Therapeutic effects of columbianadin from Angelicae Pubescentis radix on the progression of collagen-induced rheumatoid arthritis by regulating inflammation and oxidative stress

Ethnopharmacological relevance: Angelicae pubescentis radix (APR) has a long history in the treatment of rheu-matoid arthritis (RA) in China. It has the effects of dispelling wind to eliminate dampness, removing arthralgia and stopping pain in the Chinese Pharmacopeia, but its mechanisms was remained unclear. Columbianadin (CBN), one of the main bioactive compounds of APR, has many pharmacological effects including anti-inflammatory and immunosuppression. However, there are few reports on therapeutic effect of CBN on RA. Aim of the study: A comprehensive strategy via incorporating pharmacodynamics, microbiomics, metabolomics, and multiple molecular biological methods was adopted to evaluate the therapeutic effects of CBN on collagen -induced arthritis (CIA) mice and explore the potential mechanisms. Materials and methods: A variety of pharmacodynamic methods were used to evaluate the therapeutic effect of CBN on CIA mice. The microbial and metabolic characteristics of CBN anti-RA were obtained by metabolomics and 16S rRNA sequencing technology. The potential mechanism of CBN anti-RA was predicted through bioin-formatics network analysis, and verified by a variety of molecular biology methods. Results: CBN can effectively improved symptoms of rheumatoid arthritis in CIA mice, including paw swelling and arthritic scores. The inflammatory and oxidative stress were effectively regulated by the treatment of CBN. The fecal microbial communities and serum and urine metabolic compositions were significantly altered in CIA mice, CBN can ameliorate the CIA-associated gut microbiota dysbiosis, and regulate the disturbance of serum and urine metabolome. The acute toxicity test showed that the LD50 of CBN was greater than 2000 mg kg- 1. Conclusions: CBN exert anti-RA effects from four perspectives: inhibiting inflammatory response, regulating oxidative stress, and improving changes in gut microbiota and metabolites. The JAK1/STAT3, NF-& kappa;B and Keap1/ Nrf2 pathway may be important mechanism for CBN's inflammatory response and oxidative stress activity. CBN could be considered as a potential anti-RA drug for further study.