药学学报, 2019, 54(3): 494-501
引用本文:
陆龙会, 张芳, 詹常森, 熊爱珍, 杨莉, 王峥涛. 胆宁片对菊三七所致肝窦阻塞综合征的保护作用[J]. 药学学报, 2019, 54(3): 494-501.
LU Long-hui, ZHANG Fang, ZHAN Chang-sen, XIONG Ai-zhen, YANG Li, WANG Zheng-tao. The protective effect of Danning tablet against hepatic sinusoidal obstruction syndrome induced by Gynura Rhizoma[J]. Acta Pharmaceutica Sinica, 2019, 54(3): 494-501.

胆宁片对菊三七所致肝窦阻塞综合征的保护作用
陆龙会1,2, 张芳1,2, 詹常森3, 熊爱珍1, 杨莉1,2, 王峥涛1
1. 上海中医药大学中药研究所, 中药标准化教育部重点实验室暨上海市复方中药重点实验室, 上海 201203;
2. 上海中医药大学交叉科学研究院, 上海 201203;
3. 上海和黄药业有限公司, 上海 201401
摘要:
近年来,因误服菊三七所导致的肝窦阻塞综合征(hepatic sinusoidal obstruction syndrome,HSOS)引起了国内外的广泛关注。本文研究中药复方胆宁片对菊三七所致HSOS病理症状的缓解作用,并探讨其作用机制。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。连续灌胃菊三七醇提物(1 g·kg-1)40天造成小鼠HSOS损伤,并设胆宁片保护组(每日灌胃胆宁片3 g·kg-1和菊三七醇提物1 g·kg-1)和空白对照组。结果表明,胆宁片对菊三七所致HSOS有明显保护作用。胆宁片保护组血清转氨酶活性及总胆红素和胆汁酸含量均显著下降,中央静脉内皮损伤、内皮出血、肝窦出血及内皮纤维化等典型HSOS病变均有所缓解。进一步检测了纤维化相关指标,发现与HSOS小鼠比较,胆宁片保护组中肝脏羟脯氨酸含量、α-平滑肌肌动蛋白、I型胶原、Ⅲ型胶原、金属基质蛋白酶2和9的基因表达水平均显著降低;胆宁片保护组中肝脏磷酸化Smad3(p-Smad3)的表达及血清转化生长因子-β(transforming growth factor-β,TGF-β)含量亦显著低于HSOS损伤组。此外,胆宁片保护组肝脏肿瘤坏死因子-α和白介素-1β的基因表达水平也有所降低。结果表明,胆宁片对菊三七所致HSOS的保护作用与抑制TGF-β/p-Smad3信号通路及炎症信号通路的激活有关,为临床上应用胆宁片治疗HSOS提供了理论依据。
关键词:   
The protective effect of Danning tablet against hepatic sinusoidal obstruction syndrome induced by Gynura Rhizoma
LU Long-hui1,2, ZHANG Fang1,2, ZHAN Chang-sen3, XIONG Ai-zhen1, YANG Li1,2, WANG Zheng-tao1
1. The Ministry of Education 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 201203, China;
2. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;
3. Shanghai Hutchison Pharmaceuticals Co., Ltd., Shanghai 201401, China
Abstract:
Recently, hepatic sinusoidal obstruction syndrome (HSOS) caused by Gynura Rhizoma (Tusanqi) has gained global attention. The purpose of this research is to investigate the effects and mechanisms of Danning tablet, a traditional Chinese formula, on protecting against HSOS induced by Gynura Rhizoma. All experiments were approved by the Animal Research Committee of Shanghai University of Traditional Chinese Medicine. Animal welfare and the animal experimental protocols were strictly consistent with related ethics regulations of Shanghai University of Traditional Chinese Medicine. HSOS was induced by intragastrical administration of Gynura Rhizoma extract (1 g·kg-1·d-1) for 40 consencutive days. On the other hand, mice in the protection group were intragastrical administration of Danning tablet powder (3 g·kg-1·d-1) 4 hours before treatment of Gynura Rhizoma extract. The results showed that Danning tablet could significantly attenuate the liver injury in HSOS mice. Mice in the protection group showed decreased serum activity of spartate amino transferase, and levels of total bile acids and total bilirubin. In addition, the endothelial damage to the central venules, subendothelial hemorrhage, sinusoidal hemorrhage, and subendothelial fibrosis in HSOS mice were clearly attenuated in the protection group. Measurements of the key factors involved in liver fibrosis revealed that protection group showed significantly reduction in hepatic hydroxyproline concentration, mRNA expression of α-smooth muscle actin and fibrosis-related genes such as Collagen-1, Collagen-3, Mmp2 and Mmp9, as well as Smad3 phosphorylation (p-Smad) and serum transforming growth factor-β (TGF-β). Moreover, pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, were also reversed in the protection group. All these results demonstrate the key roles of the TGF-β/p-Smad3 and inflammatory signaling pathways in the protection effect of Danning tablet on Gynura Rhizoma-induced HSOS, and pointing to the possibility of utilizing Danning tablet for protection against Gynura Rhizoma induced HSOS clinically.
Key words:   
收稿日期: 2018-08-29
DOI: 10.16438/j.0513-4870.2018-0793
基金项目: 国家自然科学基金资助项目(81603384);上海市自然科学基金资助项目(16ZR1434200);上海市优秀学科带头人计划(17XD1403500);上海市青年科技启明星计划(17QA1403600);上海市科技成果转化与产业化项目(17DZ1920100).
通讯作者: 杨莉, 熊爱珍
Email: yl7@shutcm.edu.cn;a.z.xiong@hotmail.com
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