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Antioxidants
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Oxidative Stress in Diabetic Retinopathy
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Oxidative Stress in Diabetic Retinopathy

A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 68995

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Ángel Luis Ortega

E-Mail Website
Guest Editor
Department of Physiology, Faculty of Pharmacy, University of Valencia, Vicente Andrés Estellés Av. s/n, 46100 Burjassot, Spain
Interests: diabetic retinopathy; oxidative stress; inflammation; vascular dysfunction; natural antioxidants; exosomes; early biomarkers of diabetic retinopathy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetic retinopathy is an asymptomatic and progressive microvascular complication of diabetes. The increase in the prevalence of diabetic retinopathy acquires special importance, because it is the main cause of loss of vision of the active population and causes a high personal and social impact. Although diabetic retinopathy has a complex etiology, the oxidative stress induced by hyperglycemia is a key factor in retinal damage and diabetic retinopathy development. In fact, many in vitro and in vivo studies have shown the capacity of antioxidants to inhibit, delay or prevent the retinal oxidative damage induced by diabetes. In recent years, new therapeutic strategies have been developed to delay diabetic retinopathy progression in advanced stages; however, damage to retinal blood vessels and neuronal functions in early stages is irreversible. Therefore, a complete understanding of the developmental factors involved and new targets and therapies are needed to prevent or treat retinal damage induced by hyperglycemia.

We invite authors to contribute clinical trials, original research articles or reviews papers focused on the role of oxidative stress in the pathogenesis of diabetic retinopathy and the relationship with intercellular communication, systemic influence on the development of diabetic retinopathy, identification of molecular biomarkers for early diagnosis, exploration of new targets, and effective antioxidant and anti-inflammatory therapies.

Dr. Ángel Luis Ortega
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Diabetic retinopathy
  • Natural antioxidants
  • Polyphenols
  • Oxidative stress
  • Intercellular communication
  • Epigenetic mechanisms
  • Biomarkers

Published Papers (16 papers)

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Editorial

Jump to: Research, Review

3 pages, 180 KiB  
Editorial
Oxidative Stress in Diabetic Retinopathy
by Ángel L. Ortega
Antioxidants 2021, 10(1), 50; https://doi.org/10.3390/antiox10010050 - 4 Jan 2021
Cited by 9 | Viewed by 2265
Abstract
Diabetic Retinopathy (DR) is a progressive asymptomatic neuro-vascular complication of diabetes that triggers irreversible retinal damage [...] Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)

