Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, China.
Department of Traditional Chinese Medicine, The First Hospital of Jilin University, Changchun, China.
Chem Biol Interact. 2019 Apr 1;302:93-100. doi: 10.1016/j.cbi.2019.02.001. Epub 2019 Feb 6.
NF-E2 p45-related factor 2 (Nrf2), which regulates the cellular antioxidant response, is a target for limiting tissue damage due to exposure to environmental toxicants, including arsenic. Daphnetin (Daph), a natural coumarin derivative, has been shown to induce remarkable antioxidant activity. The present study aimed to examine the protective effects and molecular mechanisms of Daph on arsenic-induced cytotoxicity in human lung epithelial cells. Our results demonstrate that Daph dramatically upregulated the antioxidant enzyme in a dose dependent manner, in association with induction of Nrf2 nuclear translocation and decreased Keap1 protein expression. Importantly, Daph also markedly induced the activation of AMP-activated protein kinase (AMPK), c-Jun NH-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) phosphorylation. Furthermore, Daph antagonized the arsenic-induced decreases in cell viability and the generation of reactive oxygen species (ROS). Notably, Daph pretreatment reversed the arsenic-induced decrease in anti-apoptotic factor B-cell lymphoma-2 (Bcl-2) and the increase in pro-apoptotic factor Bcl-2-associated X protein (Bax). The effects of Daph on Nrf2 and HO-1 activation, and arsenic-induced cell viability were largely weakened when Nrf2 was depleted in vitro. Accordingly, Daph might ameliorate arsenic-induced cytotoxicity and apoptosis, which may be linked to the induction of Nrf2-dependent antioxidant responses as well as stabilization of the anti-apoptotic factor Bcl-2 in human lung epithelial cells.
NF-E2 p45-related factor 2 (Nrf2)，调节细胞抗氧化反应，是限制因暴露于环境毒物（包括砷）而导致组织损伤的靶标。瑞香素（Daph），一种天然香豆素衍生物，已被证明具有显著的抗氧化活性。本研究旨在探讨 Daph 对人肺上皮细胞砷诱导细胞毒性的保护作用及其分子机制。我们的结果表明，Daph 以剂量依赖的方式显著上调抗氧化酶，同时诱导 Nrf2 核易位和 Keap1 蛋白表达减少。重要的是，Daph 还显著诱导 AMP 激活的蛋白激酶（AMPK）、c-Jun NH2-末端激酶（JNK）和细胞外信号调节激酶（ERK）磷酸化。此外，Daph 拮抗砷诱导的细胞活力降低和活性氧（ROS）生成。值得注意的是，Daph 预处理可逆转砷诱导的抗凋亡因子 B 细胞淋巴瘤-2（Bcl-2）减少和促凋亡因子 Bcl-2 相关 X 蛋白（Bax）增加。体外敲低 Nrf2 后，Daph 对 Nrf2 和 HO-1 激活以及砷诱导的细胞活力的影响大大减弱。因此，Daph 可能通过诱导 Nrf2 依赖性抗氧化反应以及稳定抗凋亡因子 Bcl-2 来减轻人肺上皮细胞砷诱导的细胞毒性和凋亡。
