Antioxidants

Research

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14 pages, 3158 KiB

Open AccessArticle

The Prolyl Oligopeptidase Inhibitor KYP-2047 Is Cytoprotective and Anti-Inflammatory in Human Retinal Pigment Epithelial Cells with Defective Proteasomal Clearance

by Maija Toppila, Maria Hytti, Eveliina Korhonen, Sofia Ranta-aho, Niina Harju, Markus M. Forsberg, Kai Kaarniranta, Aaro Jalkanen and Anu Kauppinen

Antioxidants 2023, 12(6), 1279; https://doi.org/10.3390/antiox12061279 - 15 Jun 2023

Cited by 1 | Viewed by 1509

Abstract

Increased oxidative stress, dysfunctional cellular clearance, and chronic inflammation are associated with age-related macular degeneration (AMD). Prolyl oligopeptidase (PREP) is a serine protease that has numerous cellular functions, including the regulation of oxidative stress, protein aggregation, and inflammation. PREP inhibition by KYP-2047 (4-phenylbutanoyl-L-prolyl1(S)-cyanopyrrolidine) [...] Read more.

Increased oxidative stress, dysfunctional cellular clearance, and chronic inflammation are associated with age-related macular degeneration (AMD). Prolyl oligopeptidase (PREP) is a serine protease that has numerous cellular functions, including the regulation of oxidative stress, protein aggregation, and inflammation. PREP inhibition by KYP-2047 (4-phenylbutanoyl-L-prolyl1(S)-cyanopyrrolidine) has been associated with clearance of cellular protein aggregates and reduced oxidative stress and inflammation. Here, we studied the effects of KYP-2047 on inflammation, oxidative stress, cell viability, and autophagy in human retinal pigment epithelium (RPE) cells with reduced proteasomal clearance. MG-132-mediated proteasomal inhibition in ARPE-19 cells was used to model declined proteasomal clearance in the RPEs of AMD patients. Cell viability was assessed using LDH and MTT assays. The amounts of reactive oxygen species (ROS) were measured using 2′,7′-dichlorofluorescin diacetate (H2DCFDA). ELISA was used to determine the levels of cytokines and activated mitogen-activated protein kinases. The autophagy markers p62/SQSTM1 and LC3 were measured with the western blot method. MG-132 induced LDH leakage and increased ROS production in the ARPE-19 cells, and KYP-2047 reduced MG-132-induced LDH leakage. Production of the proinflammatory cytokine IL-6 was concurrently alleviated by KYP-2047 when compared with cells treated only with MG-132. KYP-2047 had no effect on autophagy in the RPE cells, but the phosphorylation levels of p38 and ERK1/2 were elevated upon KYP-2047 exposure, and the inhibition of p38 prevented the anti-inflammatory actions of KYP-2047. KYP-2047 showed cytoprotective and anti-inflammatory effects on RPE cells suffering from MG-132-induced proteasomal inhibition. Full article

(This article belongs to the Special Issue Retinal Diseases Associated with Oxidative Stress: Advances in Pathophysiology and Therapeutic Approaches)

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27 pages, 5314 KiB

Open AccessArticle

Mammalian Animal and Human Retinal Organ Culture as Pre-Clinical Model to Evaluate Oxidative Stress and Antioxidant Intraocular Therapeutics

by Martina Kropp, Mohit Mohit, Cristina Ioana Leroy-Ciocanea, Laura Schwerm, Nina Harmening, Thais Bascuas, Eline De Clerck, Andreas J. Kreis, Bojan Pajic, Sandra Johnen and Gabriele Thumann

Antioxidants 2023, 12(6), 1211; https://doi.org/10.3390/antiox12061211 - 03 Jun 2023

Viewed by 1569

Abstract

Oxidative stress (OS) is involved in the pathogenesis of retinal neurodegenerative diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) and an important target of therapeutic treatments. New therapeutics are tested in vivo despite limits in terms of transferability and ethical [...] Read more.

