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Oxidative Stress and Inflammation in Retinal Degeneration

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 30337

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Dr. Pamela M. Martin

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Professor of Biochemistry and Molecular Biology, Ophthalmology and Graduate Studies, Georgia Cancer Center and Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, GA, USA
Interests: retina; diabetes; diabetic retinopathy; microRNA; sickle cell retinopathy; age-related macular degeneration; retinal pigment epithelium
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Dr. Ravirajsinh N. Jadeja

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Department Biochemistry & Molecular Biology, The Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
Interests: gut microbiome; liver diseases; aging; energy metabolism; natural compounds
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Robust experimental evidence points to a prominent role for inflammation and oxidative stress in the pathogenesis of many degenerative diseases of the retina (e.g., age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, and retinitis pigmentosa). This is supported by confirmatory studies conducted using human ocular tissues. The retina is exposed to high levels of oxidative stress on a consistent basis as a normal consequence of significant light exposure, visual signal transduction pathways that generate considerable amounts of reactive oxygen species, the oxidation of polyunsaturated fatty acids, etc. Therefore, normal healthy retinal cells do an excellent job of squelching pro-oxidant factors to maintain homeostasis. However, in aging and/or disease, the efficiency of these normal homeostatic mechanisms often declines, disrupting the balance between pro- and anti-oxidative signaling. This contributes to excessive oxidative stress, related inflammation, dysregulated immune responses, potential blood-retinal barrier compromise and tissue damage. Thus, understanding better the mechanisms governing the cellular and molecular events that underlie the switch that precipitates the failure of retina to respond adequately to oxidative and/or inflammatory insults, leaving the tissue susceptible to degenerative processes, may support the discovery of new therapeutic targets to prevent and treat irreversible vision loss and blindness. As such, this Special Issue welcomes submissions of original research and review articles, and clinical trials related to any aspect of the role of oxidative stress and inflammation in the pathogenesis retinal degeneration, identification and exploration of novel targets, and development and testing of antioxidant and anti-inflammatory therapies.

Dr. Pamela M. Martin
Dr. Ravirajsinh Jadeja
Guest Editors

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Keywords

retinal degeneration
antioxidants
oxidative stress
age-related macular degeneration
retinal inflammation
therapeutic targets
aging retina

Published Papers (10 papers)

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Editorial

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4 pages, 165 KiB

Open AccessEditorial

Oxidative Stress and Inflammation in Retinal Degeneration

by Ravirajsinh N. Jadeja and Pamela M. Martin

Antioxidants 2021, 10(5), 790; https://doi.org/10.3390/antiox10050790 - 17 May 2021

Cited by 25 | Viewed by 2239

Abstract

Inflammation and oxidative stress play prominent roles in the pathogenesis of many degenerative diseases of the retina, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal vein occlusion, and retinitis pigmentosa [...] Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Retinal Degeneration)

Research

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22 pages, 6930 KiB

Open AccessArticle

Exacerbation of AMD Phenotype in Lasered CNV Murine Model by Dysbiotic Oral Pathogens

by Pachiappan Arjunan, Radhika Swaminathan, Jessie Yuan, Mohamed Elashiry, Amany Tawfik, Mohamed Al-Shabrawey, Pamela M. Martin, Thangaraju Muthusamy and Christopher W. Cutler

Antioxidants 2021, 10(2), 309; https://doi.org/10.3390/antiox10020309 - 18 Feb 2021

