Uncovering pharmacological mechanisms of Wu-tou decoction acting on rheumatoid arthritis through systems approaches: drug-target prediction, network analysis and experimental validation

TLDR

Wu‑tou decoction (WTD) is widely used to treat rheumatoid arthritis, yet its pharmacological mechanisms remain poorly understood due to insufficient methods. The study aimed to predict putative targets of WTD’s constituent compounds using drugCIPHER‑CS. Using drugCIPHER‑CS, the authors predicted WTD compound targets and then constructed an interaction network with known RA targets to identify hub nodes. The analysis identified 79 major hubs linked to nervous, endocrine, and immune system imbalance, and experimental validation in collagen‑induced arthritis rats showed that WTD prevented inflammation and joint destruction and regulated these targets, suggesting WTD attenuates RA by restoring NEI balance.

Abstract

Abstract Wu-tou decoction (WTD) has been extensively used for the treatment of rheumatoid arthritis (RA). Due to lack of appropriate methods, pharmacological mechanisms of WTD acting on RA have not been fully elucidated. In this study, a list of putative targets for compositive compounds containing in WTD were predicted by drugCIPHER-CS. Then, the interaction network of the putative targets of WTD and known RA-related targets was constructed and hub nodes were identified. After constructing the interaction network of hubs, four topological features of each hub, including degree, node betweenness, closeness and k-coreness, were calculated and 79 major hubs were identified as candidate targets of WTD, which were implicated into the imbalance of the nervous, endocrine and immune (NEI) systems, leading to the main pathological changes during the RA progression. Further experimental validation also demonstrated the preventive effects of WTD on inflammation and joint destruction in collagen-induced arthritis (CIA) rats and its regulatory effects on candidate targets both in vitro and in vivo systems. In conclusion, we performed an integrative analysis to offer the convincing evidence that WTD may attenuate RA partially by restoring the balance of NEI system and subsequently reversing the pathological events during RA progression.