Purpose: Age-related Macular Degeneration (AMD) is a severe neurodegenerative disease and a major cause of blindness in the elderly worldwide. Oxidative stress is a common feature of AMD pathogenesis, and a positive modulation of Nrf2 activity has been demonstrated to be protective. Natural products are generally a rich source of therapeutics; we recently combined polyphenols from curcumin and diallyl sulfide in new chemical entities to produce hybrids with anti-oxidant activity. To confirm Nrf2 pathway as a valuable therapeutic target, we studied the modulation of this cascade by our new hybrids. Methods: The human retinal pigment epithelium cell line ARPE-19 was exposed to increasing concentrations of the new nature-inspired hybrids. Cell viability was evaluated by MTT assay. Nrf2 nuclear translocation and target gene expression were measured by Western blotting. Results: New nature-inspired hybrids induce Nrf2 nuclear translocation and modulation of its target genes involved in phase II response in ARPE-19 cells. These molecules show a potency on Nrf2 activation profile comparable to that induced by the reference compounds curcumin and dimethylfumarate, the latter being currently used in clinic for multiple sclerosis. Conclusion: The new nature-inspired hybrids show to be promising to counteract some features related to AMD pathogenesis, thus suggesting the potential use of Nrf2 activators as therapeutics.
Nature-inspired Nrf2 activators in retinal pigment epithelial cells: a source for therapeutics in Age-related Macular Degeneration
AMADIO, MARIALAURA
;SERAFINI, MELANIA MARIA;MARCHESI, NICOLETTA;CATANZARO, MICHELE;SIMONI, ELENA;PASCALE, ALESSIA ANGELA;LANNI, CRISTINA
2017-01-01
Abstract
Purpose: Age-related Macular Degeneration (AMD) is a severe neurodegenerative disease and a major cause of blindness in the elderly worldwide. Oxidative stress is a common feature of AMD pathogenesis, and a positive modulation of Nrf2 activity has been demonstrated to be protective. Natural products are generally a rich source of therapeutics; we recently combined polyphenols from curcumin and diallyl sulfide in new chemical entities to produce hybrids with anti-oxidant activity. To confirm Nrf2 pathway as a valuable therapeutic target, we studied the modulation of this cascade by our new hybrids. Methods: The human retinal pigment epithelium cell line ARPE-19 was exposed to increasing concentrations of the new nature-inspired hybrids. Cell viability was evaluated by MTT assay. Nrf2 nuclear translocation and target gene expression were measured by Western blotting. Results: New nature-inspired hybrids induce Nrf2 nuclear translocation and modulation of its target genes involved in phase II response in ARPE-19 cells. These molecules show a potency on Nrf2 activation profile comparable to that induced by the reference compounds curcumin and dimethylfumarate, the latter being currently used in clinic for multiple sclerosis. Conclusion: The new nature-inspired hybrids show to be promising to counteract some features related to AMD pathogenesis, thus suggesting the potential use of Nrf2 activators as therapeutics.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
