Zhao Qing, Ren Xia, Song Shu-Yue, Yu Ri-Lei, Li Xin, Zhang Peng, Shao Chang-Lun, Wang Chang-Yun
Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
Front Pharmacol. 2022 Apr 25;13:884480. doi: 10.3389/fphar.2022.884480. eCollection 2022.
Le-Cao-Shi (LCS) has long been used as a folk traditional Chinese medicine formula against liver injuries, whereas its pharmacological mechanisms remain elusive. Our study aims to investigate the underlying mechanism of LCS in treating liver injuries integrated network pharmacology, metabonomics, and experimental validation. By network pharmacology, 57 compounds were screened as candidate compounds based on ADME parameters from the LCS compound bank (213 compounds collected from the literature of three single herbs). According to online compound-target databases, the aforementioned candidate compounds were predicted to target 87 potential targets related to liver injuries. More than 15 pathways connected with these potential targets were considered vital pathways in collectively modulating liver injuries, which were found to be relevant to cancer, xenobiotic metabolism by cytochrome P450 enzymes, bile secretion, inflammation, and antioxidation. Metabonomics analysis by using the supernatant of the rat liver homogenate with UPLC-Q-TOF/MS demonstrated that 18 potential biomarkers could be regulated by LCS, which was closely related to linoleic acid metabolism, glutathione metabolism, cysteine and methionine metabolism, and glycerophospholipid metabolism pathways. Linoleic acid metabolism and glutathione metabolism pathways were two key common pathways in both network pharmacology and metabonomics analysis. In ELISA experiments with the CCl-induced rat liver injury model, LCS was found to significantly reduce the levels of inflammatory parameters, decrease liver malondialdehyde (MDA) levels, and enhance the activities of hepatic antioxidant enzymes, which validated that LCS could inhibit liver injuries through anti-inflammatory property and by suppressing lipid peroxidation and improving the antioxidant defense system. Our work could provide new insights into the underlying pharmacological mechanisms of LCS against liver injuries, which is beneficial for its further investigation and modernization.
勒草石（LCS）长期以来一直被用作治疗肝损伤的民间传统中药配方，但其药理机制仍不清楚。我们的研究旨在综合网络药理学、代谢组学和实验验证来探究LCS治疗肝损伤的潜在机制。通过网络药理学，基于LCS化合物库（从三种单味草药文献中收集的213种化合物）的ADME参数筛选出57种化合物作为候选化合物。根据在线化合物-靶点数据库，上述候选化合物被预测靶向87个与肝损伤相关的潜在靶点。与这些潜在靶点相关的15条以上通路被认为是共同调节肝损伤的关键通路，发现它们与癌症、细胞色素P450酶的异源生物代谢、胆汁分泌、炎症和抗氧化有关。使用超高效液相色谱-四极杆飞行时间质谱联用仪（UPLC-Q-TOF/MS）对大鼠肝匀浆上清液进行代谢组学分析表明，LCS可调节18种潜在生物标志物，这与亚油酸代谢、谷胱甘肽代谢、半胱氨酸和甲硫氨酸代谢以及甘油磷脂代谢途径密切相关。亚油酸代谢和谷胱甘肽代谢途径是网络药理学和代谢组学分析中两个关键的共同途径。在四氯化碳诱导的大鼠肝损伤模型的酶联免疫吸附测定（ELISA）实验中，发现LCS可显著降低炎症参数水平，降低肝脏丙二醛（MDA）水平，并增强肝脏抗氧化酶的活性，这证实LCS可通过抗炎特性以及抑制脂质过氧化和改善抗氧化防御系统来抑制肝损伤。我们的工作可为LCS抗肝损伤的潜在药理机制提供新的见解，这有利于其进一步研究和现代化。
