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Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions

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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 (31 January 2022) | Viewed by 32400

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Dr. Michele Marino

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Department of Clinical and Experimental Medicine, Endocrinology Unit II, University of Pisa and University Hospital of Pisa, Pisa, Italy
Interests: Graves’ orbitopathy; Graves’ disease; thyroid autoimmunity; thyrid physiology; thyroid diseases

Special Issue Information

Dear Colleagues,

A prominent role for oxidative stress in diseases of the eye has been established in the last decade. Several approaches based on antioxidant supplementation or delivery have been proposed to alleviate oxidant stress-induced injury in ocular tissues. Tissue hypoxia participates in the pathogenesis of a number of eye disorders arising mainly from generation of oxy-free radicals, as documented in several in vitro and by clinical studies. Thus, antioxidant agents that scavenge the oxyradicals and peroxides assume therapeutic significance. For example, in Graves’ Orbitopathy (GO), a randomized clinical trial has provided evidence for a beneficial effect of selenium. In addition to selenium, other endogenous and exogenous agents and their prodrugs (for example, those of N-acetyl cysteine and its derivatives in age-related macular degeneration) have potential for therapeutic applications in the clinic.

This Special Issue invites significant, novel, and new advances made on the role of several types of oxidative stress in ocular disease and modalities of intervention by antioxidant moieties. It is hoped that this information will be of help in the clinical practice of primary care physicians, ophthalmologists, endocrinologists, and general internists.

Dr. Michele Marino
Guest Editor

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Keywords

Graves’ orbitopathy
oxidative stress
Graves’ disease

Published Papers (11 papers)

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Research

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26 pages, 4267 KiB

Open AccessArticle

Is There an Optimal Combination of AREDS2 Antioxidants Zeaxanthin, Vitamin E and Vitamin C on Light-Induced Toxicity of Vitamin A Aldehyde to the Retina?

by Małgorzata B. Różanowska, Barbara Czuba-Pełech and Bartosz Różanowski

Antioxidants 2022, 11(6), 1132; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11061132 - 09 Jun 2022

Cited by 5 | Viewed by 2241

Abstract

Vitamins C and E and zeaxanthin are components of a supplement tested in a large clinical trial—Age-Related Eye Disease Study 2 (AREDS2)—and it has been demonstrated that they can inhibit the progression of age-related macular degeneration. The aim of this study was to determine the optimal combinations of these antioxidants to prevent the phototoxicity mediated by vitamin A aldehyde (ATR), which can accumulate in photoreceptor outer segments (POS) upon exposure to light. We used cultured retinal pigment epithelial cells ARPE-19 and liposomes containing unsaturated lipids and ATR as a model of POS. Cells and/or liposomes were enriched with lipophilic antioxidants, whereas ascorbate was added just before the exposure to light. Supplementing the cells and/or liposomes with single lipophilic antioxidants had only a minor effect on phototoxicity, but the protection substantially increased in the presence of both ways of supplementation. Combinations of zeaxanthin with α-tocopherol in liposomes and cells provided substantial protection, enhancing cell viability from ~26% in the absence of antioxidants to ~63% in the presence of 4 µM zeaxanthin and 80 µM α-tocopherol, and this protective effect was further increased to ~69% in the presence of 0.5 mM ascorbate. The protective effect of ascorbate disappeared at a concentration of 1 mM, whereas 2 mM of ascorbate exacerbated the phototoxicity. Zeaxanthin or α-tocopherol partly ameliorated the cytotoxic effects. Altogether, our results suggest that the optimal combination includes upper levels of zeaxanthin and α-tocopherol achievable by diet and/or supplementations, whereas ascorbate needs to be at a four-fold smaller concentration than that in the vitreous. The physiological relevance of the results is discussed. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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13 pages, 5596 KiB

Open AccessArticle

Proteins Associated with Phagocytosis Alteration in Retinal Pigment Epithelial Cells Derived from Age-Related Macular Degeneration Patients

by Audrey Voisin, Afsaneh Gaillard, Anaïs Balbous and Nicolas Leveziel

Antioxidants 2022, 11(4), 713; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11040713 - 05 Apr 2022

