Apigenin Alleviates Intestinal Ischemia/Reperfusion Injury via Upregulating Nrf2-Mediated Tight Junction Integrity

Abstract

Epithelial barrier dysfunction, critically involved in intestinal ischemia/reperfusion (I/R) injury, is significantly regulated by Nrf2-mediated oxidative stress. Apigenin, a flavonoid commonly found in fruits and vegetables with diverse biological properties, has an unclear impact on intestinal I/R injury. We hypothesize that apigenin improves intestinal barrier dysfunction by activating Nrf2 signaling. Thirty rats were randomly divided into five groups to establish an I/R model using superior mesenteric artery occlusion. Hypoxia and re-oxygenation (H/R) model was developed utilizing Caco-2 and IEC-6 cells, which were exposed to hypoxic conditions followed by re-oxygenation. Apigenin protected against intestinal mucosal damage by suppressing inflammatory cytokines release (TNF-α, IL-1β, IL-6, MPO, p < 0.01), ameliorating oxidative stress (MDA, SOD, GSH, GSH-Px, p < 0.01), and improving barrier dysfunction (DAO and TEER, p < 0.01) both in vivo and in vitro, without causing significant changes in the corresponding normal controls (p > 0.05). Apigenin up-regulated the protein expression of Nrf2, HO-1, and tight junction (TJ) proteins (p < 0.01). Furthermore, the knockdown of Nrf2 significantly abrogated apigenin-enhanced the TJ expression. Apigenin pretreatment alleviates intestinal I/R-induced barrier damage through Nrf2 activation and TJ upregulation, offering new strategies for preventing or treating I/R-associated intestinal diseases.