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Qi X, Guo H, Xia X, Liu Y, Qiu S, Lin T, He W, Jin L, Cheng J, Hao L, Liu W, Hu H. Paeoniflorin alleviated STZ-induced diabetic retinopathy via regulation of the PDI/ADAM17/MerTK pathway. Int Immunopharmacol 2025; 155:114571. [PMID: 40209310 DOI: 10.1016/j.intimp.2025.114571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/11/2025] [Accepted: 03/26/2025] [Indexed: 04/12/2025]
Abstract
BACKGROUND Diabetic retinopathy (DR) is a severe microvascular complication of diabetes and a leading cause of vision impairment in diabetic patients. The accumulation of apoptotic cells and inflammation are key pathological mechanisms in DR. The Mer tyrosine kinase (MerTK) receptor plays a critical role in maintaining retinal homeostasis. Proteolytic cleavage of MerTK by disintegrin and metalloproteinase-17 (ADAM17) disrupts MerTK-dependent clearance of apoptotic cells and diminishes its anti-inflammatory effects. Therefore, reducing the cleavage activity ADAM17's and promoting MerTK-dependent anti-inflammatory effects may represent potent strategy to alleviate DR. METHODS The DR mouse model was established using streptozotocin (STZ), and a high-glucose (HG)-induced in vitro model was developed using human retinal pigment epithelial (ARPE-19) cells. Relevant signaling molecules were analyzed through western blotting and immunohistochemistry. RESULTS Hyperglycemia promoted the accumulation of apoptotic cells and disrupted retinal microvascular growth. In both vivo and vitro model, MerTK expression was significantly reduced, while ADAM17 phosphorylation levels were markedly increased. In STZ-treated mice, protein disulfide isomerase (PDI) secretion initially rose but subsequently declined, whereas PDI secretion decreased under HG conditions. We then utilized paeoniflorin to increase the expression of this endogenous inhibitor of ADAM17. Results showed that paeoniflorin upregulated PDI production, suppressed ADAM17 expression, and enhanced MerTK phosphorylation in the eye tissues of STZ-induced mice. Additionally, paeoniflorin elevated the expression of suppressor of cytokine signaling 3 (SOCS3) and decreased the level of matrix metalloproteinase 9 (MMP9) both in vivo and in vitro. CONCLUSION Paeoniflorin may alleviate diabetic retinopathy by suppressing inflammation through modulation of the PDI/ADAM17/MerTK signaling pathway.
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Affiliation(s)
- Xiuting Qi
- Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211100, China
| | - Haiyue Guo
- Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211100, China
| | - Xinyue Xia
- The First Clinical College, Nanjing Medical University, Nanjing 211166, China
| | - Yanmei Liu
- The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Jiangsu 224005, China
| | - Shenghui Qiu
- Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211100, China
| | - Tongtong Lin
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligence Manufacture, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Wenqi He
- Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211100, China
| | - Lai Jin
- Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211100, China
| | - Jing Cheng
- Department of Gastroenterology, Lianyungang Municipal Oriental Hospital, Lianyungang, Jiangsu, China; Department of Gastroenterology,Shanghai General Hospial of Nanjing Medical University, Shanghai, China
| | - Lanxiang Hao
- The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Jiangsu 224005, China.
| | - Wentao Liu
- Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211100, China.
| | - Haitao Hu
- The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Jiangsu 224005, China.
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Mu J, Zhang Z, Jiang C, Geng H, Duan J. Role of Tau Protein Hyperphosphorylation in Diabetic Retinal Neurodegeneration. J Ophthalmol 2025; 2025:3278794. [PMID: 40109357 PMCID: PMC11922625 DOI: 10.1155/joph/3278794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 12/25/2024] [Accepted: 02/22/2025] [Indexed: 03/22/2025] Open
Abstract
Diabetic retinal neurodegeneration (DRN) is an early manifestation of diabetic retinopathy (DR) characterized by neurodegeneration that precedes microvascular abnormalities in the retina. DRN is characterized by apoptosis of retinal ganglion cells (involves alterations in retinal ganglion cells [RGCs], photoreceptors, amacrine cells and bipolar cells and so on), reactive gliosis, and reduced retinal neuronal function. Tau, a microtubule-associated protein, is a key mediator of neurotoxicity in neurodegenerative diseases, with functions in phosphorylation-dependent microtubule assembly and stabilization, axonal transport, and neurite outgrowth. The hyperphosphorylated tau (p-tau) loses its ability to bind to microtubules and aggregates to form paired helical filaments (PHFs), which further form neurofibrillary tangles (NFTs), leading to abnormal cell scaffolding and cell death. Studies have shown that p-tau can cause degeneration of RGCs in DR, making tau pathology a new pathophysiological model for DR. Here, we review the mechanisms by which p-tau contribute to DRN, including insulin resistance or lack of insulin, mitochondrial damage such as mitophagy impairment, mitochondrial axonal transport defects, mitochondrial bioenergetics dysfunction, and impaired mitochondrial dynamics, Abeta toxicity, and inflammation. Therefore, this article proposes that tau protein hyperphosphorylation plays a crucial role in the pathogenesis of DRN and may serve as a novel therapeutic target for combating DRN.
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Affiliation(s)
- Jingyu Mu
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Zengrui Zhang
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Chao Jiang
- College of Life and Health Sciences, Institute of Neuroscience, Northeastern University, Shenyang, China
| | - Haoming Geng
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Junguo Duan
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
- Ineye Hospital of Chengdu University of TCM, Chengdu, Sichuan, China
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Albertos-Arranz H, Martínez-Gil N, Sánchez-Sáez X, Molina-Martín JC, Lax P, Cuenca N. Neuronal Degeneration and Glial Activation in the Absence of Vascular Changes in Human Retinas of Patients With Diabetes. Invest Ophthalmol Vis Sci 2025; 66:53. [PMID: 40131295 PMCID: PMC11951059 DOI: 10.1167/iovs.66.3.53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 03/02/2025] [Indexed: 03/26/2025] Open
Abstract
Purpose This study assessed retinal cells in the macula of human donors with diabetes with or without retinopathy. Methods Seventeen human donor retinas were classified as diabetes mellitus (DM, n = 7), diabetes with diabetic retinopathy (DR, n = 3), or control (n = 8). Macular transversal sections were analyzed for photoreceptors, bipolar cells, horizontal cells, ganglion cells, their synaptic connections, and Müller cells using immunohistochemistry and confocal microscopy. The densities of bipolar cells, horizontal cells, and ganglion cells and the thickness of the inner plexiform layer (IPL) were quantified around the fovea. Results In the macula, cone photoreceptors elongated their axons to establish synapses with bipolar and horizontal cells in intraretinal cysts. Bipolar cells were reduced in the DM group compared to the control (P < 0.001), and rod bipolar cells showed morphological alterations in the cell body and synaptic terminals in both diabetic groups. Morphological changes were observed in both plexiform layers, with a decrease in the IPL thickness in DR. Horizontal cell terminals sprouted into the outer and inner retina in DR, despite no density differences existing between DM and control (P = 0.498). Ganglion cell density was reduced in the DM retinas compared to control (P < 0.001). Müller cells exhibited thickening of their cell bodies and end feet in all diabetic retinas. Conclusions The degeneration of neurons and synaptic connectivity within the macula in individuals with DM, even in the absence of clinical vascular signs, is associated with impaired visual function. These early changes suggest potential new biomarkers for imaging techniques and emphasize the need for therapies for diabetic patients without clinical signs.
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Affiliation(s)
- Henar Albertos-Arranz
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Natalia Martínez-Gil
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Xavier Sánchez-Sáez
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | | | - Pedro Lax
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Nicolas Cuenca
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
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Balas M, Issa M, Popovic MM, Zajner C, Moayad L, Aponte PO, Hamli H, Yan P, Wright T, Melo IM, Muni RH. Correlation Between Photoreceptor and Vascular Parameters in Diabetic Retinopathy Using Adaptive Optics. Ophthalmic Surg Lasers Imaging Retina 2025; 56:150-158. [PMID: 39535418 DOI: 10.3928/23258160-20241015-03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
BACKGROUND AND OBJECTIVE This study aimed to investigate correlations between photoreceptor and vascular parameters in varying stages of diabetic retinopathy (DR) using adaptive optics (AO) imaging. PATIENTS AND METHODS In this single-center, prospective cohort study, 29 participants (46 eyes) were classified into control/mild non-proliferative DR (NPDR), moderate/severe NPDR, and proliferative DR. AO images of photoreceptors and retinal vasculature were analyzed, and Spearman's correlation (ρ) was used to assess relationships between photoreceptor density and vascular parameters. RESULTS Higher cone density was inversely associated with total vessel (ρ = 0.22, P = 0.03) and lumen diameters (ρ = -0.24, P = 0.01), while higher dispersion was associated with total vessel (ρ = 0.19, P = 0.06) and lumen diameters (ρ = 0.21, P = 0.04). These associations were primarily significant in mild NPDR. No significant correlations were found in advanced DR stages. CONCLUSION This study underscores intricate neurovascular correlations in early-stage DR, suggesting these parameters may aid in early disease detection. Further research is needed to understand whether similar correlations exist in advanced DR. [Ophthalmic Surg Lasers Imaging Retina 2025;56:150-158.].
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Canz MJ, Baguña-Torres J, Huerta J, Isla-Magrané H, Zufiaurre-Seijo M, Salas A, Hernandez C, Simó R, García-Arumí J, Herance JR, Bogdanov P, Duarri A. Diabetic retinopathy features in lund MetS rats. Exp Eye Res 2025; 252:110274. [PMID: 39923911 DOI: 10.1016/j.exer.2025.110274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 01/22/2025] [Accepted: 02/05/2025] [Indexed: 02/11/2025]
Abstract
The Lund MetS rat (BBDR.cg-Leprdb/db.cp/LundRj) is a novel animal model that has a congenic leptin receptor deficiency (LepR-/-) and males exhibit a variety of metabolic abnormalities mimicking the human metabolic syndrome, including hyperglycemia, dyslipidemia, severe obesity, and a type 2 diabetes-like condition from 14 weeks of age. However, whether Lund MetS rats (LM rats) develop diabetic retinopathy is still unknown. The purpose is to investigate the features of diabetic retinopathy in this model. In this study, male LM rats aged 15 and 30 weeks were analyzed for pathological retinal changes, including vasculopathy, inflammation, reactive gliosis, oxidative stress, and neurodegeneration features on the retinas by histological, immunohistochemical, and gene and protein expression analysis. Compared with the non-diabetic LM rats, diabetic LM rats, mainly at 30 weeks of age, had a decrease in retinal thickness and loss of retinal ganglion cells and photoreceptors, indicating retinal neurodegeneration. They also presented an increase in VEGF-A expression, Endra, Icam-1, Vcam-1, and Endrb vascular genes, and albumin suggesting neurovascular unit dysfunction. Furthermore, retinas presented reactive gliosis and infiltration of microglia, TNF-α-positive vessels and expressed elevated levels of inflammatory genes Tnf-α, IL-18 and IL-6, and oxidative stress markers Sod2 and 8-hydroxy-2-deoxyguanosine (8-OHdG). Our results suggest that diabetic LM rats reproduce the early neurodegenerative and altered neuro-vascular features that also occur in the human diabetic eye.