Cited by 3 | Viewed by 2296

Abstract

Age-related macular degeneration (AMD) is partially characterized by retinal pigment epithelial (RPE) cell dysfunction. This study focused on phagocytosis activity and its involvement in AMD. Phagocytic activity was analyzed by flow cytometry using porcine photoreceptor outer segment (POS) and fluorescent beads in basal and under oxidative stress condition induced by Fe-NTA in fifteen hiPSC-RPE cell lines (six controls, six atrophic AMD and three exudative AMD). Oxidative stress exposure inhibited phagocytosis in the same manner for control, atrophic AMD (AMDa) and exudative AMD (AMDe) cell lines. However, altered phagocytosis in basal condition in hiPSC-RPE AMDa/e was observed compared to control cell lines. Gene expression after 3 or 24 h of POS incubation was analyzed by RNA-Seq based transcriptomic profiling. Differential gene expression was observed by RNA seq after 3 and 24 h POS exposure. We have focused on the genes involved in mTOR/PI3K-AKT/MEK-ERK pathway. We investigated differences in gene expression by analyzing the expression levels and activity of the corresponding proteins by Western blot. We showed the involvement of three proteins essential for phagocytosis activity: fak, tuberin and rictor. These findings demonstrate that hiPSC-RPE AMDa/e cells have a typical disease phenotype characterized by alteration of the main function of RPE cells, phagocytosis activity. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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15 pages, 2506 KiB

Open AccessArticle

Human iPSC- and Primary-Retinal Pigment Epithelial Cells for Modeling Age-Related Macular Degeneration

by Cody R. Fisher, Mara C. Ebeling, Zhaohui Geng, Rebecca J. Kapphahn, Heidi Roehrich, Sandra R. Montezuma, James R. Dutton and Deborah A. Ferrington

Antioxidants 2022, 11(4), 605; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11040605 - 22 Mar 2022

Cited by 6 | Viewed by 2558

Abstract

Primary cultures of retinal pigment epithelium (RPE) from human adult donors (haRPE) and induced pluripotent stem cell derived-RPE (iPSC-RPE) are valuable model systems for gaining mechanistic insight and for testing potential therapies for age-related macular degeneration (AMD). This study evaluated the treatment response of haRPE and iPSC-RPE to oxidative stress and potential therapeutics addressing mitochondrial defects. haRPE and iSPC-RPE were derived from donors with or without AMD. Mitochondrial function was measured after treatment with menadione, AICAR, or trehalose and the response to treatment was compared between cell models and by disease status. In a subset of samples, haRPE and iPSC-RPE were generated from the same human donor to make a side-by-side comparison of the two cell models’ response to treatment. Disease-specific responses to all three treatments was observed in the haRPE. In contrast, iPSC-RPE had a similar response to all treatments irrespective of disease status. Analysis of haRPE and iPSC-RPE generated from the same human donor showed a similar response for donors without AMD, but there were significant differences in treatment response between cell models generated from AMD donors. These results support the use of iPSC-RPE and haRPE when investigating AMD mechanisms and new therapeutics but indicates that attention to experimental conditions is required. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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15 pages, 1580 KiB

Open AccessArticle

Supplementation with a Highly Concentrated Docosahexaenoic Acid (DHA) in Non-Proliferative Diabetic Retinopathy: A 2-Year Randomized Double-Blind Placebo-Controlled Study

by Purificación Piñas García, Francisco Javier Hernández Martínez, Núria Aznárez López, Luis Castillón Torre and Mª Eugenia Tena Sempere

Antioxidants 2022, 11(1), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11010116 - 05 Jan 2022

