Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway

The late stage of dry age-related macular degeneration (AMD), or geographic atrophy (GA), is characterized by extensive retinal pigment epithelial (RPE) cell death, and a cure is not available currently. We have recently demonstrated that RPE cells die from necrosis in response to oxidative stress, providing a potential novel mechanism for RPE death in AMD. In this study, we screened U.S. Food and Drug Administration-approved natural compounds and identified gossypol acetic acid (GAA) as a potent inhibitor of oxidative stress-induced RPE cell death. GAA induces antioxidative response and inhibits accumulation of excessive reactive oxygen species in cells, through which it prevents the activation of intrinsic necrotic pathway in response to oxidative stress. Sestrin2 (SESN2) is found to mediate GAA function in antioxidative response and RPE survival upon oxidative stress. Moreover, Forkhead box O3 transcription factor (FoxO3) is further found to be required for GAA-mediated SESN2 expression and RPE survival. Mechanistically, GAA promotes FoxO3 nuclear translocation and binding to theSESN2enhancer, which in turn increases its transcriptional activity. Taken together, we have identified GAA as a potent inhibitor of oxidative stress-induced RPE necrosis by regulating the FoxO3/SESN2 pathway. This study may have significant implications in the therapeutics of age-related diseases, especially GA.

Download Full-text

Prevention of Oxidative Stress-Induced Retinal Pigment Epithelial Cell Death by the PPARγAgonist, 15-Deoxy-Delta 12, 14-ProstaglandinJ2

PPAR Research ◽

10.1155/2008/720163 ◽

2008 ◽

Vol 2008 ◽

pp. 1-7 ◽

Cited By ~ 13

Author(s):

Jason Y. Chang ◽

Puran S. Bora ◽

Nalini S. Bora

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Retinal Pigment Epithelial ◽

Retinal Pigment Epithelial Cell ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Experimental Conditions ◽

Pigment Epithelial ◽

Age Related ◽

Epithelial Cell Death

Cellular oxidative stress plays an important role in retinal pigment epithelial (RPE) cell death during aging and the development of age-related macular degeneration. Early reports indicate that during phagocytosis of rod outer segments, there is an increase of RPE oxidative stress and an upregulation of PPARγmRNA in these cells. These studies suggest that activation of PPARγmay modulate cellular oxidative stress. This paper presents a brief review of recent studies that investigate RPE oxidative stress under various experimental conditions. This is followed by a detailed review on those reports that examine the protective effect of the natural PPARγligand, 15d-PGJ2, against RPE oxidative stress. This agent can upregulate glutathione and prevent oxidant-induced intracellular reactive oxygen species accumulation, mitochondrial depolarization, and apoptosis. The cytoprotective effect of this agent, however, is not shared by other PPARγagonists. Nonetheless, this property of 15d-PGJ2may be useful in future development of pharmacological tools against retinal diseases caused by oxidative stress.

Download Full-text

Oxidative stress induces ferroptotic cell death in retinal pigment epithelial cells

Experimental Eye Research ◽

10.1016/j.exer.2018.08.019 ◽

2019 ◽

Vol 181 ◽

pp. 316-324 ◽

Cited By ~ 17

Author(s):

Kiyohito Totsuka ◽

Takashi Ueta ◽

Takatoshi Uchida ◽

Murilo F. Roggia ◽

Suguru Nakagawa ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Epithelial Cells ◽

Retinal Pigment Epithelial ◽

Retinal Pigment ◽

Retinal Pigment Epithelial Cells ◽

Pigment Epithelial ◽

Pigment Epithelial Cells

Download Full-text

S-Allylmercapro-N-Acetylcysteine Attenuates the Oxidation-Induced Lens Opacification and Retinal Pigment Epithelial Cell Death In Vitro

Antioxidants ◽

10.3390/antiox8010025 ◽

2019 ◽

Vol 8 (1) ◽

pp. 25 ◽

Cited By ~ 1

Author(s):

Naphtali Savion ◽

Samia Dahamshi ◽

Milana Morein ◽

Shlomo Kotev-Emeth

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Retinal Pigment Epithelial ◽

Retinal Pigment Epithelial Cell ◽

Retinal Pigment ◽

Lens Opacity ◽

Glutathione Level ◽

Rpe Cells ◽

Pigment Epithelial ◽

Lens Opacification

The capacity of S-Allylmercapto-N-acetylcysteine (ASSNAC) to protect human retinal pigment epithelial (RPE) cells (line ARPE-19) and porcine lenses from oxidative stress was studied. Confluent ARPE-19 cultures were incubated with ASSNAC or N-acetyl-cysteine (NAC) followed by exposure to oxidants and glutathione level and cell survival were determined. Porcine lenses were incubated with ASSNAC and then exposed to H2O2 followed by lens opacity measurement and determination of glutathione (reduced (GSH) and oxidized (GSSG)) in isolated lens adhering epithelial cells (lens capsule) and fiber cells consisting the lens cortex and nucleus (lens core). In ARPE-19 cultures, ASSNAC (0.2 mM; 24 h) increased glutathione level by 2–2.5-fold with significantly higher increase in GSH compared to NAC treated cultures. Similarly, ex-vivo exposure of lenses to ASSNAC (1 mM) significantly reduced the GSSG level and prevented H2O2 (0.5 mM)-induced lens opacification. These results demonstrate that ASSNAC up-regulates glutathione level in RPE cells and protects them from oxidative stress-induced cell death as well as protects lenses from oxidative stress-induced opacity. Further validation of these results in animal models may suggest a potential use for ASSNAC as a protective therapy in retinal degenerative diseases as well as in attenuation of oxidative stress-induced lens opacity.

