Upregulation of heme oxygenase-1 expression by dehydrodiconiferyl alcohol (DHCA) through the AMPK-Nrf2 dependent pathway
Upregulation of heme oxygenase-1 expression by dehydrodiconiferyl alcohol (DHCA) through the AMPK-Nrf2 dependent pathway
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DOI：
10.1016/j.taap.2014.07.011
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发表时间：
2014-11-15
影响因子：
3.8
通讯作者：
Kim, Sunyoung
中科院分区：
文献类型：
--
作者：
Lee, Junghun;Kim, Sunyoung
氧化应激是由自由基积累引起的，导致细胞氧化还原状态不平衡，这与多种人类疾病有关。脱氢二聚醇 (DHCA) 是一种从 Cucurbita moschata 中分离出来的木酚素化合物，此前曾有报道称其对 3T3-L1 细胞和原代 MEF 具有抗脂肪生成和抗脂肪生成作用（Abraham 和 Kappas，2008）。在本研究中，使用Raw264.7小鼠巨噬细胞系测试了DHCA是否会影响HO-1的表达。 DHCA 增加了 HO-1 的蛋白质和 RNA 水平并上调其启动子活性。瞬时转染测定数据表明，位于 HO-1 启动子 E1 区域的 ARE 对于 DHCA 介导的 HO-1 表达诱导非常重要。 DHCA 还被证明可以增强 Nrf2 的核转位以及与相应 DNA 序列的结合。在来自野生型动物的原代巨噬细胞中也观察到 DHCA 对 HO-1 表达的上调，但在来自 Nrf2 KO 小鼠的原代巨噬细胞中没有观察到。当细胞用 AMPK 抑制剂、化合物 C 处理时，DHCA 对 HO-1 和 Nrf2 的影响减弱，但用 PI3K/Akt 或 MAPK 抑制剂处理则不会。使用 HO-1 特异性 siRNA 或化学抑制剂的实验数据表明，DHCA 介导的 HO-1 蛋白诱导可以抑制 LPS 刺激的 NO 产生。综上所述，我们的数据表明，DHCA 通过 AMPK-Nrf2 途径控制 HO-1 启动子活性来诱导 HO-1 的表达，最终导致 NO 产生减少，因此可能具有作为有效抗氧化剂的潜力。 (C) 2014 爱思唯尔公司保留所有权利。
Oxidative stress is induced by the accumulation of free radicals, resulting in an imbalanced cellular redox state, which has been implicated in a variety of human diseases. Dehydrodiconiferyl alcohol (DHCA), a lignan compound isolated from Cucurbita moschata, has previously been reported to contain anti-adipogenic and anti-lipogenic effects on 3T3-L1 cells and primary MEFs (Abraham and Kappas, 2008). In this study, it was tested whether DHCA could affect the expression of HO-1, using Raw264.7 mouse macrophage cell line. DHCA increased the protein and RNA levels of HO-1 and upregulated its promoter activity. Data from transient transfection assays indicated that ARE located in the E1 region of the HO-1 promoter are important in this DHCA-mediated induction of HO-1 expression. DHCA was also shown to enhance the nuclear translocation and binding of Nrf2 to the respective DNA sequences. The upregulation of HO-1 expression by DHCA was also observed in primary macrophages derived from wild type animals, but not in those from Nrf2 KO mice. Effects of DHCA on HO-1 and Nrf2 were reduced when cells were treated with an AMPK inhibitor, Compound C, but not by PI3K/Akt or MAPK inhibitors. Data from an experiment using a specific siRNA or chemical inhibitor for HO-1 suggested that the DHCA-mediated induction of the HO-1 protein could suppress the LPS-stimulated production of NO. Taken together, our data suggest that DHCA induces the expression of HO-1 by controlling its promoter activity through the AMPK-Nrf2 pathway, eventually leading to the reduction of NO production, and may thus have potential as an effective antioxidant. (C) 2014 Elsevier Inc All rights reserved.