Cited by 6 | Viewed by 1524

Abstract

We assessed the effect of a 2-year supplementation with a highly concentrated docosahexaenoic acid (DHA) product with antioxidant activity on non-proliferative diabetic retinopathy (NPDR) in a randomized double-blind placebo-controlled study. A total of 170 patients with diabetes were randomly assigned to the DHA group (n = 83) or the placebo group (n = 87). NPDR was diagnosed using non-contact slit lamp biomicroscopy examination, and classified into mild, moderate, and severe stages. Patients in the DHA group received a high rich DHA triglyceride (1050 mg/day) nutritional supplement, and those in the placebo group received olive oil capsules. The percentages of mild NPDR increased from 61.7% at baseline to 75.7% at the end of the study in the DHA group, and from 61.9% to 73.1% in the placebo group. Moderate NPDR stages decreased from 35.1% at baseline to 18.7% at the end of the study in the DHA group, and from 36.8% to 26.0% in the placebo group. In the DHA group, there were five eyes with severe NPDR at baseline, which increased to one more at the end of the study. In the placebo group, of two eyes with severe NPDR at baseline, one eye remained at the end of the study. Changes in visual acuity were not found. There were improvements in the serum levels of HbA1c in both groups, but significant differences between the DHA and the placebo groups were not found. In this study, the use of a DHA triglyceride nutraceutical supplement for 2 years did not appear to influence the slowing of the progression of NPDR. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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20 pages, 1820 KiB

Open AccessArticle

Fine Tuning of an Oxidative Stress Model with Sodium Iodate Revealed Protective Effect of NF-κB Inhibition and Sex-Specific Difference in Susceptibility of the Retinal Pigment Epithelium

by Xue Yang, Usha Rai, Jin-Yong Chung and Noriko Esumi

Antioxidants 2022, 11(1), 103; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11010103 - 31 Dec 2021

Cited by 8 | Viewed by 2479

Abstract

Oxidative stress of the retinal pigment epithelium (RPE) is a major risk factor for age-related macular degeneration (AMD). As a dry AMD model via oxidative stress, sodium iodate (NaIO₃), which is primarily toxic to the RPE, has often been used at a high dose to cause RPE death for studying photoreceptor degeneration. Thus, characterization of RPE damage by a low dose of NaIO₃ is still limited. To quantify RPE damage caused by NaIO₃ in mice, we recently developed a morphometric method using RPE flat-mounts. Here, we report that NaIO₃ has a narrow range of dose–effect correlation at 11–18 mg/kg body weight in male C57BL/6J mice. We evaluated the usefulness of our quantification method in two experimental settings. First, we tested the effect of NF-κB inhibition on NaIO₃-induced RPE damage in male C57BL/6J mice. IKKβ inhibitor BAY 651942 suppressed upregulation of NF-κB targets and protected the RPE from oxidative stress. Second, we tested sex-specific differences in NaIO₃-induced RPE damage in C57BL/6J mice using a low dose near the threshold. NaIO₃ caused more severe RPE damage in female mice than in male mice. These results demonstrate the usefulness of the quantification method and the importance of fine-tuning of the NaIO₃ dose. The results also show the therapeutic potential of IKKβ inhibition for oxidative stress-related RPE diseases, and reveal previously-unrecognized sex-specific differences in RPE susceptibility to oxidative stress. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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16 pages, 8008 KiB

Open AccessArticle

Release of Iron-Loaded Ferritin in Sodium Iodate-Induced Model of Age Related Macular Degeneration: An In-Vitro and In-Vivo Study

by Ajay Ashok, Suman Chaudhary, Aaron S. Wise, Neil A. Rana, Dallas McDonald, Alexander E. Kritikos, Ewald Lindner and Neena Singh

Antioxidants 2021, 10(8), 1253; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10081253 - 05 Aug 2021

