Melatonin-mediated MT2 attenuates colitis induced by dextran sodium sulfate via PI3K/AKT/Nrf2/SIRT1/RORα/NF-cB signaling pathways

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-113, TNF-alpha, iNOS, NLRP3, MDA, Bax, Caspase3, Cytochrome C and Caspase9, as well as the reduction of body weight, colon length, Card9, IFN-gamma, IL-10, T-AOC, Calpain1, Mfn2, VDAC1, ROR alpha and SIRT1 proteins in DSStreated 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/ROR alpha/SIRT1 pathway and suppressed NF-cB pathway, ultimately improved DSS-induced colitis, which provides evidence for melatonin as an efficient therapy against oxidative stress associated IBD.

Automated summary

The study demonstrated that melatonin improved DSS-induced colitis by activating multiple signaling pathways and inhibiting the NF-κB pathway, providing evidence for melatonin as an effective therapy against oxidative stress associated IBD.