<i>N</i>-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model

Wang, Linna; Huang, Baixiong; Zeng, Yaling; Yang, Jiujie; Li, Zhi; Ng, Jerome P. L.; Xu, Xiongfei; Su, Lu; Yun, Xiaoyun; Qu, Liqun; Chen, Ruihong; Luo, Weidan; Wang, Yuping; Chen, Chang; Yang, Lijun; Qu, Yuanqing; Zhang, Wei; Chan, Joyce Tsz Wai; Wang, Xingxia; Law, Betty Yuen Kwan; Mok, Simon Wing Fai; Chung, Sookja Kim; Wong, Vincent Kam Wai

doi:10.7150/ijbs.85028

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Int J Biol Sci 2023; 19(13):4082-4102. doi:10.7150/ijbs.85028 This issue Cite

Research Paper

N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model

Linna Wang¹, Baixiong Huang¹, Yaling Zeng¹, Jiujie Yang^1,5, Zhi Li^3,5, Jerome P. L. Ng¹, Xiongfei Xu¹, Lu Su¹, Xiaoyun Yun¹, Liqun Qu¹, Ruihong Chen¹, Weidan Luo¹, Yuping Wang¹, Chang Chen¹, Lijun Yang¹, Yuanqing Qu¹, Wei Zhang¹, Joyce Tsz Wai Chan¹, Xingxia Wang¹, Betty Yuen Kwan Law¹, Simon Wing Fai Mok², Sookja Kim Chung^1,2,4✉, Vincent Kam Wai Wong^1✉

1. Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
2. Faculty of Medicine, Macau University of Science and Technology, Macau, China.
3. Centro Hospitalar Conde de São Januário, Macau, China.
4. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.
5. Macau Medical Science and Technology Research Association, Macau, China.

Citation:

Wang L, Huang B, Zeng Y, Yang J, Li Z, Ng JPL, Xu X, Su L, Yun X, Qu L, Chen R, Luo W, Wang Y, Chen C, Yang L, Qu Y, Zhang W, Chan JTW, Wang X, Law BYK, Mok SWF, Chung SK, Wong VKW. N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model. Int J Biol Sci 2023; 19(13):4082-4102. doi:10.7150/ijbs.85028. https://www.ijbs.com/v19p4082.htm

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Abstract

Epalrestat, an aldose reductase inhibitor (ARI), has been clinically adopted in treating diabetic neuropathy in China and Japan. Apart from the involvement in diabetic complications, AR has been implicated in inflammation. Here, we seek to investigate the feasibility of clinically approved ARI, epalrestat, for the treatment of rheumatoid arthritis (RA).

The mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression. Epalrestat significantly suppressed lipopolysaccharide (LPS) induced TNF-α, IL-1β, and IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly, epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Interestingly, the combined treatment of epalrestat with N-Acetylcysteine (NAC), an anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory cytokines, and significantly improved the arthritic condition.

Taken together, the anti-arthritic effect of epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of epalrestat, suggesting that the combined therapy of epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need epalrestat for the treatment of diabetic complications.

Keywords: Epalrestat, AR inhibitor, Rheumatoid arthritis, 4-hydroxynonenal, N-acetylcysteine

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APA

Wang, L., Huang, B., Zeng, Y., Yang, J., Li, Z., Ng, J.P.L., Xu, X., Su, L., Yun, X., Qu, L., Chen, R., Luo, W., Wang, Y., Chen, C., Yang, L., Qu, Y., Zhang, W., Chan, J.T.W., Wang, X., Law, B.Y.K., Mok, S.W.F., Chung, S.K., Wong, V.K.W. (2023). N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model. International Journal of Biological Sciences, 19(13), 4082-4102. https://doi.org/10.7150/ijbs.85028.

ACS

Wang, L.; Huang, B.; Zeng, Y.; Yang, J.; Li, Z.; Ng, J.P.L.; Xu, X.; Su, L.; Yun, X.; Qu, L.; Chen, R.; Luo, W.; Wang, Y.; Chen, C.; Yang, L.; Qu, Y.; Zhang, W.; Chan, J.T.W.; Wang, X.; Law, B.Y.K.; Mok, S.W.F.; Chung, S.K.; Wong, V.K.W. N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model. Int. J. Biol. Sci. 2023, 19 (13), 4082-4102. DOI: 10.7150/ijbs.85028.

NLM

CSE

Wang L, Huang B, Zeng Y, Yang J, Li Z, Ng JPL, Xu X, Su L, Yun X, Qu L, Chen R, Luo W, Wang Y, Chen C, Yang L, Qu Y, Zhang W, Chan JTW, Wang X, Law BYK, Mok SWF, Chung SK, Wong VKW. 2023. N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model. Int J Biol Sci. 19(13):4082-4102.

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