摘要
近年来,我国由于误服含吡咯里西啶生物碱(pyrrolizidine alkaloids,PAs)的中草药而导致药源性肝损伤的报道逐年增多。丹酚酸B(salvianolic acid B,Sal B)是丹参(Salvia miltiorrhiza Bge.)中的主要水溶性有效成分,具有抗凝血和抗氧化等作用。本研究旨在研究丹酚酸B对千里光碱(senecionine,SEN)肝毒性的保护作用及其可能的作用机制。实验方案经上海中医药大学动物实验伦理委员会批准,所有程序均严格按照动物使用和护理的伦理原则进行。实验采用SEN(50 mg·kg^(-1))单次灌胃造成小鼠急性肝损伤模型,使用Sal B(10 mg·kg^(-1))进行干预。结果表明,Sal B能显著改善SEN致小鼠肝损伤,降低血清谷丙转氨酶和谷草转氨酶活力,并明显改善肝窦内出血、肝细胞坏死等病理状况,血清PAs毒性标志物吡咯蛋白加合物的含量也明显减少。进一步检测凝血、氧化应激和纤维化等相关通路关键因子,发现Sal B可降低纤溶酶原激活物抑制因子1的表达以抑制凝血系统,可调节谷胱甘肽及超氧化物歧化酶水平等改善机体的抗氧化应激能力,还可以通过影响基质金属蛋白酶9、转化生长因子-β1、信号传导蛋白和转录激活物3、趋化因子1等肝纤维化相关因子改善细胞外基质的过度沉积及延缓肝纤维化进程。本研究表明,丹酚酸B对千里光碱肝毒性的保护作用与调控凝血系统、改善氧化应激以及调控肝纤维化相关因子等有关,为临床上应用丹酚酸B治疗PAs肝损伤提供了理论依据。
In recent years,there has been an increase in the incidence of herbal-induced liver injury due to the accidental ingestion of herbal medicines containing pyrrolizidine alkaloids(PAs)in domestic.Salvianolic acid B(Sal B),a hydrophilic component in Salvia miltiorrhiza Bge.,shows activities of anticoagulation,antioxidation,and other pharmacological activities.This research aims to investigate the protective effect of Sal B on hepatotoxicity induced by senecionine(SEN)and its potential mechanism.The animal experiment was approved by the Experimental Animal Ethical Committee of Shanghai University of Traditional Chinese Medicine,and all mice have received humane care in compliance with the institutional animal care guidelines.Mice were treated with Sal B(10 mg·kg^(-1))3 days before and 1 day after SEN(50 mg·kg^(-1))treatment.The animals were sacrificed 48 h after SEN administration.As a result,Sal B effectively ameliorated SEN-induced liver injury.The mice in the group treated with Sal B showed lower serum activities of alanine aminotransferase and aspartate aminotransferase,less hepatic sinusoidal hemorrhage,and reduced hepatocyte necrosis.Besides,contents of pyrrole-protein adducts,the marker for PA-induced toxicity,were also decreased in serum.The key factors related to coagulation,oxidative stress,and liver fibrosis were further analyzed.It was found that Sal B inhibited the coagulant system by reducing the expression of plasminogen activator inhibitor-1.Sal B also modulated glutathione and superoxide dismutase levels and improved the anti-oxidative defense system.In addition,Sal B decreased the excessive deposition of extracellular matrix and inhibited the progression of liver fibrosis via down-regulating several key factors related to liver fibrosis,including matrix metalloproteinase 9,transforming growth factor-β1,signal transducer and activator of transcription 3,and chemokine 1.In conclusion,Sal B ameliorated SEN-induced liver injury in mice by regulating the blood coagulation system,improving oxidative stress,and modulating liver fibrosis-related factors.Our present study pointed to the possibility of utilizing salvianolic acid B for protection against PA-induced liver injury clinically.
作者
叶铉玲
姜凯元
杨莉
熊爱珍
王峥涛
YE Xuan-ling;JIANG Kai-yuan;YANG Li;XIONG Ai-zhen;WANG Zheng-tao(The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines,Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Shanghai R&D Center for Standardization of Traditional Chinese Medicines,Shanghai 201203,China)
出处
《药学学报》
CAS
CSCD
北大核心
2021年第4期1079-1085,共7页
Acta Pharmaceutica Sinica
基金
上海市自然科学基金资助项目(20ZR1473300)
上海市进一步加快中医药事业发展三年行动计划[ZY(2018-2020)-CCCX-5002]
上海市人才发展资金
上海中医药大学“杏林学者”计划
上海中医药大学“研究生创新培养专项”科研项目(Y2020031)。
关键词
丹参
丹酚酸B
吡咯里西啶生物碱
千里光碱
药源性肝损伤
纤溶酶原激活物抑制因子1
Salvia miltiorrhiza Bge.
salvianolic acid B
pyrrolizidine alkaloid
senecionine
drug-induced liver injury
plasminogen activator inhibitor-1
作者简介
通讯作者:杨莉,E-mail:yl7@shutcm.edu.cn;通讯作者:熊爱珍,Tel:86-21-51322506,Fax:86-21-51322519,E-mail:a.z.xiong@hotmail.com。
