Flavonoid derivatives treat dextran sodium sulfate-induced experimental colitis in mice by inhibiting MAPK/NF-κB pathway activation

Abstract

Flavonoids are widely found in plants and diets and are considered to possess a variety of biological activities. Therefore, in this study, 8 novel compounds derivating from the precursor compound 1a, were designed and synthesized, and their activities against ulcerative colitis(UC) were evaluated to provide the most active molecule 2d. Both a cellular inflammation model by LPS(Lipopolysaccharide)-induced RAW 264.7 cells and the UC model in 2 % Dextran Sulfate Sodium(DSS) intragastrically injected mice were established and employed to detect and validate the effects and mechanisms of compound 2d on ulcerative colitis. Cell experiments showed that compound 2d possesses the best anti-UC activity among all derivatives (2a-d, 3a-d). Compound 2d could significantly inhibit the release of inflammatory cytokines such as TNF-α, IL-6, IL-1β and IL-8 in RAW264.7 cells induced by LPS at 10 μM. RAW264.7 cells. In vivo experiments further demonstrated that compound 2d could effectively treat UC in mice induced by DSS. The results indicated that compound 2d restored MPO oxidative stress, reduced the secretion of inflammatory factors, and regulated the expression of NF-κB and MAPK pathway-related proteins, which was consistent with the results at the cellular level. The results of the relevant intestinal flora showed that compound 2d could normalize the intestinal flora of mice with ulcerative colitis. In summary, compound 2d may inhibit inflammation and oxidative stress by regulating NF-κB and MAPK pathways, and restore the diversity of intestinal microbiota to treat ulcerative colitis. It provides a new approach for the clinical application of flavonoids.