Integrated analysis of phytochemical composition, pharmacokinetics, and network pharmacology to probe distinctions between the stems of and based on antidepressant activity.

(CH), as a nutritional and functional supplement used in food and health care products for centuries, consists of the stems of and . Our previous studies confirmed that the stems of exerted advantageous antidepressant effect. However, whether the difference in the phytochemical compositions between the stems of and would lead to diverse bioavailability and accompanying antidepressant effects remain unclear, as well as their specific bioactive compounds and underlying mechanism. In this study, a series of comparative studies showed that the antidepressant activity of extract (CTE) was stronger than that of the extract (CDE), which was accompanied with the discovery of 10 differential markers from 52 identified compounds between CTE and CDE, and different pharmacokinetic behaviors of 9 prototype and 4 metabolites belonging to the glycosides between the CTE-treated and CDE-treated group in normal and depressive rats were simultaneously found by a validated UPLC-QTRAP-MS/MS method. Subsequently, network pharmacology prediction, and experiment verification from these differential markers further revealed that 7 compounds were confirmed to contribute to the antidepressant action of CH by inhibiting neuronal apoptosis mediated by mitochondrial function and activation of the AKT/GSK3β signaling pathway, synchronously indicating most of those, with higher bioavailability after CTE administration, that were responsible for the stronger antidepressant effect of CTE over CDE. Hence, the integrated analysis of phytochemical composition, pharmacokinetics, and network pharmacology provide new insights into the applications of CH from different botanical origins against depression.