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Cellular Responses of Antioxidants Related to Degenerative Eye Disease Research

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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: 10 December 2024 | Viewed by 16202

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Special Issue Editors

Prof. Dr. Wonkyu Ju

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Guest Editor

Hamilton Glaucoma Center and Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California, San Diego, La Jolla, CA 92039, USA
Interests: retinal ganglion cell; glial cells; oxidative stress; mitochondrial dysfunction; mitochondrial protection; neuroinflammation; glaucoma; Alzheimer’s disease

Dr. Niina Harju

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Guest Editor

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland
Interests: retinal pigment epithelium; inflammation; oxidative stress; antioxidants; age-related macular degeneration; retinal detachment

Special Issue Information

Dear Colleagues,

Oxidative stress, mitochondrial dysfunction, and inflammation are critical to degenerative retinal diseases, a group of eye diseases (e.g., age-related macular degeneration, retinal detachment, retinitis pigmentosa, and glaucoma) that cause vision loss. Antioxidants are considered potential therapeutic strategies in retinal eye diseases. In age-related macular degeneration (AMD), retinal pigment epithelial (RPE) cell loss leads to retinal degeneration and visual defects. Dry AMD induces RPE cell degeneration, whereas the wet form causes neovascularization and exudate formation following RPE cell loss. Rhegmatogenous retinal detachment occurs because a tear or hole in the retina leads to vitreous fluid penetrating the sub-retinal space, which induces photoreceptors’ separation from the RPE cell layer. Glaucoma induces progressive retinal ganglion cell (RGC) axon degeneration, resulting in RGC death and visual deficits.

The retina is a thin layer in the posterior part of the eye that collects visual information and transfers it into the brain via the optic nerve. The retina consists of RPE cells, photoreceptor rods and cones, glial cells, and neuronal cells, including RGCs. All layers are essential for vision and are affected by retinal degeneration. RPE cells support the homeostasis of the retina and photoreceptors, complete the heterocycle of outer photoreceptor segments and enable nutrition transport from the choroid and removal of waste material into the choroid. RGCs are the most prominent cell type in the ganglion cell layer, which is the innermost neural layer of the retina. Both RPE and RGC degeneration leads to vision loss, and antioxidants could protect these cells against oxidative stress, mitochondrial dysfunction, and/or inflammation in degenerative retinal eye diseases.

We invite all scientists studying cellular responses of antioxidants related to pre-clinical degenerative retinal eye disease research to participate in this Special Issue. Original research articles, reviews, or shorter perspective articles on all aspects related to antioxidants in degenerative retinal eye diseases are welcome, including topics such as antioxidants, oxidative stress, mitochondrial dysfunction, inflammation, RPE cells, photoreceptors, glia cells, RGCs, and studies of potential new treatment options for retinal degeneration.

Prof. Dr. Wonkyu Ju
Dr. Niina Harju
Guest Editors

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Keywords

antioxidants
retinal degeneration
oxidative stress
mitochondrial dysfunction
mitochondrial protection
inflammation
retinal eye diseases
RPE cells
photoreceptors
retinal ganglion cells
glial cells

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Published Papers (9 papers)

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20 pages, 6780 KiB

Open AccessArticle

AIBP Protects Müller Glial Cells Against Oxidative Stress-Induced Mitochondrial Dysfunction and Reduces Retinal Neuroinflammation

by Seunghwan Choi, Soo-Ho Choi, Tonking Bastola, Keun-Young Kim, Sungsik Park, Robert N. Weinreb, Yury I. Miller and Won-Kyu Ju

Antioxidants 2024, 13(10), 1252; https://doi.org/10.3390/antiox13101252 - 17 Oct 2024