Oxidative stress (OS) is involved in the pathogenesis of retinal neurodegenerative diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) and an important target of therapeutic treatments. New therapeutics are tested in vivo despite limits in terms of transferability and ethical concerns. Retina cultures using human tissue can deliver critical information and significantly reduce the number of animal experiments along with increased transferability. We cultured up to 32 retina samples derived from one eye, analyzed the model’s quality, induced OS, and tested the efficiency of antioxidative therapeutics. Bovine, porcine, rat, and human retinae were cultured in different experimental settings for 3–14 d. OS was induced by a high amount of glucose or hydrogen peroxide (H₂O₂) and treated with scutellarin, pigment epithelium-derived factor (PEDF), and/or granulocyte macrophage colony-stimulating factor (GM-CSF). The tissue morphology, cell viability, inflammation, and glutathione level were determined. The retina samples showed only moderate necrosis (23.83 ± 5.05 increased to 27.00 ± 1.66 AU PI-staining over 14 d) after 14 days in culture. OS was successfully induced (reduced ATP content of 288.3 ± 59.9 vs. 435.7 ± 166.8 nM ATP in the controls) and the antioxidants reduced OS-induced apoptosis (from 124.20 ± 51.09 to 60.80 ± 319.66 cells/image after the scutellarin treatment). Enhanced mammalian animal and human retina cultures enable reliable, highly transferable research on OS-triggered age-related diseases and pre-clinical testing during drug development. Full article

(This article belongs to the Special Issue Retinal Diseases Associated with Oxidative Stress: Advances in Pathophysiology and Therapeutic Approaches)

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14 pages, 2757 KiB

Open AccessArticle

Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE Pathway

by Sarah Naguib, Carlisle R. DeJulius, Jon R. Backstrom, Ameer A. Haider, John M. Ang, Andrew M. Boal, David J. Calkins, Craig L. Duvall and Tonia S. Rex

Antioxidants 2023, 12(3), 556; https://doi.org/10.3390/antiox12030556 - 23 Feb 2023

Cited by 4 | Viewed by 1668

Abstract

Erythropoietin (EPO) is neuroprotective in multiple models of neurodegenerative diseases, including glaucoma. EPO-R76E retains the neuroprotective effects of EPO but diminishes the effects on hematocrit. Treatment with EPO-R76E in a glaucoma model increases expression of antioxidant proteins and is neuroprotective. A major pathway [...] Read more.

Erythropoietin (EPO) is neuroprotective in multiple models of neurodegenerative diseases, including glaucoma. EPO-R76E retains the neuroprotective effects of EPO but diminishes the effects on hematocrit. Treatment with EPO-R76E in a glaucoma model increases expression of antioxidant proteins and is neuroprotective. A major pathway that controls the expression of antioxidant proteins is the NRF2/ARE pathway. This pathway is activated endogenously after elevation of intraocular pressure (IOP) and contributes to the slow onset of pathology in glaucoma. In this study, we explored if sustained release of EPO-R76E in the eye would activate the NRF2/ARE pathway and if this pathway was key to its neuroprotective activity. Treatment with PLGA.EPO-E76E prevented increases in retinal superoxide levels in vivo, and caused phosphorylation of NRF2 and upregulation of antioxidants. Further, EPO-R76E activates NRF2 via phosphorylation by the MAPK pathway rather than the PI3K/Akt pathway, used by the endogenous antioxidant response to elevated IOP. Full article

(This article belongs to the Special Issue Retinal Diseases Associated with Oxidative Stress: Advances in Pathophysiology and Therapeutic Approaches)

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31 pages, 4543 KiB

Open AccessArticle

An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice

by Lorena Olivares-González, Sheyla Velasco, Idoia Gallego, Marina Esteban-Medina, Gustavo Puras, Carlos Loucera, Alicia Martínez-Romero, María Peña-Chilet, José Luis Pedraz and Regina Rodrigo

Antioxidants 2023, 12(1), 98; https://doi.org/10.3390/antiox12010098 - 30 Dec 2022

Cited by 7 | Viewed by 2437

Abstract

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), [...] Read more.