Cited by 5 | Viewed by 3309

Abstract

Emerging evidence underscores an association between age-related macular degeneration (AMD) and periodontal disease (PD), yet the biological basis of this linkage and the specific role of oral dysbiosis caused by PD in AMD pathophysiology remains unclear. Furthermore, a simple reproducible model that emulates characteristics of both AMD and PD has been lacking. Hence, we established a novel AMD+PD murine model to decipher the potential role of oral infection (ligature-enhanced) with the keystone periodontal pathogen Porphyromonas gingivalis, in the progression of neovasculogenesis in a laser-induced choroidal-neovascularization (Li-CNV) mouse retina. By a combination of fundus photography, optical coherence tomography, and fluorescein angiography, we documented inflammatory drusen-like lesions, reduced retinal thickness, and increased vascular leakage in AMD+PD mice retinae. H&E further confirmed a significant reduction of retinal thickness and subretinal drusen-like deposits. Immunofluorescence microscopy revealed significant induction of choroidal/retinal vasculogenesis in AMD+PD mice. qPCR identified increased expression of oxidative-stress, angiogenesis, pro-inflammatory mediators, whereas antioxidants and anti-inflammatory genes in AMD+PD mice retinae were notably decreased. Through qPCR, we detected Pg and its fimbrial 16s-RrNA gene expression in the AMD+PD mice retinae. To sum-up, this is the first in vivo study signifying a role of periodontal infection in augmentation of AMD phenotype, with the aid of a pioneering AMD+PD murine model established in our laboratory. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Retinal Degeneration)

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14 pages, 1744 KiB

Open AccessArticle

Cytoprotective Effects of Punicalagin on Hydrogen–Peroxide–Mediated Oxidative Stress and Mitochondrial Dysfunction in Retinal Pigment Epithelium Cells

by Maria Elisabetta Clementi, Giuseppe Maulucci, Giada Bianchetti, Michela Pizzoferrato, Beatrice Sampaolese and Giuseppe Tringali

Antioxidants 2021, 10(2), 192; https://doi.org/10.3390/antiox10020192 - 29 Jan 2021

Cited by 12 | Viewed by 3026

Abstract

The retinal pigment epithelium (RPE) is a densely pigmented, monostratified epithelium that provides metabolic and functional support to the outer segments of photoreceptors. Endogenous or exogenous oxidative stimuli determine a switch from physiological to pathological conditions, characterized by an increase of intracellular levels of reactive oxygen species (ROS). Accumulating evidence has elucidated that punicalagin (PUN), the major ellagitannin in pomegranate, is a potent antioxidant in several cell types. The present study aimed to investigate the protective effect of PUN on mitochondrial dysfunction associated with hydrogen peroxide (H₂O₂)–induced oxidative stress. For this purpose, we used a human RPE cell line (ARPE–19) exposed to H₂O₂ for 24 h. The effects of PUN pre–treatment (24 h) were examined on cell viability, mitochondrial ROS levels, mitochondrial membrane potential, and respiratory chain complexes, then finally on caspase–3 enzymatic activity. The results showed that supplementation with PUN: (a) significantly increased cell viability; (b) kept the mitochondrial membrane potential (ΔΨm) at healthy levels and limited ROS production; (c) preserved the activity of respiratory complexes; (d) reduced caspase–3 activity. In conclusion, due to its activity in helping mitochondrial functions, reducing oxidative stress, and subsequent induction of cellular apoptosis, PUN might be considered a useful nutraceutical agent in the treatment of oxidation–associated disorders of RPE. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Retinal Degeneration)

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19 pages, 18799 KiB

Open AccessArticle

Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

by Lara Macchioni, Davide Chiasserini, Letizia Mezzasoma, Magdalena Davidescu, Pier Luigi Orvietani, Katia Fettucciari, Leonardo Salviati, Barbara Cellini and Ilaria Bellezza

Antioxidants 2021, 10(1), 25; https://doi.org/10.3390/antiox10010025 - 29 Dec 2020

Cited by 11 | Viewed by 2507

Abstract

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H₂O₂ for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Retinal Degeneration)

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17 pages, 3170 KiB

Open AccessArticle

Selenomethionine (Se-Met) Induces the Cystine/Glutamate Exchanger SLC7A11 in Cultured Human Retinal Pigment Epithelial (RPE) Cells: Implications for Antioxidant Therapy in Aging Retina

by Sudha Ananth, Seiji Miyauchi, Muthusamy Thangaraju, Ravirajsinh N. Jadeja, Manuela Bartoli, Vadivel Ganapathy and Pamela M. Martin

