Zuojinwan (ZJW), a classic herbal formula, has been extensively used to treat gastric symptoms in clinical practice in China for centuries. However, the pharmacological mechanisms of ZJW still remain vague to date. In the present work, a network pharmacology-based strategy was proposed to elucidate its underlying multi-component, multi-target, and multi-pathway mode of action against gastritis. First we collected putative targets of ZJW based on TCMSP and STITCH databases, and a network containing the interactions between the putative targets of ZJW and known therapeutic targets of gastritis was built. Then four topological parameters, “degree”, “betweenness”, “closeness”, and “coreness” were calculated to identify the major targets in the network. Furthermore, the major hubs were imported to the Metacore database to perform a pathway enrichment analysis. A total of 118 nodes including 59 putative targets of ZJW were picked out as major hubs in terms of their topological importance. The results of pathway enrichment analysis indicated that putative targets of ZJW mostly participated in various pathways associated with anti-inflammation response, growth and development promotion and G-protein-coupled receptor signaling. More importantly, five putative targets of ZJW (EGFR, IL-6, IL-1β, TNF-α and MCP-1) and two known therapeutic targets of gastritis (CCKBR and IL-12β) and a link target NF-κB were recognized as active factors involved in the main biological functions of treatment, implying the underlying mechanisms of ZJW acting on gastritis. ZJW could alleviate gastritis through the molecular mechanisms predicted by network pharmacology, and this research demonstrates that the network pharmacology approach can be an effective tool to reveal the mechanisms of traditional Chinese medicine (TCM) from a holistic perspective.

Carthamus tinctorius L. is widely used in traditional Chinese medicines for the treatment of cardiovascular disease. However, our current understanding of the molecular mechanisms supporting its clinical application still lags behind. In this study, a systems pharmacology approach integrating drug-likeness evaluation, oral bioavailability prediction, target exploration, GO enrichment analysis, KEGG pathway performance and network construction was adopted to explore its therapeutic mechanism. A total of 21 active ingredients contained in Carthamus tinctorius L. and 113 major proteins were screened out as effective players in the treatment of cardiovascular disease through some related pathways. And the association among the active ingredients, major hubs and main pathways was investigated, implying the potential biological progression of Carthamus tinctorius L. acting on cardiovascular disease. Importantly, the majority of hubs and pathways were found to be highly related with platelet activation process. Core genes that can be regulated by Carthamus tinctorius L. in platelet activation pathway were PRKACA, PIK3R1, MAPK1, PPP1CC, PIK3CA and SYK, and they may play a central role in suppressing platelet aggregation. The systems pharmacology approach used in this study may provide a feasible tool to clarify the mechanism of traditional Chinese medicines and further develop their therapeutic potentials.

Metabolic study of bioactive compounds that undergo a dynamic and sequential process of metabolism is still a great challenge. Salidroside, one of the most active ingredients of Rhodiola crenulata, can be metabolized in different sites before being absorbed into the systemic blood stream. This study proposed an approach for describing the sequential biotransformation process of salidroside based on comparative analysis. In vitro incubation, in situ closed-loop and in vivo blood sampling were used to determine the relative contribution of each site to the total metabolism of salidroside. The results showed that salidroside was stable in digestive juice, and it was metabolized primarily by the liver and the intestinal flora and to a lesser extent by the gut wall. The sequential metabolism method described in this study could be a general approach to characterizing the metabolic routes in the digestive system for natural products.

Topiroxostat is a selective xanthine oxidoreductase (XOR) inhibitor for the management of hyperuricemia in patients with or without gout. In this work, we aim to employ the physiologically based pharmacokinetic (PBPK) model with the drug-target residence time model to predict and characterize both the pharmacokinetics (PK) and pharmacodynamics (PD) of topiroxostat in humans. The plasma concentration-time profile of topiroxostat was simulated based on drug properties and human physiology parameters. The predictive power of this PBPK model was then demonstrated by comparison of stimulated to observed pharmacokinetic parameters. The utility of the model was further demonstrated through predicting the oral absorption and disposition characteristics of topiroxostat in humans. Finally, by combining the PBPK model and the drug-target residence time model, we successfully predicted the target occupancy and built the relationship between PK and PD using in vitro, in vivo and in silico information. The results showed that topiroxostat exhibited significant in vivo pharmacological activity even after the complete clearance of this drug from the liver (target site), which may be due to the long residence time of the binary topiroxostat-XOR complex. This work may be helpful to guide future investigations of topiroxostat and also provides a novel strategy for PK/PD studies.

Areca catechu L. nut, a well-known toxic traditional herbal medicine, has been widely used to treat various diseases in China and many other Asian countries for centuries. However, to date the in vivo absorption and metabolism of its multiple bioactive or toxic components still remain unclear. In this study, liquid chromatography coupled with tandem mass spectrometry was used to analyze the major components and their metabolites in rat plasma and urine after oral administration of Areca catechu L. nut extract (ACNE). A total of 12 compounds, including 6 alkaloids, 3 tannins and 3 amino acids, were confirmed or tentatively identified from ACNE. In vivo, 40 constituents, including 8 prototypes and 32 metabolites were identified in rat plasma and urine samples. In summary, this study showed an insight into the metabolism of ACNE in vivo, which may provide helpful chemical information for better understanding of the toxicological and pharmacological profiles of ACNE.