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Affiliation(s)
- María José Canz
- Ophthalmology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain
| | - Julia Baguña-Torres
- Medical Molecular Imaging Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain
| | - Jordi Huerta
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, 08035, Barcelona, Spain
| | - Helena Isla-Magrané
- Ophthalmology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain
| | | | - Anna Salas
- Ophthalmology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain
| | - Cristina Hernandez
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, 08035, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBER-DEM), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, 08035, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBER-DEM), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - José García-Arumí
- Ophthalmology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain; Departments of Medicine and Ophthalmology, Universitat Autonoma de Barcelona, Bellaterra, 08193, Spain
| | - Jose Raul Herance
- Medical Molecular Imaging Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain; CIBER-BBN (ISCIII), Instituto de Salud Carlos III (ISCIII), 28040, Madrid, Spain
| | - Patricia Bogdanov
- Medical Molecular Imaging Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBER-DEM), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.
| | - Anna Duarri
- Ophthalmology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain.
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Chang MC, Lin DPC, Chang HH. Hepatic Satellite Cell Activation and Alteration of Vitamin A Status Are Relevant to the Aggravation of Retinopathy by T2DM. Invest Ophthalmol Vis Sci 2025; 66:7. [PMID: 39903179 PMCID: PMC11801389 DOI: 10.1167/iovs.66.2.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 12/28/2024] [Indexed: 02/06/2025] Open
Abstract
Purpose Type 2 diabetes mellitus (T2DM) leads to diabetic retinopathy (DR) and hepatic impairments. The potential mutual interaction and the intermediator between these two injuries are not well elucidated. Both the retina and liver are involved in vitamin A metabolism, suggesting a potential involvement of vitamin A and its metabolites in this mutual interaction. This study aimed to elucidate the impact of either DR or hepatic impairment on the pathogenesis and vitamin A status of each during injury progression. Methods A streptozotocin (STZ)-high-fat diet (HFD)-induced T2DM rodent model was applied to examine via electroretinography (ERG) retinal and hepatic histopathology at 0, 12, 16, 20, 24, 28, and 30 weeks after T2DM induction. The levels of retinol in the retina, liver, serum, all-trans-retinal in the retina, and retinyl palmitate in the liver were measured at various time points after T2DM induction. Results Retinal dysfunction, evidenced by reduced ERG responses, appeared at week 12, followed by photoreceptor and ganglion cell damage after the 16th week. Hepatic impairments began with hepatic stellate cell activation and decreased retinyl palmitate storage, concurrent with reduced retinal retinol and increased all-trans-retinal. Serum retinol levels remained stable, but reductions in transthyretin (TTR) and retinol-binding protein 4 (RBP4) were found, likely disrupting vitamin A transport in the serum. Conclusions These results provide novel insights into hepatic injury and vitamin A status, implicating both in the aggravation of retinopathy under the influence of T2DM. The current results may raise clinical awareness on hepatic issues and vitamin A involvement during DR progression.
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Affiliation(s)
- Min-Chun Chang
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan
| | - David Pei-Cheng Lin
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Department of Ophthalmology, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Han-Hsin Chang
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan
- Department of Ophthalmology, Chung Shan Medical University Hospital, Taichung, Taiwan
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Yang S, Xin Z, Cheng W, Zhong P, Liu R, Zhu Z, Zhu LZ, Shang X, Chen S, Huang W, Zhang L, Wang W. Photoreceptor metabolic window unveils eye-body interactions. Nat Commun 2025; 16:697. [PMID: 39814712 PMCID: PMC11736035 DOI: 10.1038/s41467-024-55035-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 11/26/2024] [Indexed: 01/18/2025] Open
Abstract
Photoreceptors are specialized neurons at the core of the retina's functionality, with optical accessibility and exceptional sensitivity to systemic metabolic stresses. Here we show the ability of risk-free, in vivo photoreceptor assessment as a window into systemic health and identify shared metabolic underpinnings of photoreceptor degeneration and multisystem health outcomes. A thinner photoreceptor layer thickness is significantly associated with an increased risk of future mortality and 13 multisystem diseases, while systematic analyses of circulating metabolomics enable the identification of 109 photoreceptor-related metabolites, which in turn elevate or reduce the risk of these health outcomes. To translate these insights into a practical tool, we developed an artificial intelligence (AI)-driven photoreceptor metabolic window framework and an accompanying interpreter that comprehensively captures the metabolic landscape of photoreceptor-systemic health linkages and simultaneously predicts 16 multisystem health outcomes beyond established approaches while retaining interpretability. Our work, replicated across cohorts of diverse ethnicities, reveals the potential of photoreceptors to inform systemic health and advance a multisystem perspective on human health by revealing eye-body connections and shared metabolic influences.
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Affiliation(s)
- Shaopeng Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Study Center for Ocular Diseases, Guangzhou, China
| | - Zhuoyao Xin
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Weijing Cheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Study Center for Ocular Diseases, Guangzhou, China
| | - Pingting Zhong
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Study Center for Ocular Diseases, Guangzhou, China
| | - Riqian Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Study Center for Ocular Diseases, Guangzhou, China
| | - Ziyu Zhu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Study Center for Ocular Diseases, Guangzhou, China
| | - Lisa Zhuoting Zhu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, VIC, Australia
| | - Xianwen Shang
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, VIC, Australia
| | - Shida Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Study Center for Ocular Diseases, Guangzhou, China
| | - Wenyong Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Study Center for Ocular Diseases, Guangzhou, China
| | - Lei Zhang
- Clinical Medical Research Center, Children's Hospital of Nanjing Medical University, Nanjing, China
- Artificial Intelligence and Modelling in Epidemiology Program, Melbourne Sexual Health Centre, Alfred Health, Melbourne, Australia
- Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Wei Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Study Center for Ocular Diseases, Guangzhou, China.
- Hainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Haikou, Hainan Province, China.
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Morya AK, Ramesh PV, Nishant P, Kaur K, Gurnani B, Heda A, Salodia S. Diabetic retinopathy: A review on its pathophysiology and novel treatment modalities. World J Methodol 2024; 14:95881. [PMID: 39712561 PMCID: PMC11287547 DOI: 10.5662/wjm.v14.i4.95881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 05/28/2024] [Accepted: 07/10/2024] [Indexed: 07/26/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic non-communicable disease with the ability to cause serious microvascular and macrovascular complications throughout the body, including in the eye. Diabetic retinopathy (DR), present in one-third of patients with diabetes, is a vision-threatening complication caused by uncontrolled diabetes, which greatly affects the retinal blood vessels and the light-sensitive inner retina, eventually leading to blindness. Several epidemiological studies elucidate that DR can vary by age of onset, duration, types of diabetes, and ethnicity. Recent studies show that the pathogenesis of diabetic retinopathy has spread its roots beyond merely being the result of hyperglycemia. The complexity of its etiopathology and diagnosis makes therapeutic intervention challenging. This review throws light on the pathological processes behind DR, the cascade of events that follow it, as well as the available and emerging treatment options.
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Affiliation(s)
- Arvind Kumar Morya
- Head of the Department, Department of Ophthalmology, All India Institute of Medical Sciences, Hyderabad 508126, Telangana, India
| | - Prasanna Venkatesh Ramesh
- Glaucoma Medical Officer, Department of Glaucoma and Research, Mahathma Eye Hospital Private Limited, Trichy 620017, Tamil Nadu, India
| | - Prateek Nishant
- Department of Ophthalmology, ESIC Medical College, Patna 801103, Bihar, India
| | - Kirandeep Kaur
- Department of Pediatric Ophthalmology and Strabismus, Gomabai Netralaya and Research Centre, Neemuch 458441, Madhya Pradesh, India
| | - Bharat Gurnani
- Cornea and Refractive Services, Gomabai Netralaya and Research Centre, Neemuch 458441, Madhya Pradesh, India
| | - Aarti Heda
- Department of Ophthalmology, National Institute of Ophthalmology, Pune 411000, Maharashtra, India
| | - Sarika Salodia
- Global Medical Safety, Lundbeck, Singapore 569933, Singapore, Singapore
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Fradot V, Augustin S, Fontaine V, Marazova K, Guillonneau X, Sahel JA, Picaud S. Rodent Models of Retinal Degeneration: From Purified Cells in Culture to Living Animals. Cold Spring Harb Perspect Med 2024; 14:a041311. [PMID: 37848250 PMCID: PMC11444255 DOI: 10.1101/cshperspect.a041311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023]
Abstract
Rodent models of retinal degeneration are essential for the development of therapeutic strategies. In addition to living animal models, we here also discuss models based on rodent cell cultures, such as purified retinal ganglion cells and retinal explants. These ex vivo models extend the possibilities for investigating pathological mechanisms and assessing the neuroprotective effect of pharmacological agents by eliminating questions on drug pharmacokinetics and bioavailability. The number of living rodent models has greatly increased with the possibilities to achieve transgenic modifications in animals for knocking in and out genes and mutations. The Cre-lox system has further enabled investigators to target specific genes or mutations in specific cells at specific stages. However, chemically or physically induced models can provide alternatives to such targeted gene modifications. The increased diversity of rodent models has widened our possibility to address most ocular pathologies for providing initial proof of concept of innovative therapeutic strategies.
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Affiliation(s)
- Valérie Fradot
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris F-75012, France
| | - Sébastien Augustin
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris F-75012, France
| | - Valérie Fontaine
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris F-75012, France
| | - Katia Marazova
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris F-75012, France
| | - Xavier Guillonneau
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris F-75012, France
| | - José A Sahel
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris F-75012, France
- Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
| | - Serge Picaud
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris F-75012, France
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10
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Gholami M, Coleman-Fuller N, Salehirad M, Darbeheshti S, Motaghinejad M. Neuroprotective Effects of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors (Gliflozins) on Diabetes-Induced Neurodegeneration and Neurotoxicity: A Graphical Review. Int J Prev Med 2024; 15:28. [PMID: 39239308 PMCID: PMC11376549 DOI: 10.4103/ijpvm.ijpvm_5_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 02/20/2024] [Indexed: 09/07/2024] Open
Abstract
Diabetes is a chronic endocrine disorder that negatively affects various body systems, including the nervous system. Diabetes can cause or exacerbate various neurological disorders, and diabetes-induced neurodegeneration can involve several mechanisms such as mitochondrial dysfunction, activation of oxidative stress, neuronal inflammation, and cell death. In recent years, the management of diabetes-induced neurodegeneration has relied on several types of drugs, including sodium-glucose cotransporter-2 (SGLT2) inhibitors, also called gliflozins. In addition to exerting powerful effects in reducing blood glucose, gliflozins have strong anti-neuro-inflammatory characteristics that function by inhibiting oxidative stress and cell death in the nervous system in diabetic subjects. This review presents the molecular pathways involved in diabetes-induced neurodegeneration and evaluates the clinical and laboratory studies investigating the neuroprotective effects of gliflozins against diabetes-induced neurodegeneration, with discussion about the contributing roles of diverse molecular pathways, such as mitochondrial dysfunction, oxidative stress, neuro-inflammation, and cell death. Several databases-including Web of Science, Scopus, PubMed, Google Scholar, and various publishers, such as Springer, Wiley, and Elsevier-were searched for keywords regarding the neuroprotective effects of gliflozins against diabetes-triggered neurodegenerative events. Additionally, anti-neuro-inflammatory, anti-oxidative stress, and anti-cell death keywords were applied to evaluate potential neuronal protection mechanisms of gliflozins in diabetes subjects. The search period considered valid peer-reviewed studies published from January 2000 to July 2023. The current body of literature suggests that gliflozins can exert neuroprotective effects against diabetes-induced neurodegenerative events and neuronal dysfunction, and these effects are mediated via activation of mitochondrial function and prevention of cell death processes, oxidative stress, and inflammation in neurons affected by diabetes. Gliflozins can confer neuroprotective properties in diabetes-triggered neurodegeneration, and these effects are mediated by inhibiting oxidative stress, inflammation, and cell death.
