title: Amelioration of intracellular stress and reduction of neural tube defects in embryos of diabetic mice by phytochemical quercetin.
abstract: Diabetes mellitus in early pregnancy causes birth defects, including neural tube defects (NTDs). Hyperglycemia increases production of nitric oxide (NO) through NO synthase 2 (Nos2) and reactive oxygen species (ROS), generating nitrosative and oxidative stress conditions in the embryo. The present study aimed to target nitrosative stress using a naturally occurring Nos2 inhibitor, quercetin, to prevent NTDs in the embryos of diabetic mice. Daily administration of quercetin to diabetic pregnant mice during the hyperglycemia-susceptible period of organogenesis significantly reduced NTDs and cell apoptosis in the embryos, compared with those of vehicle-treated diabetic pregnant mice. Using HPLC-coupled ESI-MS/MS, quercetin metabolites, including methylated and sulfonylated derivatives, were detected in the conceptuses. The methylated metabolite, 3-O-methylquercetin, was shown to reduce ROS level in embryonic stem cells cultured in high glucose. Quercetin treatment decreased the levels of Nos2 expression, protein nitrosylation, and protein nitration, alleviating nitrosative stress. Quercetin increased the expression of superoxide dismutase 1 and 2, and reduced the levels of oxidative stress markers. Expression of genes of redox regulating enzymes and DNA damage repair factors was upregulated. Our study demonstrates that quercetin ameliorates intracellular stresses, regulates gene expression, and reduces embryonic malformations in diabetic pregnancy.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Lixue
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.|College of Marine Technology and Environment, Dalian Ocean University, Dalian, China.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Tan
authors.affiliation: College of Marine Technology and Environment, Dalian Ocean University, Dalian, China.
authors.forename: Fantong
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Peiyan
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: E Albert
authors.initials: EA
authors.lastname: Reece
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051379:Mice; D009436:Neural Tube Defects / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000378:metabolism* / Q000473:pathology; D011794:Quercetin / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D052247:Nitric Oxide Synthase Type II; D011794:Quercetin; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2; C496317:Nos2 protein, mouse; C000606291:Sod1 protein, mouse