姜黄素介导IL-6/STAT3信号通路修复结肠癌5-FU化疗引起的肠黏膜损伤  

Curcumin mediates IL-6/STAT3 signaling pathway to repair intestinal mucosal injury induced by 5-FU chemotherapy for colon cancer

作　　者：徐露 王娴[2] 王宣璎 姚庆华 陈寅波 XU Lu;WANG Xian;WANG Xuan-ying;YAO Qing-hua;CHEN Yin-bo(Cancer Hospital of University of Chinese Academy of Sciences(Zhejiang Cancer Hospital),Hangzhou 310022,China;the Second Clinical Medical College of Zhejiang Chinese Medical University,Hangzhou 310022,China;Sir Run Run Shaw Hospital Affiliated to Medical College of Zhejiang University,Hangzhou 310053,China)

机构地区：[1]中国科学院大学附属肿瘤医院(浙江省肿瘤医院),浙江杭州310022 [2]浙江大学医学院附属邵逸夫医院,浙江杭州310020 [3]浙江中医药大学第二临床医学院,浙江杭州310053

出　　处：《中国中药杂志》2021年第3期670-677,共8页China Journal of Chinese Materia Medica

基　　金：浙江省中医药管理局项目(2019ZA018,2014ZB069)。

摘　　要：探讨姜黄素介导白细胞介素6(interleukin-6,IL-6)/信号转导和转录激活因子3(signal transducer and activator of transcription 3,STAT3)信号通路修复结肠癌5-氟尿嘧啶(5-fluorouracil,5-FU)化疗引起的肠黏膜损伤的潜在作用机制。SD大鼠腹腔注射60 mg·kg^(-1)·d^(-1)5-FU,连续注射4 d,制备5-FU化疗肠黏膜损伤模型,随机分为模型组(等体积生理盐水)和姜黄素低、中、高剂量组(50,100,200 mg·kg^(-1)),以正常SD大鼠为对照组(等体积生理盐水),各组连续4 d灌胃给药,并记录每日体质量及粪便变化情况。给药结束后,心脏取血,收集空肠组织。酶联免疫吸附(ELISA)法检测各组大鼠血清白细胞介素1β(interleukin-1β,IL-1β)、肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)表达水平,同时测定空肠组织伊文斯蓝(Evans blue,EB)浓度。苏木精-伊红(HE)染色法观察大鼠空肠组织病理状态并测量空肠绒毛长度及隐窝深度。免疫组化法测定紧密连接蛋白(claudin,occludin,ZO-1)阳性表达。Western blot法检测空肠组织IL-6,p-STAT3,E-cadherin,vimentin,N-cadherin蛋白表达水平。结果显示,姜黄素可升高大鼠体质量、粪便质量(P<0.05或P<0.01),降低粪便评分、EB浓度、IL-1β和TNF-α水平(P<0.05或P<0.01);可较大程度上维持空肠组织黏膜表面与绒毛结构的完整性,减轻病理改变,且呈剂量依赖性。同时姜黄素可升高occludin,claudin,ZO-1阳性表达(P<0.05或P<0.01),修复肠道屏障功能,下调空肠组织中IL-6,p-STAT3,vimentin,N-cadherin蛋白表达水平(P<0.05或P<0.01),上调E-cadherin蛋白表达水平(P<0.05)。由此可知,姜黄素可修复结肠癌5-FU化疗诱导的肠黏膜损伤,其作用机制可能与抑制IL-6/STAT3信号通路,进而抑制上皮间充质转化(epithelial-mesenchymal transition,EMT)进程有关。This study aims to investigate the potential mechanism of curcumin in mediating interleukin-6(IL-6)/signal transducer and activator of transcription 3(STAT3)signaling pathway to repair intestinal mucosal injury induced by 5-fluorouracil(5-FU)chemotherapy for colon cancer.SD rats were intraperitoneally injected with 60 mg·kg^(-1)·d^(-1)5-FU for 4 days to establish a model of intestinal mucosal injury.Then the rats were randomly divided into model group(equal volume of normal saline),curcumin low,medium and high dose groups(50,100,200 mg·kg^(-1)),and normal SD rats were used as control group(equal volume of normal saline).Each group received gavage administration for 4 consecutive days,and the changes of body weight and feces were recorded every day.After administration,blood was collected from the heart,and jejunum tissues were collected.The levels of serum interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α)were detected by ELISA,and at the same time,the concentration of Evans blue(EB)in jejunum was measured.Hematoxylin-eosin(HE)staining was used to observe the pathological state of jejunum,and the length of jejunum villi and the depth of crypt were measured.The positive expression levels of claudin,occludin and ZO-1 were detected by immunohistochemistry.Western blot was used to detect the protein expression of IL-6,p-STAT3,E-cadherin,vimentin and N-cadherin in jejunum tissues.The results showed that,curcumin significantly increased body weight and fecal weight(P<0.05 or P<0.01),decreased fecal score,EB concentration,IL-1βand TNF-αlevels(P<0.05 or P<0.01)in rats.In addition,curcumin maintained the integrity of mucosal surface and villi structure of jejunum to a large extent,and reduced pathological changes in a dose-dependent manner.Meanwhile,curcumin could increase the positive expression of occludin,claudin and ZO-1(P<0.05 or P<0.01),repair intestinal barrier function,downregulate the protein expression of IL-6,p-STAT3,vimentin and N-cadherin in jejunum tissues(P<0.05 or P<0.01),and upregulate the p

关 键 词：结肠癌 姜黄素 IL-6/STAT3信号通路 5-氟尿嘧啶(5-FU) 肠黏膜损伤 

分 类 号：R285[医药卫生—中药学]