Enhancement of epithelial cell autophagy induced by sinensetin alleviates epithelial barrier dysfunction in colitis. (October 2019)

• Record Type: Journal Article
• Authors: Xiong, Yong-jian; Deng, Zhao-bin; Liu, Jia-ni; Qiu, Juan-juan; Guo, Li; Feng, Pan-pan; Sui, Jing-ru; Chen, Da-peng; Guo, Hui-shu
• Is Part Of: Pharmacological research. Volume 148(2019)
• Publication Date: 2019-10
• Subjects: Sinensetin -- Colitis -- Epithelial barrier loss -- Epithelial autophagy; IBD inflammatory bowel diseases -- TJ tight junction -- AMPK 5′ adenosine monophosphate-activated protein kinase -- ULK1 UNC-51 like autophagy activating kinase 1 -- TNBS 24, 6-trinitrobenzene sulfonic acid -- DSS dextran sulfate sodium -- FD-4 fluorescein isothiocyanate-dextran -- TEER transepithelial electrical resistance; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104461
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Intestinal epithelial barrier dysfunction is a key pathology of colitis. Autophagy of epithelial cells maintains homeostasis of the intestinal barrier by inhibiting apoptosis and stimulating degradation of the tight junction protein claudin-2. This study investigated the effects and mechanism of activity of sinensetin, a polymethylated flavonoid isolated from tangerine peel and citrus, on intestinal barrier dysfunction in colitis. Animal model of colitis were established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid and oral treatment with dextran sulfate sodium. Epithelial barrier function was evaluated by measuring the serum recovery of fluorescein isothiocyanate-4 kD dextran in vivo and transepithelial electrical resistance in Caco-2 cells, respectively. Epithelial cell autophagy assayed by autophagosome formation and expression of autophagy-related protein. Sinensetin reversed colitis-associated increase in intestinal permeability, significantly promoted epithelial cell autophagy, and further decreased epithelial cell apoptosis, and reduced mucosal claudin-2. Sinenstetin alleviated colitis symptoms rats and mice with colitis. Knockdown of 5′ adenosine monophosphate-activated protein kinase (AMPK) reversed the promotion of epithelial autophagy by sinensetin. In conclusion, sinensetin significantly alleviated intestinal barrier dysfunction in colitis by promoting epithelial cell autophagy, and further inhibiting apoptosis and promoting claudin-2 degradation. The results highlighted novel potential benefits of sinensetin in colitis.