Department of ODS & Research, School of Dentistry, Meharry Medical College, Nashville, TN, USA.
Biostatistics, School of Graduate Studies & Research, Meharry Medical College, Nashville, TN, USA.
Biomed Pharmacother. 2021 May;137:111370. doi: 10.1016/j.biopha.2021.111370. Epub 2021 Feb 22.
Diabetic gastroparesis (DG) exhibits delayed gastric emptying (GE) due to impaired gastric non-adrenergic, non-cholinergic (NANC) relaxation. These defects are due to loss or reduction of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) that causes reduced expression and/or dimerization of neuronal nitric oxide synthase alpha (nNOSα) gene expression and function. We investigated the effect of potent Nrf2 activators (cinnamaldehyde [CNM] & curcumin [CUR]) on GE in obesity-induced diabetic female mice. We fed adult female homozygous Nfe2l2 (Nrf2 KO) and wild-type (WT) female mice with either a high-fat diet (HFD) or a normal diet (ND) for a period of 16 weeks. Groups of HFD mice were fed with CUR or CNM either at 6th or 10th week respectively. Our results demonstrate that supplementation of CNM or CUR restored impaired nitrergic relaxation and attenuated delayed GE in HFD fed mice. Supplementation of CNM or CUR normalized altered gastric antrum protein expression of (1) p-ERK/p-JNK/MAPK/p-GSK-3β, (2) BH (Cofactor of nNOS) biosynthesis enzyme GCH-1 and the GSH/GSSG ratio, (3) nNOSα protein & dimerization and soluble guanylate cyclase (sGC), (4) AhR and ER expression, (5) inflammatory cytokines (TNF α, IL-1β, IL-6), (6)TLR-4, as well as (7) reduced oxidative stress markers in WT but not in Nrf2 KO obesity-induced chronic diabetic female mice. Immunoprecipitation experiments revealed an interaction between nNOS and Nrf2 proteins. Our results conclude that Nrf2 activation restores nitrergic-mediated gastric motility and GE by normalizing inflammation and oxidative stress induced by obesity-induced chronic diabetes.
糖尿病性胃轻瘫（DG）表现为胃排空延迟（GE），这是由于胃非肾上腺素能、非胆碱能（NANC）松弛受损所致。这些缺陷是由于核因子（红系衍生 2 型）-样 2（Nrf2）的丧失或减少引起的，导致神经元型一氧化氮合酶α（nNOSα）基因表达和功能的减少和/或二聚化。我们研究了强效 Nrf2 激活剂（肉桂醛[CNM]和姜黄素[CUR]）对肥胖型糖尿病雌性小鼠 GE 的影响。我们用高脂肪饮食（HFD）或正常饮食（ND）喂养成年雌性同型合子 Nfe2l2（Nrf2 KO）和野生型（WT）雌性小鼠 16 周。HFD 组的小鼠分别在第 6 或第 10 周开始用 CUR 或 CNM 喂养。我们的结果表明，CNM 或 CUR 的补充恢复了 HFD 喂养小鼠受损的氮能松弛并减轻了延迟的 GE。CNM 或 CUR 的补充使改变的胃窦蛋白表达正常化，（1）p-ERK/p-JNK/MAPK/p-GSK-3β，（2）BH（nNOS 的辅助因子）生物合成酶 GCH-1 和 GSH/GSSG 比，（3）nNOSα蛋白和二聚化和可溶性鸟苷酸环化酶（sGC），（4）AhR 和 ER 表达，（5）炎症细胞因子（TNFα、IL-1β、IL-6），（6）TLR-4，以及（7）WT 而非 Nrf2 KO 肥胖诱导的慢性糖尿病雌性小鼠中的氧化应激标志物减少。免疫沉淀实验揭示了 nNOS 和 Nrf2 蛋白之间的相互作用。我们的结果得出结论，Nrf2 激活通过使肥胖诱导的慢性糖尿病引起的炎症和氧化应激正常化，恢复了氮能介导的胃动力和 GE。
