Research and Teaching Department of Comparative Medicine (L.W., B.S., Y.H., J.C., D.P.) and College of Basic Medical Science (S.Z.), Dalian Medical University, Dalian 116044, China.
Research and Teaching Department of Comparative Medicine (L.W., B.S., Y.H., J.C., D.P.) and College of Basic Medical Science (S.Z.), Dalian Medical University, Dalian 116044, China
J Pharmacol Exp Ther. 2021 Nov;379(2):147-155. doi: 10.1124/jpet.121.000677. Epub 2021 Aug 16.
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 , 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.
基于 5-氟尿嘧啶（5-FU）的化疗会导致肠道粘膜炎，使患者承受巨大痛苦，并阻碍癌症治疗进展。葛根素是中药葛根的主要活性成分，具有抗炎和抗氧化作用。然而，葛根素对 5-FU 诱导的肠道粘膜炎是否有作用尚不清楚。我们通过腹腔注射 5-FU 建立了小鼠肠道粘膜炎模型，然后连续 7 天腹腔注射葛根素（50 和 100mg/kg）。通过检测体重、摄食量和腹泻发生率等常规参数来评估葛根素对小鼠肠道粘膜炎的作用。本研究还通过测量血清中荧光素异硫氰酸 4kD 葡聚糖的恢复来评估肠道屏障的功能。通过测定炎症因子、炎症介质、氧化反应和凋亡标志物蛋白的表达水平，阐明了葛根素对肠道粘膜炎的作用机制。模型小鼠出现了典型的 5-FU 诱导的肠道粘膜炎的症状和组织病理学改变。除了剧烈的炎症反应、氧化反应和细胞凋亡外，Janus 激酶（JAK）也明显被激活。葛根素通过阻断 JAK 的激活，降低了 5-FU 诱导的粘膜炎中炎症介质、氧化反应和凋亡相关蛋白的表达水平。葛根素通过抑制 JAK 的激活，减少炎症、氧化反应和凋亡，保护肠道屏障功能，从而改善 5-FU 诱导的肠道粘膜炎。本研究为 5-FU 诱导的肠道粘膜炎的病理机制（和治疗选择）提供了新的见解。
意义：本研究揭示了葛根素在 5-氟尿嘧啶诱导的肠道粘膜炎中的保护作用机制。葛根素抑制 JAK 的激活，从而抑制炎症、氧化反应、细胞凋亡，保护肠道屏障功能，改善 5-FU 诱导的肠道粘膜炎。总之，我们的研究结果表明，葛根素可以作为一种潜在的天然 JAK 抑制剂用于治疗 5-FU 诱导的肠道粘膜炎。