Viewed by 781

Abstract

Glaucoma, an optic neuropathy with the loss of retinal ganglion cells (RGCs), is a leading cause of irreversible vision loss. Oxidative stress and mitochondrial dysfunction have a significant role in triggering glia-driven neuroinflammation and subsequent glaucomatous RGC degeneration in the context of glaucoma. It has previously been shown that apolipoprotein A-I binding protein (APOA1BP or AIBP) has an anti-inflammatory function. Moreover, Apoa1bp^−/− mice are characterized by retinal neuroinflammation and RGC loss. In this study, we found that AIBP deficiency exacerbated the oxidative stress-induced disruption of mitochondrial dynamics and function in the retina, leading to a further decline in visual function. Mechanistically, AIBP deficiency-induced oxidative stress triggered a reduction in glycogen synthase kinase 3β and dynamin-related protein 1 phosphorylation, optic atrophy type 1 and mitofusin 1 and 2 expression, and oxidative phosphorylation, as well as the activation of mitogen-activated protein kinase (MAPK) in Müller glia dysfunction, leading to cell death and inflammatory responses. In vivo, the administration of recombinant AIBP (rAIBP) effectively protected the structural and functional integrity of retinal mitochondria under oxidative stress conditions and prevented vision loss. In vitro, incubation with rAIBP safeguarded the structural integrity and bioenergetic performance of mitochondria and concurrently suppressed MAPK activation, apoptotic cell death, and inflammatory response in Müller glia. These findings support the possibility that AIBP promotes RGC survival and restores visual function in glaucomatous mice by ameliorating glia-driven mitochondrial dysfunction and neuroinflammation. Full article

(This article belongs to the Special Issue Cellular Responses of Antioxidants Related to Degenerative Eye Disease Research)

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17 pages, 3891 KiB

Open AccessArticle

Protective Effects of 7S,15R-Dihydroxy-16S,17S-Epoxy-Docosapentaenoic Acid (diHEP-DPA) against Blue Light-Induced Retinal Damages in A2E-Laden ARPE-19 Cells

by Seung-Yub Song, Dae-Hun Park, Sung-Ho Lee, Han-Kyu Lim, Jin-Woo Park, Jeong-Woo Seo and Seung-Sik Cho

Antioxidants 2024, 13(8), 982; https://doi.org/10.3390/antiox13080982 - 13 Aug 2024

Viewed by 778

Abstract

The purpose of this study was to investigate the protective effects of 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA) in retinal pigment epithelial (RPE) cell damage. ARPE-19 cells, a human RPE cell line, were cultured with diHEP-DPA and Bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), followed by exposure to BL. Cell viability and cell death rates were determined. Western blotting was performed to determine changes in apoptotic factors, mitogen-activated protein kinase (MAPK) family proteins, inflammatory proteins, and oxidative and carbonyl stresses. The levels of pro-inflammatory cytokines in the culture medium supernatants were also measured. Exposure to A2E and BL increased the ARPE-19 cell death rate, which was alleviated by diHEP-DPA in a concentration-dependent manner. A2E and BL treatments induced apoptosis in ARPE-19 cells, which was also alleviated by diHEP-DPA. Analysis of the relationship with MAPK proteins revealed that the expression of p-JNK and p-P38 increased after A2E and BL treatments and decreased with exposure to diHEP-DPA in a concentration-dependent manner. DiHEP-DPA also affected the inflammatory response by suppressing the expression of inflammatory proteins and the production of pro-inflammatory cytokines. Furthermore, it was shown that diHEP-DPA regulated the proteins related to oxidative and carbonyl stresses. Taken together, our results provide evidence that diHEP-DPA can inhibit cell damage caused by A2E and BL exposure at the cellular level by controlling various pathways involved in apoptosis and inflammatory responses. Full article

(This article belongs to the Special Issue Cellular Responses of Antioxidants Related to Degenerative Eye Disease Research)

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17 pages, 4024 KiB

Open AccessArticle

The microRNA Let-7f Induces Senescence and Exacerbates Oxidative Stress in Retinal Pigment Epithelial Cells

by Christina Ortiz, Houda Tahiri, Chun Yang, Claudia Gilbert, Carl Fortin and Pierre Hardy

Antioxidants 2024, 13(6), 646; https://doi.org/10.3390/antiox13060646 - 25 May 2024

Viewed by 1208

Abstract

This study aims to investigate the role of microRNA let-7f in the dysfunction and degeneration of retinal pigment epithelium (RPE) cells through the induction of senescence and oxidative stress. Furthermore, we explore whether let-7f inhibition can protect these cells against sodium iodate (SI)-induced oxidative stress. Oxidative stress and let-7f expression are reciprocally regulated in retinal pigment epithelial cells. Overexpression of let-7f in ARPE-19 cells induced oxidative stress as demonstrated by increased reactive oxygen species (ROS) production as well as senescence. Inhibition of let-7f successfully protected RPE cells from the detrimental effects induced by SI. In addition, let-7f overexpression induced RPE cellular dysfunction by diminishing their migratory capabilities and reducing the phagocytosis of porcine photoreceptor outer segments (POS). Results were further confirmed in vivo by intravitreal injections of SI and let-7f antagomir in C57BL/6 mice. Our results provide strong evidence that let-7f is implicated in the dysfunction of RPE cells through the induction of senescence and oxidative injury. These findings may help to uncover novel and relevant processes in the pathogenesis of dry AMD. Full article