Download Full-text

Protective effects of delphinidin against H2O2–induced oxidative injuries in human retinal pigment epithelial cells

Bioscience Reports ◽

10.1042/bsr20190689 ◽

2019 ◽

Vol 39 (8) ◽

Cited By ~ 6

Author(s):

Timin Ni ◽

Wanju Yang ◽

Yiqiao Xing

Keyword(s):

Oxidative Stress ◽

Protein Expression ◽

Retinal Pigment Epithelial ◽

Retinal Pigment ◽

Retinal Pigment Epithelial Cells ◽

Age Related Macular Degeneration ◽

Ros Generation ◽

Dependent Manner ◽

Pigment Epithelial ◽

Age Related

Abstract Age-related macular degeneration (AMD) is now one of the leading causes of blindness in the elderly population and oxidative stress-induced damage to retinal pigment epithelial (RPE) cells occurs as part of the pathogenesis of AMD. In the present study, we evaluated the protective effect of delphinidin (2-(3,4,5-trihydroxyphenyl) chromenylium-3,5,7-triol) against hydrogen peroxide (H2O2)-induced toxicity in human ARPE-19 cells and its molecular mechanism. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and flow cytometry demonstrated that pretreatment of ARPE-19 cells with delphinidin (25, 50, and 100 μg/ml) significantly increased cell viability and reduced the apoptosis from H2O2 (0.5 mM)-induced oxidative stress in a concentration-dependent manner, which was achieved by the inhibition of Bax, cytochrome c, and caspase-3 protein expression and enhancement of Bcl-2 protein. The same tendency was observed in ARPE-19 cells pre-treated with 15 mM of N-acetylcysteine (NAC) before the addition of H2O2. Furthermore, pre-incubation of ARPE-19 cells with delphinidin markedly inhibited the intracellular reactive oxygen species (ROS) generation and Nox1 protein expression induced by H2O2. Moreover, the decreased antioxidant enzymes activities of superoxide dismutase (SOD), catalase (CAT), and glutathione-peroxidase (GSH-PX) and elevated (MDA) level in H2O2-treated cells were reversed to the normal standard by the addition of delphinidin, which was regulated by increasing nuclear Nrf2 protein expression in ARPE-19 cells. Our results suggest that delphinidin effectively protects human ARPE-19 cells from H2O2-induced oxidative damage via anti-apoptotic and antioxidant effects.

Download Full-text

Cytoprotective Effects of Natural Highly Bio-Available Vegetable Derivatives on Human-Derived Retinal Cells

Nutrients ◽

10.3390/nu12030879 ◽

2020 ◽

Vol 12 (3) ◽

pp. 879 ◽

Cited By ~ 1

Author(s):

Ingrid Munia ◽

Laurent Gafray ◽

Marie-Agnès Bringer ◽

Pablo Goldschmidt ◽

Lil Proukhnitzky ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Metabolic Activity ◽

Retinal Pigment Epithelial ◽

Caspase 3 ◽

Retinal Pigment ◽

Retinal Pigment Epithelial Cells ◽

Pigment Epithelial ◽

Pre Treatment ◽

Pigment Epithelial Cells

Retinal pigment epithelial cells are crucial for retina maintenance, making their cytoprotection an excellent way to prevent or slow down retinal degeneration. In addition, oxidative stress, inflammation, apoptosis, neovascularization, and/or autophagy are key pathways involved in degenerative mechanisms. Therefore, here we studied the effects of curcumin, lutein, and/or resveratrol on human retinal pigment epithelial cells (ARPE-19). Cells were incubated with individual or combined agent(s) before induction of (a) H2O2-induced oxidative stress, (b) staurosporin-induced apoptosis, (c) CoCl2-induced hypoxia, or (d) a LED-autophagy perturbator. Metabolic activity, cellular survival, caspase 3/7 activity (casp3/7), cell morphology, VEGF levels, and autophagy process were assessed. H2O2 provoked a reduction in cell survival, whereas curcumin reduced metabolic activity which was not associated with cell death. Cell death induced by H2O2 was significantly reduced after pre-treatment with curcumin and lutein, but not resveratrol. Staurosporin increased caspase-3/7 activity (689%) and decreased cell survival by 32%. Curcumin or lutein protected cells from death induced by staurosporin. Curcumin, lutein, and resveratrol were ineffective on the increase of caspase 3/7 induced by staurosporin. Pre-treatment with curcumin or lutein prevented LED-induced blockage of autophagy flux. Basal-VEGF release was significantly reduced by lutein. Therefore, lutein and curcumin showed beneficial protective effects on human-derived retinal cells against several insults.

Download Full-text