Research

Jump to: Editorial, Review

12 pages, 4092 KiB  
Article
Beneficial Effects of Glucagon-Like Peptide-1 (GLP-1) in Diabetes-Induced Retinal Abnormalities: Involvement of Oxidative Stress
by Hugo Ramos, Patricia Bogdanov, Joel Sampedro, Jordi Huerta, Rafael Simó and Cristina Hernández
Antioxidants 2020, 9(9), 846; https://doi.org/10.3390/antiox9090846 - 10 Sep 2020
Cited by 22 | Viewed by 3105
Abstract
Background: Hyperglycemia-induced oxidative stress plays a key role in diabetic complications, including diabetic retinopathy. The main goal of this study was to assess whether the topical administration (eye drops) of glucagon-like peptide-1 (GLP-1) has any effect on oxidative stress in the retina. Methods: [...] Read more.
Background: Hyperglycemia-induced oxidative stress plays a key role in diabetic complications, including diabetic retinopathy. The main goal of this study was to assess whether the topical administration (eye drops) of glucagon-like peptide-1 (GLP-1) has any effect on oxidative stress in the retina. Methods: db/db mice were treated with eye drops of GLP-1 or vehicle for three weeks, with db/+ mice being used as control. Studies included the assessment by western blot of the antioxidant defense markers CuZnSOD, MnSOD, glutathione peroxidase and reductase; immunofluorescence measurements of DNA/RNA damage, nitro tyrosine and Ki67 and Babam2 proteins. Results: GLP-1 eye drops protected from oxidative stress by increasing the protein levels of glutathione reductase, glutathione peroxidase and CuZnSOD and MnSOD in diabetic retinas. This was associated with a significant reduction of DNA/RNA damage and the activation of proteins involved in DNA repair in the retina (Babam2) and Ki67 (a biomarker of cell proliferation). Conclusions: GLP-1 modulates the antioxidant defense system in the diabetic retina and has a neuroprotective action favoring DNA repair and neuron cells proliferation. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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18 pages, 10520 KiB  
Article
Vitamin D Protects against Oxidative Stress and Inflammation in Human Retinal Cells
by Patricia Fernandez-Robredo, Jorge González-Zamora, Sergio Recalde, Valentina Bilbao-Malavé, Jaione Bezunartea, Maria Hernandez and Alfredo Garcia-Layana
Antioxidants 2020, 9(9), 838; https://doi.org/10.3390/antiox9090838 - 8 Sep 2020
Cited by 28 | Viewed by 4292
Abstract
Diabetic retinopathy is a vision-threatening microvascular complication of diabetes and is one of the leading causes of blindness. Oxidative stress and inflammation play a major role in its pathogenesis, and new therapies counteracting these contributors could be of great interest. In the current [...] Read more.
Diabetic retinopathy is a vision-threatening microvascular complication of diabetes and is one of the leading causes of blindness. Oxidative stress and inflammation play a major role in its pathogenesis, and new therapies counteracting these contributors could be of great interest. In the current study, we investigated the role of vitamin D against oxidative stress and inflammation in human retinal pigment epithelium (RPE) and human retinal endothelial cell lines. We demonstrate that vitamin D effectively counteracts the oxidative stress induced by hydrogen peroxide (H2O2). In addition, the increased levels of proinflammatory proteins such as Interleukin (IL)-6, IL-8, Monocyte chemoattractant protein (MCP)-1, Interferon (IFN)-γ, and tumor necrosis factor (TNF)-α triggered by lipopolysaccharide (LPS) exposure were significantly decreased by vitamin D addition. Interestingly, the increased IL-18 only decreased by vitamin D addition in endothelial cells but not in RPE cells, suggesting a main antiangiogenic role under inflammatory conditions. Moreover, H2O2 and LPS induced the alteration and morphological damage of tight junctions in adult retinal pigment epithelium (ARPE-19) cells that were restored under oxidative and inflammatory conditions by the addition of vitamin D to the media. In conclusion, our data suggest that vitamin D could protect the retina by enhancing antioxidant defense and through exhibiting anti-inflammatory properties. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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15 pages, 2826 KiB  
