柴胡皂苷b2通过调控沉默信息调节因子6介导的糖代谢通路减轻二乙基亚硝胺诱导的小鼠原发性肝癌  

Inhibitory effect of saikosaponin b2 on diethyl nitrosamine-induced primary liver cancer of mice by regulating SIRT6-mediated glucose metabolism pathway

作　　者：有曼 张虹 何广宏 孟璐 李瑞芳[2] 王红伟[2] YOU Man;ZHANG Hong;HE Guang-hong;MENG Lu;LI Rui-fang;WANG Hong-wei(Pharmaceutical Department,Luoyang Orthopedic-Traumatological Hospital of Henan Province(Henan Provincial Orthopedic Hospital),Luoyang 471000,China;Department of Pharmacy,Basic Medical College,Henan University of Science and Technology,Luoyang 471000,China)

机构地区：[1]河南省洛阳正骨医院(河南省骨科医院)药学部,河南洛阳471000 [2]河南科技大学基础医学院药学系,河南洛阳471000

出　　处：《中国药理学与毒理学杂志》2022年第10期739-745,共7页Chinese Journal of Pharmacology and Toxicology

基　　金：河南省科技攻关重点项目(202102310486)。

摘　　要：目的探讨柴胡皂苷b2(SSb2)对二乙基亚硝胺(DEN)诱导的原发性肝癌小鼠的肝癌抑制作用及对沉默信息调节因子6(SIRT6)介导的糖代谢通路的影响。方法BALB/c小鼠随机分为正常对照组、肝癌模型组(DEN 50 mg·kg^(-1))、模型+SSb21.5,3.0和6.0 mg·kg^(-1)组及模型+多柔比星(DOX)1 mg·kg^(-1)组。除正常对照组外,其余组小鼠ip给予DEN 50 mg·kg^(-1),每周2次;第5周开始DEN给药减为每周1次,同时按分组给予SSb2和DOX,正常对照组在建模期间给予等体积生理盐水,给药持续19周。第19周末,收集小鼠血清和肝。计算肝指数,采用HE染色观察肝组织病理变化,试剂盒检测血清中谷草转氨酶(GOT)、谷丙转氨酶(GPT)、乳酸脱氢酶(LDH)和甲胎蛋白(AFP)水平;Western印迹法检测肝组织中SIRT6、低氧诱导因子1α(HIF-1α)、葡萄糖转运蛋白1(GLUT1)、丙酮酸脱氢酶激酶同工酶1(PDK1)和乳酸脱氢酶A(LDHA)蛋白表达水平。结果与正常对照组相比,模型组小鼠肝指数明显升高(P<0.01);与模型组相比,模型+SSb2各剂量组和模型+DOX组小鼠肝指数显著降低(P<0.01)。HE染色结果显示,模型组肝细胞异形性明显,癌巢组织多发,模型+SSb26.0 mg·kg^(-1)组和模型+DOX组细胞坏死增多,异形核及癌巢减少。血清指标结果显示,与正常对照组相比,模型组血清中GOT,GPT,LDH和AFP水平均显著升高(P<0.01);与模型组相比,模型+SSb23.0和6.0 mg·kg^(-1)组及模型+DOX组小鼠血清中GOT,GPT,LDH和AFP水平均显著降低(P<0.01),模型+SSb21.5 mg·kg^(-1)组GOT,LDH和AFP水平显著降低(P<0.01)。Western印迹结果显示,与正常对照组相比,模型组肝组织中SIRT6蛋白的表达显著降低(P<0.01),HIF-1α,GLUT1,PDK1和LDHA蛋白表达水平显著升高(P<0.01);与模型组相比,模型+SSb2各剂量组和模型+DOX组肝组织SIRT6蛋白的表达显著升高(P<0.01),而模型+SSb23.0和6.0 mg·kg^(-1)组及模型+DOX组肝组织HIF-1α,GLUT1,PDK1和LDHA蛋白表达水平均显著降低(POBJECTIVE To study the inhibitory effect of saikosaponin b2(SSb2)on primary liver cancer induced by diethyl nitrosamine(DEN)in mice and the effect on the glucose metabolism pathway mediated by silent information regulator 6(SIRT6).METHODS BALB/c mice were randomly divided into the normal control group,model group(DEN,50 mg·kg^(-1)),model+SSb21.5,3.0,6.0 mg·kg^(-1)groups and model+doxorubicin(DOX)1 mg·kg^(-1)group.Except the normal control group,these groups were given DEN 50 mg·kg^(-1),twice a week.From the 5thweek,DEN administration was reduced to once a week,and SSb2 and DOX were given according to groups.The normal control group was given the same volume of saline during modeling,and the administration lasted for 19 weeks.At the end of the19thweek,serum was collected from the mice which were killed before their livers were stripped away and weighed to calculate the liver index.HE staining was performed to observe the morphological changes of liver tissue.In addition,the levels of glutamic oxaloacetic transaminase(GOT),glutamate pyruvic transaminase(GPT),lactate dehydrogenase(LDH)and alpha fetoprotein(AFP)in serum were detected.The expressions of SIRT6,hypoxia inducible factor 1α(HIF-1α),glucose transporter 1(GLUT1),pyruvate dehydrogenase kinase isozyme 1(PDK1)and lactate dehydrogenase A(LDHA)in tumor tissue of DEN-induced mice were investigated by Western blotting.RESULTS Compared with the normal control group,the liver index of the model group was significantly increased(P<0.01).Compared with the model group,the liver indexs were significantly decreased in model+SSb2 groups and model+DOX group(P<0.01).The results of HE staining showed that there were many heteromorphic hepatocytes and a large number of cancer nests in the liver tissue of the model group.Compared with the model group,the necrotic cells in the model+SSb26.0 mg·kg^(-1)group and model+DOX group were increased,while the number of heteromorphic nucleuses and cancer nests was significantly reduced.According to the serological results,the seru

关 键 词：柴胡皂苷b2 原发性肝癌 沉默信息调节因子6 糖代谢 

分 类 号：R285.5[医药卫生—中药学] R979.1[医药卫生—中医学]