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Affiliation(s)
- Mina Gholami
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Natalie Coleman-Fuller
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, USA
| | - Mahsa Salehirad
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sepideh Darbeheshti
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Motaghinejad
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
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11
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Lin Y, Du W, Fu X, Huang L, Hong Y, Tan H, Xiao L, Ren X, Wang Y, Chen D. Hyperglycemia-independent neonatal streptozotocin-induced retinopathy (NSIR) in rats. Front Pharmacol 2024; 15:1395887. [PMID: 39108749 PMCID: PMC11300211 DOI: 10.3389/fphar.2024.1395887] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 07/01/2024] [Indexed: 03/17/2025] Open
Abstract
Introduction: Chemicals, such as MNU (N-methyl-N-nitrosourea) and NaIO3 (sodium iodate), are widely used to induce retinal degeneration in rodents. Streptozotocin (STZ) is an analog of N-acetyl glucosamine in which an MNU moiety is linked to a hexose and has a special toxic effect on insulin-producing pancreatic β-cells. It is commonly used to induce hyperglycemia to model diabetes. While intracerebroventricular injection of STZ can produce Alzheimer's disease independent of hyperglycemia, most retinal studies using STZ focus on the effects of hyperglycemia on the retina, but whether STZ has any impact on retinal cells independent of hyperglycemia is unknown. We aimed to investigate the role of cytotoxicity of STZ in rat retina. Methods: Intravitreal or subcutaneous injection of STZ was performed on newborn rats. Electroretinogram (ERG) and H&E staining investigated retinal function and morphological changes. Retinal cell types, cell death, proliferation, inflammation, and angiogenesis were studied by immunostaining. RNA sequencing was performed to examine the transcriptome changes of retinal cells after intravitreal injection of STZ. Results: Intravitreal (5 μg or 10 μg) or subcutaneous (30 mg/kg) injection of STZ at the early stage of newborn rats couldn't induce hyperglycemia but caused NSIR (Neonatal STZ-induced retinopathy), including reduced ERG amplitudes, retinal rosettes and apoptosis, cell cycle arrest, microglial activation, and delayed retinal angiogenesis. STZ did not affect the early-born retinal cell types but significantly reduced the late-born ones. Short-term and long-term hyperglycemia had no significant effects on the NSIR phenotypes. RNA sequencing revealed that STZ induces oxidative stress and activates the p53 pathway of retinal cells. Locally or systemically, STZ injection after P8 couldn't induce SINR when all retinal progenitors exit the cell cycle. Conclusion: NSIR in rats is independent of hyperglycemia but due to STZ's direct cytotoxic effects on retinal progenitor cells. NSIR is a typical reaction to STZ-induced retinal oxidative stress and DNA damage. This significant finding suggests that NSIR may be a valuable model for studying retinal progenitor DNA damage-related diseases, potentially leading to new insights and treatments.
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Affiliation(s)
- Yu Lin
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wenyu Du
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangyu Fu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ling Huang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yiwen Hong
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Haishan Tan
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lirong Xiao
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Ren
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yujiao Wang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Danian Chen
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Li J, Zhao T, Sun Y. Interleukin-17A in diabetic retinopathy: The crosstalk of inflammation and angiogenesis. Biochem Pharmacol 2024; 225:116311. [PMID: 38788958 DOI: 10.1016/j.bcp.2024.116311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 05/19/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
Diabetic retinopathy (DR) is a severe ocular complication of diabetes which can leads to irreversible vision loss in its late-stage. Chronic inflammation results from long-term hyperglycemia contributes to the pathogenesis and progression of DR. In recent years, the interleukin-17 (IL-17) family have attracted the interest of researchers. IL-17A is the most widely explored cytokine in IL-17 family, involved in various acute and chronic inflammatory diseases. Growing body of evidence indicate the role of IL-17A in the pathogenesis of DR. However, the pro-inflammatory and pro-angiogenic effect of IL-17A in DR have not hitherto been reviewed. Gaining an understanding of the pro-inflammatory role of IL-17A, and how IL-17A control/impact angiogenesis pathways in the eye will deepen our understanding of how IL-17A contributes to DR pathogenesis. Herein, we aimed to thoroughly review the pro-inflammatory role of IL-17A in DR, with focus in how IL-17A impact inflammation and angiogenesis crosstalk.
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Affiliation(s)
- Jiani Li
- Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Tantai Zhao
- Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Yun Sun
- Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China.
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Li N, Gao S, Gao S, Wang Y, Huang H, Wang J, Shen X. Knockdown of thioredoxin interacting protein in Müller cells attenuates photoreceptor apoptosis in streptozotocin-induced diabetic mouse model. Int J Biol Macromol 2024; 271:132731. [PMID: 38815945 DOI: 10.1016/j.ijbiomac.2024.132731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 04/28/2024] [Accepted: 05/16/2024] [Indexed: 06/01/2024]
Abstract
We explored the effect of inhibition of thioredoxin interacting protein (Txnip) on neuroprotection in Müller cells under high glucose. Wild-type (WT) and Txnip knockout (Txnip-/-) mice were used to establish a streptozotocin (STZ)-induced diabetes model and a Müller cells high glucose model. We detected BDNF expression and PI3K/AKT/CREB pathway activation levels in the retina and Müller cells of each group in vivo and in vitro experiments. The Txnip-/- STZ group showed higher expression of BDNF and phosphorylation of PI3K/AKT/CREB in retina, and less retinal photoreceptor apoptosis was observed in Txnip-/- diabetic group than in WT. After using an inhibitor of PI3K signaling pathway, BDNF expression was reduced; In vitro co-cultured with Müller cells in different groups, 661 W cells showed different situations, Txnip-/- Müller cells maximum downregulated Cleaved-caspase 3 expression in 661 W, accompanied by an increase in Bcl-2/Bax ratio. These findings indicate that inhibiting endogenous Txnip in mouse Müller cells can promote their expression and secretion of BDNF, thereby reducing HG induced photoreceptor apoptosis and having important neuroprotective effects on DR. The regulation of BDNF expression by Txnip may be achieved by activating the PI3K/AKT/CREB pathway. This study suggests that regulating Txnip may be a potential target for DR treatment.
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Affiliation(s)
- Na Li
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Shuang Gao
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Sha Gao
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yanuo Wang
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hanwen Huang
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jing Wang
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Xi Shen
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China.
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Hein M, Qambari H, An D, Balaratnasingam C. Current understanding of subclinical diabetic retinopathy informed by histology and high-resolution in vivo imaging. Clin Exp Ophthalmol 2024; 52:464-484. [PMID: 38363022 DOI: 10.1111/ceo.14363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/21/2024] [Accepted: 01/26/2024] [Indexed: 02/17/2024]
Abstract
The escalating incidence of diabetes mellitus has amplified the global impact of diabetic retinopathy. There are known structural and functional changes in the diabetic retina that precede the fundus photography abnormalities which currently are used to diagnose clinical diabetic retinopathy. Understanding these subclinical alterations is important for effective disease management. Histology and high-resolution clinical imaging reveal that the entire neurovascular unit, comprised of retinal vasculature, neurons and glial cells, is affected in subclinical disease. Early functional manifestations are seen in the form of blood flow and electroretinography disturbances. Structurally, there are alterations in the cellular components of vasculature, glia and the neuronal network. On clinical imaging, changes to vessel density and thickness of neuronal layers are observed. How these subclinical disturbances interact and ultimately manifest as clinical disease remains elusive. However, this knowledge reveals potential early therapeutic targets and the need for imaging modalities that can detect subclinical changes in a clinical setting.
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Affiliation(s)
- Martin Hein
- Physiology and Pharmacology Group, Lions Eye Institute, Perth, Western Australia, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia
| | - Hassanain Qambari
- Physiology and Pharmacology Group, Lions Eye Institute, Perth, Western Australia, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia
| | - Dong An
- Physiology and Pharmacology Group, Lions Eye Institute, Perth, Western Australia, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia
| | - Chandrakumar Balaratnasingam
- Physiology and Pharmacology Group, Lions Eye Institute, Perth, Western Australia, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia
- Department of Ophthalmology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
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15
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Tang S, Huang M, Wang R, Li M, Dong N, Wu R, Chi Z, Gao L. Drp1-dependent mitochondrial fragmentation mediates photoreceptor abnormalities in type 1 diabetic retina. Exp Eye Res 2024; 242:109860. [PMID: 38467174 DOI: 10.1016/j.exer.2024.109860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 01/27/2024] [Accepted: 03/08/2024] [Indexed: 03/13/2024]
Abstract
Recent studies have highlighted that retinal neurodegeneration precedes microvascular changes in diabetic retinopathy (DR), but the specific mechanisms remain unclear. Given the pivotal role of dysfunctional mitochondria and oxidative stress in early DR, our objective was to observe mitochondria-related alterations in the neural retina of type one diabetic mellitus mice with no evidence of DR (T1DM-NDR). We aimed to identify the key mitochondrial-related proteins contributing to mitochondrial injury. Our study revealed that T1DM-NDR mice exhibited outer retina thinning, including the ellipsoid zone, inner segment, and outer segment. Additionally, there was an impaired amplitude of the b-wave in electroretinogram (ERG) and a disorganized arrangement of the photoreceptor layer. In both the retina of DM mice and high glucose (HG)-treated 661w cells, mitochondria appeared swollen and fragmented, with disrupted cristae, disorganized or shortened branches in the mitochondrial network, and decreased mitochondrial membrane potential. Among the mitochondrial-related proteins, dynamin-related protein 1 (Drp1) was upregulated, and the ratio of phosphorylated Drp1 protein at serine 616 (S616) and serine 637 (S637) sites significantly increased in the retina of DM mice. The administration of Mdivi-1 ameliorated high-glucose-induced dysfunctional mitochondria, thereby protecting T1DM-NDR mice retina from morphological and functional injuries. Our findings suggest that hyperglycemia promotes Drp1-mediated mitochondrial dysfunction, which may be a significant factor in the development of DR. The inhibition of high-glucose-induced mitochondrial fission emerges as a potential and innovative intervention strategy for preventing DR.
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Affiliation(s)
- Shuyu Tang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Mengling Huang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ruixuan Wang
- Bourns Engineering, The University of California, Riverside, Riverside, CA, 92521, United States
| | - Ming Li
- Department of Immunology, College of Basic Medical Immunology, Central South University, Changsha, China
| | - Ning Dong
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ronghan Wu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China; National Clinical Research Center for Ocular Diseases, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zailong Chi
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China; National Clinical Research Center for Ocular Diseases, Eye Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Ling Gao
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China; State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China; National Clinical Research Center for Ocular Diseases, Eye Hospital of Wenzhou Medical University, Wenzhou, China.
