Faculty of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China.
School of Medical Equipment, Shenyang Pharmaceutical University, Shenyang, 110016, China.
J Ethnopharmacol. 2022 Oct 28;297:115567. doi: 10.1016/j.jep.2022.115567. Epub 2022 Jul 20.
Liver fibrosis is a chronic liver disease that can lead to cirrhosis, liver failure, and hepatocellular carcinoma, and it is associated with long-term adverse outcomes and mortality. As a primary resource for complementary and alternative medicine, traditional Chinese medicine (TCM) has accumulated a large number of effective formulas for the treatment of liver fibrosis in clinical practice. However, studies on how to systematically optimize TCM formulas are still lacking.
To provide a methodological reference for the systematic optimization of TCM formulae against liver fibrosis and explored the underlying molecular mechanisms; To provide an efficient method for searching for lead compounds from natural sources and developing from herbal medicines; To enable clinicians and patients to make more reasonable choices and promote the effective treatment toward those patients with liver fibrosis.
TCM formulas related to treating liver fibrosis were collected from the Web of Science, PubMed, the China National Knowledge Infrastructure (CNKI), Wan Fang, and the Chinese Scientific Journals Database (VIP). Furthermore, the TCM compatibility patterns were mined using association analysis. The core TCM combinations were found by designing an optimized formulas algorithm. Finally, the hub target proteins, potential molecular mechanisms, and active compounds were explored through integrative pharmacology and docking-based inverse virtual screening (IVS) approaches.
We found that the herbs for reinforcing deficiency, activating blood, removing blood stasis, and clearing heat were the basis of TCM formulae patterns. Furthermore, the combination of Salviae Miltiorrhizae (Salvia miltiorrhiza Bunge; Chinese salvia/Danshen), Astragali Radix (Astragalus membranaceus (Fisch.) Bunge; Astragalus/Huangqi), and Radix Bupleuri (Bupleurum chinense DC.; Bupleurum/Chaihu) was identified as core groups. A total of six targets (TNF, STAT3, EGFR, IL2, ICAM1, PTGS2) play a pivotal role in TCM-mediated liver fibrosis inhibition. (-)-Cryptotanshinone, Tanshinaldehyde, Ononin, Thymol, Daidzein, and Formononetin were identified as active compounds in TCM. And mechanistically, TCM could affect the development of liver fibrosis by regulating inflammation, immunity, angiogenesis, antioxidants, and involvement in TNF, MicroRNAs, Jak-STAT, NF-kappa B, and C-type lectin receptors (CLRs) signaling pathways. Molecular docking results showed that key components had good potential to bind to the target genes.
In summary, this study provides a methodological reference for the systematic optimization of TCM formulae and exploration of underlying molecular mechanisms.
肝纤维化是一种慢性肝病，可导致肝硬化、肝衰竭和肝细胞癌，并与长期不良后果和死亡率相关。作为补充和替代医学的主要资源，传统中药（TCM）在临床实践中积累了大量治疗肝纤维化的有效方剂。然而，关于如何系统优化 TCM 方剂的研究仍然缺乏。
为 TCM 方剂治疗肝纤维化的系统优化提供方法学参考，并探讨其潜在的分子机制；为从天然来源中寻找先导化合物和开发草药提供有效方法；使临床医生和患者能够做出更合理的选择，并促进有效治疗肝纤维化患者。
从 Web of Science、PubMed、中国知网（CNKI）、万方和中国科学期刊数据库（VIP）中收集与治疗肝纤维化相关的 TCM 方剂。此外，使用关联分析挖掘 TCM 配伍模式。通过设计优化配方算法找到核心 TCM 组合。最后，通过整合药理学和基于对接的反向虚拟筛选（IVS）方法探索枢纽靶标蛋白、潜在分子机制和活性化合物。
我们发现，补虚、活血、化瘀、清热的草药是 TCM 方剂模式的基础。此外，鉴定出丹参、黄芪和柴胡的组合为核心组。共有 6 个靶点（TNF、STAT3、EGFR、IL2、ICAM1、PTGS2）在 TCM 介导的肝纤维化抑制中发挥关键作用。鉴定出（-）-隐丹参酮、丹参醛、芒柄花苷、百里酚、大豆苷和芒柄花黄素为 TCM 中的活性化合物。并且从机制上看，TCM 可以通过调节炎症、免疫、血管生成、抗氧化剂以及参与 TNF、MicroRNAs、Jak-STAT、NF-kappa B 和 C 型凝集素受体（CLRs）信号通路来影响肝纤维化的发展。分子对接结果表明，关键成分与靶基因具有良好的结合潜力。
总之，本研究为 TCM 方剂的系统优化和潜在分子机制的研究提供了方法学参考。
