Ting Gao1, Tie Wang1, Zixu Wang1, Jing Cao1, Yulan Dong1, Yaoxing Chen2. 1. Laboratory of Anatomy of Domestic Animals, College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China. 2. Laboratory of Anatomy of Domestic Animals, College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China. Electronic address: yxchen@cau.edu.cn.
Abstract
BACKGROUND: Inflammatory bowel disease (IBD) is an inflammatory response relative chronic disease in the intestinal tract. Our previous study demonstrated melatonin exerts an improvement effect on stress related IBD. The present study was further performed to clarify the mechanism of melatonin in dextran sodium sulfate (DSS)-induced colitis in mice. METHODS: We successfully established a DSS-induced colitis mouse model and hydrogen peroxide (H2O2)-treated intestinal epithelial cells (IECs) with or without melatonin supplementation to explore the improvement of melatonin in the DSS-induced colitis. RESULTS: Melatonin supplementation normalized the colitis, oxidative stress, mitochondria dysfunction, apoptosis and inflammation response, including the increase of intestinal permeability, histological score and the level of IL-1β, TNF-α, iNOS, NLRP3, MDA, Bax, Caspase3, Cytochrome C and Caspase9, as well as the reduction of body weight, colon length, Card9, IFN-γ, IL-10, T-AOC, Calpain1, Mfn2, VDAC1, RORα and SIRT1 proteins in DSS-treated mice. However, the improvement effects of melatonin were blocked by MT2 antagonist 4P-PDOT, PI3K antagonist LY294002, AKT antagonist GSK690693 and Nrf2 antagonist ML385, while mimicked by P65 antagonist PDTC in H2O2-IECs. CONCLUSION: Melatonin-mediated MT2 activated PI3K/AKT/Nrf2/RORα/SIRT1 pathway and suppressed NF-κB pathway, ultimately improved DSS-induced colitis, which provides evidence for melatonin as an efficient therapy against oxidative stress associated IBD.
BACKGROUND: Inflammatory bowel disease (IBD) is an inflammatory response relative chronic disease in the intestinal tract. Our previous study demonstrated melatonin exerts an improvement effect on stress related IBD. The present study was further performed to clarify the mechanism of melatonin in dextran sodium sulfate (DSS)-induced colitis in mice. METHODS: We successfully established a DSS-induced colitis mouse model and hydrogen peroxide (H2O2)-treated intestinal epithelial cells (IECs) with or without melatonin supplementation to explore the improvement of melatonin in the DSS-induced colitis. RESULTS: Melatonin supplementation normalized the colitis, oxidative stress, mitochondria dysfunction, apoptosis and inflammation response, including the increase of intestinal permeability, histological score and the level of IL-1β, TNF-α, iNOS, NLRP3, MDA, Bax, Caspase3, Cytochrome C and Caspase9, as well as the reduction of body weight, colon length, Card9, IFN-γ, IL-10, T-AOC, Calpain1, Mfn2, VDAC1, RORα and SIRT1 proteins in DSS-treated mice. However, the improvement effects of melatonin were blocked by MT2 antagonist 4P-PDOT, PI3K antagonist LY294002, AKT antagonist GSK690693 and Nrf2 antagonist ML385, while mimicked by P65 antagonist PDTC in H2O2-IECs. CONCLUSION: Melatonin-mediated MT2 activated PI3K/AKT/Nrf2/RORα/SIRT1 pathway and suppressed NF-κB pathway, ultimately improved DSS-induced colitis, which provides evidence for melatonin as an efficient therapy against oxidative stress associated IBD.
Authors: Se Hui Lee; Jin A Lee; Mi-Rae Shin; Hae-Jin Park; Seong-Soo Roh Journal: Evid Based Complement Alternat Med Date: 2022-05-17 Impact factor: 2.650
Authors: Karsten Peters; David Dahlgren; Péter Pál Egerszegi; Hans Lennernäs; Markus Sjöblom Journal: Int J Mol Sci Date: 2022-03-08 Impact factor: 5.923