Article
Antioxidative Effects of Ascorbic Acid and Astaxanthin on ARPE-19 Cells in an Oxidative Stress Model
by Sanghyeon Oh, Young Joo Kim, Eun Kyoung Lee, Sung Wook Park and Hyeong Gon Yu
Antioxidants 2020, 9(9), 833; https://doi.org/10.3390/antiox9090833 - 6 Sep 2020
Cited by 28 | Viewed by 5970
Abstract
Oxidative stress has been implicated as critical pathogenic factors contributing to the etiology of diabetic retinopathy and other retinal diseases. This study investigated antioxidative effect of ascorbic acid and astaxanthin on ARPE-19 cells within an oxidative stress model induced by common biological sources [...] Read more.
Oxidative stress has been implicated as critical pathogenic factors contributing to the etiology of diabetic retinopathy and other retinal diseases. This study investigated antioxidative effect of ascorbic acid and astaxanthin on ARPE-19 cells within an oxidative stress model induced by common biological sources of reactive oxygen species (ROS). Hydrogen peroxide (H2O2) at concentrations of 0.1–0.8 mM and 20–100 mJ/cm2 of ultraviolet B (UVB) were treated to ARPE-19 cells. Cell viability and intracellular ROS level changes were measured. With the sublethal and lethal dose of each inducers, 0–750 μM of ascorbic acid and 0–40 μM of astaxanthin were treated to examine antioxidative effect on the model. Ascorbic acid at concentrations of 500 and 750 μM increased the cell viability not only in the UVB model but also in the H2O2 model, but 20 and 40 μM of astaxanthin only did so in the UVB model. The combination of ascorbic acid and astaxanthin showed better antioxidative effect compared to each drug alone, suggesting a synergistic effect. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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16 pages, 2808 KiB  
Article
A Higher Proportion of Eicosapentaenoic Acid (EPA) When Combined with Docosahexaenoic Acid (DHA) in Omega-3 Dietary Supplements Provides Higher Antioxidant Effects in Human Retinal Cells
by Manuel Saenz de Viteri, María Hernandez, Valentina Bilbao-Malavé, Patricia Fernandez-Robredo, Jorge González-Zamora, Laura Garcia-Garcia, Nahia Ispizua, Sergio Recalde and Alfredo Garcia-Layana
Antioxidants 2020, 9(9), 828; https://doi.org/10.3390/antiox9090828 - 4 Sep 2020
Cited by 25 | Viewed by 4229
Abstract
Retinal pigment epithelium (RPE) is a key regulator of retinal function and is directly related to the transport, delivery, and metabolism of long-chain n-3 polyunsaturated fatty acids (n3-PUFA), in the retina. Due to their functions and location, RPE cells are constantly exposed to [...] Read more.
Retinal pigment epithelium (RPE) is a key regulator of retinal function and is directly related to the transport, delivery, and metabolism of long-chain n-3 polyunsaturated fatty acids (n3-PUFA), in the retina. Due to their functions and location, RPE cells are constantly exposed to oxidative stress. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown to have antioxidant effects by different mechanisms. For this reason, we designed an in vitro study to compare 10 formulations of DHA and EPA supplements from different origins and combined in different proportions, evaluating their effect on cell viability, cell proliferation, reactive oxygen species production, and cell migration using ARPE-19 cells. Furthermore, we assessed their ability to rescue RPE cells from the oxidative conditions seen in diabetic retinopathy. Our results showed that the different formulations of n3-PUFAs have a beneficial effect on cell viability and proliferation and are able to restore oxidative induced RPE damage. We observed that the n3-PUFA provided different results alone or combined in the same supplement. When combined, the best results were obtained in formulations that included a higher proportion of EPA than DHA. Moreover, n3-PUFA in the form of ethyl-esters had a worse performance when compared with triglycerides or phospholipid based formulations. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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Graphical abstract

