Synergistic enhancement and hepatoprotective effect of combination of total phenolic extracts of Citrus aurantium L. and methotrexate for treatment of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder characterized by joint destruction and bone damage. Methotrexate (MTX) is recommended as the first-line disease-modifying agent for the treatment of RA. However, the clinical efficacy of MTX is limited due to its low response and side effects, especially hepatotoxicity. Total phenolic extracts of Citrus aurantium L. (TPE-CA) are rich in dietary bioactive flavonoids, which show beneficial effects on liver health and are regarded as therapeutic tools against inflammatory diseases. In this study, the efficacy of MTX, alone or in combination with TPE-CA, for the treatment of collagen-induced arthritis and protection against hepatic injury in rats was investigated. TPE-CA and MTX combination effectively reduced the inflammatory symptoms and joint damage by inhibiting the NF-κB pathway. Moreover, TPE-CA significantly ameliorated MTXinduced chronic hepatic injury by enhancing antioxidant enzymes activities, suppressing hepatic cytochrome P450 2E1 expression, and modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. This combination regimen not only provided synergistic enhancement but also exhibited hepatoprotective effect against chemically induced chronic hepatotoxicity. This could be an alternative strategy to improve the low response of MTX in RA treatment. KEYWORDS antiinflammation, hepatotoxicity, methotrexate, rheumatoid arthritis, total phenolic extracts of Citrus aurantium L.

Naringenin ameliorates homocysteine induced endothelial damage via the AMPKα/Sirt1 pathway

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Naturally Occurring TPE-CA Maintains Gut Microbiota and Bile Acids Homeostasis via FXR Signaling Modulation of the Liver–Gut Axis

“…The specific contents of 32 phenolic compounds are recorded in the Table S1, Figure S1. The TPE-CA samples were stored at −20°C in a freezer and brought to room temperature before use (He et al, 2019).…”

“…The total phenolic extracts of C. aurantium L. (TPE-CA) were prepared in our laboratory, and primarily contain dietary flavonoids and their glycosyl derivatives, flavones, flavonols, polymethoxyflavones and coumarins. Our r ec e nt r es e a r ch r e ve a l ed t h a t, T P E -CA ex hi bi te d hepatoprotective effects on exogenetic chemical induced hepatic injury via modulation of the cytochrome P450 enzymes (Shu et al, 2017;He et al, 2019). Bile acid synthesis occurs in the liver, via the cytochrome P450 enzymes (CYPs).…”

The Effect of Chinese Medicine Compound in the Treatment of Rheumatoid Arthritis on the Level of Rheumatoid Factor and Anti-Cyclic Citrullinated Peptide Antibodies: A Systematic Review and Meta-Analysis

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