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in rd10 mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in rd10 mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement. Full article

(This article belongs to the Special Issue Retinal Diseases Associated with Oxidative Stress: Advances in Pathophysiology and Therapeutic Approaches)

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15 pages, 5628 KiB

Open AccessArticle

Palmitic Acid Induced a Long-Lasting Lipotoxic Insult in Human Retinal Pigment Epithelial Cells, which Is Partially Counteracted by TRAIL

by Domenico Sergi, Enrico Zauli, Fabio Casciano, Paola Secchiero, Giorgio Zauli, Matteo Fields and Elisabetta Melloni

Antioxidants 2022, 11(12), 2340; https://doi.org/10.3390/antiox11122340 - 26 Nov 2022

Cited by 1 | Viewed by 1724

Abstract

Hyperglycaemia and increased circulating saturated fatty acids are key metabolic features of type 2 diabetes mellitus (T2DM) that contribute to diabetic retinopathy pathogenesis. Contrarily, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to improve or prevent T2DM. This study aimed at [...] Read more.

Hyperglycaemia and increased circulating saturated fatty acids are key metabolic features of type 2 diabetes mellitus (T2DM) that contribute to diabetic retinopathy pathogenesis. Contrarily, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to improve or prevent T2DM. This study aimed at investigating the effect of TRAIL in an in vitro model of human retinal pigment epithelium: the ARPE-19 cell line, treated with palmitic acid (PA) in the presence of high glucose concentration. PA caused a drop in cellular metabolic activity and cell viability as well as an increase in apoptosis rates, which were paralleled by an upregulation of reactive oxygen species (ROS) generation as well as mitochondrial fragmentation. Despite ARPE-19 cells expressing TRAIL-R2 at the cell surface, TRAIL failed to counteract the cytotoxic effects of PA. However, when TRAIL was used alongside PA and then removed or used alone following PA challenge, it partially attenuated PA-induced lipotoxicity. This effect of TRAIL appeared to rely upon the modulation of inflammation and ROS production. Thus, TRAIL exerted a trophic effect on ARPE-19 cells, which became evident only when the lipotoxic insult was removed. Nevertheless, whether recombinant TRAIL might have a therapeutic potential for the treatment of diabetic retinopathy requires further investigation. Full article

(This article belongs to the Special Issue Retinal Diseases Associated with Oxidative Stress: Advances in Pathophysiology and Therapeutic Approaches)

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Graphical abstract

27 pages, 8663 KiB

Open AccessArticle

Time-Course Changes in Oxidative Stress and Inflammation in the Retinas of rds Mice: A Retinitis Pigmentosa Model

by Antolín Cantó, Javier Martínez-González, Inmaculada Almansa, Rosa López-Pedrajas, Vicente Hernández-Rabaza, Teresa Olivar and María Miranda

Antioxidants 2022, 11(10), 1950; https://doi.org/10.3390/antiox11101950 - 29 Sep 2022

Cited by 2 | Viewed by 1917

Abstract

(1) Background: Retinitis pigmentosa (RP) is characterized by progressive photoreceptor death. A Prph2Rd2 or an rds mouse is an RP model that closely reflects human RP. The objective of this study was to investigate the relationship of rod and cone death with oxidative [...] Read more.

(1) Background: Retinitis pigmentosa (RP) is characterized by progressive photoreceptor death. A Prph2Rd2 or an rds mouse is an RP model that closely reflects human RP. The objective of this study was to investigate the relationship of rod and cone death with oxidative stress and inflammation in rds mice. (2) Methods: The retinas of control and rds mice on postnatal days (PN) 11, 17, 21, 28, 35, and 42 were used. Oxidative damage to macromolecules, glutathione (GSH and GSSG), GSH synthesis enzymes, glial fibrillar acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba1), and cluster of differentiation 68 (CD68) was studied. (3) Results: The time sequence of oxidative stress and inflammation changes in rds mice occurs as follows: (i) At PN11, there is a small increase in photoreceptor death and in the microglial cells; (ii) at PN17, damage to the macromolecules is observed; (iii) at PN21, the maximum photoreceptor death rate is detected and there is an increase in GSH-GSSG and GFAP; (iv) at PN21, the microglial cells are activated; and(v) at PN28, there is a decrease in GSH synthesis enzymes. (4) Conclusions: These findings contribute to the understanding of RP physiopathology and help us to understand whether oxidative stress and inflammation are therapeutic targets. These findings contribute to our understanding that, in RP, oxidative stress and inflammation evolution and their relationship are time-dependent. In this sense, it is important to highlight that both processes are potential therapeutic targets in this disease. Full article

