Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China; Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Taiyuan 030006, China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Taiyuan 030006, China.
Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China.
Chin J Nat Med. 2023 Mar;21(3):197-213. doi: 10.1016/S1875-5364(23)60421-2.
Angelicae Sinensis Radix (AS) is reproted to exert anti-depression effect (ADE) and nourishing blood effect (NBE) in a rat model of depression. The correlation between the two therapeutic effects and its underlying mechanisms deserves further study. The current study is designed to explore the underlying mechanisms of correlation between the ADE and NBE of AS based on hepatic metabonomics, network pharmacology and molecular docking. According to metabolomics analysis, 30 metabolites involved in 11 metabolic pathways were identified as the potential metabolites for depression. Furthermore, principal component analysis and correlation analysis showed that glutathione, sphinganine, and ornithine were related to pharmacodynamics indicators including behavioral indicators and hematological indicators, indicating that metabolic pathways such as sphingolipid metabolism were involved in the ADE and NBE of AS. Then, a target-pathway network of depression and blood deficiency syndrome was constructed by network pharmacology analysis, where a total of 107 pathways were collected. Moreover, 37 active components obtained from Ultra Performance Liquid Chromatography-Triple-Time of Flight Mass Spectrometer (UPLC-Triple-TOF/MS) in AS extract that passed the filtering criteria were used for network pharmacology, where 46 targets were associated with the ADE and NBE of AS. Pathway enrichment analysis further indicated the involvement of sphingolipid metabolism in the ADE and NBE of AS. Molecular docking analysis indciated that E-ligustilide in AS extract exhibited strong binding activity with target proteins (PIK3CA and PIK3CD) in sphingolipid metabolism. Further analysis by Western blot verified that AS regulated the expression of PIK3CA and PIK3CD on sphingolipid metabolism. Our results demonstrated that sphingolipid metabolic pathway was the core mechanism of the correlation between the ADE and NBE of AS.
当归被报道在抑郁模型大鼠中具有抗抑郁作用（ADE）和养血作用（NBE）。这两种治疗效果之间的相关性及其潜在机制值得进一步研究。本研究旨在基于肝代谢组学、网络药理学和分子对接技术，探讨当归 ADE 和 NBE 相关性的潜在机制。根据代谢组学分析，确定了 30 种涉及 11 种代谢途径的代谢物为与抑郁相关的潜在代谢物。此外，主成分分析和相关性分析表明，谷胱甘肽、神经鞘氨醇和鸟氨酸与行为指标和血液学指标等药效学指标相关，表明鞘脂代谢等代谢途径参与了当归的 ADE 和 NBE。然后，通过网络药理学分析构建了抑郁和血虚证的靶-途径网络，共收集了 107 条途径。此外，从当归提取物的超高效液相色谱-三重飞行时间质谱（UPLC-Triple-TOF/MS）中获得了 37 个符合过滤标准的活性成分，用于网络药理学分析，其中 46 个靶点与当归的 ADE 和 NBE 相关。通路富集分析进一步表明，鞘脂代谢参与了当归的 ADE 和 NBE。分子对接分析表明，当归提取物中的 E-藁本内酯与鞘脂代谢中的靶蛋白（PIK3CA 和 PIK3CD）具有较强的结合活性。Western blot 进一步分析验证了当归对鞘脂代谢中 PIK3CA 和 PIK3CD 表达的调节。我们的研究结果表明，鞘脂代谢途径是当归 ADE 和 NBE 相关性的核心机制。
