Rhapontin ameliorates colonic epithelial dysfunction in experimental colitis through SIRT1 signaling.

Abstract

Rhapontin (3, 3', 5-trihydroxy-4'-methoxystilbene-3-O-glucoside) has anti-thrombotic, anti-allergic and anti-diabetic activities. This study aimed to assess the protective effects of rhapontin on intestinal damage in vivo and in vitro. In a dextran sodium sulfate (DSS)-induced mouse model, oral administration of rhapontin (100mg/kg) significantly attenuated colonic pathological damage and remarkably inhibited infiltration by inflammatory cells, myeloperoxidase (MPO) activity, NLRP3 inflammasome activation and SIRT1 expression in the colon. Moreover, rhapontin prevented DSS-induced impairment in the colon epithelium barrier by increasing the expression of tight junction proteins, such as zonula occludens-1(ZO-1) and occludin, and reduced apoptosis-associated protein (cyt-c, the ratio of bcl-2/bax and cleaved-capase9) expression in the colon. The in vitro results showed that rhapontin significantly reduced NLRP3 inflammasome activation and cleaved caspase-1 expression as well as lowered IL-1β secretion in LPS-stimulated human-THP-1-derived macrophages. Further study revealed that compound EX257 (an SIRT1 inhibitor) blocked the inhibitory effects of rhapontin on NLRP3-dependent caspase-1 activation and IL-β production in activated macrophages. In addition, in TNF-α-stimulated intestinal epithelial NCM460 cells, rhapontin significantly increased the expressions of occludin and ZO-1 and notably reduced the ratio of bcl-2/bax and cleaved-capase9 expression through SRIT1 signaling. In sum, the protective effect of rhapontin is from blocking the NLRP3 priming cascade reaction and is dependent on SIRT1 activation. Our findings demonstrate that rhapontin might be a potential agent for the treatment of colitis by targeting SIRT1.

• Authors: Wencheng Wei, Lei Wang, Kai Zhou, Haifeng Xie, Mian Zhang, Chaofeng Zhang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 42 Pg. 185-194 (Jan 2017) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 27930969 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Stilbenes
• Dextran Sulfate
• Sirt1 protein, mouse
• Sirtuin 1
• rhapontin

Topics

• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Apoptosis (drug effects)
• Cell Line
• Colitis (chemically induced, drug therapy)
• Colon (drug effects, pathology)
• Dextran Sulfate
• Epithelial Cells (drug effects, physiology)
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Models, Animal
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Signal Transduction (drug effects)
• Sirtuin 1 (metabolism)
• Stilbenes (therapeutic use)
• Transcriptional Activation (drug effects)