system. 7-NI prevents convulsions, including 2-amino-4-methylphosphinobutyric acid (glufosinate)-induced convulsions, in experimental models. Herein, we examined nNOS involvement in glufosinate-induced convulsions and the specificity of 7-NI for nNOS. Another nNOS inhibitor, 1-[2-(trifluoromethyl)phenyl]imidazole (TRIM), inhibited NOS activity in vivo, and it prevented glufosinate-induced convulsions. In contrast, an endothelial NOS inhibitor, N(5)-(1-iminoethyl)-l-ornithine, inhibited NOS activity in vivo, but it did not prevent the convulsions. These results suggest the involvement of nNOS in glufosinate-induced convulsions. However, a nonspecific NOS inhibitor, N(omega)-nitro-l-arginine methyl ester, inhibited NOS activity in vivo, but it failed to prevent glufosinate-induced convulsions. 6-NI and indazole, which did not inhibit NOS activity in vivo, suppressed glufosinate-induced convulsions. Moreover, glufosinate elicited convulsions in nNOS-deficient mice. These results suggest the anticonvulsant effects of 7-NI and TRIM on glufosinate-induced convulsions do not involve nNOS inhibition, instead possibly being related to an undefined property of nitrogen-containing chemical structures.
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PMID:Activities of 7-nitroindazole and 1-(2-(trifluoromethylphenyl)-imidazole independent of neuronal nitric-oxide synthase inhibition. 1827 Mar 16


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