Elucidating the molecular basis of Salvia miltiorrhiza Salvianolic acids and Tanshinones in treating ischemic stroke: A multidimensional strategy of in vivo Chemomics, targeted network pharmacology, and metabolomics.

Salvia miltiorrhiza, recognized as a neuroprotective agent in traditional Chinese medicine, has been extensively utilized in the treatment of cerebrovascular diseases and ischemic stroke (IS). While current evidence substantiates the therapeutic efficacy and proposed mechanisms of Salvia miltiorrhiza in IS, there remains a paucity of comprehensive comparative studies that examine and contrast the differential therapeutic contributions and systemic mechanisms of its two primary bioactive fractions: the water-soluble salvianolic acids and the liposoluble tanshinones. This gap in research is particularly significant for understanding their overall impact on physiological circulation and their distinct pathways in mitigating IS. Therefore, this study centers on Salvia miltiorrhiza, with the objective of thoroughly investigating the potential pharmacological properties and effects of its lipophilic and hydrophilic components in the treatment of IS. By integrating network pharmacology, metabolomics, and molecular docking methodologies, the research constructs a Disease-Gene-Pathway-Components network and a Biomarkers-Reaction-Enzyme-Gene network. This comprehensive approach enables a detailed elucidation of the multi-compound synergism and mechanisms of action underlying the therapeutic efficacy of Salvia miltiorrhiza in the treatment of IS. As a result, 63 active components of Salvia miltiorrhiza were identified, which exert exerted therapeutic effects on IS by targeting proteins such as GAPDH, PPARG, EGFR, and PTGS2. Additionally, 27 biomarkers primarily involved in the metabolism of arachidonic acid, tryptophan, and unsaturated fatty acids, were identified through serum metabolomics analysis. These potential biomarkers can be modulated by the salvianolic acids and tanshinones present in Salvia miltiorrhiza. By integrating the above research strategies and findings to construct a Biomarker-Gene-Active Ingredient network, PTGS2, JAK2, SRC, KDR, MAPK1, PTPRC, and EGFR were identified as key targets for the treatment of IS with various components of Salvia miltiorrhiza. In conclusion, it is evident that the mechanism of Salvia miltiorrhiza in treating IS is closely associated with the alleviating the neuroinflammation. Salvia miltiorrhiza is anticipated to become a traditional medicine with a well-defined mechanism and mild effects for the treatment of IS, and it holds potential for widespread clinical application.