16 pages, 4382 KiB  
Article
Astaxanthin Protects Retinal Photoreceptor Cells against High Glucose-Induced Oxidative Stress by Induction of Antioxidant Enzymes via the PI3K/Akt/Nrf2 Pathway
by Tso-Ting Lai, Chung-May Yang and Chang-Hao Yang
Antioxidants 2020, 9(8), 729; https://doi.org/10.3390/antiox9080729 - 10 Aug 2020
Cited by 46 | Viewed by 4749
Abstract
Diabetic retinopathy (DR) is a major microvascular complication that can lead to severe visual impairment in patients with diabetes. The elevated oxidative stress and increased reactive oxygen species (ROS) production induced by hyperglycemia have been reported to play an important role in the [...] Read more.
Diabetic retinopathy (DR) is a major microvascular complication that can lead to severe visual impairment in patients with diabetes. The elevated oxidative stress and increased reactive oxygen species (ROS) production induced by hyperglycemia have been reported to play an important role in the complex pathogenesis of DR. Astaxanthin (AST), a natural carotenoid derivative, has been recently recognized as a strong free radical scavenger and might, therefore, be beneficial in different diseases, including DR. In this study, we evaluated the potential role of AST as an antioxidative and antiapoptotic agent in protecting retinal cells and also investigated the involvement of the PI3K/Akt/Nrf2 pathway in AST-mediated effects. We treated high glucose-cultured mouse photoreceptor cells (661W) with different concentrations of AST and analyzed ROS production and cell apoptosis in the different regimens. Moreover, we also analyzed the expression of PI3K, Akt, Nrf2, and Phase II enzymes after AST treatment. Our results showed that AST dose-dependently reduced ROS production and attenuated 661W cell apoptosis in a high glucose environment. Importantly, its protective effect was abolished by treatment with PI3K or Nrf2 inhibitors, indicating the involvement of the PI3K/Akt/Nrf2 pathway. These results suggest AST as a nutritional supplement that could benefit patients with DR. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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Graphical abstract