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Zhao C, Ma G, Tao S, Wang M, Chen Z, Fang Y, Shi W. Qi-Ju-Di-Huang-Pill delays the progression of diabetic retinopathy. JOURNAL OF ETHNOPHARMACOLOGY 2024; 323:117751. [PMID: 38216102 DOI: 10.1016/j.jep.2024.117751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 12/24/2023] [Accepted: 01/09/2024] [Indexed: 01/14/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Qi-Ju-Di-Huang-Pill (QJDH pill) is a Chinese decoction. Although it is commonly used to treat eye conditions, such as diabetic retinopathy (DR), its exact mechanism of action is unknown. AIM OF THE STUDY To investigate the specific mechanism by which QJDH pill slows the progression of diabetic retinopathy (DR) based on animal and cellular experiments. MATERIAL AND METHODS The major components of QJDH pill were characterized by ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLCMS/MS). C57BL/6J mice were randomly divided into five groups as follows: normal group (control group), model group (STZ group), low-dosage QJDH pill group (QJDH-L group), medium-dosage QJDH pill group (QJDH-M group) and high-dosage QJDH pill group (QJDH-H group). Changes in water intake, urination, food intake, and body mass were monitored weekly, while changes in blood glucose were monitored monthly. Fluorescein fundus angiography (FFA), optical coherence tomography angiography (OCTA), and optical coherence tomography (OCT) were utilized to analyze the changes in fundus imaging indications. Hematoxylin & eosin (H&E) and transmission electron microscopy (TEM) were employed to examine histopathologic and ultrastructural changes in retina. The levels of interleukin-6 (IL-6), interleukin-17 (IL-17), tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF) in peripheral blood were detected using Enzyme-linked immunosorbent assay (ELISA). The mouse retina apoptotic cells were labeled with green fluorescence via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (Tunel). The protein levels of Bcl-2-Associated X (Bax), B cell lymphoma 2 (Bcl-2), Caspase-3, PI3K, phosphorylated PI3K (p-PI3K), protein kinase B (AKT) and phosphorylated AKT (p-AKT) were quantified by Western blot (WB). The retinal pigment epithelium (RPE) cells were cultured and classified into five groups as follows: normal glucose group (NG group), high glucose group (HG group), high glucose + QJDH pill group (HG + QJDH group), high glucose + inhibitor group (HG + LY294002 group), and high glucose + inhibitor + QJDH pill group (HG + LY294002 + QJDH group). Cell viability and apoptosis were detected via Cell Counting Kit-8 (CCK8) and then analyzed by flow cytometry. RESULTS In vivo experiments revealed that the QJDH pill effectively reduced blood glucose, symptoms of increased water intake, elevated urination, increased food intake and decreased body mass in DR mice. QJDH pill also slowed the development of a series of fundus imaging signs, such as retinal microangiomas, tortuous dilatation of blood vessels, decreased vascular density, and thinning of retinal thickness, downregulated IL-6, IL-17, TNF-α, and VEGF levels in peripheral blood, and inhibited retinal cell apoptosis by activating the PI3K/AKT signaling pathway. Moreover, in vitro experiments showed that high glucose environment inhibited RPE cell viability and activated RPE cell apoptosis pathway. In contrast, lyophilized powder of QJDH pill increased RPE cell viability, protected RPE cells from high glucose-induced damage, and decreased apoptosis of RPE cells by activating the pi3k pathway. CONCLUSION QJDH pill induces hypoglycemic, anti-inflammatory effects, anti-VEGF and anti-retinal cell apoptosis by activating PI3K/AKT signaling pathway, and thus can protect the retina and slow the DR progression.
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Affiliation(s)
- Chunlin Zhao
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210000, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Guangcheng Ma
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210000, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Sihan Tao
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210000, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Mingyue Wang
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210000, China.
| | - Zhuolin Chen
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210000, China.
| | - Yiming Fang
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210000, China.
| | - Wei Shi
- Department of Ophthalmology, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210003, China.
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Cubillos S, Kazlauskas A. Manifestation of Pathology in Animal Models of Diabetic Retinopathy Is Delayed from the Onset of Diabetes. Int J Mol Sci 2024; 25:1610. [PMID: 38338889 PMCID: PMC10855501 DOI: 10.3390/ijms25031610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/18/2024] [Accepted: 01/22/2024] [Indexed: 02/12/2024] Open
Abstract
Diabetic retinopathy (DR) is the most common complication that develops in patients with diabetes mellitus (DM) and is the leading cause of blindness worldwide. Fortunately, sight-threatening forms of DR develop only after several decades of DM. This well-documented resilience to DR suggests that the retina is capable of protecting itself from DM-related damage and also that accumulation of such damage occurs only after deterioration of this resilience. Despite the enormous translational significance of this phenomenon, very little is known regarding the nature of resilience to DR. Rodent models of DR have been used extensively to study the nature of the DM-induced damage, i.e., cardinal features of DR. Many of these same animal models can be used to investigate resilience because DR is delayed from the onset of DM by several weeks or months. The purpose of this review is to provide a comprehensive overview of the literature describing the use of rodent models of DR in type-1 and type-2 diabetic animals, which most clearly document the delay between the onset of DM and the appearance of DR. These readily available experimental settings can be used to advance our current understanding of resilience to DR and thereby identify biomarkers and targets for novel, prevention-based approaches to manage patients at risk for developing DR.
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Affiliation(s)
- Samuel Cubillos
- University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA;
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Lu Z, Fan B, Li Y, Zhang Y. RAGE plays key role in diabetic retinopathy: a review. Biomed Eng Online 2023; 22:128. [PMID: 38115006 PMCID: PMC10729525 DOI: 10.1186/s12938-023-01194-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/11/2023] [Indexed: 12/21/2023] Open
Abstract
RAGE is a multiligand receptor for the immunoglobulin superfamily of cell surface molecules and is expressed in Müller cells, vascular endothelial cells, nerve cells and RPE cells of the retina. Diabetic retinopathy (DR) is a multifactorial disease associated with retinal inflammation and vascular abnormalities and is the leading cause of vision loss or impairment in older or working-age adults worldwide. Therapies aimed at reducing the inflammatory response and unnecessary angiogenesis can help slow the progression of DR, which in turn can save patients' vision. To maximize the efficacy and minimize the side effects, treatments that target key players in the pathophysiological process of DR need to be developed. The interaction between RAGE and its ligands is involved in a variety of cytopathological alterations in the retina, including secretion of inflammatory factors, regulation of angiogenesis, oxidative stress, structural and functional changes, and neurodegeneration. In this review, we will summarize the pathologic pathways mediated by RAGE and its ligand interactions and discuss its role in the progression of diabetic retinopathy to explore potential therapeutic targets that are effective and safe for DR.
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Affiliation(s)
- ZhiWen Lu
- Department of Ophthalmology, The Second Hospital of Jilin University, Nanguan District, No. 4026, Yatai Street, Changchun, 130000, Jilin Province, China
| | - Bin Fan
- Department of Ophthalmology, The Second Hospital of Jilin University, Nanguan District, No. 4026, Yatai Street, Changchun, 130000, Jilin Province, China.
| | - YunZhi Li
- Department of Ophthalmology, The Second Hospital of Jilin University, Nanguan District, No. 4026, Yatai Street, Changchun, 130000, Jilin Province, China
| | - YiXin Zhang
- Department of Ophthalmology, The Second Hospital of Jilin University, Nanguan District, No. 4026, Yatai Street, Changchun, 130000, Jilin Province, China
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Pfeifer CW, Walsh JT, Santeford A, Lin JB, Beatty WL, Terao R, Liu YA, Hase K, Ruzycki PA, Apte RS. Dysregulated CD200-CD200R signaling in early diabetes modulates microglia-mediated retinopathy. Proc Natl Acad Sci U S A 2023; 120:e2308214120. [PMID: 37903272 PMCID: PMC10636339 DOI: 10.1073/pnas.2308214120] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 09/25/2023] [Indexed: 11/01/2023] Open
Abstract
Diabetic retinopathy (DR) is a neurovascular complication of diabetes. Recent investigations have suggested that early degeneration of the neuroretina may occur prior to the appearance of microvascular changes; however, the mechanisms underlying this neurodegeneration have been elusive. Microglia are the predominant resident immune cell in the retina and adopt dynamic roles in disease. Here, we show that ablation of retinal microglia ameliorates visual dysfunction and neurodegeneration in a type I diabetes mouse model. We also provide evidence of enhanced microglial contact and engulfment of amacrine cells, ultrastructural modifications, and transcriptome changes that drive inflammation and phagocytosis. We show that CD200-CD200R signaling between amacrine cells and microglia is dysregulated during early DR and that targeting CD200R can attenuate high glucose-induced inflammation and phagocytosis in cultured microglia. Last, we demonstrate that targeting CD200R in vivo can prevent visual dysfunction, microglia activation, and retinal inflammation in the diabetic mouse. These studies provide a molecular framework for the pivotal role that microglia play in early DR pathogenesis and identify a potential immunotherapeutic target for treating DR in patients.
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Affiliation(s)
- Charles W. Pfeifer
- John F. Hardesty, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Neurosciences Graduate Program, Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO63110
| | - James T. Walsh
- John F. Hardesty, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO63110
| | - Andrea Santeford
- John F. Hardesty, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
| | - Joseph B. Lin
- John F. Hardesty, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Neurosciences Graduate Program, Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO63110
| | - Wandy L. Beatty
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO63110
| | - Ryo Terao
- John F. Hardesty, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo1138665, Japan
| | - Yizhou A. Liu
- John F. Hardesty, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
| | - Keitaro Hase
- John F. Hardesty, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
| | - Philip A. Ruzycki
- John F. Hardesty, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Department of Genetics, Washington University School of Medicine, St. Louis, MO63110
| | - Rajendra S. Apte
- John F. Hardesty, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO63110
- Department of Medicine, Washington University School of Medicine, St. Louis, MO63110
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20
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Haydinger CD, Oliver GF, Ashander LM, Smith JR. Oxidative Stress and Its Regulation in Diabetic Retinopathy. Antioxidants (Basel) 2023; 12:1649. [PMID: 37627644 PMCID: PMC10451779 DOI: 10.3390/antiox12081649] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/09/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Diabetic retinopathy is the retinal disease associated with hyperglycemia in patients who suffer from type 1 or type 2 diabetes. It includes maculopathy, involving the central retina and characterized by ischemia and/or edema, and peripheral retinopathy that progresses to a proliferative stage with neovascularization. Approximately 10% of the global population is estimated to suffer from diabetes, and around one in 5 of these individuals have diabetic retinopathy. One of the major effects of hyperglycemia is oxidative stress, the pathological state in which elevated production of reactive oxygen species damages tissues, cells, and macromolecules. The retina is relatively prone to oxidative stress due to its high metabolic activity. This review provides a summary of the role of oxidative stress in diabetic retinopathy, including a description of the retinal cell players and the molecular mechanisms. It discusses pathological processes, including the formation and effects of advanced glycation end-products, the impact of metabolic memory, and involvements of non-coding RNA. The opportunities for the therapeutic blockade of oxidative stress in diabetic retinopathy are also considered.
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Affiliation(s)
| | | | | | - Justine R. Smith
- College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia; (C.D.H.); (G.F.O.); (L.M.A.)
