Integration of in vivo exposure and network pharmacology to investigate the pharmacodynamic material basis and action mechanism of Sinomenii Caulis in the treatment of myocardial infarction

Abstract Background It is generally believed that the materials basis of traditional Chinese medicine (TCM) are chemical substances and their metabolites entering the systemic circulation or target organs. In this case, analyzing and screening the possible pharmacodynamic substances of drugs from the perspective of in vivo exposure might provide the basis or direction for network pharmacology, a powerful tool for exploring the bioactive components and potential targets of TCM. Based on these, this study aims to develop a novel strategy to quickly screen out the pharmacodynamic substances and mechanisms of TCM in diseases, and further applied it to the pharmacodynamic substances and action mechanism study of Sinomenii Caulis (SC) in treating myocardial infarction (MI). Methods Firstly, ultra-high performance liquid chromatography tandem high resolution mass spectrometry (UPLC-HRMS) technology was used to study the exposed components of SC in mice. According to the main exposed components, the key genes, proteins, and mechanisms of SC in MI were predicted by network pharmacology. Finally, the effects of SC and its main pharmacodynamic substances on MI were evaluated by building a model of MI in vivo , and the possible key proteins were docked and verified by molecular docking or western blotting. Results The analysis of substances exposed in vivo revealed that the main exposed substances in mice were sinomenine, magnoflorine, menisperine, and their metabolites. Network pharmacology and molecular docking, combined with exposure to substances of SC in vivo , revealed that sinomenine was the potential pharmacodynamic substance of SC. By establishing a mouse model of MI in vivo , it was found that sinomenine had the same therapeutic effect on MI as SC containing the same dose of sinomenine. By western blotting and molecular docking, sinomenine was found to play a therapeutic role by inhibiting AKT phosphorylation. Conclusions The study indicates that the rational combination of exposure research in vivo and network pharmacology might be beneficial to discover the pharmacodynamic substances and their mechanisms of TCM. Meanwhile, this is a pioneer report that sinomenine, the main exposed substance of SC, had the same therapeutic effect on MI as SC containing the same dose of and inhibited AKT phosphorylation.