18 pages, 9728 KiB  
Article
Protective Effect of Fenofibrate on Oxidative Stress-Induced Apoptosis in Retinal–Choroidal Vascular Endothelial Cells: Implication for Diabetic Retinopathy Treatment
by Ying-Jung Hsu, Chao-Wen Lin, Sheng-Li Cho, Wei-Shiung Yang, Chung-May Yang and Chang-Hao Yang
Antioxidants 2020, 9(8), 712; https://doi.org/10.3390/antiox9080712 - 5 Aug 2020
Cited by 20 | Viewed by 3644
Abstract
Diabetic retinopathy (DR) is an important microvascular complication of diabetes and one of the leading causes of blindness in developed countries. Two large clinical studies showed that fenofibrate, a peroxisome proliferator-activated receptor type α (PPAR-α) agonist, reduces DR progression. We evaluated the protective [...] Read more.
Diabetic retinopathy (DR) is an important microvascular complication of diabetes and one of the leading causes of blindness in developed countries. Two large clinical studies showed that fenofibrate, a peroxisome proliferator-activated receptor type α (PPAR-α) agonist, reduces DR progression. We evaluated the protective effects of fenofibrate on retinal/choroidal vascular endothelial cells under oxidative stress and investigated the underlying mechanisms using RF/6A cells as the model system and paraquat (PQ) to induce oxidative stress. Pretreatment with fenofibrate suppressed reactive oxygen species (ROS) production, decreased cellular apoptosis, diminished the changes in the mitochondrial membrane potential, increased the mRNA levels of peroxiredoxin (Prx), thioredoxins (Trxs), B-cell lymphoma 2 (Bcl-2), and Bcl-xl, and reduced the level of B-cell lymphoma 2-associated X protein (Bax) in PQ-stimulated RF/6A cells. Western blot analysis revealed that fenofibrate repressed apoptosis through cytosolic and mitochondrial apoptosis signal-regulated kinase-1 (Ask)-Trx-related signaling pathways, including c-Jun amino-terminal kinase (JNK) phosphorylation, cytochrome c release, caspase 3 activation, and poly (ADP-ribose) polymerase-1 (PARP-1) cleavage. These protective effects of fenofibrate on RF/6A cells may be attributable to its anti-oxidative ability. Our research suggests that fenofibrate could serve as an effective adjunct therapy for ocular oxidative stress-related disorders, such as DR. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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Graphical abstract

15 pages, 4196 KiB  
Article
Molecular Assessment of Epiretinal Membrane: Activated Microglia, Oxidative Stress and Inflammation
by Sushma Vishwakarma, Rishikesh Kumar Gupta, Saumya Jakati, Mudit Tyagi, Rajeev Reddy Pappuru, Keith Reddig, Gregory Hendricks, Michael R. Volkert, Hemant Khanna, Jay Chhablani and Inderjeet Kaur
Antioxidants 2020, 9(8), 654; https://doi.org/10.3390/antiox9080654 - 23 Jul 2020
Cited by 14 | Viewed by 4255
Abstract
Fibrocellular membrane or epiretinal membrane (ERM) forms on the surface of the inner limiting membrane (ILM) in the inner retina and alters the structure and function of the retina. ERM formation is frequently observed in ocular inflammatory conditions, such as proliferative diabetic retinopathy [...] Read more.
Fibrocellular membrane or epiretinal membrane (ERM) forms on the surface of the inner limiting membrane (ILM) in the inner retina and alters the structure and function of the retina. ERM formation is frequently observed in ocular inflammatory conditions, such as proliferative diabetic retinopathy (PDR) and retinal detachment (RD). Although peeling of the ERM is used as a surgical intervention, it can inadvertently distort the retina. Our goal is to design alternative strategies to tackle ERMs. As a first step, we sought to determine the composition of the ERMs by identifying the constituent cell-types and gene expression signature in patient samples. Using ultrastructural microscopy and immunofluorescence analyses, we found activated microglia, astrocytes, and Müller glia in the ERMs from PDR and RD patients. Moreover, oxidative stress and inflammation associated gene expression was significantly higher in the RD and PDR membranes as compared to the macular hole samples, which are not associated with inflammation. We specifically detected differential expression of hypoxia inducible factor 1-α (HIF1-α), proinflammatory cytokines, and Notch, Wnt, and ERK signaling pathway-associated genes in the RD and PDR samples. Taken together, our results provide new information to potentially develop methods to tackle ERM formation. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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Graphical abstract