(This article belongs to the Special Issue Retinal Diseases Associated with Oxidative Stress: Advances in Pathophysiology and Therapeutic Approaches)

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12 pages, 614 KiB

Open AccessArticle

Fingertip-Measured Skin Carotenoids and Advanced Glycation End Product Levels in Glaucoma

by Yoichi Kadoh, Yuji Takayanagi, Junichi Sasaki and Masaki Tanito

Antioxidants 2022, 11(6), 1138; https://doi.org/10.3390/antiox11061138 - 09 Jun 2022

Cited by 3 | Viewed by 1811

Abstract

Carotenoids have antioxidant properties, and the accumulation of advanced glycation end products (AGEs) is associated with reactive oxygen species production; they have attracted attention as factors predictive of the onset and progression in glaucoma. Fingertip measurement is applicable for carotenoids and AGEs due [...] Read more.

Carotenoids have antioxidant properties, and the accumulation of advanced glycation end products (AGEs) is associated with reactive oxygen species production; they have attracted attention as factors predictive of the onset and progression in glaucoma. Fingertip measurement is applicable for carotenoids and AGEs due to its noninvasiveness and simplicity. The study included 663 eyes of 663 Japanese subjects (357 males, 306 females). The mean age was 69.9 years with a standard deviation of 11.0. The study population comprised participants with primary open-angle glaucoma (PG) (n = 358), exfoliation glaucoma (EG) (n = 168), and controls (n = 137). Multivariate models suggested that lower skin carotenoid (SC) levels were associated with male gender (standard β = −0.14), AGE scores (−0.24), and a history of intraocular surgery (−0.22). Higher SC levels were associated with higher vegetable intake scores (0.21 for score 3) and diabetes (0.10). However, no association was seen between SCs and glaucoma type. AGEs levels were negatively associated with carotenoid scores (−0.25), PG (−0.15), and smoking habits (−0.26) and positively correlated with EG (0.14). SCs and AGEs were negatively correlated in the single regression analysis (r = −0.20, p < 0.0001). In conclusion, higher levels of AGEs may be candidates for systemic biomarkers of glaucoma associated with the exfoliation syndrome. SC levels can reflect self-reported daily vegetable intake. Full article

(This article belongs to the Special Issue Retinal Diseases Associated with Oxidative Stress: Advances in Pathophysiology and Therapeutic Approaches)

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Review

Jump to: Research

21 pages, 1709 KiB

Open AccessReview

Aldehyde Dehydrogenase and Aldo-Keto Reductase Enzymes: Basic Concepts and Emerging Roles in Diabetic Retinopathy

by Burak Mugdat Karan, Karis Little, Josy Augustine, Alan W. Stitt and Tim M. Curtis

Antioxidants 2023, 12(7), 1466; https://doi.org/10.3390/antiox12071466 - 21 Jul 2023

Viewed by 1986

Abstract

Diabetic retinopathy (DR) is a complication of diabetes mellitus that can lead to vision loss and blindness. It is driven by various biochemical processes and molecular mechanisms, including lipid peroxidation and disrupted aldehyde metabolism, which contributes to retinal tissue damage and the progression [...] Read more.

Diabetic retinopathy (DR) is a complication of diabetes mellitus that can lead to vision loss and blindness. It is driven by various biochemical processes and molecular mechanisms, including lipid peroxidation and disrupted aldehyde metabolism, which contributes to retinal tissue damage and the progression of the disease. The elimination and processing of aldehydes in the retina rely on the crucial role played by aldehyde dehydrogenase (ALDH) and aldo-keto reductase (AKR) enzymes. This review article investigates the impact of oxidative stress, lipid-derived aldehydes, and advanced lipoxidation end products (ALEs) on the advancement of DR. It also provides an overview of the ALDH and AKR enzymes expressed in the retina, emphasizing their growing importance in DR. Understanding the relationship between aldehyde metabolism and DR could guide innovative therapeutic strategies to protect the retina and preserve vision in diabetic patients. This review, therefore, also explores various approaches, such as gene therapy and pharmacological compounds that have the potential to augment the expression and activity of ALDH and AKR enzymes, underscoring their potential as effective treatment options for DR. Full article

