Abstract
Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease with a relapsing–remitting course. Although its etiology remains unknown, excessive oxidative stress in colon is a major intermediate factor that can promote the progression of UC. In the present study, we investigated the effect and the underlying mechanisms of 4-Octyl itaconate (OI) on dextran sulfate sodium (DSS)-induced UC in mice. Our work identified that OI alleviated the colitis by reducing the oxidative stress and the apoptosis in colon tissue, then increasing the tight junction proteins expression and in turn enhancing the intestinal barrier function, thereby creating less severe inflammatory responses. Moreover, our results demonstrated that OI reduced the Kelch-like ECH-associated protein 1 (KEAP1) expression and subsequent upregulated nuclear factor E2-related factor (NRF2) expression and its nuclear translocation which in turn induced the expression of glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition, ML385, a NRF2 antagonist, can inhibit the protective effects of OI on UC, indicating that the role of OI in this colitis model could be dependent on the activation of KEAP1-NRF2 pathway. Notably, OI co-administration significantly enhanced the therapeutic effects of mesalazine or 1400W on UC. Collectively, itaconate may have a great potential for use in the treatment of IBD.
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This research was funded by National Natural Science Foundation of China (grant number 81470910) and Shandong Provincial Natural Science Foundation (grant number ZR2020MH051).
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XM conceived the idea for this study and wrote the original draft; Y W, X Z, and C Z performed the experiment; Y W and YG analyzed the data; JL, BX, and SW designed the experiment and provided technical support; CL designed the experiment and reviewed the manuscript. All authors read and approved the final manuscript.
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All animal procedures were approved by the Medical Ethics Committee for Experimental Animals, Shandong University, China (number LL-201602017).
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Wang, Y., Zhao, X., Gao, Y. et al. 4-Octyl itaconate alleviates dextran sulfate sodium-induced ulcerative colitis in mice via activating the KEAP1-NRF2 pathway. Inflammopharmacol (2024). https://doi.org/10.1007/s10787-024-01490-3
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DOI: https://doi.org/10.1007/s10787-024-01490-3