Diabetes mellitus in pregnancy is one of the maternal diseases that cause congenital birth defects in infants. Even prenatal care is available in the United States;the rate of birth defects associated with maternal diabetes has not significantly declined. This crisis is being serious when the number of diabetic women in child- bearing age is increasing rapidly. Clinical studies have shown that diabetes-induced structural defects occur in many organ systems, with most common in the central nervous and cardiovascular systems. Research using animal models has shown that cell proliferation (mitosis) and death (apoptosis) are intimately associated with embryonic malformations. The induction of deceased mitosis and increased apoptosis is associated with hyperglycemia-disturbed intracellular metabolism and signaling. One of the major events in response to hyperglycemia is elevation of nitric oxide (NO) level by NO synthases (NOSes). The important role of iNOS, but not the endothelial and neural isoforms (eNOS and nNOS), in diabetic embryopathy has been demonstrated using an inos gene knockout animal model, suggesting that targeting iNOS may be a promising strategy to eliminate embryonic malformations. Recently, we have also shown that inhibition of iNOS using an inhibitor significantly reduces embryonic malformation rate, showing a feasible approach in vivo. Since interventions should be easily accessible and harmless to the embryo and mother, we aim to develop an approach using naturally occurring phytochemicals via dietary supplementation to inhibit iNOS, alleviate nitrosative stress, and eventually eliminate embryonic malformations in diabetic embryopathy. As a proof-of-concept study for future in depth investigations and translation to clinical application, we will, in Specific Aim 1, investigate if candidate dietary supplements, curcumin (from turmeric) and quercetin (from fruits), reduce fetal malformations in diabetic mouse models. Their effects on mitosis and apoptosis as well as inhibition of iNOS and nitrosative stress will also be examined.
In Specific Aim 2, we will investigate the mechanisms underlying the action of these polyphenols in alleviation of nitrosative stress. Expression and activity of iNOS, eNOS, and nNOS will be examined. The potential involvement of NF-?B and AP-1 transcription factors in regulation of iNOS expression will be investigated. When completed, this small scale research (R03) will determine whether curcumin and/or quercetin can alleviate nitrosative stress and eliminate fetal abnormalities, to provide solid basis for further investigations into in-depth mechanisms and translation into interventional application in humans.

Public Health Relevance

Diabetes mellitus in pregnancy causes congenital birth defects in infants. This public health problem imposes a tremendous challenge on the healthcare system as diabetic population is fast growing in the US. Basic research has gain information about mechanisms underlying the maternal diabetes-induced fetal abnormalities. This research proposal aims to explore a novel approach for therapeutic interventions to prevent birth defects in diabetic pregnancies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
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Developmental Biology Subcommittee (CHHD)
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Javois, Lorette Claire
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University of Maryland Baltimore
Obstetrics & Gynecology
Schools of Medicine
United States
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Tan, Chengyu; Meng, Fantong; Reece, E Albert et al. (2018) Modulation of nuclear factor-?B signaling and reduction of neural tube defects by quercetin-3-glucoside in embryos of diabetic mice. Am J Obstet Gynecol 219:197.e1-197.e8
Kim, Gyuyoup; Cao, Lixue; Reece, E Albert et al. (2017) Impact of protein O-GlcNAcylation on neural tube malformation in diabetic embryopathy. Sci Rep 7:11107
Zhao, Zhiyong; Cao, Lixue; Reece, E Albert (2017) Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects. Proc Natl Acad Sci U S A 114:4489-4494
Cao, Lixue; Tan, Chengyu; Meng, Fantong et al. (2016) Amelioration of intracellular stress and reduction of neural tube defects in embryos of diabetic mice by phytochemical quercetin. Sci Rep 6:21491
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Cao, Lixue; Liu, Peiyan; Gill, Kirandeep et al. (2016) Identification of novel cell survival regulation in diabetic embryopathy via phospholipidomic profiling. Biochem Biophys Res Commun 470:599-605
Li, Xuezheng; Zhao, Zhiyong (2014) MicroRNA biomarkers for early detection of embryonic malformations in pregnancy. J Biomol Res Ther 3: