Irisin pretreatment ameliorates intestinal ischemia/reperfusion injury in mice through activation of the Nrf2 pathway
Irisin pretreatment ameliorates intestinal ischemia/reperfusion injury in mice through activation of the Nrf2 pathway
复制标题
鸢尾素预处理通过激活 Nrf2 通路改善小鼠肠道缺血/再灌注损伤
DOI：
10.1016/j.intimp.2019.05.011
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发表时间：
2019-08-01
影响因子：
5.6
通讯作者：
Zhou, Jun
中科院分区：
文献类型：
--
作者：
Du, Juan;Fan, Xin;Zhou, Jun
肠缺血/再灌注损伤（Intestinal ischemia/reperfusion injury，MR）是一种严重的临床事件，可导致肠粘膜损伤，其主要机制包括活性氧（reactive oxygen species，ROS）的产生、炎症介质的释放和细胞凋亡的诱导。Irisin被认为是一种对许多病理性损伤具有有效保护作用的药物。本研究旨在观察鸢尾素预处理对小鼠肠I/R损伤和IEC-6细胞缺氧/复氧（H/R）模型肠损伤的保护作用，并探讨其机制。结果表明，鸢尾素预处理可减轻I/R和H/R引起的离体和体内损伤。此外，鸢尾素降低了肠道中肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1 β和白细胞介素（IL）-6的水平。与I/R组相比，Irisin预处理可有效降低肠组织中丙二醛（MDA）和髓过氧化物酶（MPO）水平，提高超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）活性，显著减轻氧化应激。此外，鸢尾素预处理下调Bax和切割Caspase-3在蛋白水平上，并增加Bcl-2蛋白的量，显着减少肠I/R小鼠的细胞凋亡。此外，在体内和体外的结果表明，鸢尾素预处理显着上调核因子（红细胞衍生2）样2（Nrf 2）蛋白。同时，Nrf 2 siRNA治疗部分取消了鸢尾素预处理对H/R诱导的细胞损伤、炎症反应、氧化应激和细胞凋亡的保护作用。这些结果表明，鸢尾素预处理改善I/R诱导的肠道炎症反应，减少氧化应激和抑制细胞凋亡，这可能是，至少部分，与Nrf 2通路激活。
Intestinal ischemia/reperfusion (MR) injury is a serious clinical event that may induce intestinal mucosal injury, whose major underlying mechanisms include reactive oxygen species (ROS) generation, release of inflammatory mediators and induction of apoptosis. Irisin is considered an agent with potent protection against many pathological injures. The aim of this study was to investigate the protective effect of irisin pretreatment on intestinal injury and explore its underlying mechanisms in a mouse model of intestinal I/R injury as well as a cell model (IEC-6 cell) of hypoxia/reoxygenation (H/R). The results showed that irisin pretreatment ameliorated I/R and H/R-induced injury in vivo and in vitro. In addition, irisin reduced the levels of tumor necrosis factor (TNF)-alpha, interleukin(IL)-1 beta and interleukin(IL)-6 in the intestine. Compared with the I/R group, irisin pretreatment effectively reduced malondialdehyde (MDA) and myeloperoxidase (MPO) levels, but increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the intestine, and significantly reduced oxidative stress. Furthermore, irisin pretreatment downregulated Bax and cleaved Caspase-3 at the protein level, and increased Bcl-2 protein amounts, significantly reducing apoptosis in the intestine of I/R mice. Moreover, both in vivo and in vitro results showed that irisin pretreatment significantly upregulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein. Meanwhile, Nrf2 siRNA treatment partially abrogated the protective effects of irisin pretreatment on H/R induced cellular damage, inflammatory response, oxidative stress, and apoptosis in IEC-6 cells. These findings suggest that irisin pretreatment improves I/R-induced intestinal inflammatory response, reduces oxidative stress and inhibits apoptosis, which could be, at least partially, associated with Nrf2 pathway activation.