[Xianglian Pills ameliorate ulcerative colitis combined with depression in mice via histone demethylation]

The present work aims to study the mechanism by which Xianglian Pills(XLP) treat ulcerative colitis(UC) combined with depression. The mouse model of UC combined with depression was induced by dextran sulfate sodium(DSS) in combination with chronic unpredictable mild stress(CUMS). Fifty male C57BL/6 mice were randomized into control, model, XLP(2.7, 5.4 mg·g~(-1)), and 5-aminosalicylic acid+fluoxetine groups. The disease activity index(DAI) and colon length were monitored and pathologic examination was conducted to assess UC conditions in mice. The sucrose preference test, tail suspension test, and forced swimming test were performed to assess depressive-like behavior in mice. Microglia activation status was determined by immunofluorescence detection of ionized calcium-binding adaptor molecule 1(Iba-1). The levels of tumor necrosis factor-α(TNF-α), interleukin(IL)-1β, IL-6, and IL-23 in the cerebral cortical area and the colon tissue were determined by ELISA. The transcript levels of IL-6 and IL-23α were measured by RT-qPCR. The levels of lysine demethylase 5B(KDM5B) and trimethylation of histone H3 lysine 4(H3K4me3) were determined by Western blot. Chromatin immunoprecipitation was adopted to examine the binding of KDM5B to the promoters of IL-6 and IL-23α. The results showed that XLP treatment reduced DAI and protected the colonic tissue structure. XLP increased the sucrose preference rate and decreased the immobilization time and the number of Iba-1-positive cells, compared with the model group. Furthermore, XLP lowered the levels of TNF-α, IL-1β, IL-6, and IL-23, down-regulated the transcript levels of IL-6 and IL-23α and the protein level of H3K4me3 while up-regulating the protein level of KDM5B in the cerebral cortical area and the colon tissue, and increased the binding of KDM5B to the IL-6 and IL-23α promoters. XLP may affect H3K4me3 demethylation through KDM5B to reduce the production of inflammatory factors and alleviate the inflammatory response, thus ameliorating UC combined with depression.