八宝丹通过 Wnt/β-连环蛋白通路减轻 5-氟尿嘧啶诱导的肠道损伤。
Babao Dan Alleviates 5-Fluorouracil-Induced Intestinal Damage via Wnt/β-Catenin Pathway.
机构信息
Academy of Integrative Medicine, Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China.
Department of Medical Oncology, 900 Hospital of the Joint Logistics Team Support Force, Fuzhou, 350025, China.
出版信息
Chin J Integr Med. 2022 Nov;28(11):1000-1006. doi: 10.1007/s11655-021-3282-0. Epub 2021 Jan 9.
OBJECTIVE
To evaluate the protective function of Babao Dan (BBD) on 5-flurouracil (5-FU)-induced intestinal mucositis (IM) and uncover the underlying mechanism.
METHODS
A total of 18 male mice were randomly divided into 3 groups by a random number table, including control, 5-FU and 5-FU combined BBD groups, 6 mice in each group. A single intraperitoneal injection of 5-FU (150 mg/kg) was performed in 5-FU and 5-FU combined BBD groups on day 0. Mice in 5-FU combined BBD group were gavaged with BBD (250 mg/kg) daily from day 1 to 6. Mice in the control group were gavaged with saline solution for 6 days. The body weight and diarrhea index of mice were recorded daily. On the 7th day, the blood from the heart of mice was collected to analyze the proportional changes of immunological cells, and the mice were subsequently euthanized by mild anesthesia with 2% pentobarbital sodium. Colorectal lengths and villus heights were measured. Intestinal-cellular apoptosis and proliferation were evaluated by Tunel assay and immunohistochemical staining of proliferating cell nuclear antigen, respectively. Immunohistochemistry and Western blot were performed to investigate the expressions of components in Wnt/β-catenin pathway (Wnt3, LRP5, β-catenin, c-Myc, LRG5 and CD44).
RESULTS
BBD obviously alleviated 5-FU-induced body weight loss and diarrhea, and reversed the decrease in the number of white blood cells, including monocyte, granulocyte and lymphocyte, and platelet (P<0.01). The shortening of colon caused by 5-FU was also reversed by BBD (P<0.01). Moreover, BBD inhibited apoptosis and promoted proliferation in jejunum tissues so as to reduce the intestinal mucosal damage and improve the integrity of villus and crypts. Mechanically, the expression levels of Wnt/β -catenin mediators such as Wnt3, LRP5, β-catenin were upregulated by BBD, activating the transcription of c-Myc, LRG5 and CD44 (P<0.01).
CONCLUSIONS
BBD attenuates the adverse effects induced by 5-FU via Wnt/β-catenin pathway, suggesting it may act as a potential agent against chemotherapy-induced intestinal mucositis.
目的
评价八宝丹（BBD）对 5-氟尿嘧啶（5-FU）诱导的肠黏膜炎（IM）的保护作用，并探讨其作用机制。
方法
18 只雄性小鼠采用随机数字表法分为 3 组，分别为对照组、5-FU 组和 5-FU 联合 BBD 组，每组 6 只。5-FU 组和 5-FU 联合 BBD 组于第 0 天给予 1 次腹腔注射 5-FU（150 mg/kg），5-FU 联合 BBD 组从第 1 天开始每日灌胃 BBD（250 mg/kg），连续 6 天，对照组给予生理盐水灌胃 6 天。每日记录小鼠体质量和腹泻指数。第 7 天，经心脏采血分析免疫细胞的比例变化，随后用 2%戊巴比妥钠轻度麻醉处死小鼠。测量结肠长度和绒毛高度。通过 TUNEL 检测和增殖细胞核抗原免疫组化染色评估肠细胞凋亡和增殖。采用免疫组化和 Western blot 检测 Wnt/β-连环蛋白通路（Wnt3、LRP5、β-连环蛋白、c-Myc、LRG5 和 CD44）的组成成分表达。
结果
BBD 明显减轻了 5-FU 引起的体质量下降和腹泻，并逆转了白细胞（包括单核细胞、粒细胞和淋巴细胞）和血小板数量的减少（P<0.01）。5-FU 引起的结肠缩短也被 BBD 逆转（P<0.01）。此外，BBD 抑制了空肠组织中的细胞凋亡并促进了增殖，从而减少了肠黏膜损伤，改善了绒毛和隐窝的完整性。在机制上，BBD 上调了 Wnt3、LRP5、β-连环蛋白等 Wnt/β-连环蛋白介质的表达，激活了 c-Myc、LRG5 和 CD44 的转录（P<0.01）。
结论
BBD 通过 Wnt/β-连环蛋白通路减轻了 5-FU 引起的不良反应，表明其可能是一种治疗化疗诱导的肠黏膜炎的潜在药物。
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