Cited by 5 | Viewed by 2459

Abstract

In this report, we evaluated the role of iron in sodium iodate (NaIO₃)-induced model of age-related macular degeneration (AMD) in ARPE-19 cells in-vitro, and mouse models in-vivo. ARPE-19 cells, a human retinal pigmented epithelial cell line, were exposed to 10 mM of NaIO₃ for 24 h, and the expression and localization of major iron modulating proteins was evaluated by Western blotting (WB) and immunostaining. Synthesis and maturation of cathepsin-D (cat-D), a lysosomal enzyme, was evaluated by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) and WB respectively. For in-vivo studies, C57BL/6 mice were injected with 40 mg/kg mouse body weight of NaIO₃ intraperitoneally, and their retina was evaluated after 3 weeks as above. We observed that NaIO₃ induced a 10-fold increase in ferritin in ARPE-19 cells, which co-localized with LC3II, an autophagosomal marker, and LAMP-1, a lysosomal marker. A similar increase in ferritin was noted in retinal lysates and retinal sections of NaIO₃-injected mice by WB and immunostaining. Impaired synthesis and maturation of cat-D was also noted. Accumulated ferritin was loaded with iron, and released from retinal pigmented epithelial (RPE) cells in Perls’ and LAMP-1 positive vesicles. These observations suggest that NaIO₃ impairs lysosomal degradation of ferritin by decreasing the transcription and maturation of cat-D in RPE-19 cells. Iron-loaded ferritin accumulates in lysosomes and is released in lysosome membrane-enclosed vesicles in the extracellular milieu. Accumulation of ferritin in RPE-19 cells and fusion of ferritin-containing vesicles with adjacent photoreceptor cells is likely to create iron overload, compromising their viability. Moreover, reduced activity of cat-D is likely to promote the accumulation of other cellular debris in lysosomal vesicles, contributing to AMD-like pathology. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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Review

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23 pages, 3781 KiB

Open AccessReview

The Intertwined Roles of Oxidative Stress and Endoplasmic Reticulum Stress in Glaucoma

by Daire John Hurley, Caoimhe Normile, Mustapha Irnaten and Colm O’Brien

Antioxidants 2022, 11(5), 886; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11050886 - 29 Apr 2022

Cited by 18 | Viewed by 3597

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide, and the burden of the disease continues to grow as the global population ages. Currently, the only treatment option is to lower intraocular pressure. A better understanding of glaucoma pathogenesis will help us to develop novel therapeutic options. Oxidative stress has been implicated in the pathogenesis of many diseases. Oxidative stress occurs when there is an imbalance in redox homeostasis, with reactive oxygen species producing processes overcoming anti-oxidant defensive processes. Oxidative stress works in a synergistic fashion with endoplasmic reticulum stress, to drive glaucomatous damage to trabecular meshwork, retinal ganglion cells and the optic nerve head. We discuss the oxidative stress and endoplasmic reticulum stress pathways and their connections including their key intermediary, calcium. We highlight therapeutic options aimed at disrupting these pathways and discuss their potential role in glaucoma treatment. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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14 pages, 1013 KiB

Open AccessReview

Oxidative Stress, Vascular Endothelium, and the Pathology of Neurodegeneration in Retina

by Xin Shi, Panpan Li, Hanhan Liu and Verena Prokosch

Antioxidants 2022, 11(3), 543; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11030543 - 12 Mar 2022

Cited by 17 | Viewed by 2573

Abstract

Oxidative stress (OS) is an imbalance between free radicals/ROS and antioxidants, which evokes a biological response and is an important risk factor for diseases, in both the cardiovascular system and central nervous system (CNS). The underlying mechanisms driving pathophysiological complications that arise from OS remain largely unclear. The vascular endothelium is emerging as a primary target of excessive glucocorticoid and catecholamine action. Endothelial dysfunction (ED) has been implicated to play a crucial role in the development of neurodegeneration in the CNS. The retina is known as an extension of the CNS. Stress and endothelium dysfunction are suspected to be interlinked and associated with neurodegenerative diseases in the retina as well. In this narrative review, we explore the role of OS-led ED in the retina by focusing on mechanistic links between OS and ED, ED in the pathophysiology of different retinal neurodegenerative conditions, and how a better understanding of the role of endothelial function could lead to new therapeutic approaches for neurodegenerative diseases in the retina. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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13 pages, 713 KiB

Open AccessReview

Therapeutic Potential of α-Crystallins in Retinal Neurodegenerative Diseases

by Ashutosh S. Phadte, Zachary B. Sluzala and Patrice E. Fort

Antioxidants 2021, 10(7), 1001; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071001 - 23 Jun 2021

