芹菜素通过PDK1/AKT信号通路抑制小鼠肝纤维化  

Apigenin inhibits liver fibrosis through PDK1/AKT signaling pathway in mice

作　　者：陈鑫栋 仲威龙 闫佩瑶 匡佳妮 乔锴亮 孙涛 黄飚 秦源 CHEN Xin-dong;ZHONG Wei-long;YAN Pei-yao;KUANG Jia-ni;QIAO Kai-liang;SUN Tao;HUANG Biao;QIN Yuan(College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China;Dept of Gastroenterology,Tianjin Institute of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China;State Key Laboratory of Pharmaceutical Chemical Biology, School of Pharmacy, Nankai University,Tianjin 300350, China)

机构地区：[1]浙江理工大学生命科学与医药学院,浙江杭州310018 [2]天津医科大学总医院消化内科,天津市消化疾病研究所,天津市消化病学重点实验室,天津300052 [3]南开大学药学院,药物化学生物学国家重点实验室,天津300350

出　　处：《中国药理学通报》2022年第7期1010-1016,共7页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金青年项目(No 82000511);天津市教育委员会科研计划项目(No 2019KJ197)。

摘　　要：目的评价芹菜素对肝纤维化的治疗效果及其药理机制。方法建立四氯化碳(CCl_(4))诱导的肝纤维化小鼠模型,分别设置对照组、模型组、水飞蓟宾组(55 mg·kg^(-1)·d^(-1)),芹菜素低(15 mg·kg^(-1)·d^(-1))、中(30 mg·kg^(-1)·d^(-1))、高剂量(60 mg·kg^(-1)·d^(-1))组,评价芹菜素对疾病小鼠一般生活状态、体重、肝脏系数等影响,利用HE、Masson染色、免疫组化,Western blot检测芹菜素对各组小鼠肝脏病理变化、肝脏细胞上皮间充质转化相关标志物和信号通路的影响。结果中、高剂量芹菜素可以显著改善CCl4诱导的肝纤维化小鼠的一般生活状态、增加体质量、降低肝系数,并显著改善肝脏的病变。中、高剂量芹菜素可以显著提高模型小鼠肝脏组织中上皮标志蛋白E-cadherin的表达,显著降低间充质标志蛋白Vimentin的表达。进一步结果显示,中、高剂量芹菜素可以抑制肝纤维化小鼠肝组织磷酸化PDK1和磷酸化AKT蛋白的表达。结论芹菜素可以通过抑制PDK1/AKT信号通路抑制肝组织细胞EMT,发挥抗肝纤维化的作用。芹菜素具有进一步研发为保肝护肝、治疗肝纤维化药物的潜力。Aim To evaluate the therapeutic effect of apigenin on liver fibrosis in mice and the pharmacological mechanism.Methods Carbon tetrachloride(CCl_(4))-induced liver fibrosis mouse model was established.The mice were divided into six groups of control,model,silibinin(55 mg·kg^(-1)·d^(-1)),apigenin in high dosage(60 mg·kg^(-1)·d^(-1)),apigenin in middle dosage(30 mg·kg^(-1)·d^(-1))and apigenin in low dosage(15 mg·kg^(-1)·d^(-1)).The general life status,body weight and liver coefficient of the mice in every group were recorded.HE staining,Masson staining,immunohistochemistry and Western blot were used to evaluate the effect of apigenin on the pathological changes,the markers related to epithelial-mesenchymal transition and signaling pathways of liver tissues.Results In CCl4-induced liver fibrosis mice,middle and high-dosage of apigenin could improve the general life status,increase body weight,decrease liver coefficient,and significantly improve liver lesions.Middle and high-dosage of apigenin significantly increased the expression of the epithelial marker protein E-cadherin and significantly decreased the expression of the mesenchymal marker protein Vimentin in liver tissues of mice with the disease.The further results showed that middle and high-dosage apigenin could significantly inhibit the expression of phosphorylated PDK1 and phosphorylated AKT protein in liver tissues of model mice.Conclusions Apigenin can inhibit EMT by inhibiting PDK1/AKT signaling pathway,which plays an anti-fibrosis role.The apigenin has the potential to be further developed as a drug to protect the liver and treat liver fibrosis.

关 键 词：芹菜素 肝纤维化 上皮间充质转化 PDK1/AKT信号通路 黄酮 水飞蓟宾 

分 类 号：R-332[医药卫生] R284.1R322.47R329.25R394.2R575.2R977.6