1. Academic Validation
  2. 4-Octyl itaconate alleviates dextran sulfate sodium-induced ulcerative colitis in mice via activating the KEAP1-NRF2 pathway

4-Octyl itaconate alleviates dextran sulfate sodium-induced ulcerative colitis in mice via activating the KEAP1-NRF2 pathway

  • Inflammopharmacology. 2024 May 20. doi: 10.1007/s10787-024-01490-3.
Yujin Wang # 1 Xue Zhao # 1 Yifei Gao 1 Chenxi Zhao 1 Jingxin Li 1 Shuanglian Wang 2 Bing Xue 1 Chuanyong Liu 1 Xuelian Ma 3
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Wenhuaxi Road 44#Shandong Province, Jinan, China.
  • 2 Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
  • 3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Wenhuaxi Road 44#Shandong Province, Jinan, China. xuelianma@sdu.edu.cn.
  • # Contributed equally.
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.

Keywords

4-Octyl itaconate; Intestinal barrier; Nuclear factor E2-related factor; Oxidative stress; Ulcerative colitis.

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