14 pages, 3571 KiB  
Article
The Herbal Combination CPA4-1 Inhibits Changes in Retinal Capillaries and Reduction of Retinal Occludin in db/db Mice
by Young Sook Kim, Junghyun Kim, Chan-Sik Kim, Ik Soo Lee, Kyuhyung Jo, Dong Ho Jung, Yun Mi Lee and Jin Sook Kim
Antioxidants 2020, 9(7), 627; https://doi.org/10.3390/antiox9070627 - 16 Jul 2020
Cited by 2 | Viewed by 2693
Abstract
Increased formation of advanced glycation end products (AGEs) plays an important role in the development of diabetic retinopathy (DR) via blood-retinal barrier (BRB) dysfunction, and reduction of AGEs has been suggested as a therapeutic target for DR. In this study, we examined whether [...] Read more.
Increased formation of advanced glycation end products (AGEs) plays an important role in the development of diabetic retinopathy (DR) via blood-retinal barrier (BRB) dysfunction, and reduction of AGEs has been suggested as a therapeutic target for DR. In this study, we examined whether CPA4-1, a herbal combination of Cinnamomi Ramulus and Paeoniae Radix, inhibits AGE formation. CPA4-1 and fenofibrate were tested to ameliorate changes in retinal capillaries and retinal occludin expression in db/db mice, a mouse model of obesity-induced type 2 diabetes. CPA4-1 (100 mg/kg) or fenofibrate (100 mg/kg) were orally administered once a day for 12 weeks. CPA4-1 (the half maximal inhibitory concentration, IC50 = 6.84 ± 0.08 μg/mL) showed approximately 11.44-fold higher inhibitory effect on AGE formation than that of aminoguanidine (AG, the inhibitor of AGEs, IC50 = 78.28 ± 4.24 μg/mL), as well as breaking effect on AGE-bovine serum albumin crosslinking with collagen (IC50 = 1.30 ± 0.37 μg/mL). CPA4-1 treatment ameliorated BRB leakage and tended to increase retinal occludin expression in db/db mice. CPA4-1 or fenofibrate treatment significantly reduced retinal acellular capillary formation in db/db mice. These findings suggested the potential of CPA4-1 as a therapeutic supplement for protection against retinal vascular permeability diseases. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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19 pages, 4391 KiB  
Article
Inhibition of HDAC6 Attenuates Diabetes-Induced Retinal Redox Imbalance and Microangiopathy
by Hossameldin Abouhish, Menaka C. Thounaojam, Ravirajsinh N. Jadeja, Diana R. Gutsaeva, Folami L. Powell, Mohamed Khriza, Pamela M. Martin and Manuela Bartoli
Antioxidants 2020, 9(7), 599; https://doi.org/10.3390/antiox9070599 - 9 Jul 2020
Cited by 19 | Viewed by 3516
Abstract
We investigated the contributing role of the histone deacetylase 6 (HDAC6) to the early stages of diabetic retinopathy (DR). Furthermore, we examined the mechanism of action of HDAC6 in human retinal endothelial cells (HuREC) exposed to glucidic stress. Streptozotocin-induced diabetic rats (STZ-rats), a [...] Read more.
We investigated the contributing role of the histone deacetylase 6 (HDAC6) to the early stages of diabetic retinopathy (DR). Furthermore, we examined the mechanism of action of HDAC6 in human retinal endothelial cells (HuREC) exposed to glucidic stress. Streptozotocin-induced diabetic rats (STZ-rats), a rat model of type 1 diabetes, were used as model of DR. HDAC6 expression and activity were increased in human diabetic postmortem donors and STZ-rat retinas and were augmented in HuREC exposed to glucidic stress (25 mM glucose). Administration of the HDAC6 specific inhibitor Tubastatin A (TS) (10 mg/kg) prevented retinal microvascular hyperpermeability and up-regulation of inflammatory markers. Furthermore, in STZ-rats, TS decreased the levels of senescence markers and rescued the expression and activity of the histone deacetylase sirtuin 1 (SIRT1), while downregulating the levels of free radicals and of the redox stress markers 4-hydroxynonenal (4-HNE) and nitrotyrosine (NT). The antioxidant effects of TS, consequent to HDAC6 inhibition, were associated with preservation of Nrf2-dependent gene expression and up-regulation of thioredoxin-1 activity. In vitro data, obtained from HuREC, exposed to glucidic stress, largely replicated the in vivo results further confirming the antioxidant effects of HDAC6 inhibition by TS in the diabetic rat retina. In summary, our data implicate HDAC6 activation in mediating hyperglycemia-induced retinal oxidative/nitrative stress leading to retinal microangiopathy and, potentially, DR. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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Review

