title: 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.
abstract: 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 μM, curcumin completely protected against acrolein-induced cell oxidative damage and preserved GSH levels and mitochondrial function. Surprisingly, C3 displayed a complete protective effect at 0.5 μM, which was much more efficient than curcumin. Both 0.5 μM C3 and 5 μM 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.
authors: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Life Science, FIST, Xi'an Jiaotong University, Xi'an, China.
authors: Yuan
authors: Y
authors: Li
authors: Xuan
authors: X
authors: Zou
authors: Ke
authors: K
authors: Cao
authors: Jie
authors: J
authors: Xu
authors: Tingting
authors: T
authors: Yue
authors: Fang
authors: F
authors: Dai
authors: Bo
authors: B
authors: Zhou
authors: Wuyuan
authors: W
authors: Lu
authors: Zhihui
authors: Z
authors: Feng
authors: Jiankang
authors: J
authors: Liu
mesh_terms: D000171:Acrolein / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000171:Acrolein; D003474:Curcumin
keywords: Age-related macular degeneration; Glutathione; Mitochondrial membrane potential; Oxidative stress; Reactive oxygen species