(This article belongs to the Special Issue Cellular Responses of Antioxidants Related to Degenerative Eye Disease Research)

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18 pages, 3494 KiB

Open AccessArticle

Glutathione and a Pool of Metabolites Partly Related to Oxidative Stress Are Associated with Low and High Myopia in an Altered Bioenergetic Environment

by Salvador Mérida, Amparo Návea, Carmen Desco, Bernardo Celda, Mercedes Pardo-Tendero, José Manuel Morales-Tatay and Francisco Bosch-Morell

Antioxidants 2024, 13(5), 539; https://doi.org/10.3390/antiox13050539 - 27 Apr 2024

Cited by 1 | Viewed by 1751

Abstract

Oxidative stress forms part of the molecular basis contributing to the development and manifestation of myopia, a refractive error with associated pathology that is increasingly prevalent worldwide and that subsequently leads to an upsurge in degenerative visual impairment due to conditions that are especially associated with high myopia. The purpose of our study was to examine the interrelation of potential oxidative-stress-related metabolites found in the aqueous humor of high-myopic, low-myopic, and non-myopic patients within a clinical study. We conducted a cross-sectional study, selecting two sets of patients undergoing cataract surgery. The first set, which was used to analyze metabolites through an NMR assay, comprised 116 patients. A total of 59 metabolites were assigned and quantified. The PLS-DA score plot clearly showed a separation with minimal overlap between the HM and control samples. The PLS-DA model allowed us to determine 31 major metabolite differences in the aqueous humor of the study groups. Complementary statistical analysis of the data allowed us to determine six metabolites that presented significant differences among the experimental groups (p < 005). A significant number of these metabolites were discovered to have a direct or indirect connection to oxidative stress linked with conditions of myopic eyes. Notably, we identified metabolites associated with bioenergetic pathways and metabolites that have undergone methylation, along with choline and its derivatives. The second set consisted of 73 patients who underwent a glutathione assay. Here, we showed significant variations in both reduced and oxidized glutathione in aqueous humor among all patient groups (p < 0.01) for the first time. Axial length, refractive status, and complete ophthalmologic examination were also recorded, and interrelations among metabolic and clinical parameters were evaluated. Full article

(This article belongs to the Special Issue Cellular Responses of Antioxidants Related to Degenerative Eye Disease Research)

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19 pages, 11203 KiB

Open AccessArticle

Lemon Peel Water Extract: A Novel Material for Retinal Health, Protecting Retinal Pigment Epithelial Cells against Dynamin-Related Protein 1-Mediated Mitochondrial Fission by Blocking ROS-Stimulated Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathway

by Shang-Chun Tsou, Chen-Ju Chuang, Inga Wang, Tzu-Chun Chen, Jui-Hsuan Yeh, Chin-Lin Hsu, Yu-Chien Hung, Ming-Chung Lee, Yuan-Yen Chang and Hui-Wen Lin

Antioxidants 2024, 13(5), 538; https://doi.org/10.3390/antiox13050538 - 27 Apr 2024

Viewed by 2067

Abstract

Previous studies showed that NaIO₃ can induce oxidative stress-mediated retinal pigment epithelium (RPE) damage to simulate age-related macular degeneration (AMD). Lemon peel is rich in antioxidants and components that can penetrate the blood–retinal barrier, but their role in retinal oxidative damage remains unexplored. Here, we explore the protection of lemon peel ultrasonic-assisted water extract (LUWE), containing large amounts of flavonoids and polyphenols, against NaIO₃-induced retinal degeneration. We initially demonstrated that LUWE, orally administered, prevented retinal distortion and thinning on the inner and outer nuclei layers, downregulating cleaved caspase-3 protein expression in RPE cells in NaIO₃-induced mice. The effect of LUWE was achieved through the suppression of apoptosis and the associated proteins, such as cleaved PARP and cleaved caspase-3, as suggested by NaIO₃-induced ARPE-19 cell models. This is because LUWE reduced reactive oxygen species-mediated mitochondrial fission via regulating p-Drp-1 and Fis1 expression. We further confirmed that LUWE suppresses the expression of p-MEK-1/2 and p-ERK-1/2 in NaIO₃-induced ARPE-19 cells, thereby providing the protection described above, which was confirmed using PD98059 and U0126. These results indicated that LUWE prevents mitochondrial oxidative stress-mediated RPE damage via the MEK/ERK pathway. Elucidation of the molecular mechanism may provide a new protective strategy against retinal degeneration. Full article

