硫代葡萄糖苷治疗炎症性肠病的作用机制研究  

Study on the mechanism of glucosinolate in treating inflammatory bowel disease

作　　者：陈澍 望宇 毛旭文[2,3] CHEN Shu;WANG Yu;MAO Xu-wen(College of Traditional Chinese Medicine,Xinjiang Medical University,Urumqi 830011,China;College of Pharmacy,Xinjiang Medical University,Urumqi 830000,China;Key Laboratory of Active Component and Drug Delivery Technology of Natural Medicines,Xinjiang,Urumqi 830000,China;Third Clinical Medical College,Xinjiang Medical University,Urumqi 830011,China)

机构地区：[1]新疆医科大学中医学院,乌鲁木齐830011 [2]新疆医科大学药学院,乌鲁木齐830000 [3]新疆天然药物活性组分与释药技术重点实验室,乌鲁木齐830000 [4]新疆医科大学第三临床医学院,乌鲁木齐830011

出　　处：《天然产物研究与开发》2025年第4期694-706,共13页Natural Product Research and Development

基　　金：新疆维吾尔自治区科学技术厅自然科学基金面上项目(2022D01C190);新疆医科大学第15期大学生创新训练基金(S202010760036)。

摘　　要：研究结球甘蓝中硫代葡萄糖苷(glucosinolates,GSL;简称硫苷)治疗炎症性肠病(inflammatory bowel disease,IBD)的作用机制。利用公共数据库获得IBD和GSL的作用靶点,将二者取交集,构建蛋白互作网络,利用GO和KEGG富集分析其治疗IBD的潜在靶点。通过分子对接验证GSL中的活性单体成分3-吲哚基甲基硫苷(glucobrassicin,GBC)与核心靶点之间结合能。用葡聚糖硫酸钠建立IBD小鼠模型,检测其疾病活动指数评分、肠通透性、肠组织肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)等细胞因子水平。使用试剂盒检测人结直肠腺癌细胞增殖活性,ELISA检测脂多糖(lipopolysaccharide,LPS)诱导下该细胞释放TNF-α和白细胞介素10(interleukin-1,IL-10)水平。得到IBD与GSL交集靶点92个;GO功能分析表明调节炎症反应、调节激酶活性等多种生物过程参与IBD发展进程,获得了拓扑异构酶Ⅱα(topoisomerase II alpha,TOP2A)、细胞周期蛋白依赖性激酶1(cyclin-dependent kinase 1,CDK1)、细胞色素P4502C9(cytochrome P4502C9,CYP2C19)等10个GSL治疗IBD的核心靶点;KEGG富集相关性较高的通路为TRP通道炎症介质调节通路等;分子对接显示GBC与核心靶点有较好的结合活性。中、高剂量GSL组可减缓小鼠体重下降幅度并改善小鼠稀便和便血等情况,显著降低模型组DAI评分(P<0.001);降低小鼠肠组织TNF-α等细胞因子水平(P<0.001),升高IL-10水平(P<0.001)。在20~300μmol/L浓度范围内,GSL促进人结直肠腺癌细胞增殖,抑制LPS诱导的TNF-α分泌,升高IL-10水平。以上结果表明,GSL可能通过抑制TOP2A、CDK1蛋白表达,减轻小鼠肠道的炎性反应,缓解炎症性肠病症状。The purpose of this paper is to explore the mechanism of action of glucosinolates(GSL)in common head cabbage for the treatment of inflammatory bowel disease(IBD).Using public databases,this study obtained the targets of IBD and GSL,took the intersection of the two,constructed the protein interactions network,and analyzed their potential targets for the treatment of IBD using GO and KEGG enrichment.The binding energy between glucobrassicin(GBC),the active monomer component of GSL,and the core target was verified by molecular docking.Mice models of IBD were established with dextran sodium sulfate,and their disease activity index scores,intestinal permeabilities,intestinal tissue tumor necrosis factor-α(TNF-α)and other cytokine levels were detected.The proliferative activity of human colorectal adenocarcinoma cells was detected using a kit,and the levels of TNF-αand interleukin-1(IL-10)released from this cell induced by lipopolysaccharide(LPS)were detected by ELISA.Ninety-two intersection targets of IBD and GSL were obtained.GO functional analysis indicated that various biological processes,such as regulation of inflammatory response and modulation of kinase activity,were involved in the developmental process of IBD.Ten targets for the treatment of IBD by GSL,such as topoisomeraseⅡα(TOP2A),cell cycle protein-dependent kinase 1(CDK1),cytochrome P4502C9(CYP2C19)were obtained;In the KEGG enrichment analysis,the pathways with higher relevance included the TRP channel inflammatory mediator-regulated pathway.Molecular docking showed that GBC had better binding activity with the core targets.The medium and high GSL groups slowed down the weight loss and improved the condition of mice,such as loose stool and blood in stool,and significantly reduced the DAI score of the model group(P<0.001),lowered the levels of cytokines,such as TNF-α,in the intestinal tissues of the mice(P<0.001),and elevated the levels of IL-10(P<0.001).In the concentration range of 20-300μmol/L,GSL promoted the proliferation of human colorectal a

关 键 词：硫代葡萄糖苷 炎症性肠病 结球甘蓝 分子对接 

分 类 号：R284.1[医药卫生—中药学] R319[医药卫生—中医学]