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Activation of Nrf2 attenuates delayed gastric emptying in obesity induced diabetic (T2DM) female mice.

Sampath C, Sprouse JC, Freeman ML, Gangula PR
Free Radic Biol Med. 2019 135: 132-143

PMID: 30831189 · PMCID: PMC6738571 · DOI:10.1016/j.freeradbiomed.2019.02.029

Diabetic gastroparesis (GP) is a clinical syndrome characterized by delayed gastric emptying (DGE). Loss of Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) led to reduced nNOSα mediated gastric motility and DGE. The molecular signaling of cinnamaldehyde (CNM) mediated Nrf2 activation and its mechanistic role on DGE were further investigated in obese/T2D female mice. Adult female homozygous Nfe2l2 (C57BL/6J) and their wild-type (WT) littermates (Nfe2l2) mice were fed with high fat diet (HFD; Obese/T2D model), or normal diet (ND) with or without CNM (50 mg/kg b.w; i.p). Supplementation of CNM attenuated (p < 0.05) DGE in WT female but not in Nrf2 KO Obese/T2D mice. CNM (1) normalized serum estradiol-17β levels, (2) induced gastric Nrf2 and phase II antioxidant enzymes through extracellular signal-regulated kinase, (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK), (3) reduced glucose synthase kinase 3 beta (GSK3β) and aryl hydrocarbon receptor (AhR) and this was associated with (4) increased estrogen receptor expression, BH (Cofactor of nNOS) biosynthesis enzyme GCH-1 and nNOSα dimerization in WT Obese/T2 diabetic female mice. In addition, CNM restored impaired nitrergic relaxation in hyperglycemic conditions. These findings emphasize the importance of Nrf2 in maintaining nNOSα mediated GE and may have a translational relevance to treat obese/diabetic gastroparesis in women.

Copyright © 2019. Published by Elsevier Inc.

MeSH Terms (17)

Acrolein Animals Antioxidants Diabetes Complications Diabetes Mellitus, Type 2 Diet, High-Fat Gastric Emptying Gastroparesis Humans MAP Kinase Signaling System Mice Muscle Relaxation NF-E2-Related Factor 2 Nitric Oxide Synthase Type I Obesity p38 Mitogen-Activated Protein Kinases Stomach

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