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Background: Elderly rheumatoid arthritis (ERA) population faces multiple treatment dilemma. Here we aim to investigate if Gancao Nourishing-Yin decoction (GCNY) added to methotrexate (MTX) exhibit better effects in an ERA mice model. Methods: ERA mice model was established by adding D-galactose (Dgal) to collagen-induced arthritis (CIA) mice. The model was then assigned into control group (CIA + Dgal), MTX treatment group (MTX), GCNY treatment group (GCNY), and integrative treatment group (MTX + GCNY). Pathological scoring was performed to evaluate the severity between the groups. Proteomic analysis was applied to investigate the secretory phenotype of the ERA mouse model and the underlying mechanism of GCNY, MTX and their combination. Representative cytokines related to proteomic results were further validated by ELISAs. Results: CIA + Dgal mice showed more aggressive joints damage than the CIA mice. Besides changes in the inflammatory pathway such as Pi3k-Akt signaling pathway in both model, differential expressed proteins (DEPs) indicated metabolism-related pathways were more obvious in CIA + Dgal mice. Low-dose MTX failed to show pathological improvement in CIA + Dgal mice, while GCNY improved joints damage significantly. Besides down-regulated inflammation-related targets, GCNY-regulated DEPs (such as Apoc1 ~ 3, Grk2 and Creb3l3) were broadly enriched in metabolism-related pathways. MTX + GCNY showed the best therapeutic effect, and the DEPs enriched in a variety of inflammatory,metabolism and osteoclast differentiation signaling pathway. Notably, MTX + GCNY treatment up-regulated Dhfr, Cbr1, Shmt1 involved in folic acid biosynthesis and anti-folate resistance pathways indicated a coincidence synergic action. ELISAs confirmed CPR and Akt that elevated in CIA + Dgal mice were significantly ameliorated by treatments, and adding on GCNY elevated folic acid levels and its regulator Dhfr. Conclusion: Aging aggravated joints damage in CIA, which probably due to metabolic changes rather than more severe inflammation. GCNY showed significant effects in the ERA mice model especially when integrated with MTX to obtain a synergic action. [ABSTRACT FROM AUTHOR]

Background: Traditional Chinese medicine (TCM) has been used to treat various diseases for thousands of years. However, the uncertainty of dosage as well as the lack of systemic evaluation of pharmacology and toxicology is one major reason why TCM remains mysterious and is not accepted worldwide. Hence, we aimed to propose an integrated dose–response metabolomics strategy based on both therapeutic effects and adverse reactions to guide the TCM dosage in treatment. Methods: The proposed methodology of integrated dose–response metabolomics includes four steps: dose design, multiple comparison of metabolic features, response calculation and dose–response curve fitting. By comparing the changes of all metabolites under different doses and calculating these changes through superposition, it is possible to characterize the global disturbance and thus describe the overall effect and toxicity of TCM induced by different doses. Rhubarb, commonly used for constipation treatment, was selected as a representative TCM. Results: This developed strategy was successfully applied to rhubarb. The dose–response curves clearly showed the efficacy and adverse reactions of rhubarb at different doses. The rhubarb dose of 0.69 g/kg (corresponding to 7.66 g in clinic) was selected as the optimal dose because it was 90% of the effective dose and three adverse reactions were acceptable in this case. Conclusion: An integrated dose–response metabolomics strategy reflecting both therapeutic effects and adverse reactions was established for the first time, which we believe is helpful to uncover the mysterious veil of TCM dosage. In addition, this strategy benefits the modernization and internationalization of TCM, and broadens the application of metabolomics. [ABSTRACT FROM AUTHOR]