Jump to: Editorial, Research

25 pages, 1957 KiB  
Review
Glyoxalase System as a Therapeutic Target against Diabetic Retinopathy
by Gemma Aragonès, Sheldon Rowan, Sarah G Francisco, Wenxin Yang, Jasper Weinberg, Allen Taylor and Eloy Bejarano
Antioxidants 2020, 9(11), 1062; https://doi.org/10.3390/antiox9111062 - 30 Oct 2020
Cited by 23 | Viewed by 4118
Abstract
Hyperglycemia, a defining characteristic of diabetes, combined with oxidative stress, results in the formation of advanced glycation end products (AGEs). AGEs are toxic compounds that have adverse effects on many tissues including the retina and lens. AGEs promote the formation of reactive oxygen [...] Read more.
Hyperglycemia, a defining characteristic of diabetes, combined with oxidative stress, results in the formation of advanced glycation end products (AGEs). AGEs are toxic compounds that have adverse effects on many tissues including the retina and lens. AGEs promote the formation of reactive oxygen species (ROS), which, in turn, boost the production of AGEs, resulting in positive feedback loops, a vicious cycle that compromises tissue fitness. Oxidative stress and the accumulation of AGEs are etiologically associated with the pathogenesis of multiple diseases including diabetic retinopathy (DR). DR is a devastating microvascular complication of diabetes mellitus and the leading cause of blindness in working-age adults. The onset and development of DR is multifactorial. Lowering AGEs accumulation may represent a potential therapeutic approach to slow this sight-threatening diabetic complication. To set DR in a physiological context, in this review we first describe relations between oxidative stress, formation of AGEs, and aging in several tissues of the eye, each of which is associated with a major age-related eye pathology. We summarize mechanisms of AGEs generation and anti-AGEs detoxifying systems. We specifically feature the potential of the glyoxalase system in the retina in the prevention of AGEs-associated damage linked to DR. We provide a comparative analysis of glyoxalase activity in different tissues from wild-type mice, supporting a major role for the glyoxalase system in the detoxification of AGEs in the retina, and present the manipulation of this system as a therapeutic strategy to prevent the onset of DR. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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29 pages, 2372 KiB  
Review
Diabetic Retinopathy: The Role of Mitochondria in the Neural Retina and Microvascular Disease
by David J. Miller, M. Ariel Cascio and Mariana G. Rosca
Antioxidants 2020, 9(10), 905; https://doi.org/10.3390/antiox9100905 - 23 Sep 2020
Cited by 40 | Viewed by 4654
Abstract
Diabetic retinopathy (DR), a common chronic complication of diabetes mellitus and the leading cause of vision loss in the working-age population, is clinically defined as a microvascular disease that involves damage of the retinal capillaries with secondary visual impairment. While its clinical diagnosis [...] Read more.
Diabetic retinopathy (DR), a common chronic complication of diabetes mellitus and the leading cause of vision loss in the working-age population, is clinically defined as a microvascular disease that involves damage of the retinal capillaries with secondary visual impairment. While its clinical diagnosis is based on vascular pathology, DR is associated with early abnormalities in the electroretinogram, indicating alterations of the neural retina and impaired visual signaling. The pathogenesis of DR is complex and likely involves the simultaneous dysregulation of multiple metabolic and signaling pathways through the retinal neurovascular unit. There is evidence that microvascular disease in DR is caused in part by altered energetic metabolism in the neural retina and specifically from signals originating in the photoreceptors. In this review, we discuss the main pathogenic mechanisms that link alterations in neural retina bioenergetics with vascular regression in DR. We focus specifically on the recent developments related to alterations in mitochondrial metabolism including energetic substrate selection, mitochondrial function, oxidation-reduction (redox) imbalance, and oxidative stress, and critically discuss the mechanisms of these changes and their consequences on retinal function. We also acknowledge implications for emerging therapeutic approaches and future research directions to find novel mitochondria-targeted therapeutic strategies to correct bioenergetics in diabetes. We conclude that retinal bioenergetics is affected in the early stages of diabetes with consequences beyond changes in ATP content, and that maintaining mitochondrial integrity may alleviate retinal disease. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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36 pages, 1715 KiB  
Review
Importance of the Use of Oxidative Stress Biomarkers and Inflammatory Profile in Aqueous and Vitreous Humor in Diabetic Retinopathy
by Ana Karen López-Contreras, María Guadalupe Martínez-Ruiz, Cecilia Olvera-Montaño, Ricardo Raúl Robles-Rivera, Diana Esperanza Arévalo-Simental, José Alberto Castellanos-González, Abel Hernández-Chávez, Selene Guadalupe Huerta-Olvera, Ernesto German Cardona-Muñoz and Adolfo Daniel Rodríguez-Carrizalez
Antioxidants 2020, 9(9), 891; https://doi.org/10.3390/antiox9090891 - 20 Sep 2020
Cited by 28 | Viewed by 7832
Abstract
Diabetic retinopathy is one of the leading causes of visual impairment and morbidity worldwide, being the number one cause of blindness in people between 27 and 75 years old. It is estimated that ~191 million people will be diagnosed with this microvascular complication [...] Read more.
Diabetic retinopathy is one of the leading causes of visual impairment and morbidity worldwide, being the number one cause of blindness in people between 27 and 75 years old. It is estimated that ~191 million people will be diagnosed with this microvascular complication by 2030. Its pathogenesis is due to alterations in the retinal microvasculature as a result of a high concentration of glucose in the blood for a long time which generates numerous molecular changes like oxidative stress. Therefore, this narrative review aims to approach various biomarkers associated with the development of diabetic retinopathy. Focusing on the molecules showing promise as detection tools, among them we consider markers of oxidative stress (TAC, LPO, MDA, 4-HNE, SOD, GPx, and catalase), inflammation (IL-6, IL-1ß, IL-8, IL-10, IL-17A, TNF-α, and MMPs), apoptosis (NF-kB, cyt-c, and caspases), and recently those that have to do with epigenetic modifications, their measurement in different biological matrices obtained from the eye, including importance, obtaining process, handling, and storage of these matrices in order to have the ability to detect the disease in its early stages. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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26 pages, 1447 KiB  
