Resveratrol Stimulates Mitochondrial Bioenergetics to Protect Retinal Pigment Epithelial Cells From Oxidative Damage

ABSTRACT.Purpose: To evaluate the short-and long-term effects of most clinically used anti-vascular endothelial growth factor agents, including bevacizumab, ranibizumab or aflibercept, on cell viability, phagocytosis, mitochondrial bioenergetics and the oxidant acrolein-induced oxidative stress of human adult retinal pigment epithelial (ARPE)-19 cells. Methods: In cultured ARPE-19 cells, cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, phagocytotic activity and intracellular reactive oxygen species (ROS) level were determined by flow cytometry, mitochondrial bioenergetics was assessed using a Seahorse XF24 Extracellular Flux Analyzer, and protein expression was measured by Western blotting. Results: Long-term exposure to all three agents had no effect on cell viability; but rescued the ARPE-19 cells from acrolein-induced decrease in cell viability. Bevacizumab, but not ranibizumab or aflibercept, suppressed the phagocytotic activity of ARPE-19 cells and exerted significantly less protection against acroleininduced inhibition of phagocytosis. Both ranibizumab and aflibercept increased basal respiratory rate and maximal mitochondrial respiratory capacity after 1-hr exposure; but returned to baseline following 24-or 72-hr exposure. In contrast, both responses were reduced on short-term exposure, but augmented after long-term exposure to bevacizumab. Long-term pretreatment with all three agents reversed acrolein-induced impairment of mitochondrial bioenergetics, overproduction of ROS and phosphorylation of the mitogen-activated protein kinases in ARPE-19 cells. Conclusion: Bevacizumab might affect mitochondrial bioenergetics differently from that by ranibizumab and aflibercept. Ranibizumab and aflibercept at their therapeutic dose protect against acrolein-induced oxidative cytotoxicity in human ARPE-19 cells via an increase in mitochondrial bioenergetics. An early protective action on mitochondrial bioenergetic capacity might be used to predict possible long-term antioxidative effects of the agents in the eye.

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“…Cell viability of ARPE‐19 cells determined by this method is comparable to that determined by the lactate dehydrogenase assay (Sheu et al. ).…”

Section: Methodssupporting

confidence: 52%

“…Concentrations of blockers of different oxidative phosphorylation pathways were chosen based on the results of our previous report (Sheu et al. ).…”

Section: Methodsmentioning

confidence: 99%

Differential effects of bevacizumab, ranibizumab and aflibercept on cell viability, phagocytosis and mitochondrial bioenergetics of retinal pigment epithelial cell

Sheu

Liu

Chan

2015

Acta Ophthalmologica

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“…It was previously proposed that, because eEF2 promotes protein synthesis, its inactivation might inhibit cell division. Another group reported RSV's inhibitory effect on CNV and RSV's in vitro effect on cell survival; RSV inhibited acrolein-induced ARPE-19 cell death by increasing the mitochondria biogenesis [53].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types

Nagai

Kubota

Tsubota

et al. 2014

The Journal of Nutritional Biochemistry

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The development of choroidal neovascularization (CNV) is a critical step in the pathogenesis of age-related macular degeneration (AMD), a vision-threatening disease. In this study, we used a mouse model of AMD to study the protective effects of resveratrol (RSV) supplementation against CNV as well as the underlying molecular mechanisms. Mice were orally pretreated with RSV daily for 5 days. On the fifth day, the mice underwent laser photocoagulation to induce CNV. One week after laser treatment, CNV volume was significantly lower in the RSV-treated mice compared with vehicle-treated animals. In addition, RSV treatment significantly inhibited macrophage infiltration into the retinal pigment epithelium (RPE)-choroid and suppressed the expression of inflammatory and angiogenic molecules, including vascular endothelial growth factor, monocyte chemotactic protein-1 and intercellular adhesion molecule-1. Importantly, RSV prevented the CNV-induced decrease in activated AMP-activated protein kinase and increase in activated nuclear factor-κB in the RPE-choroid complex. The regulatory effects of RSV on these molecules were confirmed in RPE, microvascular endothelial and macrophage cell lines. Inhibition of macrophage infiltration by RSV was confirmed by in vitro scratch and migration assays. RSV suppressed CNV development, reducing the levels of multiple cytokines secreted from several cell types and inhibiting macrophage migration. The direct effects of RSV on each cell type were confirmed in vitro. Although further studies are needed, RSV could potentially be applied in the clinic to prevent CNV development in AMD.

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“…Memory enhancement by RSV was blocked in Sirt1 mutant mice, suggesting that RSV improves memory via a Sirt1-dependent pathway RSV prevented a cigarette smoke-induced increase in choroidal neovascularization following laser injury [308].…”

Section: Effect Of Rsv On Memory Functionmentioning

confidence: 92%

The pharmacology of resveratrol in animals and humans

Park

Pezzuto

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

250

202

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In addition to thousands of research papers related to resveratrol (RSV), approximately 300 review articles have been published. Earlier research tended to focus on pharmacological activities of RSV related to cardiovascular systems, inflammation, and carcinogenesis/cancer development. More recently, the horizon has been broadened by exploring the potential effect of RSV on the aging process, diabetes, neurological dysfunction, etc. Herein, we primarily focus on the in vivo pharmacological effects of RSV reported over the past 5 years (2009-2014). In addition, recent clinical intervention studies performed with resveratrol are summarized. Some discrepancies exist between in vivo studies with animals and clinical studies, or between clinical studies, which are likely due to disparate doses of RSV, experimental settings, and subject variation. Nevertheless, many positive indications have been reported with mammals, so it is reasonable to advocate for the conduct of more definitive clinical studies. Since the safety profile is pristine, an added advantage is the use of RSV as a dietary supplement. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

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Resveratrol Stimulates Mitochondrial Bioenergetics to Protect Retinal Pigment Epithelial Cells From Oxidative Damage

Cited by 53 publications

References 57 publications

Differential effects of bevacizumab, ranibizumab and aflibercept on cell viability, phagocytosis and mitochondrial bioenergetics of retinal pigment epithelial cell

Differential effects of bevacizumab, ranibizumab and aflibercept on cell viability, phagocytosis and mitochondrial bioenergetics of retinal pigment epithelial cell

Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types

The pharmacology of resveratrol in animals and humans

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