Systematic investigation of the Erigeron breviscapus mechanism for treating cerebrovascular disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Cerebrovascular diseases (CBVDs), characterized by striking morbidity and mortality, have become the most common life-threatening diseases. The existing drugs of CBVDs target one or a few of pathogenic factors, the efficacy of which is limited because of the complexity of CBVDs. Traditional Chinese medicine (TCM), featured by multi-component and multi-target endows the great effectiveness in CBVDs treatment. For instance, Erigeron breviscapus (vant.) Hand. Mazz. （Erigeron breviscapus) has been used to treat CBVDs for a long time and the efficacy has been verified through years' of practice. Nevertheless, the mechanisms of Erigeron breviscapus for treating CBVDs are still unclear.

THE AIM OF THE STUDY: Systematically decipher the mechanisms of Erigeron breviscapus for treating CBVDs.

MATERIALS AND METHODS: The systems pharmacology approach is utilized by integrating ADME pharmacokinetic screening, target fishing, protein-protein interaction (PPI), network analysis and in vitro experiments verification.

RESULTS: First, 14 potentially active molecules were screened out through in silico ADME pharmacokinetic evaluation, most of which have been reported with excellent biological activities. Then 169 targets of active molecules were read out using our in-house softwares, systems drug targeting (sysDT) and Weighted Ensemble Similarity(WES). We found that the targets of the active compounds were significantly enriched to the CBVDs therapeutic targets by analyzing their biological processes and protein-protein interactions (PPIs). A multi-layer network analysis including compound-target network, target-pathway network and "CBVDs pathway" indicated that the Erigeron breviscapus exerts a protective effect on CBVDs via regulating multiple pathways and hitting on multiple targets. Meanwhile in vitro experiments confirmed that the stigmasterol, scutellarein, and daucosterol from Erigeron breviscapus increased the MEK and PLCγ proteins levels, and decreased the expression of Bax, PI3K, and eNOS, which led to the cell survival, proliferation and contraction.

CONCLUSION: The approach used in this work offers a new exemplification for systematically understanding the mechanisms of herbal medicines, which will give an impulse to the CBVDs drug development.