17β-Estradiol Suppresses Gastric Inflammatory and Apoptotic Stress Responses and Restores nNOS-Mediated Gastric Emptying in Streptozotocin (STZ)-Induced Diabetic Female Mice

Abstract

Gastroparesis (Gp) is a severe complication of diabetes mellitus (DM) observed predominantly in women. It is characterized by abnormal gastric emptying (GE) without mechanical obstruction in the stomach. Nitric oxide (NO) is an inhibitory neurotransmitter produced by neuronal nitric oxide synthase (nNOS). It plays a critical role in gastrointestinal (GI) motility and stomach emptying. Here, we wanted to demonstrate the protective effects of supplemental 17β-estradiol (E2) on NO-mediated gastric function. We showed E2 supplementation to alleviate oxidative and inflammatory stress in streptozotocin (STZ)-induced diabetic female mice. Our findings suggest that daily administration of E2 at therapeutic doses is beneficial for metabolic homeostasis. This restoration occurs via regulating and modulating the expression/function of glycogen synthase kinase-3β (GSK-3β), nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), Phase II enzymes, MAPK- and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB)-mediated inflammatory cytokines (IL-1β, IL-6, TNFα, IGF-1), and gastric apoptotic regulators. We also showed E2 supplementation to elevate GCH-1 protein levels in female diabetic mice. Since GCH-1 facilitates the production of tetrahydrobiopterin (BH4, cofactor for nNOS), an increase in GCH-1 protein levels in diabetic mice may improve their GE and nitrergic function. Our findings provide new insights into the impact of estrogen on gastric oxidative stress and intracellular inflammatory cascades in the context of Gp.

Analysis of Network Pharmacological Efficacy and Therapeutic Effectiveness in Animal Models for Functional Dyspepsia of Foeniculi fructus

“…The mice underwent a 19 h fasting period with unrestricted access to tap water. The volume of phenol red solution (500 µL) and the 50% delayed gastric emptying time point was based on previously established study protocols [ 41 , 42 ]. After a 30 min period following the administration of 0.05% phenol red (dyeing substance that checks the level of gastric emptying), the mice were humanely euthanized.…”

Estrogen-immuno-neuromodulation disorders in menopausal depression

“…6 ). E2 treatment can not only decrease the expression of TNF-α, IL-1β and IL-6 but also improve the production of BH 4 [ 89 ].…”