Cited by 10 | Viewed by 2516

Abstract

The chaperone and anti-apoptotic activity of α-crystallins (αA- and αB-) and their derivatives has received increasing attention due to their tremendous potential in preventing cell death. While originally known and described for their role in the lens, the upregulation of these proteins in cells and animal models of neurodegenerative diseases highlighted their involvement in adaptive protective responses to neurodegeneration associated stress. However, several studies also suggest that chronic neurodegenerative conditions are associated with progressive loss of function of these proteins. Thus, while external supplementation of α-crystallin shows promise, their potential as a protein-based therapeutic for the treatment of chronic neurodegenerative diseases remains ambiguous. The current review aims at assessing the current literature supporting the anti-apoptotic potential of αA- and αB-crystallins and its potential involvement in retinal neurodegenerative diseases. The review further extends into potentially modulating the chaperone and the anti-apoptotic function of α-crystallins and the use of such functionally enhanced proteins for promoting neuronal viability in retinal neurodegenerative disease. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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Other

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11 pages, 532 KiB

Open AccessPerspective

The Retinal Renin-Angiotensin-Aldosterone System: Implications for Glaucoma

by Kazuyuki Hirooka and Yoshiaki Kiuchi

Antioxidants 2022, 11(4), 610; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11040610 - 22 Mar 2022

Cited by 8 | Viewed by 2600

Abstract

Aldosterone is one of the main effectors of the renin-angiotensin-aldosterone system (RAAS) along with having roles in hypertension, and cardiovascular and renal diseases. Recent evidence has also shown the presence of an active local RAAS within the human eye. It has been shown that at 12 h after a retinal ischemia-reperfusion injury, there is an upregulation of the protein levels of angiotensin II type 1 receptor (AT1-R) in the retina. Furthermore, at 12 h after reperfusion, there is an increase in reactive oxygen species (ROS) production in the retina that is mediated via an NADPH oxidase pathway. This ischemia-reperfusion injury-induced increase of retinal ROS levels and NADPH oxidase expression can be prevented by the administration of an AT1-R antagonist. This suggests that one of the main retinal ischemic injury pathways is via the local RAAS. It has also been reported that progressive retinal ganglion cell loss and glaucomatous optic nerve degeneration without elevated intraocular pressure occur after administration of local or systemic aldosterone. Elucidation of glaucoma pathogenesis, especially normal-tension glaucoma (NTG) subtype by our current animal model can be used for identifying potential therapeutic targets. Based on these results, we are further evaluating NTG prevalence among primary aldosteronism patients. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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37 pages, 2942 KiB

Open AccessSystematic Review

A Systematic Review of Carotenoids in the Management of Age-Related Macular Degeneration

by Drake W. Lem, Pinakin Gunvant Davey, Dennis L. Gierhart and Richard B. Rosen

Antioxidants 2021, 10(8), 1255; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10081255 - 05 Aug 2021

Cited by 35 | Viewed by 6086

Abstract

Age-related macular degeneration (AMD) remains a leading cause of modifiable vision loss in older adults. Chronic oxidative injury and compromised antioxidant defenses represent essential drivers in the development of retinal neurodegeneration. Overwhelming free radical species formation results in mitochondrial dysfunction, as well as cellular and metabolic imbalance, which becomes exacerbated with increasing age. Thus, the depletion of systemic antioxidant capacity further proliferates oxidative stress in AMD-affected eyes, resulting in loss of photoreceptors, neuroinflammation, and ultimately atrophy within the retinal tissue. The aim of this systematic review is to examine the neuroprotective potential of the xanthophyll carotenoids lutein, zeaxanthin, and meso-zeaxanthin on retinal neurodegeneration for the purpose of adjunctive nutraceutical strategy in the management of AMD. A comprehensive literature review was performed to retrieve 55 eligible publications, using four database searches from PubMed, Embase, Cochrane Library, and the Web of Science. Epidemiology studies indicated an enhanced risk reduction against late AMD with greater dietary consumption of carotenoids, meanwhile greater concentrations in macular pigment demonstrated significant improvements in visual function among AMD patients. Collectively, evidence strongly suggests that carotenoid vitamin therapies offer remarkable synergic protection in the neurosensory retina, with the potential to serve as adjunctive nutraceutical therapy in the management of established AMD, albeit these benefits may vary among different stages of disease. Full article

(This article belongs to the Special Issue Oxidative Stress-Induced Eye Diseases and Therapeutic Interventions)

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