[Exploring therapeutic mechanism of Aconitum pendulum product processed with highland barley wine on rheumatoid arthritis based on UPLC-Q-TOF-MS/MS component identification, network pharmacology, and animal experiments].

This study aims to elucidate the material basis and mechanism of action of the Aconitum pendulum Busch product processed with highland barley wine against rheumatoid arthritis(RA). UPLC-Q-TOF-MS/MS was employed to preliminarily identify 55 compounds from the product. Through network pharmacology, 19 potential active ingredients and 140 corresponding targets were screened out. The drug targets were intersected with 89 RA targets collected from the OMIM database to yield a set of potential intervention targets. The protein-protein interaction(PPI) network was constructed via STRING and topological analysis was conducted via Cytoscape, which identified eight core targets: PPARG, EGFR, SLC6A3, OPRM1, PRKCA, CYP2D6, HTR1A, and HMGCR. Gene Ontology(GO) functional and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses performed in the Metascape database revealed that these targets were significantly enriched in processes such as TRP channels, the phosphatidylinositol 3 kinase(PI3K)-protein kinase B(Akt) signaling pathway, and neutrophil extracellular traps(NETs) formation. An integrated "drug-ingredient-disease-target-pathway" network was constructed, which selected seven core ingredients(dehydrolucidusculine, linoleic acid, pyraconitine, 16-epipyroaconitine, delphinine, 1-monopalmitin, and songorine) for molecular docking with the eight core targets. The results demonstrated favorable binding activity between each ingredient and the targets. Animal experiments showed that the A. pendulum product processed with highland barley wine alleviated joint swelling and inflammatory pathological changes of synovial tissue in the rat model of adjuvant-induced arthritis(AA) in a dose-dependent manner. In terms of the serum inflammatory cytokine levels, it downregulated the expression of pro-inflammatory cytokines tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-17A(IL-17A), and interleukin-6(IL-6). Furthermore, the product significantly reduced the phosphorylation levels of PI3K and its downstream signaling molecule Akt of knee synovial tissue in the rat model of AA. In conclusion, this study preliminarily reveals that the A. pendulum product processed with highland barley wine may exert anti-RA effects through multi-ingredient, multi-target, and multi-pathway mechanisms, particularly by regulating the PI3K-Akt signaling pathway and inflammatory responses.