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  • PF-562271 br Acknowledgments This research was partially sup

    2021-12-03


    Acknowledgments This research was partially supported by the National Key Research and Development Program of China (2018YFD1000800); the National Natural Science Foundation of China (No. 31872943; No. 31501779 and No. 31372059>); 12th Five-Year State Science and Technology Support Program (2014BAD05B03); Shandong Agriculture Research System (SDAIT-05-05; SDAIT-05-07; SDAIT-05-10); and Shandong Academy of Agricultural Sciences Innovation Project of Agricultural Science and Technology (CXGC2018E08; CXGC2016B06). We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.
    Asthma is a complex disease characterized by inflammation and hyperresponsiveness of the airways. Nitric oxide (NO) signaling pathways have been implicated in the regulation of airway hyperresponsiveness in asthma., NO levels are higher in the exhaled air of asthmatic patients than in the exhaled air of unaffected individuals; cytokine-induced overexpression of NO synthase in the airways likely contributes to the increase., The biologic function of NO is conveyed mainly through S-nitrosylation of cysteine residues of proteins to form more stable S-nitrosothiols. S-nitrosothiols are potent endogenous bronchodilators that are depleted from the airway lining fluid in human asthmatic patients,, suggesting that they might play a protective role against airway hyperresponsiveness. The most common S-nitrosothiol in the airway is S-nitrosoglutathione (GSNO). S-nitrosoglutathione reductase (GSNOR) is the major enzyme that catalyzes GSNO metabolism and controls intracellular levels of S-nitrosothiols. Recent evidence demonstrates that GSNOR activity is increased in asthmatic lungs, resulting in diminished S-nitrosothiols and leading, in turn, to airway hyperresponsiveness. gene knockout mice have increased lung S-nitrosothiol levels and are protected from airway hyperresponsiveness after methacholine or allergen challenge, suggesting that GSNOR is a crucial modulator of airway tone. Because of the accumulating evidence for a role of GSNOR in PF-562271 pathogenesis,, , we used the case-parent triad design to investigate associations of polymorphisms and haplotypes with childhood asthma and atopy in asthmatic children from Mexico City. We are aware of no published data on genetic variation in and asthma risk. Methods
    Discussion Based on accumulating experimental evidence,2, 10, 11 we examined GSNOR as a potential asthma candidate gene. Carrying 1 or 2 copies of the minor A allele of the rs1154404 SNP decreased the risk of childhood asthma. This finding translates to an increased risk of asthma among homozygotes for the major T allele of this SNP. For the rs28730619 SNP, homozygotes for the minor G allele also had an increased risk of asthma development. Results of haplotype analysis agreed with the single SNP findings; the most common haplotype, the one containing the major T allele of rs1154404 and the minor G allele of rs28730619, increased the risk of asthma. NO plays dual roles in asthma pathogenesis, contributing to airway inflammation through the formation of toxic reactive nitrogen species or, in contrast, relaxing bronchial smooth muscle and leading to bronchodilation through the formation of S-nitrosothiols.7, 33 In S-nitrosylation, which occurs largely in proteins, NO covalently modifies cysteine thiols to form S-nitrosothiols. These compounds, in particular GSNO, are the reservoir of NO bioactivity. S-nitrosothiols are potent endogenous bronchodilators that regulate bronchial smooth muscle tone and protect against airway hyperresponsiveness in human asthma. The homeostasis of S-nitrosothiols is modulated by GSNOR, a very specific enzyme for GSNO metabolism. GSNOR, originally known as formaldehyde dehydrogenase, was recently identified by Liu et al as a metabolism enzyme for GSNO. The official gene name of GSNOR is alcohol dehydrogenase 5, which is located in a gene cluster with another 5 alcohol dehydrogenase genes on chromosome 4. However, GSNOR is unique in that its promoter is GC rich and does not have a TATA box. Furthermore, GSNOR differs in catalytic profile from all other alcohol dehydrogenases. For example, it appears to have no activity for ethanol oxidation, and its best known substrate is GSNO.