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21
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Weerasinghe LS, Dunn HP, Fung AT, Maberly G, Cheung NW, Weerasinghe DP, Liew G, Do H, Hng TM, Pryke A, Marks SI, Nguyen H, Jayaballa R, Gurung S, Ford B, Bishay RH, Girgis CM, Meyerowitz-Katz G, Keay L, White AJ. Diabetic Retinopathy Screening at the Point of Care (DR SPOC): detecting undiagnosed and vision-threatening retinopathy by integrating portable technologies within existing services. BMJ Open Diabetes Res Care 2023; 11:e003376. [PMID: 37532459 PMCID: PMC10401227 DOI: 10.1136/bmjdrc-2023-003376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/28/2023] [Indexed: 08/04/2023] Open
Abstract
INTRODUCTION The aim of this study was to determine the prevalence of diabetic retinopathy (DR) in a low socioeconomic region of a high-income country, as well as determine the diagnostic utility of point-of-care screening for high-risk populations in tertiary care settings. RESEARCH DESIGN AND METHODS This was a cross-sectional study of patients with diabetes attending foot ulcer or integrated care diabetes clinics at two Western Sydney hospitals (n=273). DR was assessed using portable, two-field, non-mydriatic fundus photography and combined electroretinogram/ pupillometry (ERG). With mydriatic photographs used as the reference standard, sensitivity and specificity of the devices were determined. Prevalence of DR and vision-threatening diabetic retinopathy (VTDR) were reported, with multivariate logistic regression used to identify predictors of DR. RESULTS Among 273 patients, 39.6% had any DR, while 15.8% had VTDR, of whom 59.3% and 62.8% were previously undiagnosed, respectively. Non-mydriatic photography demonstrated 20.2% sensitivity and 99.5% specificity for any DR, with a 56.7% screening failure rate. Meanwhile, mydriatic photography produced high-quality images with a 7.6% failure rate. ERG demonstrated 72.5% sensitivity and 70.1% specificity, with a 15.0% failure rate. The RETeval ERG was noted to have an optimal DR cut-off score at 22. Multivariate logistic regression identified an eGFR of ≤29 mL/min/1.73 m2, HbA1c of ≥7.0%, pupil size of <4 mm diameter, diabetes duration of 5-24 years and RETeval score of ≥22 as strong predictors of DR. CONCLUSION There is a high prevalence of vision-threatening and undiagnosed DR among patients attending high-risk tertiary clinics in Western Sydney. Point-of-care DR screening using portable, mydriatic photography demonstrates potential as a model of care which is easily accessible, targeted for high-risk populations and substantially enhances DR detection.
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Affiliation(s)
- Lakni Shahanika Weerasinghe
- Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia
- Department of Ophthalmology, Westmead Hospital, Westmead, New South Wales, Australia
| | - Hamish Paul Dunn
- Department of Ophthalmology, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia
| | - Adrian T Fung
- Department of Ophthalmology, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia
| | - Glen Maberly
- Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia
- Department of Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
| | - Ngai Wah Cheung
- Department of Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
| | - Daminda P Weerasinghe
- Department of Mathematics and Statistics, Macquarie University, Sydney, New South Wales, Australia
| | - Gerald Liew
- Department of Ophthalmology, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia
| | - Helen Do
- Department of Ophthalmology, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia
| | - Tien-Ming Hng
- Department of Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
- School of Medicine, Western Sydney University, Campbeltown, New South Wales, Australia
| | - Alison Pryke
- Department of Ophthalmology, Westmead Hospital, Westmead, New South Wales, Australia
| | - Samuel I Marks
- Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia
- Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Helen Nguyen
- School of Optometry and Vision Science, University of New South Wales, Sydney, New South Wales, Australia
| | - Rajini Jayaballa
- Department of Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
- School of Medicine, Western Sydney University, Campbeltown, New South Wales, Australia
| | - Seema Gurung
- Department of Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
| | - Belinda Ford
- Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia
- The George Institute for Global Health, UNSW Sydney, Newtown, New South Wales, Australia
| | - Ramy H Bishay
- Department of Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
- School of Medicine, Western Sydney University, Campbeltown, New South Wales, Australia
| | - Christian M Girgis
- Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia
- Department of Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
| | | | - Lisa Keay
- School of Optometry and Vision Science, University of New South Wales, Sydney, New South Wales, Australia
- The George Institute for Global Health, UNSW Sydney, Newtown, New South Wales, Australia
| | - Andrew J White
- Department of Ophthalmology, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia
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22
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Karan BM, Little K, Augustine J, Stitt AW, Curtis TM. Aldehyde Dehydrogenase and Aldo-Keto Reductase Enzymes: Basic Concepts and Emerging Roles in Diabetic Retinopathy. Antioxidants (Basel) 2023; 12:1466. [PMID: 37508004 PMCID: PMC10376360 DOI: 10.3390/antiox12071466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
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 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.
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Affiliation(s)
- Burak Mugdat Karan
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT7 1NN, UK
| | - Karis Little
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT7 1NN, UK
| | - Josy Augustine
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT7 1NN, UK
| | - Alan W Stitt
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT7 1NN, UK
| | - Tim M Curtis
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT7 1NN, UK
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23
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Zhou J, Chen B. Retinal Cell Damage in Diabetic Retinopathy. Cells 2023; 12:1342. [PMID: 37174742 PMCID: PMC10177610 DOI: 10.3390/cells12091342] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/05/2023] [Accepted: 05/06/2023] [Indexed: 05/15/2023] Open
Abstract
Diabetic retinopathy (DR), the most common microvascular complication that occurs in diabetes mellitus (DM), is the leading cause of vision loss in working-age adults. The prevalence of diabetic retinopathy is approximately 30% of the diabetic population and untreated DR can eventually cause blindness. For decades, diabetic retinopathy was considered a microvascular complication and clinically staged by its vascular manifestations. In recent years, emerging evidence has shown that diabetic retinopathy causes early neuronal dysfunction and neurodegeneration that may precede vascular pathology and affect retinal neurons as well as glial cells. This knowledge leads to new therapeutic strategies aiming to prevent dysfunction of retinal neurons at the early stage of DR. Early detection and timely treatment to protect retinal neurons are critical to preventing visual loss in DR. This review provides an overview of DR and the structural and functional changes associated with DR, and discusses neuronal degeneration during diabetic retinopathy, the mechanisms underlying retinal neurodegeneration and microvascular complications, and perspectives on current and future clinic therapies.
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Affiliation(s)
| | - Bo Chen
- Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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24
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Calbiague García V, Cadiz B, Herrera P, Díaz A, Schmachtenberg O. Evaluation of Photobiomodulation and Boldine as Alternative Treatment Options in Two Diabetic Retinopathy Models. Int J Mol Sci 2023; 24:ijms24097918. [PMID: 37175628 PMCID: PMC10178531 DOI: 10.3390/ijms24097918] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023] Open
Abstract
Diabetic retinopathy causes progressive and irreversible damage to the retina through activation of inflammatory processes, overproduction of oxidative species, and glial reactivity, leading to changes in neuronal function and finally ischemia, edema, and hemorrhages. Current treatments are invasive and mostly applied at advanced stages, stressing the need for alternatives. To this end, we tested two unconventional and potentially complementary non-invasive treatment options: Photobiomodulation, the stimulation with near-infrared light, has shown promising results in ameliorating retinal pathologies and insults in several studies but remains controversial. Boldine, on the other hand, is a potent natural antioxidant and potentially useful to prevent free radical-induced oxidative stress. To establish a baseline, we first evaluated the effects of diabetic conditions on the retina with immunofluorescence, histological, and ultrastructural analysis in two diabetes model systems, obese LepRdb/db mice and organotypic retinal explants, and then tested the potential benefits of photobiomodulation and boldine treatment in vitro on retinal explants subjected to high glucose concentrations, mimicking diabetic conditions. Our results suggest that the principal subcellular structures affected by these conditions were mitochondria in the inner segment of photoreceptors, which displayed morphological changes in both model systems. In retinal explants, lactate metabolism, assayed as an indicator of mitochondrial function, was altered, and decreased photoreceptor viability was observed, presumably as a consequence of increased oxidative-nitrosative stress. The latter was reduced by boldine treatment in vitro, while photobiomodulation improved mitochondrial metabolism but was insufficient to prevent retinal structural damage caused by high glucose. These results warrant further research into alternative and complementary treatment options for diabetic retinopathy.
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Affiliation(s)
- Víctor Calbiague García
- Ph. D. Program in Neuroscience, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
- Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
| | - Bárbara Cadiz
- Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
| | - Pablo Herrera
- Instituto de Biología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
| | - Alejandra Díaz
- Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
| | - Oliver Schmachtenberg
- Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
- Instituto de Biología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
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25
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Karami F, Jamaati H, Coleman-Fuller N, Zeini MS, Hayes AW, Gholami M, Salehirad M, Darabi M, Motaghinejad M. Is metformin neuroprotective against diabetes mellitus-induced neurodegeneration? An updated graphical review of molecular basis. Pharmacol Rep 2023; 75:511-543. [PMID: 37093496 DOI: 10.1007/s43440-023-00469-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 04/25/2023]
Abstract
Diabetes mellitus (DM) is a metabolic disease that activates several molecular pathways involved in neurodegenerative disorders. Metformin, an anti-hyperglycemic drug used for treating DM, has the potential to exert a significant neuroprotective role against the detrimental effects of DM. This review discusses recent clinical and laboratory studies investigating the neuroprotective properties of metformin against DM-induced neurodegeneration and the roles of various molecular pathways, including mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, and its related cascades. A literature search was conducted from January 2000 to December 2022 using multiple databases including Web of Science, Wiley, Springer, PubMed, Elsevier Science Direct, Google Scholar, the Core Collection, Scopus, and the Cochrane Library to collect and evaluate peer-reviewed literature regarding the neuroprotective role of metformin against DM-induced neurodegenerative events. The literature search supports the conclusion that metformin is neuroprotective against DM-induced neuronal cell degeneration in both peripheral and central nervous systems, and this effect is likely mediated via modulation of oxidative stress, inflammation, and cell death pathways.
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Affiliation(s)
- Fatemeh Karami
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Jamaati
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Natalie Coleman-Fuller
- Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN, 55108, USA
| | - Maryam Shokrian Zeini
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - A Wallace Hayes
- University of South Florida College of Public Health and Institute for Integrative Toxicology, Michigan State University, East Lansing, USA
| | - Mina Gholami
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Salehirad
- Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Darabi
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Motaghinejad
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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26
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Da'as SI, Ahmed I, Hasan WH, Abdelrahman DA, Aliyev E, Nisar S, Bhat AA, Joglekar MV, Hardikar AA, Fakhro KA, Akil ASAS. The link between glycemic control measures and eye microvascular complications in a clinical cohort of type 2 diabetes with microRNA-223-3p signature. J Transl Med 2023; 21:171. [PMID: 36869348 PMCID: PMC9985290 DOI: 10.1186/s12967-023-03893-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 01/16/2023] [Indexed: 03/05/2023] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) is a critical healthcare challenge and priority in Qatar which is listed amongst the top 10 countries in the world, with its prevalence presently at 17% double the global average. MicroRNAs (miRNAs) are implicated in the pathogenesis of (T2D) and long-term microvascular complications including diabetic retinopathy (DR). METHODS In this study, a T2D cohort that accurately matches the characteristics of the general population was employed to find microRNA (miRNA) signatures that are correlated with glycemic and β cell function measurements. Targeted miRNA profiling was performed in (471) T2D individuals with or without DR and (491) (non-diabetic) healthy controls from the Qatar Biobank. Discovery analysis identified 20 differentially expressed miRNAs in T2D compared to controls, of which miR-223-3p was significantly upregulated (fold change:5.16, p = 3.6e-02) and positively correlated with glucose and hemoglobin A1c (HbA1c) levels (p-value = 9.88e-04 and 1.64e-05, respectively), but did not show any significant associations with insulin or C-peptide. Accordingly, we performed functional validation using a miR-223-3p mimic (overexpression) under control and hyperglycemia-induced conditions in a zebrafish model. RESULTS Over-expression of miR-223-3p alone was associated with significantly higher glucose (42.7 mg/dL, n = 75 vs 38.7 mg/dL, n = 75, p = 0.02) and degenerated retinal vasculature, and altered retinal morphology involving changes in the ganglion cell layer and inner and outer nuclear layers. Assessment of retinal angiogenesis revealed significant upregulation in the expression of vascular endothelial growth factor and its receptors, including kinase insert domain receptor. Further, the pancreatic markers, pancreatic and duodenal homeobox 1, and the insulin gene expressions were upregulated in the miR-223-3p group. CONCLUSION Our zebrafish model validates a novel correlation between miR-223-3p and DR development. Targeting miR-223-3p in T2D patients may serve as a promising therapeutic strategy to control DR in at-risk individuals.