Antioxidants 2021, 10(1), 9; https://doi.org/10.3390/antiox10010009 - 24 Dec 2020

Cited by 20 | Viewed by 3036

Abstract

Oxidative damage has been identified as a major causative factor in degenerative diseases of the retina; retinal pigment epithelial (RPE) cells are at high risk. Hence, identifying novel strategies for increasing the antioxidant capacity of RPE cells, the purpose of this study, is important. Specifically, we evaluated the influence of selenium in the form of selenomethionine (Se-Met) in cultured RPE cells on system xc- expression and functional activity and on cellular levels of glutathione, a major cellular antioxidant. ARPE-19 and mouse RPE cells were cultured with and without selenomethionine (Se-Met), the principal form of selenium in the diet. Promoter activity assay, uptake assay, RT-PCR, northern and western blots, and immunofluorescence were used to analyze the expression of xc-, Nrf2, and its target genes. Se-Met activated Nrf2 and induced the expression and function of xc- in RPE. Other target genes of Nrf2 were also induced. System xc- consists of two subunits, and Se-Met induced the subunit responsible for transport activity (SLC7A11). Selenocysteine also induced xc- but with less potency. The effect of Se-met on xc- was associated with an increase in maximal velocity and an increase in substrate affinity. Se-Met increased the cellular levels of glutathione in the control, an oxidatively stressed RPE. The Se-Met effect was selective; under identical conditions, taurine transport was not affected and Na+-coupled glutamate transport was inhibited. This study demonstrates that Se-Met enhances the antioxidant capacity of RPE by inducing the transporter xc- with a consequent increase in glutathione. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Retinal Degeneration)

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24 pages, 7166 KiB

Open AccessArticle

Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline

by Luigi Donato, Concetta Scimone, Simona Alibrandi, Alessandro Pitruzzella, Federica Scalia, Rosalia D’Angelo and Antonina Sidoti

Antioxidants 2020, 9(11), 1158; https://doi.org/10.3390/antiox9111158 - 20 Nov 2020

Cited by 44 | Viewed by 3107

Abstract

Mitochondria are subject to continuous oxidative stress stimuli that, over time, can impair their genome and lead to several pathologies, like retinal degenerations. Our main purpose was the identification of mtDNA variants that might be induced by intense oxidative stress determined by N-retinylidene-N-retinylethanolamine (A2E), together with molecular pathways involving the genes carrying them, possibly linked to retinal degeneration. We performed a variant analysis comparison between transcriptome profiles of human retinal pigment epithelial (RPE) cells exposed to A2E and untreated ones, hypothesizing that it might act as a mutagenic compound towards mtDNA. To optimize analysis, we proposed an integrated approach that foresaw the complementary use of the most recent algorithms applied to mtDNA data, characterized by a mixed output coming from several tools and databases. An increased number of variants emerged following treatment. Variants mainly occurred within mtDNA coding sequences, corresponding with either the polypeptide-encoding genes or the RNA. Time-dependent impairments foresaw the involvement of all oxidative phosphorylation complexes, suggesting a serious damage to adenosine triphosphate (ATP) biosynthesis, that can result in cell death. The obtained results could be incorporated into clinical diagnostic settings, as they are hypothesized to modulate the phenotypic expression of mtDNA pathogenic variants, drastically improving the field of precision molecular medicine. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Retinal Degeneration)

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13 pages, 1427 KiB

Open AccessArticle

Inhibitory Action of Antidiabetic Drugs on the Free Radical Production by the Rod Outer Segment Ectopic Aerobic Metabolism

by Silvia Ravera, Federico Caicci, Paolo Degan, Davide Maggi, Lucia Manni, Alessandra Puddu, Massimo Nicolò, Carlo E. Traverso and Isabella Panfoli

Antioxidants 2020, 9(11), 1133; https://doi.org/10.3390/antiox9111133 - 15 Nov 2020

