目的性的硝化应激减少糖尿病胚胎期畸形
孕期糖尿病和婴儿的出生缺陷相关。孕期高血糖干扰了胚胎细胞内的代谢稳态，通过诱导的NO合成酶导致了一氧化氮（NO）的过度产生。这一导致的硝化应激不像内质网（ER）和氧化应激，它是糖尿病高血糖胚胎病的早期反应。目标性的硝化应激是一个有潜力的（治疗疾病）的介入策略，特别是类似的抗氧化应激的方法在治疗类似疾病中的失败之后。我们之前展示了iNOS抑制剂L-N6-(1-iminoethyl)-lysine在糖尿病小鼠上显著的降低了胚胎期畸形率和减轻了ER应激。为了进一步探索这一方法的介入应用，我们调查了一种天然iNOS抑制剂槲皮素在糖尿病胚胎病中在消除胚胎异常中的作用。糖尿病小鼠(C57BL/6J) 由静脉注射链脲佐菌素诱导而成并且自胚胎形成日7.5到9.5天(体内敏感器官形成期)起每天灌胃槲皮素(100 mg/公斤体重)在E10.5日检查糖尿病小鼠胚胎，显示治疗组明显的减少了神经管缺损的发生率。这一形态学结果和利用TUNEL和半胱天冬酶活化化验检验得到的神经上皮的凋亡减少结果是一致的。糖尿病组合非糖尿病对照组相比，槲皮素减少了iNOS表达所有蛋白的亚硝基化和硝基酪氨酸水平。槲皮素同时减轻了ER和氧化应激，表现为相关生物标志物水平的下降。所有这些试验证明使用天然植物化学物质进行目标性的硝化应激，消除孕期糖尿病的出生缺陷是一种很有前途的方法。
Targeting Nitrosative Stress to Reduce Embryonic Malformations in Diabetic Embryopathy
Diabetes mellitus in pregnancy is associated with birth defects in infants. Maternal hyperglycemia disturbsintracellular metabolic homeostasis in the embryo leading to overproduction of nitric oxide (NO) via inducible NOsynthase (iNOS). The resultant nitrosative stress unlike endoplasmic reticulum (ER) and oxidative stress conditions isan early response to hyperglycemia in diabetic embryopathy. Targeting nitrosative stress is potentially a promisinginterventional strategy especially when antioxidative approaches have failed to ameliorate similar diseases. We havepreviously shown that iNOS inhibitor L-N6-(1-iminoethyl)-lysine significantly reduces embryonic malformation rate andalleviates ER stress in diabetic mice. To further explore interventional application of this approach we investigated anaturally occurring iNOS inhibitor quercetin in elimination of embryonic abnormalities in diabetic embryopathy.Diabetic pregnant mice (C57BL/6J) induced by intravenous injection of streptozotocin were fed quercetin (100 mg/kgbody weight) via gavage once a day from embryonic (E) day 7.5 to 9.5 (susceptible period of organogenesis).Examination of the embryos at E10.5 showed a significant reduction in neural tube defect rate in the embryos ofdiabetic mice compared with vehicle-treated diabetic group. This morphological outcome is associated with decreasesin apoptosis in the neural epithelium assessed using TUNEL and caspase activation assays. Quercetin decreasediNOS expression global protein nitrosylation and 3-nitrotyrosine in diabetic group to the levels in non-diabeticcontrols. Quercetin also alleviated ER and oxidative stresses indicated by decreases in associated biomarkers. Allthese demonstrate that targeting nitrosative stress using naturally occurring phytochemicals is a promising approachto elimination of birth defects in diabetic pregnancy.
ADA是美国糖尿病学会 (Americn Diabetos Association)的缩写，美国糖尿病协会县美国重要的非赢利性卫生姐织，旨在提供有关糖尿病的研究进展和信息，促进糖尿病的科研、教育、诊疗等，关注一切与糖尿病有关的事务。