WITHDRAWN: Elucidating the mechanisms of Tibetan medicine Ershiwuwei Lvxue Pill in the treatment of rheumatoid arthritis via a system pharmacological approach

Abstract

Background: Ershiwuwei Lvxue Pill (ELP, མགྲིན་མཚལ་ཉེར་ལྔ།), a traditional Tibetan medicine preparation, has been used hundreds of years for the clinical treatment of rheumatoid arthritis (RA) in Tibet, China. Nevertheless, its chemical compositions and therapeutic mechanism are unclear. Methods: In this work, a system pharmacological approach based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), network pharmacology and molecular docking simulation was proposed for exploring the promising bioactive compounds and mechanisms for the treatment of RA.Results: For the first time, the compounds database of ELP was successfully established and 96 compounds were identified based on UPLC-Q-TOF/MS analysis. Among them, 22 bioactive compounds were screened according to ADME, oral bioavailability and drug likeness. Screening based on relevant databases and topological analysis revealed that 22 bioactive ingredients participated in 46 potential target proteins and 12 signaling pathways in RA. The functional enrichment analysis indicated that ELP exerted the anti-RA effects via synergistically regulating multiple biological nodes of the disease network. In that, 10 targets with high degree value including IL6, TNF, TP53, AKT1, JUN, VEGFA, MAPK3, STAT3, IL1β and PTGS2. The pathways with greater p-value contribution are PI3K-Akt signaling pathway, Cytokine-cytokine receptor interaction, JAK-STAT signaling pathway, MAPK signaling pathway, TNF signaling pathway and Toll-like receptor signaling pathway. In addition, good molecular docking scores were highlighted between five promising bioactive compounds (ellagic acid, quercetin, kaempferol, galangin, coptisine) and five core targets (PTGS2, STAT3, VEGFA, MAPK3, TNF). Conclusion: Overall, the present work revealed the material basis and potential mechanism of ELP treatment on RA and provides insight for further research. However, further studies are needed to validate the biological processes and effect pathways of ELP.