AUTHOR=Shao Meijuan , Yan Yuxi , Zhu Fenghua , Yang Xiaoqian , Qi Qing , Yang Fangming , Hao Tingting , Lin Zemin , He Peilan , Zhou Yu , Tang Wei , He Shijun , Zuo Jianping 

TITLE=Artemisinin analog SM934 alleviates epithelial barrier dysfunction via inhibiting apoptosis and caspase-1-mediated pyroptosis in experimental colitis

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.849014

DOI=10.3389/fphar.2022.849014

ISSN=1663-9812

ABSTRACT=Intestinal barrier disruption due to the intestinal epithelial cells (IECs) death is one of the critical pathological features of inflammatory bowel diseases (IBD). SM934, an artemisinin analogue, has previously been proven to ameliorate colitis induced by dextran sulfate sodium (DSS) in mice by suppressing neutrophils and macrophages. In this study, we investigated the protective effects of SM934 on epithelial barrier and the underlying mechanism in trinitrobenzene sulfonic acid (TNBS)-induced colitis mice. We demonstrated that SM934 restored the body weight, colon length and improved the intestine pathology. Further, SM934 treatment preserved the intestinal barrier via maintaining epithelial apical junctional complex (AJC)-associated protein expressions and preventing apoptosis of epithelial cells, which were observed both in the colon tissue and the tumor necrosis factor-α (TNF-α)-induced human colonic epithelial cell line HT-29. Specifically, SM934 reduced the pyroptosis of IECs exposed to pathogenic signaling, inhibited pyroptosis-related factors NOD-like receptor family pyrin domain containing 3 (NLRP3), adapter apoptosis-associated speck-like protein (ASC), cysteine protease-1 (caspase-1), gasdermin (GSDMD), interleukin-18 (IL-18) and high mobility group box1 (HMGB1) both in colon tissue and lipopolysaccharide (LPS) and adenosine triphosphate (ATP) co-stimulated HT-29 cells in vitro. Moreover, SM934 interdicted the pyroptosis via blocking the transduction of mitogen-activated protein kinase (MAPK) and nuclear factor-kB (NF-kB) signaling pathways. In conclusion, SM934 protected TNBS-induced colitis against intestinal barrier disruption by inhibiting the apoptosis and pyroptosis of epithelial cells via NLRP3/ NF-κB /MAPK signal axis, and intestinal barrier protection in company with anti-inflammatory strategy might yield greater benefit in IBD treatment.