Up-regulation of Nrf2-mediated heme oxygenase-1 expression by eckol, a phlorotannin compound, through activation of Erk and PI3K/Akt
Up-regulation of Nrf2-mediated heme oxygenase-1 expression by eckol, a phlorotannin compound, through activation of Erk and PI3K/Akt
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DOI：
10.1016/j.biocel.2009.11.009
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发表时间：
2010-02-01
影响因子：
4
通讯作者：
Hyun, Jin Won
中科院分区：
文献类型：
--
作者：
Kim, Ki Cheon;Kang, Kyoung Ah;Hyun, Jin Won
本研究的目的是检查eckol，一种在Ecklonia cava中发现的根皮单宁的细胞保护作用，并阐明其潜在的机制。血红素氧合酶-1（HO-1）是一种重要的抗氧化酶，在细胞抗氧化应激中发挥作用。Eckol诱导中国仓鼠肺成纤维细胞（V79-4）HO-1在mRNA和蛋白水平表达，导致HO-1活性增加。转录因子NF-E2相关因子2（Nrf 2）是HO-1的关键调节因子，通过与抗氧化反应元件（ARE）结合实现。Eckol处理导致Nrf 2的磷酸化形式、核转位、ARE结合和转录活性水平增强。细胞外调节激酶（Erk）和磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B（PKB，Akt）参与ARE驱动的HO-1表达。Eckol激活了Erk和Akt，并且用U 0126（Erk激酶抑制剂）、LY 294002（PI 3 K抑制剂）、特异性Erk 1 siRNA和Akt siRNA处理抑制了Eckol诱导的Nrf 2激活，导致HO-1表达降低。ZnPP（一种HO-1抑制剂）、HO-1 siRNA和Nrf 2 siRNA显著地消除了eckol对过氧化氢诱导的细胞损伤的细胞保护作用。同样，U 0126和LY 294002抑制eckol诱导的细胞保护作用，对抗氧化细胞损伤。这些研究表明，eckol通过Erk和PI 3 K/Akt信号转导激活Nrf 2介导的HO-1诱导来减弱氧化应激。(C)2009爱思唯尔有限公司保留所有权利。
The aim of the present study was to examine the cytoprotective effect of eckol, a phlorotannin found in Ecklonia cava and to elucidate underlying mechanisms. Heme oxygenase-1 (HO-1) is an important antioxidant enzyme that plays a role in cytoprotection against oxidative stress. Eckol-induced HO-1 expression both at the level of mRNA and protein in Chinese hamster lung fibroblast (V79-4) cells, resulting in increased HO-1 activity. The transcription factor NF-E2-related factor 2 (Nrf2) is a critical regulator of HO-1, achieved by binding to the antioxidant response element (ARE). Eckol treatment resulted in the enhanced level of phosphorylated form, nuclear translocation, ARE-binding, and transcriptional activity of Nrf2. Extracellular regulated kinase (Erk) and phosphaticylinositol 3-kinase (PI3K)/protein kinase B (PKB, Akt) contributed to ARE-driven HO-1 expression. Eckol activated both Erk and Akt, and treatments with U0126 (an Erk kinase inhibitor), LY294002 (a PI3K inhibitor), specific Erk1 siRNA, and Akt siRNA suppressed the eckol-induced activation of Nrf2, resulting in a decrease in HO-1 expression. ZnPP (a HO-1 inhibitor), HO-1 siRNA, and Nrf2 siRNA markedly abolished the cytoprotective effect of eckol against hydrogen peroxide-induced cell damage. Likewise, U0126 and LY294002 inhibited the eckol-induced cytoprotective effect against oxidative cell damage. These studies demonstrate that eckol attenuates oxidative stress by activating Nrf2-mediated HO-1 induction via Erk and PI3K/Akt signaling. (C) 2009 Elsevier Ltd. All rights reserved.