(This article belongs to the Special Issue Cellular Responses of Antioxidants Related to Degenerative Eye Disease Research)

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14 pages, 6180 KiB

Open AccessArticle

Buspirone Enhances Cell Survival and Preserves Structural Integrity during Oxidative Injury to the Retinal Pigment Epithelium

by Manas R. Biswal, Ryan J. Paulson, Riddhi Vichare and Alfred S. Lewin

Antioxidants 2023, 12(12), 2129; https://doi.org/10.3390/antiox12122129 - 17 Dec 2023

Cited by 2 | Viewed by 1891

Abstract

Chronic oxidative stress impairs the normal functioning of the retinal pigment epithelium (RPE), leading to atrophy of this cell layer in cases of advance age-related macular degeneration (AMD). The purpose of our study was to determine if buspirone, a partial serotonin 1A (5-HT1A) receptor agonist, protected against oxidative stress-induced changes in the RPE. We exposed differentiated human ARPE-19 cells to paraquat to induce oxidative damage in culture, and utilized a mouse model with sodium iodate (NaIO₃)-induced oxidative injury to evaluate the effect of buspirone. To investigate buspirone’s effect on protective gene expression, we performed RT–PCR. Cellular toxicities and junctional abnormalities due to paraquat induction in ARPE-19 cells and buspirone’s impact were assessed via WST-1 assays and ZO-1 immunostaining. We used spectral-domain optical coherence tomography (SD-OCT) and ZO-1 immunostaining of RPE/choroid for structural analysis. WST-1 assays showed dose-dependent protection of viability in buspirone-treated ARPE-19 cells in culture and preservation of RPE junctional integrity under oxidative stress conditions. In the NaIO₃ model, daily intraperitoneal injection (i.p.) of buspirone (30 mg/kg) for 12 days improved the survival of photoreceptors compared to those of vehicle-treated eyes. ZO-1-stained RPE flat-mounts revealed the structural preservation of RPE from oxidative damage in buspirone-treated mice, as well as in buspirone-induced Nqo1, Cat, Sqstm1, Gstm1, and Sod2 genes in the RPE/choroid compared to untreated eyes. Since oxidative stress is implicated in the pathogenesis AMD, repurposing buspirone, which is currently approved for the treatment of anxiety, might be useful in treating or preventing dry AMD. Full article

(This article belongs to the Special Issue Cellular Responses of Antioxidants Related to Degenerative Eye Disease Research)

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24 pages, 16456 KiB

Open AccessArticle

Intravitreal Injection of ZYAN1 Restored Autophagy and Alleviated Oxidative Stress in Degenerating Retina via the HIF-1α/BNIP3 Pathway

by Xiao-Na Hao, Na Zhao, Jie-Min Huang, Si-Yu Li, Dong Wei, Ning Pu, Guang-Hua Peng and Ye Tao

Antioxidants 2023, 12(11), 1914; https://doi.org/10.3390/antiox12111914 - 26 Oct 2023

Viewed by 1820

Abstract

Mitochondrial autophagy plays a contributary role in the pathogenesis of retina degeneration (RD). ZYAN1 is a novel proline hydroxylase domain (PHD) inhibitor that can enhance the expression of hypoxia-inducible factor 1-alpha (HIF-1α). This study investigated whether ZYAN1 could alleviate progressive photoreceptor loss and oxidative damage in a pharmacologically induced RD model via the modulation of mitophagy. ZYAN1 was injected into the vitreous body of the RD model, and the retinal autophagy level was analyzed. The therapeutic effects of ZYAN1 were evaluated via a function examination, a morphological assay, in situ reactive oxygen species (ROS) detection, and an immunofluorescence assay. It was shown that the thickness of the outer nuclear layer (ONL) increased significantly, and visual function was efficiently preserved via ZYAN1 treatment. The mitochondria structure of photoreceptors was more complete in the ZYAN1-treated mice, and the number of autophagosomes also increased significantly. Membrane disc shedding and ROS overproduction were alleviated after ZYAN1 treatment, and the axonal cilia were more structurally intact. A Western blot analysis showed that the expression levels of the autophagy-related proteins LC3-B, Beclin-1, and ATG5 increased significantly after ZYAN1 treatment, while the expression of P62 was down-regulated. Moreover, the expression levels of HIF-1α and BNIP3 were up-regulated after ZYAN1 treatment. Therefore, an intravitreal injection of ZYAN1 can act as part of the pharmacologic strategy to modulate mitophagy and alleviate oxidative stress in RD. These findings enrich our knowledge of RD pathology and provide insights for the discovery of a therapeutic molecule. Full article

