褪黑素介导的 MT2 通过 PI3K/AKT/Nrf2/SIRT1/RORα/NF-κB 信号通路减轻葡聚糖硫酸钠诱导的结肠炎。
Melatonin-mediated MT2 attenuates colitis induced by dextran sodium sulfate via PI3K/AKT/Nrf2/SIRT1/RORα/NF-κB signaling pathways.
机构信息
Laboratory of Anatomy of Domestic Animals, College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China.
Laboratory of Anatomy of Domestic Animals, College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China.
出版信息
Int Immunopharmacol. 2021 Jul;96:107779. doi: 10.1016/j.intimp.2021.107779. Epub 2021 May 24.
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 (HO)-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 HO-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.
背景
炎症性肠病（IBD）是一种肠道炎症的慢性疾病。我们之前的研究表明褪黑素对压力相关的 IBD 有改善作用。本研究进一步阐明了褪黑素在葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型中的作用机制。
方法
我们成功建立了 DSS 诱导的结肠炎小鼠模型和氢过氧化物（HO）处理的肠上皮细胞（IECs），并补充褪黑素，以探讨褪黑素对 DSS 诱导的结肠炎的改善作用。
结果
褪黑素补充剂使结肠炎、氧化应激、线粒体功能障碍、细胞凋亡和炎症反应正常化，包括肠道通透性、组织学评分和 IL-1β、TNF-α、iNOS、NLRP3、MDA、Bax、Caspase3、Cytochrome C 和 Caspase9 水平的增加，以及体重、结肠长度、Card9、IFN-γ、IL-10、T-AOC、Calpain1、Mfn2、VDAC1、RORα和 SIRT1 蛋白的减少，这些变化在 DSS 处理的小鼠中都得到了改善。然而，MT2 拮抗剂 4P-PDOT、PI3K 拮抗剂 LY294002、AKT 拮抗剂 GSK690693 和 Nrf2 拮抗剂 ML385 阻断了褪黑素的改善作用，而 HO-IECs 中的 P65 拮抗剂 PDTC 则模拟了褪黑素的作用。
结论
褪黑素介导的 MT2 激活了 PI3K/AKT/Nrf2/RORα/SIRT1 通路，并抑制了 NF-κB 通路，最终改善了 DSS 诱导的结肠炎，为褪黑素作为一种有效的抗氧化应激相关 IBD 治疗方法提供了证据。
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