Cited by 10 | Viewed by 1810

Abstract

Rod outer segments (OS) express the F_oF₁-ATP synthase and the respiratory chain, conducting an ectopic aerobic metabolism that produces free radicals in vitro. Diabetic retinopathy, a leading cause of vision loss, is associated with oxidative stress in the outer retina. Since metformin and glibenclamide, two anti-type 2 diabetes drugs, target the respiratory complexes, we studied the effect of these two drugs, individually or in association, on the free radical production in purified bovine rod OS. ATP synthesis, oxygen consumption, and oxidative stress production were assayed by luminometry, oximetry and flow cytometry, respectively. The expression of F_oF₁-ATP synthase was studied by immunogold electron microscopy. Metformin had a hormetic effect on the OS complex I and ATP synthetic activities, being stimulatory at concentrations below 1 mM, and inhibitory above. Glibenclamide inhibited complexes I and III, as well as ATP production in a concentration-dependent manner. Maximal concentrations of both drugs inhibited the ROI production by the light-exposed OS. Data, consistent with the delaying effect of these drugs on the onset of diabetic retinopathy, suggest that a combination of the two drugs at the beginning of the treatment might reduce the oxidative stress production helping the endogenous antioxidant defences in avoiding retinal damage. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Retinal Degeneration)

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15 pages, 3772 KiB

Open AccessArticle

Different Effects of Metformin and A769662 on Sodium Iodate-Induced Cytotoxicity in Retinal Pigment Epithelial Cells: Distinct Actions on Mitochondrial Fission and Respiration

by Chi-Ming Chan, Ponarulselvam Sekar, Duen-Yi Huang, Shu-Hao Hsu and Wan-Wan Lin

Antioxidants 2020, 9(11), 1057; https://doi.org/10.3390/antiox9111057 - 28 Oct 2020

Cited by 10 | Viewed by 2811

Abstract

Oxidative stress-associated retinal pigment epithelium (RPE) cell death is critically implicated in the pathogenesis of visual dysfunction and blindness of retinal degenerative diseases. Sodium iodate (NaIO₃) is an oxidative retinotoxin and causes RPE damage. Previously, we found that NaIO₃ can induce human ARPE-19 cell death via inducing mitochondrial fission and mitochondrial dysfunction. Although metformin has been demonstrated to benefit several diseases possibly via AMP-activated protein kinase (AMPK) activation, it remains unknown how AMPK affects retinopathy in NaIO₃ model. Therefore, in this study, we compared the effects of metformin and AMPK activator A769662 on NaIO₃-induced cellular stress and toxicity. We found that A769662 can protect cells against NaIO₃-induced cytotoxicity, while metformin exerts an enhancement in cell death. The mitochondrial reactive oxygen species (ROS) production as well as mitochondrial membrane potential loss induced by NaIO₃ were not altered by both agents. In addition, NaIO₃-induced cytosolic ROS production, possibly from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and counteracting cell death, was not altered by A769662 and metformin. Notably, NaIO₃-induced mitochondrial fission and inhibition of mitochondrial respiration for ATP turnover were reversed by A769662 but not by metformin. In agreement with the changes on mitochondrial morphology, the ERK-Akt signal axis dependent Drp-1 phosphorylation at S616 (an index of mitochondrial fission) under NaIO₃ treatment was blocked by A769662, but not by metformin. In summary, NaIO₃-induced cell death in ARPE cells primarily comes from mitochondrial dysfunction due to dramatic fission and inhibition of mitochondrial respiration. AMPK activation can exert a protection by restoring mitochondrial respiration and inhibition of ERK/Akt/Drp-1 phosphorylation, leading to a reduction in mitochondrial fission. However, inhibition of respiratory complex I by metformin might deteriorate mitochondrial dysfunction and cell death under NaIO₃ stress. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Retinal Degeneration)

