Abstract
Oxidative stress is implicated in a wide range of intestinal disorders and closely associated with their pathological processes. Resveratrol (RSV), a plant extract, plays a vital role in protecting various organs in vitro and in vivo. However, the benefits of RSV are controversial, and underlying mechanisms for its antioxidant effects on intestinal epithelial cells remain unclear. In this study, we evaluated the effects of RSV on oxidative stress induced by H2O2 in IPEC-J2 cells. We found that pretreatment with RSV significantly increased cell viability; increased expression levels of tight junction (TJ) proteins (claudin-1, occludin, and ZO-1); improved activities of superoxide dismutase-1 (SOD-1), catalase (CAT), and glutathione peroxidase (GSH-Px); and decreased intracellular reactive oxygen species (ROS) levels and apoptosis induced by H2O2 (P < 0.05). In addition, RSV upregulated Akt phosphorylation, Nrf2 phosphorylation, and expression levels of antioxidant genes HO-1, SOD-1, and CAT in a dose-dependent manner (P < 0.05) under oxidative stress. Knockdown of Nrf2 by short-hairpin RNA (shRNA) abrogated RSV-mediated protection against H2O2-induced apoptosis, RSV-induced increase of TJ protein levels, and antioxidant gene expression (SOD-1, CAT, and GSH-Px) (P < 0.05). Consistent with Nrf2 knockdown, the PI3K/Akt inhibitor LY294002 significantly suppressed RSV-induced Nrf2 phosphorylation and RSV-induced increase of TJ protein levels and antioxidant gene expression under H2O2 treatment (P < 0.05). Collectively, these results demonstrate that RSV can directly protect IPEC-J2 cells against oxidative stress through the PI3K/Akt-mediated Nrf2 signaling pathway, suggesting that RSV may be an effective feed additive against intestinal damage in livestock production.
Highlights
The intestine is a major digestive and absorptive organ for nutrients and functions as a selective barrier against toxins, pathogens, and antigens from the luminal environment [1]
We found that a concentration of 500 μM H2O2 sharply decreased cell viability to 40% compared to the control (Figure 1(b))
Given that RSV is a potent antioxidative agent promoting the expression of antioxidant genes, we investigated whether RSV relieves oxidative stress through the Akt and Nuclear factor erythroid 2-related factor 2 (Nrf2)/Keap1 signaling pathway, which is a key cellular cascade involved in cell survival and oxidative stress response. qRT-qPCR results revealed that H2O2 treatment significantly decreased the expression of Nrf2 and Keap1 genes, whereas RSV significantly reversed H2O2-induced downregulation of Nrf2 and Keap1 genes (Figure 6(a))
Summary
The intestine is a major digestive and absorptive organ for nutrients and functions as a selective barrier against toxins, pathogens, and antigens from the luminal environment [1]. When the intestinal barrier is disrupted, the luminal toxins and antigens will penetrate subepithelial tissues through the barrier, causing a mucosal oxidative stress and systemic inflammatory response [1]. Oxidative stress, defined as the imbalance between the antioxidant systems and oxidative system causing overdose of ROS, can disrupt cellular signaling and function. Under the imbalance between the antioxidant and the oxidative system, overdose of ROS can disturb epithelial cell integrity and intestinal barrier by decreasing tight junctions and cell quantity [6]. In terms of the possible importance of ROS in intestinal injury, it is essential for cells to effectively upregulate antioxidants, decrease ROS production, and scavenge free radicals, which may contribute to increased intestinal permeability and epithelial apoptosis
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