Kong Jiao, Tian Yue, Liu Chuan-Xin, Huang Jian-Mei
School of Chinese Materia Medica, Beijing University of Chinese Medicine Beijing 102488, China.
School of Chinese Materia Medica, Beijing University of Chinese Medicine Beijing 102488, China Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang City Clinical Research for Endocrinology and Metabolism,Department of Endocrinology and Metabolism, the First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology Luoyang 471003, China.
Zhongguo Zhong Yao Za Zhi. 2022 Jan;47(2):511-527. doi: 10.19540/j.cnki.cjcmm.20210914.701.
In this study, the toxicological/pharmacological research method of "quantity-weight-evidence" network was first proposed and practiced to supplement the existing methodology of network toxicology. We transformed the traditional qualitative network into a quantitative network in this study by attributing weights to toxic component content and target frequency, which improved the reliability of data and provided a research idea for the systematic safety evaluation and toxicological research of Chinese medicinal herbs. Firstly, 50% ethanol extract of Dysosma versipellis(DV) was administrated to rats via gavage and the potential hepatotoxic components were identified by serum pharmacochemistry. Then, the component targets were obtained from SwissTargetPrediction, PharmMapper and other online databases, and the target weights were given according to the relative content of components and target fishing frequency. Meanwhile, the targets of hepatotoxicity were predicted from online databases such as Comparative Toxicology Database(CTD) and GeneCards. Subsequently, protein-protein interaction analysis and KEGG pathway enrichment were performed with the STRING database. Finally, the quantitative network of "toxic components-weighted targets-pathways" was constructed. Eleven potential toxic compounds were predicted, including podophyllotoxin, podophyllotoxone, deoxypodophyllotoxin, and 6-methoxypodophyllotoxin. A total of 106 hepatotoxic targets and 65 weighted targets(e.g., Cdk2, Egfr, and Cyp2 c9) were identified. The results of Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment showed that these targets could act on PI3 K-AKT, MAPK, and Ras signaling pathways to play a role in inflammatory response and oxidative stress. However, traditional network toxicology showed that 51 targets such as AKT1, Alb, and Stat3 may lead to hepatotoxicity by mediating inflammation and cell proliferation. In conclusion, we proposed "quantity-weight-evidence" network toxicology in this study and used it to study the mechanism of DV-induced hepatotoxicity in rats. This study confirms the feasibility of this new methodology in toxicological evaluation and further improves the systematic evaluation of the safety of Chinese medicinal herbs.
在本研究中，首次提出并实践了“量-权-证”网络的毒理学/药理学研究方法，以补充现有的网络毒理学方法。在本研究中，我们通过赋予毒性成分含量和靶点频率权重，将传统的定性网络转化为定量网络，提高了数据的可靠性，为中药的系统安全性评价和毒理学研究提供了一种研究思路。首先，将八角莲50%乙醇提取物经灌胃给予大鼠，通过血清药物化学方法鉴定潜在的肝毒性成分。然后，从SwissTargetPrediction、PharmMapper等在线数据库中获取成分靶点，并根据成分的相对含量和靶点捕捞频率赋予靶点权重。同时，从比较毒理学数据库（CTD）和GeneCards等在线数据库中预测肝毒性靶点。随后，使用STRING数据库进行蛋白质-蛋白质相互作用分析和KEGG通路富集。最后，构建了“毒性成分-加权靶点-通路”的定量网络。预测了11种潜在的毒性化合物，包括鬼臼毒素、鬼臼毒素酮、脱氧鬼臼毒素和6-甲氧基鬼臼毒素。共鉴定出106个肝毒性靶点和65个加权靶点（如Cdk2、Egfr和Cyp2 c9）。京都基因与基因组百科全书（KEGG）通路富集结果表明，这些靶点可作用于PI3 K-AKT、MAPK和Ras信号通路，在炎症反应和氧化应激中发挥作用。然而，传统的网络毒理学表明，AKT1、Alb和Stat3等51个靶点可能通过介导炎症和细胞增殖导致肝毒性。总之，本研究提出了“量-权-证”网络毒理学，并将其用于研究八角莲诱导大鼠肝毒性的机制。本研究证实了这种新方法在毒理学评价中的可行性，并进一步完善了中药安全性的系统评价。
