Puerarin Ameliorates 5-Fluorouracil-Induced Intestinal Mucositis in Mice by Inhibiting JAKs.

Intestinal mucositis resulting from 5-fluorouracil (5-FU)-based chemotherapy subjects patients to great pain and hampers cancer treatment progress. Puerarin, the major active ingredient in Pueraria lobata , exerts anti-inflammatory and antioxidative effects. However, whether puerarin has an effect on 5-FU-induced intestinal mucositis remains unknown. We established a mice model of intestinal mucositis through the intraperitoneal injection of 5-FU and then injected puerarin (50 and 100 mg/kg) intraperitoneally for 7 consecutive days. Routine parameters, such as body weight, food intake, and diarrheal incidence, were examined to evaluate the effects of puerarin on intestinal mucositis in mice. The intestinal barrier's functions were also evaluated by measuring the serum recovery of fluorescein isothiocyanate-4kD dextran in this study. The expression levels of inflammatory cytokines, inflammatory mediators, oxidative reactions, as well as apoptotic marker proteins were determined to elucidate the underlying mechanisms of puerarin on intestinal mucositis. The model mice presented symptoms and histopathological changes typical of 5-FU-induced intestinal mucositis. In addition to vigorous inflammatory reactions, oxidative reactions, and cell apoptosis, Janus kinase (JAK) was markedly activated. Puerarin decreased the expression levels of those of inflammatory mediators, oxidative reactions, and apoptosis-related proteins in 5-FU-induced mucositis by blocking the activation of JAK. Puerarin decreased inflammation, oxidative reactions, and apoptosis and protected intestinal barrier functions to ameliorate 5-FU-induced intestinal mucositis by inhibiting the activation of JAK. This study provides novel insights into the pathologic mechanisms of (and treatment alternatives for) 5-FU-induced intestinal mucositis. SIGNIFICANCE STATEMENT: This study reveals the mechanism responsible for the protective effects of puerarin in 5-fluorouracil-induced intestinal mucositis. Puerarin inhibits the activation of JAK, thereby suppressing inflammation, oxidative reactions, cell apoptosis, and protected intestinal barrier functions to ameliorate 5-FU-induced intestinal mucositis. Overall, our results suggest that puerarin can serve as a potential natural JAK inhibitor in the treatment of 5-FU-induced intestinal mucositis.
(Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)