Curcumin analog 1, 5-bis (2-trifluoromethylphenyl)-1, 4-pentadien-3-one exhibits enhanced ability on Nrf2 activation and protection against acrolein-induced ARPE-19 cell toxicity
Curcumin analog 1, 5-bis (2-trifluoromethylphenyl)-1, 4-pentadien-3-one exhibits enhanced ability on Nrf2 activation and protection against acrolein-induced ARPE-19 cell toxicity
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姜黄素类似物 1, 5-bis (2-三氟甲基苯基)-1, 4-pentadien-3-one 表现出增强的 Nrf2 激活能力和针对丙烯醛诱导的 ARPE-19 细胞毒性的保护能力。
DOI：
10.1016/j.taap.2013.07.029
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发表时间：
2013-11-01
影响因子：
3.8
通讯作者：
Liu, Jiankang
中科院分区：
文献类型：
--
作者：
Li, Yuan;Zou, Xuan;Liu, Jiankang
姜黄素是香料姜黄中的一种植物化学物质，因其抗癌、抗炎和抗氧化特性而受到越来越多的关注。但姜黄素不溶于水，生物利用度低，在临床和实验上的应用受到限制。此外，姜黄素在眼部疾病中的保护作用和机制研究甚少。在本研究中，我们合成了一种姜黄素类似物，1，5-二（2-三氟甲基苯基）-1，4-二氢吡喃-3-酮（C3），它在人视网膜色素上皮细胞系（ARPE-19）中显示出改善的对丙烯醛诱导的毒性的保护作用。在5 μ M时，姜黄素完全防止丙烯醛诱导的细胞氧化损伤，并保护GSH水平和线粒体！功能令人惊讶的是，C3在0.5 μ M时显示出完全的保护作用，这比姜黄素有效得多。0.5 μ M C3和5 μ M姜黄素诱导Nrf 2核转位和Nrf 2靶基因转录相似。使用Nrf 2 siRNA的实验表明，姜黄素和C3的保护作用被Nrf 2敲低所消除。此外，姜黄素和C3都激活了PI 3/Akt通路，然而，Nrf 2的激活不依赖于该通路，因此，我们假设姜黄素和C3都通过直接破坏Nrf 2/Keap 1复合物并促进Nrf 2的核转位来激活II相酶。由于ARPE-19细胞的丙烯醛攻击已被用作吸烟和年龄相关性黄斑变性（AMD）的模型，我们得出结论，姜黄素类似物C3可能是一个更有前途的候选药物，其潜在的应用于预防和治疗眼部疾病，如AMD。(C)2013 Elsevier Inc. All rights reserved.
Curcumin, a phytochemical agent in the spice turmeric, has received increasing attention for its anticancer, anti-inflammatory and antioxidant properties. However, application of curcumin has been limited due to its insolubility in water and poor bioavailability both clinically and experimentally. In addition, the protective effects and mechanisms of curcumin in eye diseases have been poorly studied. In the present study, we synthesized a curcumin analog, 1, 5-bis (2-trifluoromethylphenyl)-1, 4-pentadien-3-one (C3), which displayed improved protective effect against acrolein-induced toxicity in a human retinal pigment epithelial cell line (ARPE-19). At 5 mu M, curcumin completely protected against acrolein-induced cell oxidative damage and preserved GSH levels and mitochondria! function. Surprisingly, C3 displayed a complete protective effect at 0.5 mu M, which was much more efficient than curcumin. Both 0.5 mu M C3 and 5 mu M curcumin induced Nrf2 nuclear translocation and Nrf2 target genes transcription similarly. Experiments using Nrf2 siRNA showed that the protective effects of curcumin and C3 were eliminated by Nrf2 knockdown. Additionally, both curcumin and C3 activated the PI3/Akt pathway, however, Nrf2 activation was independent of this pathway, and therefore, we hypothesized that both curcumin and C3 activated phase II enzymes via directly disrupting the Nrf2/Keap1 complex and promoting Nrf2's nuclear translocation. Since acrolein challenge of ARPE-19 cells has been used as a model of smoking and age-related macular degeneration (AMD), we concluded that the curcumin analog, C3, may be a more promising drug candidate for its potential application for the prevention and treatment of eye diseases, such as AMD. (C) 2013 Elsevier Inc. All rights reserved.