| Objective: Qing-Luo-Yin(QLY)is a Traditional Chinese Herbal formula used to treat heat syndrome-related rheumatoid arthritis(RA).This study was designed to investigate it’s effects on collagen induced arthritis(CIA)in SD rats and the interaction with methotrexate(MTX),and decipher relevant mechanisms using metabolomics method on an UPLC-Q-TOF/MS platform.Methods: The CIA rats were treated with QLY,methotrexate(MTX)and QLY+MTX.Their effects of these treatments on the CIA rats were evaluated by clinical parameters,radiography and histological examinations,and serological biomarkers.The metabolic characteristics of rats were analyzed by UPLC-Q-TOF/MS method.Results: The experimental data showed that QLY reduced the severity of CIA severity and protected the joints from damages.Meanwhile,it possessed obvious antagonistic effects against MTX indicated by reduced toxicities of MTX and poor clinical outcomes under the combined treatment.Metabolomics analysis found that disorders of aminoacids,fatty acids and energy metabolism in CIA rats,which were partly restored by both QLY and MTX treatments.Upon the differentiation analyses of metabolites we found that QLY changed the pentose phosphate pathway(PPP)and regulation of pyrimidine metabolism in the CIA rats and subsequently improved the disease of the CIA rats.Additionally,we found QLY induced antifolate resistance and suppressed adenosine metabolism,which contributed to the antagonism with MTX.Conclusion: Based on obtained evidences,we concluded that inhibition of PPP and pyrimidine metabolism by QLY could account for the therapeutic effects on RA,and it’s combined use with MTX should be deliberately designed in clinical practice to avoid unfavorable antagonistic effects. |
