5-demethylnobiletin and Colitis

This study investigated the preventive effect of 5-demethylnobiletin (5DN), a natural polymethoxyflavone found mainly in citrus fruits, on dextran sulfate sodium (DSS)-induced colitis in mice and explored its potential mechanisms. Our results indicated that dietary 5DN (0.05% w/w in diet) could alleviate colitis symptoms in DSS-treated mice by preventing body weight loss, reducing the disease activity index, decreasing the colon weight to colon length ratio, and lessening colon tissue damage. Additionally, 5DN inhibited the inflammatory response in colitis mice through decreasing the production of inflammatory cytokines. Immunohistochemical analysis revealed that 5DN could reverse the DSS-induced decrease in the expression of claudin-1 and ZO-1 to improve the intestinal barrier function. Furthermore, 5DN altered gut microbiota dysbiosis in DSS-treated mice

Topics: Animals; Colitis; Colon; Cytokines; Dextran Sulfate; Diet; Disease Models, Animal; Gastrointestinal Microbiome; Immunity; Mice; Mice, Inbred C57BL

5-Demethylnobiletin (5DN) is a unique flavonoid mainly found in citrus fruits. In this study, we determined the chemopreventive effects of 5DN and its major colonic metabolites on both a colitis-driven colon carcinogenesis mouse model and a human colon cancer cell model. In azoxymethane/dextran sulfate sodium-treated mice, dietary 5DN (0.05% w/w in the diet) significantly decreased the tumor incidence, multiplicity and burden, and showed potent anti-proliferative, proapoptotic, and anti-inflammatory activities in mouse colon tissue. Three major metabolites of 5DN, named 5,3'-didemethylnobiletin (M1), 5,4'-didemethylnobiletin (M2) and 5,3',4'-tridemethylnobiletin (M3), were found in the colonic mucosa of 5DN-treated mice, and the combined level of these metabolites in mouse colonic mucosa was 1.56-fold higher than that of 5DN. Cell culture studies revealed that 5DN and its colonic metabolites profoundly inhibited the growth of human colon cancer cells by inducing cell cycle arrest, triggering apoptosis and modulating key signaling proteins related to cell proliferation and apoptosis. Importantly, the colonic metabolites, especially M1, showed much stronger effects than those produced by 5DN itself. Overall, our results demonstrated that dietary 5DN significantly inhibited colitis-driven colon carcinogenesis in mice, and this chemopreventive effect was associated with its metabolites in the colon.

Topics: Animals; Anticarcinogenic Agents; Citrus; Colitis; Colorectal Neoplasms; Disease Models, Animal; Flavones; Flavonoids; Male; Mice; Mice, Inbred Strains