(This article belongs to the Special Issue Retinal Diseases Associated with Oxidative Stress: Advances in Pathophysiology and Therapeutic Approaches)

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29 pages, 1899 KiB

Open AccessReview

Antioxidative Role of Heterophagy, Autophagy, and Mitophagy in the Retina and Their Association with the Age-Related Macular Degeneration (AMD) Etiopathogenesis

by Małgorzata Nita and Andrzej Grzybowski

Antioxidants 2023, 12(7), 1368; https://doi.org/10.3390/antiox12071368 - 29 Jun 2023

Cited by 2 | Viewed by 2099

Abstract

Age-related macular degeneration (AMD), an oxidative stress-linked neurodegenerative disease, leads to irreversible damage of the central retina and severe visual impairment. Advanced age and the long-standing influence of oxidative stress and oxidative cellular damage play crucial roles in AMD etiopathogenesis. Many authors emphasize [...] Read more.

Age-related macular degeneration (AMD), an oxidative stress-linked neurodegenerative disease, leads to irreversible damage of the central retina and severe visual impairment. Advanced age and the long-standing influence of oxidative stress and oxidative cellular damage play crucial roles in AMD etiopathogenesis. Many authors emphasize the role of heterophagy, autophagy, and mitophagy in maintaining homeostasis in the retina. Relevantly modifying the activity of both macroautophagy and mitophagy pathways represents one of the new therapeutic strategies in AMD. Our review provides an overview of the antioxidative roles of heterophagy, autophagy, and mitophagy and presents associations between dysregulations of these molecular mechanisms and AMD etiopathogenesis. The authors performed an extensive analysis of the literature, employing PubMed and Google Scholar, complying with the 2013–2023 period, and using the following keywords: age-related macular degeneration, RPE cells, reactive oxygen species, oxidative stress, heterophagy, autophagy, and mitophagy. Heterophagy, autophagy, and mitophagy play antioxidative roles in the retina; however, they become sluggish and dysregulated with age and contribute to AMD development and progression. In the retina, antioxidative roles also play in RPE cells, NFE2L2 and PGC-1α proteins, NFE2L2/PGC-1α/ARE signaling cascade, Nrf2 factor, p62/SQSTM1/Keap1-Nrf2/ARE pathway, circulating miRNAs, and Yttrium oxide nanoparticles performed experimentally in animal studies. Full article

(This article belongs to the Special Issue Retinal Diseases Associated with Oxidative Stress: Advances in Pathophysiology and Therapeutic Approaches)

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21 pages, 792 KiB

Open AccessReview

Research Progress on Mitochondrial Dysfunction in Diabetic Retinopathy

by Yiwei Wu and Haidong Zou

Antioxidants 2022, 11(11), 2250; https://doi.org/10.3390/antiox11112250 - 15 Nov 2022

Cited by 7 | Viewed by 2281

Abstract

Diabetic Retinopathy (DR) is one of the most important microvascular complications of diabetes mellitus, which can lead to blindness in severe cases. Mitochondria are energy-producing organelles in eukaryotic cells, which participate in metabolism and signal transduction, and regulate cell growth, differentiation, aging, and [...] Read more.

Diabetic Retinopathy (DR) is one of the most important microvascular complications of diabetes mellitus, which can lead to blindness in severe cases. Mitochondria are energy-producing organelles in eukaryotic cells, which participate in metabolism and signal transduction, and regulate cell growth, differentiation, aging, and death. Metabolic changes of retinal cells and epigenetic changes of mitochondria-related genes under high glucose can lead to mitochondrial dysfunction and induce mitochondrial pathway apoptosis. In addition, mitophagy and mitochondrial dynamics also change adaptively. These mechanisms may be related to the occurrence and progression of DR, and also provide valuable clues for the prevention and treatment of DR. This article reviews the mechanism of DR induced by mitochondrial dysfunction, and the prospects for related treatment. Full article

(This article belongs to the Special Issue Retinal Diseases Associated with Oxidative Stress: Advances in Pathophysiology and Therapeutic Approaches)

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