Zhou Feng, Zhang Kai, Cai Zhi-Wei, Chen Yin-Fang, Zeng Xiao-Bo, He Xi-Zhe, Hu Xiao-Die, Wen Qing, Yu Ri-Yue, Huang Li-Ping
Jiangxi University of Traditional Chinese Medicine Nanchang 330004, China.
Jiangxi University of Traditional Chinese Medicine Nanchang 330004, China Jiangxi Province Key Laboratory of Traditional Chinese Medicine Pharmacology Nanchang 330004, China.
Zhongguo Zhong Yao Za Zhi. 2021 Jan;46(1):162-170. doi: 10.19540/j.cnki.cjcmm.20200901.402.
To study the time-toxicity relationship and mechanism of Gardeniae Fructus extract on the hepatoxicity in rats. Rats were randomly divided into C group(0 day), D5 group(5 days), D12 group(12 days), D19 group(19 days), and D26 group(7 days recovery after 19 days of administration). The rats in normal group received normal saline through intragastric administration, and the rats in other groups received 10 g·kg~(-1 )Gardeniae Fructus extract through intragastric administration. After the final administration, the livers were collected. Hematoxylin-eosin staining was used to observe the histopathological changes in the liver tissue. Total liver proteins were extracted for proteomic analysis, detected by the Nano-ESI liquid-mass spectrometry system and identified by Protein Disco-very software. SIEVE software was used for relative quantitative and qualitative analysis of proteins. The protein-protein interaction network was constructed based on STRING. Cytoscape software was used for cluster analysis of differential proteins. Kyoto encyclopedia of genes and genomes(KEGG) database was used to perform enrichment signal pathway analysis. Pearson correlation analysis was performed for the screened differential protein expression and liver pathology degree score. The results showed that the severity of liver injury in D5, D12 and D19 groups was significantly higher than that in group C. The degree of liver damage in D5 group was slightly higher than that in D12 and D19 groups, with no significant difference between group D26 and group C. Totally 147 key differential proteins have been screened out by proteomics and mainly formed 6 clusters, involving in drug metabolism pathways, retinol metabolism pathways, proteasomes, amino acid biosynthesis pathways, and glycolysis/gluconeogenesis pathways. The results of Pearson correlation analysis indicated that differential protein expressions had a certain temporal relationship with the change of liver pathological degree. The above results indicated that the severity of liver damage caused by Gardeniae Fructus extract did not increase with time and would recover after drug with drawal. The above pathways may be related to the mechanism of liver injury induced by Gardeniae Fructus extract.
研究栀子提取物对大鼠肝毒性的时间-毒性关系及机制。将大鼠随机分为C组（0天）、D5组（5天）、D12组（12天）、D19组（19天）和D26组（给药19天后恢复7天）。正常组大鼠经灌胃给予生理盐水，其他组大鼠经灌胃给予10 g·kg⁻¹栀子提取物。末次给药后，取肝脏。采用苏木精-伊红染色观察肝组织的组织病理学变化。提取肝脏总蛋白进行蛋白质组学分析，通过纳升电喷雾液相质谱系统检测，并用Protein Disco-very软件进行鉴定。用SIEVE软件对蛋白质进行相对定量和定性分析。基于STRING构建蛋白质-蛋白质相互作用网络。用Cytoscape软件对差异蛋白进行聚类分析。利用京都基因与基因组百科全书（KEGG）数据库进行富集信号通路分析。对筛选出的差异蛋白表达与肝脏病理程度评分进行Pearson相关性分析。结果显示，D5、D12和D19组肝损伤严重程度显著高于C组。D5组肝损伤程度略高于D12和D19组，D26组与C组无显著差异。通过蛋白质组学共筛选出147个关键差异蛋白，主要形成6个聚类，涉及药物代谢途径、视黄醇代谢途径、蛋白酶体、氨基酸生物合成途径和糖酵解/糖异生途径。Pearson相关性分析结果表明，差异蛋白表达与肝脏病理程度变化具有一定的时间关系。上述结果表明，栀子提取物所致肝损伤严重程度不随时间增加，停药后可恢复。上述途径可能与栀子提取物所致肝损伤机制有关。
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