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Affiliation(s)
- Sahar I Da'as
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar.,Zebrafish Functional Genomics, Integrated Genomic Services Core Facility, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar
| | - Ikhlak Ahmed
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Waseem H Hasan
- Zebrafish Functional Genomics, Integrated Genomic Services Core Facility, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Doua A Abdelrahman
- Zebrafish Functional Genomics, Integrated Genomic Services Core Facility, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Elbay Aliyev
- Laboratory of Genomic Medicine-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Sabah Nisar
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Ajaz Ahmad Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Mugdha V Joglekar
- Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Narellan Road & Gilchrist Drive, Campbelltown, NSW, 2560, Australia
| | - Anandwardhan A Hardikar
- Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Narellan Road & Gilchrist Drive, Campbelltown, NSW, 2560, Australia.,Department of Science and Environment, Roskilde University, Universitetsvej 1, 4000, Roskilde, Denmark
| | - Khalid A Fakhro
- Laboratory of Genomic Medicine-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar.,Department of Genetic Medicine, Weill Cornell Medical College, P.O. Box 24144, Doha, Qatar
| | - Ammira S Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar. .,Laboratory of Genomic Medicine-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
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27
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Proinflammatory Cytokines Trigger the Onset of Retinal Abnormalities and Metabolic Dysregulation in a Hyperglycemic Mouse Model. J Ophthalmol 2023; 2023:7893104. [PMID: 36895267 PMCID: PMC9991478 DOI: 10.1155/2023/7893104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/22/2023] [Accepted: 02/03/2023] [Indexed: 03/06/2023] Open
Abstract
Purpose Recent evidence has shown that retinal inflammation is a key player in diabetic retinopathy (DR) pathogenesis. To further understand and validate the metabolic biomarkers of DR, we investigated the effect of intravitreal proinflammatory cytokines on the retinal structure, function, and metabolism in an in vivo hyperglycemic mouse model. Methods C57Bl/6 mice were rendered hyperglycemic within one week of administration of a single high-dose intraperitoneal injection of streptozotocin, while control mice received vehicle injection. After confirming hyperglycemia, the mice received an intravitreal injection of either proinflammatory cytokines (TNF-α and IL-1β) or vehicle. Similarly, control mice received an intravitreal injection of either proinflammatory cytokines or vehicle. The retinal structure was evaluated using fundus imaging and optical coherence tomography, and retinal function was assessed using a focal electroretinogram (ERG), two days after cytokine injection. Retinas were collected for biochemical analysis to determine key metabolite levels and enzymatic activities. Results Hyperglycemic mice intraocularly injected with cytokines developed visible retinal vascular damage and intravitreal and intraretinal hyper-reflective spots two days after the cytokines injection. These mice also developed a significant functional deficit with reduced a-wave and b-wave amplitudes of the ERG at high light intensities compared to control mice. Furthermore, metabolic disruption was evident in these mice, with significantly higher retinal glucose, lactate, ATP, and glutamine levels and a significant reduction in glutamate levels compared with control mice. Minimal or no metabolic changes were observed in hyperglycemic mice without intraocular cytokines or in control mice with intraocular cytokines at 2 days post hyperglycemia. Conclusions Proinflammatory cytokines accelerated the development of vascular damage in the eyes of hyperglycemic mice. Significant changes were observed in retinal structure, function, and metabolic homeostasis. These findings support the idea that with the onset of inflammation in DR, there is a deficit in metabolism. Therefore, early intervention to prevent inflammation-induced retinal changes in diabetic patients may improve the disease outcome.
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28
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Ba‐Ali S, Larsen M, Andersen HU, Lund‐Andersen H. Full-field and multifocal electroretinogram in non-diabetic controls and diabetics with and without retinopathy. Acta Ophthalmol 2022; 100:e1719-e1728. [PMID: 35661609 PMCID: PMC9795888 DOI: 10.1111/aos.15184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 05/05/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To compare retinal function assessed by full-field electroretinography (ffERG) and multifocal electroretinography (mfERG) in diabetes without retinopathy, diabetes with moderate non-proliferative diabetic retinopathy (NPDR) and in the absence of diabetes. METHODS Scotopic and photopic ffERG and mfERG was made in non-fasting volunteers, including 26 diabetic participants without retinopathy, 22 diabetic participants with moderate NPDR and 22 participants without diabetes using full International Society for Clinical Electrophysiology of Vision protocols. RESULTS Of the ffERG responses, significant deviation (p ≤ 0.05, corrected for multiple sampling and other relevant confounders) from the non-diabetic participants was seen in the diabetic participants only for the OP1-OP3 oscillatory amplitudes and the OP2 implicit time. This finding was independent of whether retinopathy was present or not. For the mfERG, minor amplitude or implicit time deviations were found for a small number of rings (R2, R4 and R5). Receiver of operating characteristic analysis showed that the single most prominent abnormality of the ffERG in diabetes, regardless of whether retinopathy was present or not, was the OP2 implicit time (area under the curve ≥ 0.80). CONCLUSION This bi-modal study of electroretinographic characteristics found that the most prominent anomaly associated with diabetes was a prolongation of the implicit time of the OP2 of the scotopic ffERG, while the most prominent added effect of non-proliferative diabetic retinopathy was a further prolongation of the OP2 implicit time. Although the variation in ERG characteristics is far too large for diagnostic purposes, the close association of the oscillatory potentials with the amacrine cells of the retina indicate that their function is particularly sensitive to diabetes.
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Affiliation(s)
- Shakoor Ba‐Ali
- Department of OphthalmologyRigshospitaletGlostrupDenmark,Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Michael Larsen
- Department of OphthalmologyRigshospitaletGlostrupDenmark,Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | | | - Henrik Lund‐Andersen
- Department of OphthalmologyRigshospitaletGlostrupDenmark,Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Steno Diabetes CenterCopenhagenDenmark
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Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications. Cells 2022; 11:cells11213362. [PMID: 36359761 PMCID: PMC9655436 DOI: 10.3390/cells11213362] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/19/2022] [Accepted: 10/20/2022] [Indexed: 11/24/2022] Open
Abstract
Diabetic retinopathy (DR), with increasing incidence, is the major cause of vision loss and blindness worldwide in working-age adults. Diabetic macular edema (DME) remains the main cause of vision impairment in diabetic patients, with its pathogenesis still not completely elucidated. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of DR and DME. Currently, intravitreal injection of anti-VEGF agents remains as the first-line therapy in DME treatment due to the superior anatomic and functional outcomes. However, some patients do not respond satisfactorily to anti-VEGF injections. More than 30% patients still exist with persistent DME even after regular intravitreal injection for at least 4 injections within 24 weeks, suggesting other pathogenic factors, beyond VEGF, might contribute to the pathogenesis of DME. Recent advances showed nearly all the retinal cells are involved in DR and DME, including breakdown of blood-retinal barrier (BRB), drainage dysfunction of Müller glia and retinal pigment epithelium (RPE), involvement of inflammation, oxidative stress, and neurodegeneration, all complicating the pathogenesis of DME. The profound understanding of the changes in proteomics and metabolomics helps improve the elucidation of the pathogenesis of DR and DME and leads to the identification of novel targets, biomarkers and potential therapeutic strategies for DME treatment. The present review aimed to summarize the current understanding of DME, the involved molecular mechanisms, and the changes in proteomics and metabolomics, thus to propose the potential therapeutic recommendations for personalized treatment of DME.
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MicroRNA-150 (miR-150) and Diabetic Retinopathy: Is miR-150 Only a Biomarker or Does It Contribute to Disease Progression? Int J Mol Sci 2022; 23:ijms232012099. [PMID: 36292956 PMCID: PMC9603433 DOI: 10.3390/ijms232012099] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/05/2022] [Accepted: 10/06/2022] [Indexed: 11/18/2022] Open
Abstract
Diabetic retinopathy (DR) is a chronic disease associated with diabetes mellitus and is a leading cause of visual impairment among the working population in the US. Clinically, DR has been diagnosed and treated as a vascular complication, but it adversely impacts both neural retina and retinal vasculature. Degeneration of retinal neurons and microvasculature manifests in the diabetic retina and early stages of DR. Retinal photoreceptors undergo apoptosis shortly after the onset of diabetes, which contributes to the retinal dysfunction and microvascular complications leading to vision impairment. Chronic inflammation is a hallmark of diabetes and a contributor to cell apoptosis, and retinal photoreceptors are a major source of intraocular inflammation that contributes to vascular abnormalities in diabetes. As the levels of microRNAs (miRs) are changed in the plasma and vitreous of diabetic patients, miRs have been suggested as biomarkers to determine the progression of diabetic ocular diseases, including DR. However, few miRs have been thoroughly investigated as contributors to the pathogenesis of DR. Among these miRs, miR-150 is downregulated in diabetic patients and is an endogenous suppressor of inflammation, apoptosis, and pathological angiogenesis. In this review, how miR-150 and its downstream targets contribute to diabetes-associated retinal degeneration and pathological angiogenesis in DR are discussed. Currently, there is no effective treatment to stop or reverse diabetes-caused neural and vascular degeneration in the retina. Understanding the molecular mechanism of the pathogenesis of DR may shed light for the future development of more effective treatments for DR and other diabetes-associated ocular diseases.
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Alshaikh RA, Ryan KB, Waeber C. Sphingosine 1-phosphate, a potential target in neovascular retinal disease. Br J Ophthalmol 2022; 106:1187-1195. [PMID: 33962970 DOI: 10.1136/bjophthalmol-2021-319115] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/17/2021] [Accepted: 04/23/2021] [Indexed: 06/12/2023]
Abstract
Neovascular ocular diseases (such as age-related macular degeneration, diabetic retinopathy and retinal vein occlusion) are characterised by common pathological processes that contribute to disease progression. These include angiogenesis, oedema, inflammation, cell death and fibrosis. Currently available therapies target the effects of vascular endothelial growth factor (VEGF), the main mediator of pathological angiogenesis. Unfortunately, VEGF blockers are expensive biological therapeutics that necessitate frequent intravitreal administration and are associated with multiple adverse effects. Thus, alternative treatment options associated with fewer side effects are required for disease management. This review introduces sphingosine 1-phosphate (S1P) as a potential pharmacological target for the treatment of neovascular ocular pathologies. S1P is a sphingolipid mediator that controls cellular growth, differentiation, survival and death. S1P actions are mediated by five G protein-coupled receptors (S1P1-5 receptors) which are abundantly expressed in all retinal and subretinal structures. The action of S1P on S1P1 receptors can reduce angiogenesis, increase endothelium integrity, reduce photoreceptor apoptosis and protect the retina against neurodegeneration. Conversely, S1P2 receptor signalling can increase neovascularisation, disrupt endothelial junctions, stimulate VEGF release, and induce retinal cell apoptosis and degeneration of neural retina. The aim of this review is to thoroughly discuss the role of S1P and its different receptor subtypes in angiogenesis, inflammation, apoptosis and fibrosis in order to determine which of these S1P-mediated processes may be targeted therapeutically.