(This article belongs to the Special Issue Cellular Responses of Antioxidants Related to Degenerative Eye Disease Research)

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14 pages, 1962 KiB

Open AccessArticle

β-Asarone Alleviates High-Glucose-Induced Oxidative Damage via Inhibition of ROS Generation and Inactivation of the NF-κB/NLRP3 Inflammasome Pathway in Human Retinal Pigment Epithelial Cells

by Cheol Park, Hee-Jae Cha, Hyun Hwangbo, EunJin Bang, Su Hyun Hong, Kyoung Seob Song, Jeong Sook Noh, Do-Hyung Kim, Gi-Young Kim and Yung Hyun Choi

Antioxidants 2023, 12(7), 1410; https://doi.org/10.3390/antiox12071410 - 11 Jul 2023

Cited by 4 | Viewed by 1964

Abstract

Diabetic retinopathy (DR) is the leading cause of vision loss and a major complication of diabetes. Hyperglycemia-induced accumulation of reactive oxygen species (ROS) is an important risk factor for DR. β-asarone, a major component of volatile oil extracted from Acori graminei Rhizoma, exerts antioxidant effects; however, its efficacy in DR remains unknown. In this study, we investigated whether β-asarone inhibits high-glucose (HG)-induced oxidative damage in human retinal pigment epithelial (RPE) ARPE-19 cells. We found that β-asarone significantly alleviated cytotoxicity, apoptosis, and DNA damage in HG-treated ARPE-19 cells via scavenging of ROS generation. β-Asarone also significantly attenuated the excessive accumulation of lactate dehydrogenase and mitochondrial ROS by increasing the manganese superoxide dismutase and glutathione activities. HG conditions markedly increased the release of interleukin (IL)-1β and IL-18 and upregulated their protein expression and activation of the nuclear factor-kappa B (NF-κB) signaling pathway, whereas β-asarone reversed these effects. Moreover, expression levels of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome multiprotein complex molecules, including thioredoxin-interacting protein, NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain, and cysteinyl aspartate-specific proteinase-1, were increased in ARPE-19 cells under HG conditions. However, their expression levels remained similar to those in the control group in the presence of β-asarone. Therefore, β-asarone protects RPE cells from HG-induced injury by blocking ROS generation and NF-κB/NLRP3 inflammasome activation, indicating its potential as a therapeutic agent for DR treatment. Full article

(This article belongs to the Special Issue Cellular Responses of Antioxidants Related to Degenerative Eye Disease Research)

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43 pages, 1443 KiB

Open AccessReview

Antioxidants and Mechanistic Insights for Managing Dry Age-Related Macular Degeneration

by Deepak Basyal, Sooyeun Lee and Hye Jin Kim

Antioxidants 2024, 13(5), 568; https://doi.org/10.3390/antiox13050568 - 4 May 2024

Viewed by 2959

Abstract

Age-related macular degeneration (AMD) severely affects central vision due to progressive macular degeneration and its staggering prevalence is rising globally, especially in the elderly population above 55 years. Increased oxidative stress with aging is considered an important contributor to AMD pathogenesis despite multifaceted risk factors including genetic predisposition and environmental agents. Wet AMD can be managed with routine intra-vitreal injection of angiogenesis inhibitors, but no satisfactory medicine has been approved for the successful management of the dry form. The toxic carbonyls due to photo-oxidative degradation of accumulated bisretinoids within lysosomes initiate a series of events including protein adduct formation, impaired autophagy flux, complement activation, and chronic inflammation, which is implicated in dry AMD. Therapy based on antioxidants has been extensively studied for its promising effect in reducing the impact of oxidative stress. This paper reviews the dry AMD pathogenesis, delineates the effectiveness of dietary and nutrition supplements in clinical studies, and explores pre-clinical studies of antioxidant molecules, extracts, and formulations with their mechanistic insights. Full article

(This article belongs to the Special Issue Cellular Responses of Antioxidants Related to Degenerative Eye Disease Research)

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