Molecular mechanisms of Toddalia asiatica against rheumatoid arthritis: bioinformatics and molecular dynamics simulation

Abstract

BACKGROUND: The therapeutic potential of Toddalia asiatica in rheumatoid arthritis has garnered increasing attention, yet its mechanisms remain incompletely elucidated. OBJECTIVE: To investigate the underlying mechanisms of Toddalia asiatica in treating rheumatoid arthritis using bioinformatics combined with molecular dynamics simulation. METHODS: Active ingredients of Toddalia asiatica and their targets were retrieved. Drug targets were intersected with rheumatoid arthritis-related targets, followed by enrichment analysis of the overlapping genes. Molecular docking and molecular dynamics simulation were performed to validate the binding mechanisms of core active ingredients with key targets. RESULTS AND CONCLUSION: Through literature retrieval, 22 core active ingredients of Toddalia asiatica and their key targets against rheumatoid arthritis were identified. Enrichment analysis indicated that Toddalia asiatica may exert therapeutic effects by modulating disease-related signaling pathways (including cancer, infectious diseases, metabolic diseases, and cardiovascular diseases) as well as biological pathways related to metabolism, immunity, and inflammation. Meanwhile, the main components Dihydrochelerythrine and 8-Methoxychelerythrine specifically target phospholipase C gamma 2 (PLCG2) and mitogen-activated protein kinase 8 (MAPK8), respectively, suggesting that Toddalia asiatica may exert anti-rheumatoid arthritis effects through synergistic multi-pathway regulation.

1. Introduction

Rheumatoid arthritis is a complex autoimmune disease of unknown etiology, characterized by synovial thickening, abscess formation, and cartilage and bone damage. It imposes a heavy burden on society and patients due to high disability and mortality rates [1]. With population aging, increased life expectancy, and global environmental deterioration, the annual incidence of rheumatoid arthritis continues to rise, affecting approximately 1% of the global population, with women affected three to four times more often than men [2-3]. Current therapeutic strategies focus on modulating immune-inflammatory responses to alleviate symptoms [4], but challenges such as adverse drug reactions, limited personalized treatment options, efficacy fluctuations, and drug resistance remain significant, necessitating the exploration of novel therapeutic agents with both efficacy and safety.

Natural plants have attracted considerable attention due to their natural origin, proven efficacy, and high safety. Toddalia asiatica (L.) Lam., a traditional anti-inflammatory plant, is documented in the Chinese Herbal Medicine (Miao Medicine Volume) to have effects of dispelling wind and dampness, reducing swelling and detoxifying, and removing blood stasis and alleviating pain, which aligns with the traditional Chinese medicine pathogenesis of rheumatoid arthritis as 'dampness-turbidity and blood stasis obstruction, meridian blockage'. Modern pharmacological studies have further confirmed that Toddalia asiatica extracts exert anti-inflammatory effects through multiple pathways: they inhibit the expression of inflammatory factors in RAW 264.7 macrophages, reduce serum inflammatory factor levels in collagen-induced arthritis mice, and increase interleukin-10 expression. Additionally, Toddalia asiatica extract combined with miR-483 promotes the proliferation of osteoarthritic chondrocytes and inhibits the expression of apoptosis-related proteins P21, caspase-3, and inflammatory factors tumor necrosis factor alpha and interleukin-6 [5]. Recent studies have shown that the ethanol extract of Toddalia asiatica can regulate the balance of intestinal immune helper T cell 17/regulatory T cell-related proteins and mRNA in adjuvant-induced arthritis rat models, increase beneficial gut microbiota, reduce harmful microbiota, and reverse microbial dysbiosis [6-7].

These findings suggest that Toddalia asiatica may intervene in joint inflammation through pathways involving immune regulation, apoptosis, and gut microecology, but its anti-rheumatoid arthritis mechanism remains unclear. Moreover, the multi-component, multi-target nature of traditional Chinese medicine poses challenges for mechanistic studies. Computational biology methods, such as network pharmacology and molecular docking, can address this limitation. Network pharmacology emphasizes holism by illustrating the connections among drugs, targets, and diseases, aligning with the systemic, syndrome-differentiated, and multi-component regulatory characteristics of traditional Chinese medicine. It provides a unique approach for studying Chinese herbal components and is widely used to predict potential active ingredients and targets, as well as to deeply investigate drug mechanisms. Based on this, the present study systematically explores the molecular mechanisms of Toddalia asiatica against rheumatoid arthritis using bioinformatics and molecular dynamics simulation.