Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inducible nitric oxide (NO) synthase (iNOS)-mediated hyperproduction of NO in airways has been reported in asthmatic patients. However, the role of NO in the pathogenesis of asthma has not yet been fully elucidated. The aim of this study was to examine whether the iNOS-derived NO affects airway microvascular leakage, one of the characteristic features of asthmatic airway inflammation. Guinea-pigs were exposed to lipopolysaccharide (LPS) (1 mg x mL(-1)) by inhalation in order to induce iNOS in the airways, and the histochemical staining of reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-diaphorase activity was determined 5 h after the inhalation to confirm the iNOS induction. Airway microvascular leakage to subthreshold doses of substance P (0.3 microg x kg(-1), i.v.) was also examined in the absence and presence of an iNOS inhibitor (aminoguanidine) in LPS- or saline-exposed (control) animals using Evans blue dye and Monastral blue dye. In the LPS-exposed animals, increased NADPH-diaphorase activity was observed in the airway microvasculature compared with the control animals. Substance P caused significant airway microvascular leakage assessed by Evans blue dye in all airway levels in the LPS-exposed animals but not in the control group. This was also confirmed by Monastral blue dye extravasation. Aminoguanidine abolished this LPS-induced enhancement of plasma leakage to substance P without changing the systemic blood pressure. These results may suggest that inducible nitric oxide synthase-derived nitric oxide is capable of potentiating neurogenic plasma leakage in airways.
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PMID:Induction of nitric oxide synthase by lipopolysaccharide inhalation enhances substance P-induced microvascular leakage in guinea-pigs. 981 54

Topochemistry and activity of NADP-H diaphorase co-localized with NO synthase was examined in operative material of lungs from patients with bronchial asthma (BA), chronic nonobstructive bronchitis (CNO) and chronic obstructive bronchitis. The enzyme activity was found to be dependent upon the types of obstruction and inflammation. In CNO the state of NO synthase was not changed. In conditions of progressive irreversible airway obstruction the enzyme activity was augmented in small bronchi epithelium and alveolar macrophages (AM). In reversible obstruction the activity of NO synthase was not changed in the epithelium but appeared high in resident cells of inflammation--AM and mast cells.
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PMID:[The NADPH-diaphorase activity of the bronchial epithelium in chronic lung diseases]. 982 26

To study the role of nitric oxide synthase (NOS) in rat experimental bronchial asthma. 3H-arginine/3H-L-citrulline conversion technique was used to assay NOS activity of rat lung tissue and histochemical staining method for detect NADPH-d diaphorase. The results revealed that there were significant increase in the level of iNOS activity in asthma group from 152.39% to 249.40%, but the cNOS activity reduced from 64.84% to 61.81% (P < 0.05-0.01). Histochemical staining of NADPH-d showed deep staining of trachial and bronchial epithelium in asthma group. These results suggested that NOS plays a role in regulating airway inflammation and bronchial responsiveness. cNOS possesses a down regulatory effect, while iNOS upregulatory. The occurrence of airway inflammation is earlier than that of smooth muscle contraction and endothelial injury.
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PMID:[An experimental study on the effect of nitric oxide synthase in bronchial asthma]. 1043 84

