Ulcerative colitis (UC) is a chronic, idiopathic and relapsing inflammatory disease of the gastrointestinal tract that has a prolonged disease duration. Lindera aggregata (Sims) Kosterm. is a traditional Chinese herb which has been used to treat gastrointestinal diseases for thousand years. However, there are few reports about the application of L. aggregata in the treatment of UC at present. Herein, we investigated the therapeutic effect of the root extract of L. aggregata (LREE) against UC and explored its underlying mechanisms based on IL-6 signaling pathway and the balance of T helper (Th) 17 and regulatory T (Treg) cells. Results showed that LREE could not only decrease the production and secretion of IL-6, but also could inhibit the signal transduction of IL-6/STAT3 signaling pathway. Moreover, LREE could significantly inhibit the differentiation of CD4+ T cells to Th17 cells in vitro and decrease the proportion of Th17 cells in mesenteric lymph nodes (MLNs) of model mice in vivo. Besides, LREE could also alleviate the disease symptoms, reduce intestinal permeability and improve histopathological changes of colitis model mice. Together, LREE can significantly inhibit the production and secretion of IL-6, regulate IL-6/STAT3 signal transduction, and modulate the balance of Th17 and Treg cells and effectively attenuate UC.

目的 探究天台乌药对TNBS诱导的溃疡性结肠炎模型大鼠的抗炎作用.方法 36只雄性SD大鼠随机分为正常对照组、模型对照组、阳性对照组、乌药醇提物低、中、高剂量组.采用2,4,6-三硝基苯磺酸(TNBS)50％乙醇溶液灌肠建立UC大鼠模型.造模同时开始灌胃给予天台乌药醇提物干预9 d,实验期间通过观测大鼠体重、便血等疾病症状表现及结肠组织病变程度等指标评价乌药给药后的药效作用;通过检测大鼠结肠组织髓过氧化物酶(MPO)活性、血清中IL-6、TNF-α含量及外周血中Treg等淋巴细胞亚群比例等指标初步探讨其可能机制.结果 与模型对照组比较,天台乌药各剂量组大鼠疾病症状及结肠组织病变均有所减轻;外周血中Treg占辅助性T细胞比例均有所升高;结直肠重量及单位长度重量显著降低(P<0.05).天台乌药中剂量组结直肠长度显著增加(P<0.05).天台乌药各剂量组大鼠血清中IL-6含量均显著降低(P<0.01);天台乌药低、中剂量组大鼠血清中TNF-α 含量及结肠组织中MPO活性均显著降低(P<0.05).结论 天台乌药能够改善TNBS诱导的UC模型大鼠的疾病症状及组织病理学改变,具有良好的抗UC作用.乌药的抗UC作用可能与其降低IL-6等炎性细胞因子含量有关,具体机制仍有待进一步研究.

In standard nonclinical drug safety evaluation studies, limitations exist in predicting the clinical risk of a drug based only on data from healthy animals. To obtain more comprehensive toxicological information on norisoboldine (NOR), we conducted an exploratory study using C57BL/6 mice in addition to healthy mice as models of dextran sodium sulfate (DSS) colitis to evaluate the safety of NOR. The healthy mice and DSS colitis mice were exposed to 30 or 90 mg NOR/kg body weight or water for 15 days. Compared with the model control group, 90 mg/kg of NOR aggravated the symptoms and colonic lesions of the DSS colitis mice and even caused death in two animals. No significant adverse effects were observed in the healthy mice. These different toxic reactions to NOR in the healthy and DSS colitis mice indicate that NOR toxicity varies by status among animals and suggests that the DSS colitis mouse model may be more susceptible, accurate and comprehensive in evaluating the safety of NOR. In conclusion, 90 mg/kg of NOR may be safe for healthy mice but not for DSS colitis mice. The DSS colitis mouse model, with many features similar to those of human colitis patients, may be a novel choice to counteract the deficiencies of using healthy mice to evaluate the safety of anti-inflammatory bowel disease (IBD) drugs, and further research is required.