Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Multi-component of Traditional Chinese Medicine and Microecology Research Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
J Ethnopharmacol. 2023 Dec 5;317:116765. doi: 10.1016/j.jep.2023.116765. Epub 2023 Jun 15.
Liver cancer is a worldwide malignant tumor, and currently lacks effective treatments. Clinical studies have shown that epimedium (YYH) has therapeutic effects on liver cancer, and some of its prenylflavonoids have demonstrated anti-liver cancer activity through multiple mechanisms. However, there is still a need for systematic research to uncover the key pharmacodynamic material basis and mechanism of YYH.
This study aimed to screen the anti-cancer material basis of YYH via integrating spectrum-effect analysis with serum pharmacochemistry, and explore the multi-target mechanisms of YYH against liver cancer by combining network pharmacology with metabolomics.
The anti-cancer effect of the extract of YYH (E-YYH) was first evaluated in mice with xenotransplantation H22 tumor cells burden and cultured hepatic cells. Then, the interaction between E-YYH compounds and the cytotoxic effects was revealed through spectrum-effect relationship analysis. And the cytotoxic effects of screened compounds were verified in hepatic cells. Next, UHPLC-Q-TOF-MS/MS was employed to identify the absorbed components of E-YYH in rat plasma to distinguish anti-cancer components. Subsequently, network pharmacology based on anti-cancer materials and metabolomics were used to discover the potential anti-tumor mechanisms of YYH. Key targets and biomarkers were identified and pathway enrichment analysis was performed.
The anti-cancer effect of E-YYH was verified through in vitro and in vivo experiments. Six anti-cancer compounds in plasma (icariin, baohuoside Ⅰ, epimedin C, 2″-O-rhamnosyl icariside Ⅱ, epimedin B and sagittatoside B) were screened out by spectrum-effect analysis. Forty-five liver-cancer-related targets were connected with these compounds. Among these targets, PTGS2, TNF, NOS3 and PPARG were considered to be the potential key targets preliminarily verified by molecular docking. Meanwhile, PI3K/AKT signaling pathway and arachidonic acid metabolism were found to be associated with E-YYH's efficacy in network pharmacology and metabolomics analysis.
Our research revealed the characteristics of multi-component, multi-target and multi-pathway mechanism of E-YYH. This study also provided an experimental basis and scientific evidence for the clinical application and rational development of YYH.
肝癌是一种全球性的恶性肿瘤，目前缺乏有效的治疗方法。临床研究表明淫羊藿（YYH）对肝癌具有治疗作用，其一些类黄酮具有通过多种机制抗肝癌的活性。然而，仍需要进行系统研究以揭示 YYH 的关键药效物质基础和作用机制。
本研究旨在通过整合谱效分析与血清药化，筛选 YYH 的抗癌物质基础，并结合网络药理学与代谢组学探讨 YYH 抗肝癌的多靶点作用机制。
首先评价 YYH 提取物（E-YYH）对荷移植性 H22 肿瘤细胞小鼠和培养的肝肿瘤细胞的抗癌作用。然后，通过谱效关系分析揭示 E-YYH 化合物与细胞毒性作用的相互关系。并在肝肿瘤细胞中验证筛选化合物的细胞毒性作用。接下来，采用 UHPLC-Q-TOF-MS/MS 鉴定 E-YYH 在大鼠血浆中的吸收成分，以区分抗癌成分。随后，基于抗癌物质和代谢组学的网络药理学用于发现 YYH 的潜在抗肿瘤机制。鉴定关键靶标和生物标志物，并进行通路富集分析。
通过体内外实验验证了 E-YYH 的抗癌作用。通过谱效分析筛选出 6 种血浆中具有抗癌作用的化合物（朝藿定 C、宝藿苷 I、淫羊藿苷、2″-O-鼠李糖苷朝藿定Ⅱ、淫羊藿素 B 和淫羊藿次苷 B）。这些化合物与 45 个肝癌相关靶标相连。其中，PTGS2、TNF、NOS3 和 PPARG 被认为是通过分子对接初步验证的潜在关键靶标。同时，在网络药理学和代谢组学分析中发现，PI3K/AKT 信号通路和花生四烯酸代谢与 E-YYH 的疗效相关。
本研究揭示了 E-YYH 的多成分、多靶点和多途径作用机制的特点。本研究为 YYH 的临床应用和合理开发提供了实验依据和科学证据。
