Abstract
Demethyleneberberine (DMB) is a natural product from traditional Chinese medicinal herb the rhizome of Coptis chinensis Franch., which has been reported to possess multiple pharmacological activities, especially anti-inflammation and immunoregulation. However, the potential mechanism of DMB in inflammation is still a mystery. In this study, a mouse model of ulcerative colitis (UC) was induced by Dextran sulfate sodium salt (DSS), and in vitro experiments were performed in RAW264.7 macrophages and the primary intestinal macrophages which obtained from Toll-Like receptor 4 (TLR4) and NOD-Like receptor protein 3 (NLRP3) knockout fetal mouse. Mitochondrial was increased by overexpression of peroxlsome proliferator-activated receptor-γ coactlvator-1α (PGC-1α) and exhausted by adding Ethidium Bromide (EtBr) in RAW264.7 to evaluate the function of mitochondria in the maturation of IL-1β. Additionally, the safety of DMB (50 mg/kg/d) in mice was assessed by orally administrating for 98 days. DMB siginificantly improved colon atrophy, colonic tissue mass score, neutrophil infiltration and histological damage, which was mainly attributed to the anti-inflammatory effect of DMB. Further in vitro analysis showed that DMB blocked the excessive mitochondrial biosynthesis and maintained the homeostasis of mitochondria in inflammatory response. Moreover, the maturation of IL-1β was suppressed by DMB in a mitochondria dependent manner. Crucially, DMB was a candidate agent for UC with free of toxicity and side effects. These findings demonstrated that DMB ameliorated inflammatory response by inhibiting TLR4-mitochondria signaling, and revealed the effectiveness and mechanism of DMB for alleviation of UC and provided an additional strategy for UC intervention.