Melatonin-mediated MT2 attenuates colitis induced by dextran sodium sulfate via PI3K/AKT/Nrf2/SIRT1/RORα/NF-cB signaling pathways
Melatonin-mediated MT2 attenuates colitis induced by dextran sodium sulfate via PI3K/AKT/Nrf2/SIRT1/RORα/NF-cB signaling pathways
复制标题
褪黑激素介导的 MT2 通过 PI3K/AKT/Nrf2/SIRT1/RORα/NF-κB 信号通路减轻右旋糖酐硫酸钠诱导的结肠炎
DOI：
10.1016/j.intimp.2021.107779
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发表时间：
2021-05-24
影响因子：
5.6
通讯作者：
Chen, Yaoxing
中科院分区：
文献类型：
--
作者：
Gao, Ting;Wang, Tie;Chen, Yaoxing
背景：炎症性肠病（Inflammatoryboweldisease，IBD）是一种与肠道炎症反应相关的慢性疾病.我们先前的研究表明褪黑素对应激相关的IBD具有改善作用。本研究进一步阐明褪黑素对葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎的作用机制。研究方法：我们成功地建立了DSS诱导的结肠炎小鼠模型和过氧化氢（H2O2）处理的肠上皮细胞（IEC）与或不补充褪黑素，以探讨褪黑素在DSS诱导的结肠炎中的改善作用。结果如下：褪黑素补充使结肠炎、氧化应激、线粒体功能障碍、细胞凋亡和炎症反应正常化，包括肠通透性、组织学评分和IL-113、TNF-α、iNOS、NLRP 3、MDA、Bax、Caspase 3、细胞色素C和Caspase 9水平的增加，以及体重、结肠长度、Card9、IFN-γ、IL-10、T-AOC、Calpain 1、Mfn 2、DSS处理小鼠中的VDAC 1、ROR α和SIRT 1蛋白。MT 2拮抗剂4P-PDOT、PI3K拮抗剂LY294002、AKT拮抗剂GSK690693和Nrf2拮抗剂ML385可阻断褪黑素对H2O2-IEC的促凋亡作用，而P65拮抗剂PDTC可模拟褪黑素对H2O2-IEC的促凋亡作用。结论：MT 2通过激活PI3K/AKT/Nrf2/ROR alpha/SIRT1通路，抑制NF-cB通路，最终改善DSS诱导的结肠炎，为MT 2作为抗氧化应激相关IBD的有效治疗药物提供了证据。
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.