In:
Current Pharmaceutical Biotechnology, Bentham Science Publishers Ltd., Vol. 24 ( 2023-04-20)
Abstract:
Gouty arthritis (GA) is a common form of inflammatory arthritis caused by intra-articular deposition of monosodium urate (MSU) crystals; however, there is a tremendous lack of safe and effective therapy in the clinic. Objective: The goal of this work was to investigate a novel leflunomide analogue, N-(2,4-dihydroxyphenyl)-5-methyl -1,2-oxazole-3-carboxamide (UTLOH-4e), for its potential to prevent/treat gouty arthritis. Methods: In this study, the anti-inflammatory activity of UTLOH-4e was evaluated by MSU-induced GA model in vivo and in vitro, and the molecular docking test was applied to estimate the affinity of UTLOH-4e/UTL-5g/b for MAPKs, NF-κB, and NLRP3. Results: In vitro, UTLOH-4e (1~100 M) treatment inhibited the inflammatory reaction with no obvious cytotoxicity in PMA-induced THP-1 macrophages exposed to MSU crystals for 24 h, involving the prominent decreased production and gene expression of IL-1β, TNF-, and IL-6. Western blot analyses demonstrated that UTLOH-4e (1~100 M) significantly suppressed the activation of NLRP3 inflammasomes, NF-κB, and MAPK pathways. Furthermore, the data from the experiment on gouty rats induced by intra-articular injection of MSU crystal confirmed that UTLOH-4e markedly ameliorated rat paw swelling, articular synovium inflammation and reduced the concentration of IL-1β and TNF- in serum through down-regulating NLRP3 protein expression. Conclusion: These results manifested that UTLOH-4e ameliorates GA induced by MSU crystals, which contributes to the modulation of NF-B/ NLRP3 signaling pathway, suggesting that UTLOH-4e is a promising and potent drug candidate for the prevention and treatment of gouty arthritis.
Type of Medium:
Online Resource
ISSN:
1389-2010
DOI:
10.2174/1389201024666230420101219
Language:
English
Publisher:
Bentham Science Publishers Ltd.
Publication Date:
2023
SSG:
15,3
