Curcumin suppresses the Wnt/β‐catenin signaling pathway by inhibiting NKD2 methylation to ameliorate intestinal ischemia/reperfusion injury

Abstract

AbstractIntestinal ischemia/reperfusion (I/R) injury is a life‐threatening condition with no effective treatment currently available. Curcumin (CCM), a polyphenol compound in Curcuma Longa, reportedly has positive effects against intestinal I/R injury. However, the mechanism underlying the protective effect of CCM against intestinal I/R injury has not been fully clarified. To determine whether the protective effect of CCM was mediated by epigenetic effects on Wnt/β‐catenin signaling, the effect of CCM was examined in vivo and in vitro. An intestinal I/R model was established in Sprague–Dawley (SD) rats with superior mesenteric artery occlusion, and Caco‐2 cells were subjected to hypoxia/reoxygenation (H/R) for in vivo simulation of I/R. The results showed that CCM significantly reduced inflammatory, cell apoptosis, and oxidative stress induced by I/R insult in vivo and in vitro. Western blot analysis showed that CCM preconditioning reduced the protein levels of β‐catenin, p‐GSK3β, and cyclin‐D1 and increased the protein level of GSK3β compared with the I/R group. Overexpressing β‐catenin aggravated H/R injury, and knocking down β‐catenin relieved H/R injury by improving intestinal permeability and reducing the cell apoptosis. Moreover, Naked cuticle homolog 2(NKD2) mRNA and protein levels were upregulated in the CCM‐pretreated group. 5‐aza‐2′‐deoxycytidine (5‐AZA) treatment improved intestinal epithelial barrier impairment induced by H/R. Besides, the protein levels of total β‐catenin, phosphor‐β‐catenin and cyclin‐D1 were reduced after overexpressing NKD2 in Caco‐2 cells following H/R insult. In conclusion, Our study suggests that CCM could attenuate intestinal I/R injury in vitro and in vivo by suppressing the Wnt/β‐catenin signaling pathway via inhibition of NKD2 methylation.