Diesel exhaust particles (DEP) induce pulmonary diseases including asthma and chronic bronchitis. Comprehensive evaluation is required to know the effects of pollutants including DEP on these and other lung diseases. Alveolar macrophages (AM) and epithelial cells are important cellular targets for pollutants such as DEP in the lung. Alveolar macrophages encounter and phagocytose DEP in the alveolar space, and their biological responses have been implicated in DEP-induced pulmonary diseases. Expression profiles of genes induced by DEP in AM will lead to better understanding of the mechanisms involved in pulmonary diseases. To characterize the effect of the DEP extract on AM systematically, we analyzed the gene expression in AM exposed to DEP extract using the Atlas Rat Toxicology Array II. The finding in cDNA microarray was further confirmed by Northern blot analysis. AM were exposed to 10 microg/ml of DEP extract for 6 h in order to elucidate early response to DEP extract in AM. Early response to DEP extract in AM may affect the alteration of gene expression in subsequent responses so that it is important to identify the alteration in early response. In this study, the transcription of 6 genes in the cDNA microarray was significantly elevated by exposure of the AM to DEP extract. These genes were heme oxygenase (HO)-1 and -2, thioredoxin peroxidase 2 (TDPX-2), glutathione S-transferase P subunit (GST-P), NAD(P)H dehydrogenase, and proliferating cell nuclear antigen (PCNA). The antioxidative enzymes such as HO, TDPX-2, GST-P, and NAD(P)H dehydrogenase may play a role in the pulmonary defense against oxidative stress caused by various pollutants including DEP. PCNA may have contributed to the repair of DNA damage and to cell proliferation caused by exposure to these pollutants. Our results suggest that cDNA microarray analysis is a useful tool to investigate the biological responses to pulmonary toxicants.
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PMID:cDNA microarray analysis of gene expression in rat alveolar macrophages in response to organic extract of diesel exhaust particles. 1201 83

Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) M1 are phase II enzymes important in response to oxidative stress, such as occurs during exposure to ozone. We examined the relationship between functionally significant polymorphisms in NQO1 (Pro187Ser) and GSTM1 (homozygous deletion) and asthma risk in children with high lifetime exposure to ozone. We enrolled children with asthma from the allergy referral clinic at a public pediatric hospital in Mexico City, together with their parents. We assayed for the Pro187Ser polymorphism in NQO1 using a polymerase chain reaction-restriction fragment length polymorphism assay and for the presence of GSTM1 by polymerase chain reaction among 218 case-parent triads. We did not find strong evidence of an association between NQO1 genotype alone and asthma risk. However, among subjects with homozygous deletion of GSTM1, carriers of a serine allele were at significantly reduced risk of asthma compared with Pro/Pro homozygotes (relative risk = 0.4; 95% confidence interval, 0.2-0.8). The p value for difference in relative risk for NQO1 by GSTM1 genotype = 0.013. These data are consistent with a protective effect of the NQO1 Ser allele in this population of GSTM1-null children with high ozone exposure.
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PMID:Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase and glutathione S-transferase M1 polymorphisms and childhood asthma. 1296 68

An efficient testing strategy called the "focused interaction testing framework" (FITF) was developed to identify susceptibility genes involved in epistatic interactions for case-control studies of candidate genes. In the FITF approach, likelihood-ratio tests are performed in stages that increase in the order of interaction considered. Joint tests of main effects and interactions are performed conditional on significant lower-order effects. A reduction in the number of tests performed is achieved by prescreening gene combinations with a goodness-of-fit chi2 statistic that depends on association among candidate genes in the pooled case-control group. Multiple testing is accounted for by controlling false-discovery rates. Simulation analysis demonstrated that the FITF approach is more powerful than marginal tests of candidate genes. FITF also outperformed multifactor dimensionality reduction when interactions involved additive, dominant, or recessive genes. In an application to asthma case-control data from the Children's Health Study, FITF identified a significant multilocus effect between the nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase gene (NQO1), myeloperoxidase gene (MPO), and catalase gene (CAT) (unadjusted P = .00026), three genes that are involved in the oxidative stress pathway. In an independent data set consisting primarily of African American and Asian American children, these three genes also showed a significant association with asthma status (P = .0008).
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PMID:A testing framework for identifying susceptibility genes in the presence of epistasis. 1638 46