Review
Extracellular Vesicles and MicroRNA: Putative Role in Diagnosis and Treatment of Diabetic Retinopathy
by Beatriz Martins, Madania Amorim, Flávio Reis, António Francisco Ambrósio and Rosa Fernandes
Antioxidants 2020, 9(8), 705; https://doi.org/10.3390/antiox9080705 - 4 Aug 2020
Cited by 20 | Viewed by 4670
Abstract
Diabetic retinopathy (DR) is a complex, progressive, and heterogenous retinal degenerative disease associated with diabetes duration. It is characterized by glial, neural, and microvascular dysfunction, being the blood-retinal barrier (BRB) breakdown a hallmark of the early stages. In advanced stages, there is formation [...] Read more.
Diabetic retinopathy (DR) is a complex, progressive, and heterogenous retinal degenerative disease associated with diabetes duration. It is characterized by glial, neural, and microvascular dysfunction, being the blood-retinal barrier (BRB) breakdown a hallmark of the early stages. In advanced stages, there is formation of new blood vessels, which are fragile and prone to leaking. This disease, if left untreated, may result in severe vision loss and eventually legal blindness. Although there are some available treatment options for DR, most of them are targeted to the advanced stages of the disease, have some adverse effects, and many patients do not adequately respond to the treatment, which demands further research. Oxidative stress and low-grade inflammation are closely associated processes that play a critical role in the development of DR. Retinal cells communicate with each other or with another one, using cell junctions, adhesion contacts, and secreted soluble factors that can act in neighboring or long-distance cells. Another mechanism of cell communication is via secreted extracellular vesicles (EVs), through exchange of material. Here, we review the current knowledge on deregulation of cell-to-cell communication through EVs, discussing the changes in miRNA expression profiling in body fluids and their role in the development of DR. Thereafter, current and promising therapeutic agents for preventing the progression of DR will be discussed. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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22 pages, 6935 KiB  
Review
The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies
by Marcella Nebbioso, Alessandro Lambiase, Marta Armentano, Giosuè Tucciarone, Vincenza Bonfiglio, Rocco Plateroti and Ludovico Alisi
Antioxidants 2020, 9(8), 666; https://doi.org/10.3390/antiox9080666 - 26 Jul 2020
Cited by 16 | Viewed by 3632
Abstract
High-mobility group box 1 (HMGB1) is a protein that is part of a larger family of non-histone nuclear proteins. HMGB1 is a ubiquitary protein with different isoforms, linked to numerous physiological and pathological pathways. HMGB1 is involved in cytokine and chemokine release, leukocyte [...] Read more.
High-mobility group box 1 (HMGB1) is a protein that is part of a larger family of non-histone nuclear proteins. HMGB1 is a ubiquitary protein with different isoforms, linked to numerous physiological and pathological pathways. HMGB1 is involved in cytokine and chemokine release, leukocyte activation and migration, tumorigenesis, neoangiogenesis, and the activation of several inflammatory pathways. HMGB1 is, in fact, responsible for the trigger, among others, of nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), toll-like receptor-4 (TLR-4), and vascular endothelial growth factor (VEGF) pathways. Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM) that is rapidly growing in number. DR is an inflammatory disease caused by hyperglycemia, which determines the accumulation of oxidative stress and cell damage, which ultimately leads to hypoxia and neovascularization. Recent evidence has shown that hyperglycemia is responsible for the hyperexpression of HMGB1. This protein activates numerous pathways that cause the development of DR, and HMGB1 levels are constantly increased in diabetic retinas in both proliferative and non-proliferative stages of the disease. Several molecules, such as glycyrrhizin (GA), have proven effective in reducing diabetic damage to the retina through the inhibition of HMGB1. The main focus of this review is the growing amount of evidence linking HMGB1 and DR as well as the new therapeutic strategies involving this protein. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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20 pages, 1686 KiB  
Review
Eicosanoids and Oxidative Stress in Diabetic Retinopathy
by Mong-Heng Wang, George Hsiao and Mohamed Al-Shabrawey
Antioxidants 2020, 9(6), 520; https://doi.org/10.3390/antiox9060520 - 12 Jun 2020
Cited by 37 | Viewed by 4257
Abstract
Oxidative stress is an important factor to cause the pathogenesis of diabetic retinopathy (DR) because the retina has high vascularization and long-time light exposition. Cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes can convert arachidonic acid (AA) into eicosanoids, which are important [...] Read more.
Oxidative stress is an important factor to cause the pathogenesis of diabetic retinopathy (DR) because the retina has high vascularization and long-time light exposition. Cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes can convert arachidonic acid (AA) into eicosanoids, which are important lipid mediators to regulate DR development. COX-derived metabolites appear to be significant factors causative to oxidative stress and retinal microvascular dysfunction. Several elegant studies have unraveled the importance of LOX-derived eicosanoids, including LTs and HETEs, to oxidative stress and retinal microvascular dysfunction. The role of CYP eicosanoids in DR is yet to be explored. There is clear evidence that CYP-derived epoxyeicosatrienoic acids (EETs) have detrimental effects on the retina. Our recent study showed that the renin-angiotensin system (RAS) activation augments retinal soluble epoxide hydrolase (sEH), a crucial enzyme degrading EETs. Our findings suggest that EETs blockade can enhance the ability of RAS blockade to prevent or mitigate microvascular damage in DR. This review will focus on the critical information related the function of these eicosanoids in the retina, the interaction between eicosanoids and reactive oxygen species (ROS), and the involvement of eicosanoids in DR. We also identify potential targets for the treatment of DR. Full article
(This article belongs to the Special Issue Oxidative Stress in Diabetic Retinopathy)
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