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Affiliation(s)
- Rasha A Alshaikh
- School of Pharmacy, University College Cork, Cork, Ireland
- Department of Pharmaceutical Technology, Tanta University, Tanta, Egypt
| | - Katie B Ryan
- School of Pharmacy, University College Cork, Cork, Ireland
- SSPC The SFI Research Centre for Pharmaceuticals, School of Pharmacy, University College Cork, Cork, Ireland
| | - Christian Waeber
- School of Pharmacy, University College Cork, Cork, Ireland
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
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Antioxidant and anti-apoptotic effects of tocotrienol-rich fraction against streptozotocin-induced diabetic retinopathy in rats. Biomed Pharmacother 2022; 153:113533. [DOI: 10.1016/j.biopha.2022.113533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/08/2022] [Accepted: 08/08/2022] [Indexed: 11/22/2022] Open
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O-GlcNAc Modification and Its Role in Diabetic Retinopathy. Metabolites 2022; 12:metabo12080725. [PMID: 36005597 PMCID: PMC9415332 DOI: 10.3390/metabo12080725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022] Open
Abstract
Diabetic retinopathy (DR) is a leading complication in type 1 and type 2 diabetes and has emerged as a significant health problem. Currently, there are no effective therapeutic strategies owing to its inconspicuous early lesions and complex pathological mechanisms. Therefore, the mechanism of molecular pathogenesis requires further elucidation to identify potential targets that can aid in the prevention of DR. As a type of protein translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification is involved in many diseases, and increasing evidence suggests that dysregulated O-GlcNAc modification is associated with DR. The present review discusses O-GlcNAc modification and its molecular mechanisms involved in DR. O-GlcNAc modification might represent a novel alternative therapeutic target for DR in the future.
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Lechner J, Medina RJ, Lois N, Stitt AW. Advances in cell therapies using stem cells/progenitors as a novel approach for neurovascular repair of the diabetic retina. Stem Cell Res Ther 2022; 13:388. [PMID: 35907890 PMCID: PMC9338609 DOI: 10.1186/s13287-022-03073-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/20/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Diabetic retinopathy, a major complication of diabetes mellitus, is a leading cause of sigh-loss in working age adults. Progressive loss of integrity of the retinal neurovascular unit is a central element in the disease pathogenesis. Retinal ischemia and inflammatory processes drive interrelated pathologies such as blood retinal barrier disruption, fluid accumulation, gliosis, neuronal loss and/or aberrant neovascularisation. Current treatment options are somewhat limited to late-stages of the disease where there is already significant damage to the retinal architecture arising from degenerative, edematous and proliferative pathology. New preventive and interventional treatments to target early vasodegenerative and neurodegenerative stages of the disease are needed to ensure avoidance of sight-loss. MAIN BODY Historically, diabetic retinopathy has been considered a primarily microvascular disease of the retina and clinically it is classified based on the presence and severity of vascular lesions. It is now known that neurodegeneration plays a significant role during the pathogenesis. Loss of neurons has been documented at early stages in pre-clinical models as well as in individuals with diabetes and, in some, even prior to the onset of clinically overt diabetic retinopathy. Recent studies suggest that some patients have a primarily neurodegenerative phenotype. Retinal pigment epithelial cells and the choroid are also affected during the disease pathogenesis and these tissues may also need to be addressed by new regenerative treatments. Most stem cell research for diabetic retinopathy to date has focused on addressing vasculopathy. Pre-clinical and clinical studies aiming to restore damaged vasculature using vasoactive progenitors including mesenchymal stromal/stem cells, adipose stem cells, CD34+ cells, endothelial colony forming cells and induced pluripotent stem cell derived endothelial cells are discussed in this review. Stem cells that could replace dying neurons such as retinal progenitor cells, pluripotent stem cell derived photoreceptors and ganglion cells as well as Müller stem cells are also discussed. Finally, challenges of stem cell therapies relevant to diabetic retinopathy are considered. CONCLUSION Stem cell therapies hold great potential to replace dying cells during early and even late stages of diabetic retinopathy. However, due to the presence of different phenotypes, selecting the most suitable stem cell product for individual patients will be crucial for successful treatment.
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Affiliation(s)
- Judith Lechner
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK.
| | - Reinhold J Medina
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Noemi Lois
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Alan W Stitt
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK.
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Sener H, Gulmez Sevim D, Erkilic K, Oner A, Gunay Sener AB. Evaluation of Ring Amplitude and Factors Affecting Ring Amplitude in Multifocal Electroretinography in Diabetic Eyes. Semin Ophthalmol 2022; 37:895-901. [PMID: 35834721 DOI: 10.1080/08820538.2022.2100714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
PURPOSE The aim of this paper was to evaluate the ring amplitudes in diabetic patients and to evaluate the effect of the risk factors for diabetic retinopathy on the ring amplitudes. We also aimed to investigate the success of ring amplitudes in classifying diabetic retinopathy. METHODS The study included 32 eyes of 32 diabetic patients without retinopathy (DM), 34 eyes of 34 patients with mild non-proliferative diabetic retinopathy (NPDR) without macular edema, and 62 eyes of 62 age- and sex-matched controls (CG). All subjects were evaluated using mfERG. The relationship between age, diabetes duration, HbA1c and ring amplitudes and the effect of diabetes and hypertension on ring amplitudes were evaluated. Three-way ROC analysis was performed to evaluate the discrimination power of the ring amplitudes. RESULTS In the comparison of the ring amplitudes, the amplitudes of the DM and NPDR groups were statistically significantly decreased compared to the CG (p < .05). A moderate to strong correlation was found between the duration of diabetes, HbA1c and ring amplitudes (p < .05). The effect of diabetes decreased towards the peripheral rings and hypertension did not affect ring amplitudes. Volume under the ROC surface of R1 = 0.65 had p < .05 and 95% CI [0.50-0.72], and the best cut-off point pair to differentiate the three classes was found to be c1 = 217.3, c2 = 151.2 in three-way ROC analysis. CONCLUSION In conclusion, the effects of diabetes are unevenly distributed on the retina topographically. Diabetes affects the central rings more than peripheral rings in multifocal ERG. Both ring densities and ring ratios are effective ways to identify early changes in retinal function.
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Affiliation(s)
- Hidayet Sener
- Department of Ophthalmology, Cukurca State Hospital, Hakkari, Turkey
| | - Duygu Gulmez Sevim
- Department of Ophthalmology, Erciyes University School of Medicine, Kayseri, Turkey
| | - Kuddusi Erkilic
- Department of Ophthalmology, Erciyes University School of Medicine, Kayseri, Turkey
| | - Ayse Oner
- Department of Ophthalmology, Acibadem Hospital, Kayseri, Turkey
| | - Ayse Busra Gunay Sener
- Department of Medical Informatics and Biostatistics, Erciyes University School of Medicine, Kayseri, Turkey
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Zhu M, Gao S, Gao S, Wang Y, Li N, Shen X. Interleukin-17A attenuates photoreceptor cell apoptosis in streptozotocin-induced diabetic mouse model. Bioengineered 2022; 13:14175-14187. [PMID: 35730427 PMCID: PMC9342149 DOI: 10.1080/21655979.2022.2084241] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Diabetic retinopathy (DR) represents an important microvascular complication of diabetes, which is the top etiology of vision impairment worldwide. Although interleukin (IL)-17A is increasingly implicated in DR development, the underlying cellular mechanisms remain poorly defined. This work aims to evaluate IL-17A levels in the retina of streptozotocin (STZ)-induced diabetic mice and elucidate their potential roles. We found IL-17A was upregulated in diabetic retina after intraperitoneal injection of STZ and high-glucose (HG)-cultured primary Müller cells. IL-17A knockout (IL-17A−/−) downregulated glial fibrillary acidic protein (GFAP) and inhibited the conversion of proneurotrophin-3 (proNT-3) to mature NT-3 in retinal specimens from diabetic mice as well as in Müller cells cultured under HG conditions. Induced apoptosis and upregulated Bax and cleaved caspase-3 were observed in retinal specimens from IL-17A−/− diabetic mice and photoreceptor (661 W) cells after co-culture with IL-17A−/− Müller cells. Moreover, RNA interference-induced gene silencing of tyrosine kinase C receptor (TrkC) in 661 W cells reversed the anti-apoptotic effect of IL-17A under HG conditions. Taken together, our findings suggest that IL-17A/NT-3/TrkC axis regulation suppresses apoptosis in photoreceptor cells, providing a new treatment strategy for DR.
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Affiliation(s)
- Minqi Zhu
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Shuang Gao
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Sha Gao
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yanuo Wang
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Na Li
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xi Shen
- Department of Ophthalmology, Ruijin Hospital, Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China
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Carpi-Santos R, de Melo Reis RA, Gomes FCA, Calaza KC. Contribution of Müller Cells in the Diabetic Retinopathy Development: Focus on Oxidative Stress and Inflammation. Antioxidants (Basel) 2022; 11:617. [PMID: 35453302 PMCID: PMC9027671 DOI: 10.3390/antiox11040617] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/01/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
Diabetic retinopathy is a neurovascular complication of diabetes and the main cause of vision loss in adults. Glial cells have a key role in maintenance of central nervous system homeostasis. In the retina, the predominant element is the Müller cell, a specialized cell with radial morphology that spans all retinal layers and influences the function of the entire retinal circuitry. Müller cells provide metabolic support, regulation of extracellular composition, synaptic activity control, structural organization of the blood-retina barrier, antioxidant activity, and trophic support, among other roles. Therefore, impairments of Müller actions lead to retinal malfunctions. Accordingly, increasing evidence indicates that Müller cells are affected in diabetic retinopathy and may contribute to the severity of the disease. Here, we will survey recently described alterations in Müller cell functions and cellular events that contribute to diabetic retinopathy, especially related to oxidative stress and inflammation. This review sheds light on Müller cells as potential therapeutic targets of this disease.
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Affiliation(s)
- Raul Carpi-Santos
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (R.C.-S.); (F.C.A.G.)
| | - Ricardo A. de Melo Reis
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil;
| | - Flávia Carvalho Alcantara Gomes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (R.C.-S.); (F.C.A.G.)
| | - Karin C. Calaza
- Instituto de Biologia, Departamento de Neurobiologia, Universidade Federal Fluminense, Niteroi 24210-201, RJ, Brazil
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Elsner AE, Walker BR, Gilbert RN, Parimi V, Papay JA, Gast TJ, Burns SA. Cone Photoreceptors in Diabetic Patients. Front Med (Lausanne) 2022; 9:826643. [PMID: 35372411 PMCID: PMC8968172 DOI: 10.3389/fmed.2022.826643] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/31/2022] [Indexed: 11/13/2022] Open
Abstract
Purpose Cones in diabetic patients are at risk due to metabolic and vascular changes. By imaging retinal vessel modeling at high magnification, we reduced its impact on cone distribution measurements. The retinal vessel images and retinal thickness measurements provided information about cone microenvironment. Methods We compared cone data in 10 diabetic subjects (28–78 yr) to our published norms from 36 younger and 10 older controls. All subjects were consented and tested in a manner approved by the Indiana University Institutional Review Board, which adhered to the Declaration of Helsinki. Custom adaptive optics scanning laser ophthalmoscopy (AOSLO) was used to image cones and retinal microcirculation. We counted cones in a montage of foveal and temporal retina, using four non-contiguous samples within 0.9–7 deg that were selected for best visibility of cones and least pathology. The data were fit with a two parameter exponential model: ln(cone density) = a * microns eccentricity + b. These results were compared to retinal thickness measurements from SDOCT. Results Diabetic cone maps were more variable than in controls and included patches, or unusually bright and dark cones, centrally and more peripherally. Model parameters and total cones within the central 14 deg of the macula differed across diabetic patients. Total cones fell into two groups: similar to normal for 5 vs. less than normal for 2 of 2 younger diabetic subjects and 3 older subjects, low but not outside the confidence limits. Diabetic subjects had all retinal vascular remodeling to varying degrees: microaneurysms; capillary thickening, thinning, or bends; and vessel elongation including capillary loops, tangles, and collaterals. Yet SD-OCT showed that no diabetic subject had a Total Retinal Thickness in any quadrant that fell outside the confidence limits for controls. Conclusions AOSLO images pinpointed widespread retinal vascular remodeling in all diabetic eyes, but the SDOCT showed no increased retinal thickness. Cone reflectivity changes were found in all diabetic patients, but significantly low cone density in only some. These results are consistent with early changes to neural, glial, or vascular components of the retinal without significant retinal thickening due to exudation.
