白及多糖改善5-FU化疗毒副作用的非靶向代谢组学研究  

Bletilla striata polysaccharide improves toxic and side effects induced by 5-FU:an untargeted metabolomics study

作　　者：张江涛 刘鹏 汪文龙 谢欣序 何桃红 崔亚茹[2,3] 余军 ZHANG Jiang-tao;LIU Peng;WANG Wen-long;XIE Xin-xu;HE Tao-hong;CUI Ya-ru;YU Jun(Centre for Translational Medicine,Jiangxi University of Chinese Medicine,Nanchang 330006,China;Jiangxi Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Vascular Remodeling Diseases,Jiangxi University of Chinese Medicine,Nanchang 330006,China;National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herb Medicine,Jiangxi University of Chinese Medicine,Nanchang 330006,China;Lewis Katz School of Medicine,Temple University,Philadelphia PA19140,USA)

机构地区：[1]江西中医药大学转化医学中心,江西南昌330006 [2]江西中医药大学,江西省中药防治血管重塑相关疾病重点实验室,江西南昌330006 [3]江西中医药大学,中药固体制剂制造技术国家工程研究中心,江西南昌330006 [4]天普大学路易斯卡茨医学院,费城PA19140

出　　处：《中国中药杂志》2023年第13期3612-3622,共11页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(81960791)。

摘　　要：通过非靶向代谢组学技术研究白及多糖(Bletilla striata polysaccharide,BSP)对5-氟尿嘧啶(5-fluorouracil,5-FU)化疗的荷瘤小鼠血清中内源性代谢物的影响,探讨BSP改善5-FU引起的机体毒副反应的作用机制。将雄性BALB/C小鼠随机分为正常组、模型组、5-FU组和5-FU+BSP组,每组8只。除正常组外,其余各组均通过皮下接种CT26小鼠结肠癌细胞构建荷瘤小鼠模型,造模第2天起开始5-FU化疗和BSP给药。给药期间记录各组小鼠体质量变化、腹泻情况及外周血白细胞数量变化。模型组小鼠瘤重达到约1 g时终止化疗进行取材。通过TUNEL荧光染色检测各组小鼠小肠组织中细胞凋亡情况;流式细胞术检测小鼠骨髓中造血干细胞和髓系祖细胞占比;每组随机选取5个血清样本进行非靶向代谢组学分析。实验结果表明,BSP抑制小鼠结肠癌效果不明显,但经BSP干预后5-FU化疗引起的腹泻、白细胞减少及体质量下降等情况得到显著改善,小肠组织中凋亡细胞减少,骨髓造血干细胞和髓系祖细胞占比明显升高。代谢组学分析结果显示,5-FU毒副作用导致小鼠血清中29种代谢物含量显著降低,22种代谢物含量显著升高;其中19种发生紊乱的代谢物在BSP用药后向正常水平回调,通路富集显示这些代谢物所涉及代谢通路主要包括嘧啶代谢、花生四烯酸代谢和类固醇生物激素合成等。因此,BSP改善5-FU引起的肠道和骨髓毒副作用的机制可能与调控核苷酸合成、炎症损伤和激素生成相关。This study aimed to analyze the effect of Bletilla striata polysaccharide(BSP) on endogenous metabolites in serum of tumor-bearing mice treated with 5-fluorouracil(5-FU) by untargeted metabolomics techniques and explore the mechanism of BSP in alleviating the toxic and side effects induced by 5-FU.Male BALB/C mice were randomly divided into a normal group,a model group,a 5-FU group,and a 5-FU + BSP group,with eight mice in each group.Mouse colon cancer cells(CT26) were transplanted into the mice except for those in the normal group to construct the tumor-bearing mouse model by subcutaneous injection,and 5-FU chemotherapy and BSP treatment were carried out from the second day of modeling.The changes in body weight,diarrhea,and white blood cell count in the peripheral blood were recorded.The mice were sacrificed and sampled when the tumor weight of mice in the model group reached approximately 1 g.TUNEL staining was used to detect the cell apoptosis in the small intestine of each group.The proportions of hematopoietic stem cells and myeloid progenitor cells in bone marrow were measured by flow cytometry.Five serum samples were selected randomly from each group for untargeted metabolomics analysis.The results showed that BSP was not effective in inhibiting colon cancer in mice,but diarrhea,leukopenia,and weight loss caused by 5-FU chemotherapy were significantly improved after BSP intervention.In addition,apoptotic cells decreased in the small intestinal tissues and the percentages of hematopoietic stem cells and myeloid progenitor cells in bone marrow were significantly higher after BSP treatment.Metabolomics results showed that the toxic and side effects of 5-FU resulted in significant decrease in 29 metabolites and significant increase in 22 metabolites in mouse serum.Among them,19 disordered metabolites showed a return to normal levels in the 5-FU+BSP group.The results of pathway enrichment indicated that metabolic pathways mainly involved pyrimidine metabolism,arachidonic acid metabolism,and steroid hormone bio

关 键 词：白及多糖 化疗性腹泻 化疗性骨髓抑制 非靶向代谢组学 

分 类 号：R285.5[医药卫生—中药学]