期刊
ANTIOXIDANTS
卷 11, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/antiox11071385
关键词
autophagy; age-related macular degeneration (AMD); cytoprotection; Nrf2; pharmacological modulation; SQSTM1; p62; oxidative stress; retinal pigment epithelium (RPE)
资金
- University of Pavia [1744747]
- University of Pavia, Dept. of Drug Sciences' Research Funding FRG 2021
- University of Bologna
- European Union [722717]
- Academy of Finland [296840, 333302]
- Kuopio University Hospital VTR grant [5503770]
- Sigrid Juselius Foundation
- Paivikki and Sakari Sohlberg Foundation
- Finnish Eye Foundation
- Academy of Finland (AKA) [333302] Funding Source: Academy of Finland (AKA)
Antioxidant systems play key roles in elderly diseases, including age-related macular degeneration (AMD). This study investigated the protective effects of nature-inspired hybrids on retinal pigment epithelial (RPE) cells. The hybrids increased the expression of Nrf2-target genes and improved intracellular redox balance without affecting autophagy flux. Furthermore, the hybrids enhanced cell survival and reduced inflammation when exposed to proteasome and autophagy inhibitors. The study suggests that Nrf2 is a valuable target for treating AMD.
Antioxidant systems play key roles in many elderly diseases, including age-related macular degeneration (AMD). Oxidative stress, autophagy impairment and inflammation are well-described in AMD, especially in retinal pigment epithelial (RPE) cells. The master regulator of antioxidant defense Nrf2 has been linked to AMD, autophagy and inflammation. In this study, in human ARPE-19 cells, some nature-inspired hybrids (NIH1-3) previously shown to induce Nrf2-mediated protection against oxidative stress were further investigated for their potential against cellular stress caused by dysfunction of protein homeostasis. NIH1-3 compounds increased the expression of two Nrf2-target genes coding defense proteins, HO-1 and SQSTM1/p62, in turn exerting beneficial effects on intracellular redox balance without modification of the autophagy flux. NIH1-3 treatments predisposed ARPE-19 cells to a better response to following exposure to proteasome and autophagy inhibitors, as revealed by the increase in cell survival and decreased secretion of the pro-inflammatory IL-8 compared to NIH-untreated cells. Interestingly, NIH4 compound, through an Nrf2-independent pathway, also increased cell viability and decreased IL-8 secretion, although to a lesser extent than NIH1-3, suggesting that all NIHs are worthy of further investigation into their cytoprotective properties. This study confirms Nrf2 as a valuable pharmacological target in contexts characterized by oxidative stress, such as AMD.
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