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Current Pharmaceutical Biotechnology

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ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

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Research Article

Novel Leflunomide Analog, UTLOH-4e, Ameliorates Gouty Arthritis Induced by Monosodium Urate Via NF-κB/NLRP3 Signaling Pathway

Author(s): Tianmin Yuan, Shilong Chen, Yifeng Yin, Jiajiu Shaw, Jin Zeng, Li Li, Lei Song, Yiguan Zhang, Zhujun Yin* and Junning Zhao*

Volume 25, Issue 3, 2024

Published on: 22 September, 2023

Page: [350 - 364] Pages: 15

DOI: 10.2174/1389201024666230420101219

Price: $65

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Abstract

Background: 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 MSUinduced 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 μM) 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-α, and IL-6. Western blot analyses demonstrated that UTLOH-4e (1~100 μM) 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-α 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-κB/ NLRP3 signaling pathway, suggesting that UTLOH- 4e is a promising and potent drug candidate for the prevention and treatment of gouty arthritis.

Keywords: UTLOH-4e, gouty arthritis, monosodium urate, nuclear factor-κB, pyrin domain-containing protein 3 (NLRP3) inflammasome, inflammation.

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