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4-Acetoxyphenol Prevents RPE Oxidative Stress-Induced Necrosis by Functioning as an NRF2 Stabilizer.
Invest Ophthalmol Vis Sci. 2015 Aug; 56(9):5048-59.IO

Abstract

PURPOSE

Oxidative stress has been suggested to be a major risk factor for the pathogenesis of AMD. Retinal pigment epithelial (RPE) cells are essential for maintaining the homeostasis of the retina, and RPE cell death and the resultant photoreceptor apoptosis have been observed in dry AMD, especially in geographic atrophy. The purpose of this article was to identify and repurpose the Food and Drug Administration-approved natural compound 4-Acetoxyphenol (4-AC), and to evaluate its effect and mechanism in protecting against oxidative stress-induced RPE necrosis.

METHODS

We exposed ARPE-19 cells to tert-Butyl hydroperoxide (tBHP) after pretreatment with 4-AC, and measured cell viability by MTT assay. Aggregation of RIPK3 and HMGB1 nuclear release were analyzed by transfected reporter genes. Reactive oxygen species (ROS) were measured using a commercially available ROS detection system. The importance of the NRF2/NQO1/HO-1 pathway in mediating 4-AC function was corroborated by siRNA studies, qRT-PCR, and immunostaining.

RESULTS

We have identified a natural antioxidant, 4-AC, which demonstrates strong abilities to protect RPE cells from oxidative stress-induced necrosis. Mechanistically, 4-AC blocked the increase of cellular ROS induced by oxidative stress, and upregulated NQO1 and HO-1 genes by stabilizing and inducing the nuclear translocation of NRF2 transcription factor. The NQO1, HO-1, and NRF2 were further shown to be required for 4-AC protection of RPE cells from death induced by tBHP. The tBHQ, an NRF2 stabilizer, consistently mimicked the protective effect of 4-AC against tBHP-induced RPE death.

CONCLUSIONS

The compound 4-AC protects ARPE-19 cells from oxidative stress-induced necrosis through upregulation of NQO1 and HO-1 genes by stabilization of NRF2.

Authors+Show Affiliations

Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, United States.Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, United States.Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, United States.Southern Eye Bank, Metairie, Louisiana, United States.Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, United States 3Department of Ophthalmology, Tulane University, New Orleans, Louisiana, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26241392

Citation

Hanus, Jakub, et al. "4-Acetoxyphenol Prevents RPE Oxidative Stress-Induced Necrosis By Functioning as an NRF2 Stabilizer." Investigative Ophthalmology & Visual Science, vol. 56, no. 9, 2015, pp. 5048-59.
Hanus J, Kolkin A, Chimienti J, et al. 4-Acetoxyphenol Prevents RPE Oxidative Stress-Induced Necrosis by Functioning as an NRF2 Stabilizer. Invest Ophthalmol Vis Sci. 2015;56(9):5048-59.
Hanus, J., Kolkin, A., Chimienti, J., Botsay, S., & Wang, S. (2015). 4-Acetoxyphenol Prevents RPE Oxidative Stress-Induced Necrosis by Functioning as an NRF2 Stabilizer. Investigative Ophthalmology & Visual Science, 56(9), 5048-59. https://doi.org/10.1167/iovs.15-16401
Hanus J, et al. 4-Acetoxyphenol Prevents RPE Oxidative Stress-Induced Necrosis By Functioning as an NRF2 Stabilizer. Invest Ophthalmol Vis Sci. 2015;56(9):5048-59. PubMed PMID: 26241392.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 4-Acetoxyphenol Prevents RPE Oxidative Stress-Induced Necrosis by Functioning as an NRF2 Stabilizer. AU - Hanus,Jakub, AU - Kolkin,Alexander, AU - Chimienti,Julia, AU - Botsay,Sara, AU - Wang,Shusheng, PY - 2015/8/5/entrez PY - 2015/8/5/pubmed PY - 2015/10/28/medline SP - 5048 EP - 59 JF - Investigative ophthalmology & visual science JO - Invest. Ophthalmol. Vis. Sci. VL - 56 IS - 9 N2 - PURPOSE: Oxidative stress has been suggested to be a major risk factor for the pathogenesis of AMD. Retinal pigment epithelial (RPE) cells are essential for maintaining the homeostasis of the retina, and RPE cell death and the resultant photoreceptor apoptosis have been observed in dry AMD, especially in geographic atrophy. The purpose of this article was to identify and repurpose the Food and Drug Administration-approved natural compound 4-Acetoxyphenol (4-AC), and to evaluate its effect and mechanism in protecting against oxidative stress-induced RPE necrosis. METHODS: We exposed ARPE-19 cells to tert-Butyl hydroperoxide (tBHP) after pretreatment with 4-AC, and measured cell viability by MTT assay. Aggregation of RIPK3 and HMGB1 nuclear release were analyzed by transfected reporter genes. Reactive oxygen species (ROS) were measured using a commercially available ROS detection system. The importance of the NRF2/NQO1/HO-1 pathway in mediating 4-AC function was corroborated by siRNA studies, qRT-PCR, and immunostaining. RESULTS: We have identified a natural antioxidant, 4-AC, which demonstrates strong abilities to protect RPE cells from oxidative stress-induced necrosis. Mechanistically, 4-AC blocked the increase of cellular ROS induced by oxidative stress, and upregulated NQO1 and HO-1 genes by stabilizing and inducing the nuclear translocation of NRF2 transcription factor. The NQO1, HO-1, and NRF2 were further shown to be required for 4-AC protection of RPE cells from death induced by tBHP. The tBHQ, an NRF2 stabilizer, consistently mimicked the protective effect of 4-AC against tBHP-induced RPE death. CONCLUSIONS: The compound 4-AC protects ARPE-19 cells from oxidative stress-induced necrosis through upregulation of NQO1 and HO-1 genes by stabilization of NRF2. SN - 1552-5783 UR - https://www.unboundmedicine.com/medline/citation/26241392/4_Acetoxyphenol_Prevents_RPE_Oxidative_Stress_Induced_Necrosis_by_Functioning_as_an_NRF2_Stabilizer_ L2 - http://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.15-16401 DB - PRIME DP - Unbound Medicine ER -