Nitric oxide synthase 1 (NOS1) is a major determinant of bronchial responsiveness in mice and has been proposed as an asthma gene in man. Nevertheless, how nitric oxide production by NOS1 contributes to airway responsiveness remains unclear. Although NOS1 is usually closely associated with nerves, it has also been found in a variety of other cell types, particularly epithelium. We sought to better understand the role of NOS1 by determining its major site of expression in murine airways. Using nicotinamide adenine dinucleotide phosphate-diaphorase (diaphorase), which non-selectively detects nitric oxide synthase (NOS), we found strong evidence of NOS in the airways largely restricted to the airway epithelium and trachea glands. In contrast, diaphorase staining of NOS1-deficient mutant mice demonstrated a marked reduction in epithelial cells of the trachea but not bronchioles, suggesting that the epithelium is the major site of NOS1 expression. This was supported by immunohistochemistry, which also demonstrated significant staining in glands and to a lesser degree in airway smooth muscle. Double immunofluorescence staining of tracheas for NOS1 and the nerve marker PGP 9.5 failed to demonstrate co-localization, indicating that nerves are not an important source of NOS1 in the murine airway wall. Finally, removal of the trachea epithelium by digestion resulted in a marked decrease in NOS1 detection by Western blotting, confirming the epithelium as the major site of NOS1 expression in the murine airway. These findings support the notion that the role of NOS1 in murine bronchial responsiveness involves the epithelium of the central airways.
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PMID:Localization and distribution of NOS1 in murine airways. 1757 82

There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).
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PMID:Genetic susceptibility to the respiratory effects of air pollution. 1963 9

The management of moderate to severe childhood asthma remains empirical. Genotypic variation has been proposed as a way to tailor specific pharmaceutical regimens to individual patients. The objective of this study was to determine the factors associated with asthma treatment progression, including functional polymorphisms of phase II detoxification enzymes, demographics, and environmental factors. In a study of 120 asthmatic children cared for in a single pediatric pulmonary practice, intensity of medical treatment over the year prior was modeled as a function of null mutations of glutathione S transferase (GST) M1 and T1, ile105val variant of GSTP1, and pro187ser variant of NAD(P)H:quinone oxidoreductase 1 (NQO1). The model included demographics, medical information, and environmental factors obtained via questionnaire analyzed with multivariate logistic regression and artificial neural networks. Multivariate logistic regression with bootstrapped validation identified a polymorphic variant of NQO1 as significantly contributing to increasing the odds of receiving more aggressive medical therapy (odds ratio, 11.56; p=0.0001). Parent income and education inversely correlated with medical treatment (odds ratio, 1.50; p=0.001 and odds ratio, 0.375; p=0.002, respectively). Age and reporting restricted physical activity due to asthma also impacted medical treatment (odds ratio, 0.63; p=0.0001 and odds ratio, 5.90; p=0.004, respectively). The optimism-adjusted discriminative ability (c-index) of the model was 0.881 (close to Bayes optimum of 0.902) with 80% overall classification accuracy. Our study supports the role of NQO1 polymorphism as an important factor determining the intensity of medical therapy in asthmatic children after adjusting for significance relating to parental income and education level, age, and restricted physical activity. Asthmatic children with a functional polymorphism of NQO1 may require more intensive pharmaceutical treatment to effectively control their asthma.
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PMID:Functional polymorphism of detoxification gene NQO1 predicts intensity of empirical treatment of childhood asthma. 1902 76

Environmental tobacco smoke (ETS) exposure might increase the risk for childhood asthma, and we hypothesized the effect may be modified by the phase II genes NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutathione S-transferase (GST) M1. To investigate the genetic and environmental associations with asthma, GSTM1 and NQO1 functional polymorphisms and ETS were analyzed in a two-staged cross-sectional study among elementary schoolchildren in Taiwan. Multiple logistic regression analysis revealed a significant association between the Ser allele of the NQO1 Pro187Ser polymorphism and asthma (OR=1.6, 95% CI 1.3-1.8). Although GSTM1 genotype itself was not significantly associated with asthma (OR=1.0, 95% CI 0.8-1.1), the GSTM1 genotype modified the association between the NQO1 polymorphism and asthma in children exposed to ETS (p=0.0002). The NQO1 gene might be involved in the development of asthma, especially in children carrying the GSTM1 null genotype who are exposed to ETS.
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PMID:NAD(P)H: Quinone oxidoreductase 1, glutathione S-transferase M1, environmental tobacco smoke exposure, and childhood asthma. 1959 59


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