Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Aug;32(4):2555-2574.
doi: 10.1007/s10787-024-01490-3. Epub 2024 May 20.

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

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

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

Yujin Wang et al. Inflammopharmacology. 2024 Aug.

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.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

References

    1. Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, Korenfeld D, Mathyer ME, Kim H, Huang LH, Duncan D, Bregman H, Keskin A, Santeford A, Apte RS, Sehgal R, Johnson B, Amarasinghe GK, Soares MP, Satoh T, Akira S, Hai T, de Guzman SC, Auclair K, Roddy TP, Biller SA, Jovanovic M, Klechevsky E, Stewart KM, Randolph GJ, Artyomov MN (2018) Electrophilic properties of itaconate and derivatives regulate the IkappaBzeta-ATF3 inflammatory axis. Nature 556(7702):501–504. https://doi.org/10.1038/s41586-018-0052-z - DOI - PubMed - PMC
    1. Bazan L, Bendas ER, El Gazayerly ON, Badawy SS (2016) Comparative pharmaceutical study on colon targeted micro-particles of celecoxib: in-vitro-in-vivo evaluation. Drug Deliv 23(9):3339–3349. https://doi.org/10.1080/10717544.2016.1178824 - DOI - PubMed
    1. Bel S, Elkis Y, Lerer-Goldstein T, Nyska A, Shpungin S, Nir U (2012) Loss of TMF/ARA160 protein renders colonic mucus refractory to bacterial colonization and diminishes intestinal susceptibility to acute colitis. J Biol Chem 287(30):25631–25639. https://doi.org/10.1074/jbc.M112.364786 - DOI - PubMed - PMC
    1. Burri E, Maillard MH, Schoepfer AM, Seibold F, Van Assche G, Riviere P, Laharie D, Manz M, Swiss Ibdnetaowgot SSoG (2020) Treatment algorithm for mild and moderate-to-severe ulcerative colitis: an update. Digestion 101(Suppl 1):2–15. https://doi.org/10.1159/000504092 - DOI - PubMed
    1. Cai C, Ma H, Peng J, Shen X, Zhen X, Yu C, Zhang P, Ji F, Wang J (2023) USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice. Nat Commun 14(1):3648. https://doi.org/10.1038/s41467-023-39412-6 - DOI - PubMed - PMC