Colitis Is Effectively Ameliorated by (±)-8-Acetonyl-dihydrocoptisine via the XBP1-NF-κB Pathway

Ulcerative colitis (UC) is a recurrent, chronic intestinal disease. Available treatments for UC are poor effective and/or cause severe adverse events. X-box binding protein 1 (XBP1) and nuclear factor-kappa B (NF-kappa B) have been reported to play important roles in UC. Specifically, deletion or downregulation of XBP1 leads to spontaneous enteritis and results in imbalanced secretion of NF-kappa B and other proinflammatory cytokines. (+/-)-8-acetonyl-dihydrocoptisine, i.e., (+/-)-8-ADC, is a monomer semi-synthesized from coptisine. In vitro, (+/-)-8-ADC activated the transcriptional activity of XBP1, inhibited expression of NF-kappa B, and reduced production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), in lipopolysaccharide-stimulated IEC6 cells. Therefore, silencing XBP1 would reduce the inhibition effect of (+/-)-8-ADC on NF-kappa B expression and the cytokines secretion in vitro. In a dextran sulfate sodium-induced colitis mouse model, oral administration of (+/-)-8-ADC ameliorated weight loss and colon contracture, and decreased the average disease activity index score and pathological damage. Simultaneously, (+/-)-8-ADC also increased XBP1 expression, and decreased NF-kappa B expression and secretion of myeloperoxidase, TNF-alpha, IL-6 and IL-1 beta in the colon. Therefore, (+/-)-8-ADC may ameliorate UC via the XBP1-NF-kappa B pathway and should be considered as a therapeutic candidate for UC.