Resveratrol enhances the protective effects of JBP485 against indomethacin-induced rat intestinal damage in vivo and vitro through up-regulating oligopeptide transporter 1 (Pept1)

Abstract

JBP485 is a hydrophilic dipeptide with protective effects on intestine, liver and kidney. However, oral bioavailability of JBP485 is limited due to the impaired absorptive function during intestinal injury. The purpose of this study was to investigate the effect of resveratrol (Res) on the protective effect of JBP485 against indomethacin-induced intestinal injury in rats and in IEC-6 cells. JBP485 treatment ameliorated indomethacin-induced enteropathy characterized by severe histopathological changes and a large number of TUNEL-positive cells in rat intestinal epithelium, elevated levels of MDA, MPO, TNF-α, IL-6, IL-1β and increased expression of COX-2, and reduced levels of SOD, GSH, CAT, HDL-c, PGE2, expression of COX-1 and Bcl-2/Bax ratio in rat intestinal tissues. Co-treatment with Res enhanced activity of JBP485 against indomethacin-induced intestinal injury in rats and in IEC-6 cells. Furthermore, Res increased the plasma concentration of JBP485 in both indomethacin-treated and healthy rats, as well as the intracellular accumulation of JBP485 in IEC-6 cells, through upregulation of Pept1. In conclusion, JBP485 alleviated indomethacin-induced intestinal injury through restoring the redox balance, suppressing inflammation, reducing apoptosis, which was further enhanced by Res via upregulation of Pept1 and improvement of bioavailability of JBP485, at least in part.

Keywords: Absorption; Indomethacin; JBP485; Pept1; Resveratrol.