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17 pages, 3332 KiB

Open AccessArticle

Ethanol-Induced Oxidative Stress Modifies Inflammation and Angiogenesis Biomarkers in Retinal Pigment Epithelial Cells (ARPE-19): Role of CYP2E1 and its Inhibition by Antioxidants

by Natalia Martinez-Gil, Lorena Vidal-Gil, Miguel Flores-Bellver, Rosa Maisto, Javier Sancho-Pelluz, Manuel Diaz-Llopis, Jorge M. Barcia and Francisco J. Romero

Antioxidants 2020, 9(9), 776; https://doi.org/10.3390/antiox9090776 - 21 Aug 2020

Cited by 7 | Viewed by 3276

Abstract

The retinal pigment epithelium (RPE) plays a key role in retinal health, being essential for the protection against reactive oxygen species (ROS). Nevertheless, excessive oxidative stress can induce RPE dysfunction, promoting visual loss. Our aim is to clarify the possible implication of CYP2E1 in ethanol (EtOH)-induced oxidative stress in RPE alterations. Despite the increase in the levels of ROS, measured by fluorescence probes, the RPE cells exposed to the lowest EtOH concentrations were able to maintain cell survival, measured by the Cell Proliferation Kit II (XTT). However, EtOH-induced oxidative stress modified inflammation and angiogenesis biomarkers, analyzed by proteome array, ELISA, qPCR and Western blot. The highest EtOH concentration used stimulated a large increase in ROS levels, upregulating the cytochrome P450-2E1 (CYP2E1) and promoting cell death. The use of antioxidants such as N-acetylcysteine (NAC) and diallyl sulfide (DAS), which is also a CYP2E1 inhibitor, reverted cell death and oxidative stress, modulating also the upstream angiogenesis and inflammation regulators. Because oxidative stress plays a central role in most frequent ocular diseases, the results herein support the proposal that CYP2E1 upregulation could aggravate retinal degeneration, especially in those patients with high baseline oxidative stress levels due to their ocular pathology and should be considered as a risk factor. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Retinal Degeneration)

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Review

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22 pages, 2303 KiB

Open AccessReview

Metabolic Dysregulation and Neurovascular Dysfunction in Diabetic Retinopathy

by Thangal Yumnamcha, Michael Guerra, Lalit Pukhrambam Singh and Ahmed S. Ibrahim

Antioxidants 2020, 9(12), 1244; https://doi.org/10.3390/antiox9121244 - 08 Dec 2020

Cited by 45 | Viewed by 4220

Abstract

Diabetic retinopathy is a major cause of ocular complications in patients with type 1 and type 2 diabetes in developed countries. Due to the continued increase in the number of people with obesity and diabetes in the United States of America and globally, the incidence of diabetic retinopathy is expected to increase significantly in the coming years. Diabetic retinopathy is widely accepted as a combination of neurodegenerative and microvascular changes; however, which change occurs first is not yet understood. Although the pathogenesis of diabetic retinopathy is very complex, regulated by numerous signaling pathways and cellular processes, maintaining glucose homeostasis is still an essential component for normal physiological functioning of retinal cells. The maintenance of glucose homeostasis is finely regulated by coordinated interplay between glycolysis, Krebs cycle, and oxidative phosphorylation. Glycolysis is the most conserved metabolic pathway in biology and is tightly regulated to maintain a steady-state concentration of glycolytic intermediates; this regulation is called scheduled or regulated glycolysis. However, an abnormal increase in glycolytic flux generates large amounts of intermediate metabolites that can be shunted into different damaging pathways including the polyol pathway, hexosamine pathway, diacylglycerol-dependent activation of the protein kinase C pathway, and Amadori/advanced glycation end products (AGEs) pathway. In addition, disrupting the balance between glycolysis and oxidative phosphorylation leads to other biochemical and molecular changes observed in diabetic retinopathy including endoplasmic reticulum-mitochondria miscommunication and mitophagy dysregulation. This review will focus on how dysregulation of glycolysis contributes to diabetic retinopathy. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Retinal Degeneration)

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