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Structure based modification of chalcone analogue activates Nrf2 in the human retinal pigment epithelial cell line ARPE-19.
Free Radical Biology and Medicine ( IF 7.4 ) Pub Date : 2019-12-27 , DOI: 10.1016/j.freeradbiomed.2019.12.033
Yuting Cui 1 , Yuan Li 2 , Na Huang 3 , Yue Xiong 1 , Ruijun Cao 3 , Lingjie Meng 3 , Jiankang Liu 4 , Zhihui Feng 4
Affiliation  

Oxidative stress-induced degeneration of retinal pigment epithelial (RPE) cells is known to be a key contributor to the development of age-related macular degeneration (AMD). Activation of the nuclear factor-(erythroid-derived 2)-related factor-2 (Nrf2)-mediated cellular defense system is believed to be a valid therapeutic approach. In the present study, we designed and synthesized a novel chalcone analogue, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), as a Nrf2 activator. The potency of Tak was measured in RPE cells by the induction of the Nrf2-dependent antioxidant genes HO-1, NQO-1, GCLc, and GCLm, which were regulated through the Erk pathway. We also showed that Tak could protect RPE cells against oxidative stress-induced cell death and mitochondrial dysfunction. Furthermore, by modifying the α, β unsaturated carbonyl entity in Tak, we showed that the induction of antioxidant genes was abolished, indicating that this unique feature in Tak was responsible for the Nrf2 activation. These results suggest that Tak is a potential candidate for clinical application against AMD.

中文翻译:

查耳酮类似物的基于结构的修饰激活人视网膜色素上皮细胞系ARPE-19中的Nrf2。

氧化应激诱导的视网膜色素上皮细胞(RPE)变性是导致与年龄有关的黄斑变性(AMD)发展的关键因素。核因子-(类胡萝卜素衍生的2)-相关因子2(Nrf2)介导的细胞防御系统的激活被认为是一种有效的治疗方法。在本研究中,我们设计并合成了一种新型查耳酮类似物1-(2,3,4-三甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙烯酮(Tak),作为Nrf2活化剂。通过诱导依赖于Nrf2的抗氧化剂基因HO-1,NQO-1,GCLc和GCLm来测量Tak在RPE细胞中的能力,这些基因是通过Erk途径调控的。我们还表明,Tak可以保护RPE细胞免受氧化应激诱导的细胞死亡和线粒体功能障碍。此外,通过修改α,Tak中的β不饱和羰基实体,我们表明抗氧化剂基因的诱导被取消,表明Tak中的这一独特特征是Nrf2活化的原因。这些结果表明,Tak是抗AMD临床应用的潜在候选者。
更新日期:2019-12-27
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