Zhou Shanshan, Ai Zhongzhu, Li Weinan, You Pengtao, Wu Chaoyan, Li Liang, Hu Yuanyang, Ba Yuanming
Clinical College of TCM, Hubei University of Chinese Medicine, Wuhan, China.
Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China.
Front Pharmacol. 2020 Apr 16;11:425. doi: 10.3389/fphar.2020.00425. eCollection 2020.
Taohe-Chengqi decoction (THCQ), a classical traditional Chinese medicinal (TCM) formula, has been extensively used for treating chronic kidney disease (CKD). However, the biological activity and mechanisms of action of its constituents against renal fibrosis have not yet been investigated thoroughly. This study was aimed at devising an integrated strategy for investigating the bioactivity constituents and possible pharmacological mechanisms of the n-butanol extract of THCQ (NE-THCQ) against renal fibrosis. The n-butanol extract of THCQ was prepared by the solvent extraction method. The components of NE-THCQ were analyzed using UPLC-Q/TOF-MS/MS techniques and applied for screening the active components of NE-THCQ according to their oral bioavailability and drug-likeness index. Then, we speculated the potential molecular mechanisms of NE-THCQ against renal fibrosis through pharmacological network analysis. Based on data mining techniques and topological parameters, gene ontology, and pathway enrichment, we established compound-target (C-T), protein-protein interaction (PPI) and compound-target-pathway (C-T-P) networks by Cytoscape to identify the hub targets and pathways. Finally, the potential molecular mechanisms of NE-THCQ against renal fibrosis, as predicted by the network pharmacology analyses, were validated experimentally in renal tubular epithelial cells (HK-2) and against unilateral ureteral obstruction models in the rat . We identified 26 components in NE-THCQ and screened seven bioactive ingredients. A total of 118 consensus potential targets associated with renal fibrosis were identified by the network pharmacology approach. The experimental validation results demonstrated that NE-THCQ might inhibit the inflammatory processes, reduce ECM deposition and reverse EMT PI3K/AKT/mTOR and HIF-1α/VEGF signaling pathways to exert its effect against renal fibrosis. This study identified the potential ingredients of the NE-THCQ by UPLC-Q/TOF-MS/MS and explained the possible mechanisms of NE-THCQ against renal fibrosis by integrating network pharmacology and experimental validation.
桃核承气汤（THCQ）是一种经典的中药方剂，已被广泛用于治疗慢性肾脏病（CKD）。然而，其成分抗肾纤维化的生物活性及作用机制尚未得到充分研究。本研究旨在设计一种综合策略，以研究THCQ正丁醇提取物（NE-THCQ）抗肾纤维化的生物活性成分及可能的药理机制。采用溶剂萃取法制备THCQ正丁醇提取物。运用超高效液相色谱-四极杆飞行时间串联质谱（UPLC-Q/TOF-MS/MS）技术分析NE-THCQ的成分，并根据其口服生物利用度和类药指数筛选NE-THCQ的活性成分。然后，通过药理网络分析推测NE-THCQ抗肾纤维化的潜在分子机制。基于数据挖掘技术、拓扑参数、基因本体和通路富集，利用Cytoscape构建化合物-靶点（C-T）、蛋白质-蛋白质相互作用（PPI）和化合物-靶点-通路（C-T-P）网络，以识别核心靶点和通路。最后，通过网络药理学分析预测的NE-THCQ抗肾纤维化的潜在分子机制在肾小管上皮细胞（HK-2）和大鼠单侧输尿管梗阻模型中进行了实验验证。我们在NE-THCQ中鉴定出26种成分，并筛选出7种生物活性成分。通过网络药理学方法共鉴定出118个与肾纤维化相关的潜在共同靶点。实验验证结果表明，NE-THCQ可能通过抑制炎症过程减少细胞外基质沉积并逆转上皮-间质转化（EMT），通过磷脂酰肌醇-3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）和缺氧诱导因子-1α/血管内皮生长因子（HIF-1α/VEGF）信号通路发挥抗肾纤维化作用。本研究通过UPLC-Q/TOF-MS/MS鉴定了NE-THCQ的潜在成分，并通过整合网络药理学和实验验证解释了NE-THCQ抗肾纤维化的可能机制。
