Punicalagin Induces Nrf2/HO-1 Expression via Upregulation of PI3K/AKT Pathway and Inhibits LPS-Induced Oxidative Stress in RAW264.7 Macrophages.
Punicalagin Induces Nrf2/HO-1 Expression via Upregulation of PI3K/AKT Pathway and Inhibits LPS-Induced Oxidative Stress in RAW264.7 Macrophages.
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DOI：
10.1155/2015/380218
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发表时间：
2015
影响因子：
4.6
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Xu X;Li H;Hou X;Li D;He S;Wan C;Yin P;Liu M;Liu F;Xu J
活性氧（ROS）和氧化应激被认为在增强巨噬细胞活化、引起过度炎症、组织损伤和败血症中起核心作用。最近，我们发现punicalagin （PUN）在lps刺激的巨噬细胞中具有抗炎活性。然而，PUN在巨噬细胞中的潜在抗氧化作用尚不清楚。揭示这些作用将有助于了解其抑制过度巨噬细胞激活的机制。血红素加氧酶-1 （HO-1）在巨噬细胞中表现出抗氧化活性。因此，我们假设HO-1是PUN的潜在靶点，并试图揭示其抗氧化机制。在这里，PUN处理增加了HO-1及其上游介质核因子-红细胞2 p45相关因子2 （Nrf2）的表达。然而，brusatol（一种特异性Nrf2抑制剂）对Nrf2的特异性抑制显著阻断了punn诱导的HO-1表达。既往研究表明，PI3K/Akt通路作为上游信号分子在调控Nrf2/HO-1蛋白表达中起着至关重要的作用。这里，特异性PI3K/Akt抑制剂LY294002抑制pun诱导的HO-1表达，导致巨噬细胞中ROS积累。此外，PUN通过减少ROS和NO的生成，增加超氧化物歧化酶（SOD） 1 mRNA的表达，抑制lps诱导的巨噬细胞氧化应激。这些发现为使用抗氧化药物和化合物治疗氧化应激和过度炎症性疾病（包括组织损伤、败血症和内毒素休克）提供了新的治疗方法。
Reactive oxygen species (ROS) and oxidative stress are thought to play a central role in potentiating macrophage activation, causing excessive inflammation, tissue damage, and sepsis. Recently, we have shown that punicalagin (PUN) exhibits anti-inflammatory activity in LPS-stimulated macrophages. However, the potential antioxidant effects of PUN in macrophages remain unclear. Revealing these effects will help understand the mechanism underlying its ability to inhibit excessive macrophage activation. Hemeoxygenase-1 (HO-1) exhibits antioxidant activity in macrophages. Therefore, we hypothesized that HO-1 is a potential target of PUN and tried to reveal its antioxidant mechanism. Here, PUN treatment increased HO-1 expression together with its upstream mediator nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). However, specific inhibition of Nrf2 by brusatol (a specific Nrf2 inhibitor) dramatically blocked PUN-induced HO-1 expression. Previous research has demonstrated that the PI3K/Akt pathway plays a critical role in modulating Nrf2/HO-1 protein expression as an upstream signaling molecule. Here, LY294002, a specific PI3K/Akt inhibitor, suppressed PUN-induced HO-1 expression and led to ROS accumulation in macrophages. Furthermore, PUN inhibited LPS-induced oxidative stress in macrophages by reducing ROS and NO generation and increasing superoxide dismutase (SOD) 1 mRNA expression. These findings provide new perspectives for novel therapeutic approaches using antioxidant medicines and compounds against oxidative stress and excessive inflammatory diseases including tissue damage, sepsis, and endotoxemic shock.
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影响因子：
11.2
作者：
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影响因子：
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作者：
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