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Pitale PM, Gorbatyuk MS. Diabetic Retinopathy: From Animal Models to Cellular Signaling. Int J Mol Sci 2022; 23:ijms23031487. [PMID: 35163410 PMCID: PMC8835767 DOI: 10.3390/ijms23031487] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM), a metabolic disorder characterized by elevation in blood glucose level. The pathogenesis of DR includes vascular, neuronal, and inflammatory components leading to activation of complex cellular molecular signaling. If untreated, the disease can culminate in vision loss that eventually leads to blindness. Animal models mimicking different aspects of DM complications have been developed to study the development and progression of DR. Despite the significant contribution of the developed DR models to discovering the mechanisms of DR and the recent achievements in the research field, the sequence of cellular events in diabetic retinas is still under investigation. Partially, this is due to the complexity of molecular mechanisms, although the lack of availability of models that adequately mimic all the neurovascular pathobiological features observed in patients has also contributed to the delay in determining a precise molecular trigger. In this review, we provide an update on the status of animal models of DR to help investigators choose an appropriate system to validate their hypothesis. We also discuss the key cellular and physiological events of DR in these models.
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Affiliation(s)
- Priyamvada M. Pitale
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Marina S. Gorbatyuk
- Department of Optometry and Vision Science, School of Optometry, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence: ; Tel.: +1-205-934-6762; Fax: +1-205-934-3425
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Canovai A, Amato R, Melecchi A, Dal Monte M, Rusciano D, Bagnoli P, Cammalleri M. Preventive Efficacy of an Antioxidant Compound on Blood Retinal Barrier Breakdown and Visual Dysfunction in Streptozotocin-Induced Diabetic Rats. Front Pharmacol 2022; 12:811818. [PMID: 35046830 PMCID: PMC8762314 DOI: 10.3389/fphar.2021.811818] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
In diabetic retinopathy (DR), high blood glucose drives chronic oxidative stress and inflammation that trigger alterations of the neurovascular balance finally resulting in vascular abnormalities and retinal cell death, which converge towards altered electroretinogram (ERG). In the last years, a growing body of preclinical evidence has suggested that nutrients with anti-inflammatory/antioxidant properties can be able to hamper DR progression since its very early stages. In the present study, we used a streptozotocin-induced rat model of DR, which mimics most aspects of the early stages of human DR, to test the preventive efficacy of a novel compound containing cyanidin-3-glucoside (C3G), verbascoside and zinc as nutrients with antioxidant and anti-inflammatory properties. Western blot, immunofluorescence and electroretinographic analyses demonstrated a dose-dependent inhibition of oxidative stress- and inflammation-related mechanisms, with a significant counterpart in preventing molecular mechanisms leading to DR-associated vasculopathy and its related retinal damage. Preventive efficacy of the compound on dysfunctional a- and b-waves was also demonstrated by electroretinography. The present demonstration that natural compounds, possibly as a consequence of vascular rescue following ameliorated oxidative stress and inflammation, may prevent the apoptotic cascade leading to ERG dysfunction, adds further relevance to the potential application of antioxidants as a preventive therapy to counteract DR progression.
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Affiliation(s)
| | - Rosario Amato
- Department of Biology, University of Pisa, Pisa, Italy
| | | | - Massimo Dal Monte
- Department of Biology, University of Pisa, Pisa, Italy.,Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy
| | | | - Paola Bagnoli
- Department of Biology, University of Pisa, Pisa, Italy
| | - Maurizio Cammalleri
- Department of Biology, University of Pisa, Pisa, Italy.,Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy
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Datlinger F, Wassermann L, Reumueller A, Hajdu D, Steiner I, Salas M, Drexler W, Pircher M, Schmidt-Erfurth U, Pollreisz A. Assessment of Detailed Photoreceptor Structure and Retinal Sensitivity in Diabetic Macular Ischemia Using Adaptive Optics-OCT and Microperimetry. Invest Ophthalmol Vis Sci 2021; 62:1. [PMID: 34605880 PMCID: PMC8496411 DOI: 10.1167/iovs.62.13.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose The purpose of this study was to assess density and morphology of cone photoreceptors (PRs) and corresponding retinal sensitivity in ischemic compared to nonischemic retinal capillary areas of diabetic eyes using adaptive optics optical coherence tomography (AO-OCT) and microperimetry (MP). Methods In this cross-sectional, observational study five eyes of four patients (2 eyes with proliferative diabetic retinopathy (DR) and 3 eyes moderate nonproliferative DR) were included. PR morphology and density was manually assessed in AO-OCT en face images both at the axial position of the inner-segment outer segment (IS/OS) and cone outer segment tips (COSTs). Retinal sensitivity was determined by fundus-controlled microperimetry in corresponding areas (MP-3, Nidek). Results In AO-OCT, areas affected by capillary nonperfusion showed severe alterations of cone PR morphology at IS/OS and COST compared to areas with intact capillary perfusion (84% and 87% vs. 9% and 8% of area affected for IS/OS and COST, respectively). Mean reduction of PR signal density in affected areas compared to those with intact superficial capillary plexus (SCP) and deep capillary plexus (DCP) perfusion of similar eccentricity was -38% at the level of IS/OS (P = 0.01) and -39% at the level of COST (P = 0.01). Mean retinal sensitivity was 10.8 ± 5.4 in areas affected by DCP nonperfusion and 28.2 ± 1.5 outside these areas (P < 0.001). Conclusions Cone PR morphology and signal density are severely altered in areas of capillary nonperfusion. These structural changes are accompanied by a severe reduction of retinal sensitivity, indicating the importance of preventing impaired capillary circulation in patients with DR.
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Affiliation(s)
- Felix Datlinger
- Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria
| | - Lorenz Wassermann
- Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria
| | - Adrian Reumueller
- Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria
| | - Dorottya Hajdu
- Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria
| | - Irene Steiner
- Center of Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Matthias Salas
- Center of Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Drexler
- Center of Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria
| | - Michael Pircher
- Center of Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria
| | - Ursula Schmidt-Erfurth
- Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria
| | - Andreas Pollreisz
- Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria
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Van Bergen T, Hu TT, Little K, De Groef L, Moons L, Stitt AW, Vermassen E, Feyen JHM. Targeting Plasma Kallikrein With a Novel Bicyclic Peptide Inhibitor (THR-149) Reduces Retinal Thickening in a Diabetic Rat Model. Invest Ophthalmol Vis Sci 2021; 62:18. [PMID: 34677569 PMCID: PMC8556562 DOI: 10.1167/iovs.62.13.18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 08/27/2021] [Indexed: 11/24/2022] Open
Abstract
Purpose To investigate the effect of plasma kallikrein (PKal)-inhibition by THR-149 on preventing key pathologies associated with diabetic macular edema (DME) in a rat model. Methods Following streptozotocin-induced diabetes, THR-149 or its vehicle was administered in the rat via either a single intravitreal injection or three consecutive intravitreal injections (with a 1-week interval; both, 12.5 µg/eye). At 4 weeks post-diabetes, the effect of all groups was compared by histological analysis of Iba1-positive retinal inflammatory cells, inflammatory cytokines, vimentin-positive Müller cells, inwardly rectifying potassium and water homeostasis-related channels (Kir4.1 and AQP4, respectively), vascular leakage (fluorescein isothiocyanate-labeled bovine serum albumin), and retinal thickness. Results Single or repeated THR-149 injections resulted in reduced inflammation, as depicted by decreasing numbers and activation state of immune cells and IL-6 cytokine levels in the diabetic retina. The processes of reactive gliosis, vessel leakage, and retinal thickening were only significantly reduced after multiple THR-149 administrations. Individual retinal layer analysis showed that repeated THR-149 injections significantly decreased diabetes-induced thickening of the inner plexiform, inner nuclear, outer nuclear, and photoreceptor layers. At the glial-vascular interface, reduced Kir4.1-channel levels in the diabetic retina were restored to control non-diabetic levels in the presence of THR-149. In contrast, little or no effect of THR-149 was observed on the AQP4-channel levels. Conclusions These data demonstrate that repeated THR-149 administration reduces several DME-related key pathologies such as retinal thickening and neuropil disruption in the diabetic rat. These observations indicate that modulation of the PKal pathway using THR-149 has clinical potential to treat patients with DME.
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Affiliation(s)
| | | | - Karis Little
- Queen's University Belfast, Belfast, United Kingdom
| | - Lies De Groef
- Neural Circuit Development and Regeneration Research Group, Department of Biology and Leuven Brain Institute, KU Leuven, Leuven, Belgium
| | - Lieve Moons
- Neural Circuit Development and Regeneration Research Group, Department of Biology and Leuven Brain Institute, KU Leuven, Leuven, Belgium
| | - Alan W. Stitt
- Oxurion NV, Heverlee, Belgium
- Queen's University Belfast, Belfast, United Kingdom
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Midena E, Torresin T, Longhin E, Midena G, Pilotto E, Frizziero L. Early Microvascular and Oscillatory Potentials Changes in Human Diabetic Retina: Amacrine Cells and the Intraretinal Neurovascular Crosstalk. J Clin Med 2021; 10:jcm10184035. [PMID: 34575150 PMCID: PMC8466765 DOI: 10.3390/jcm10184035] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 08/31/2021] [Accepted: 09/03/2021] [Indexed: 12/22/2022] Open
Abstract
To analyze the early microvascular retinal changes and oscillatory potentials alterations secondary to diabetic retinal damage, 44 eyes of 22 diabetic patients without and with mild diabetic retinopathy (DR) and 18 eyes of 9 healthy controls were examined. All subjects underwent spectral domain optical coherence tomography (SD-OCT), OCT angiography (OCTA), and electroretinography of oscillatory potentials (OPs). At OCTA, vessel area density (VAD), vessel length fraction (VLF), and fractal dimension (FD) were significantly reduced in the superficial vascular plexus (SVP), VLF and FD in the intermediate capillary plexus (ICP), and FD in the deep capillary plexus (DCP) in the diabetic group compared to the control group. The amplitude (A) of OP2, OP3, OP4 and the sum of OPs were significantly reduced in the diabetic group versus the controls, and the last two parameters were reduced also in patients without DR versus the controls. Moreover, in the diabetic group, a significant direct correlation was found between the A of OP1, OP2, OP3 and sOP and the VLF and FD in the SVP, while a statistically significant inverse correlation was found between the A of OP3 and OP4 and the VDI in the ICP and DCP. The reduced oscillatory potentials suggest a precocious involvement of amacrine cells in diabetic eyes, independently of DR presence, and their correlation with vascular parameters underlines the relevance of the crosstalk between these cells and vascular components in the pathophysiology of this chronic disease.
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Affiliation(s)
- Edoardo Midena
- Department of Neuroscience—Ophthalmology, University of Padova, 35128 Padova, Italy; (T.T.); (E.L.); (E.P.); (L.F.)
- IRCCS—Fondazione Bietti, 00198 Rome, Italy;
- Correspondence: ; Tel.: +39-049-821-2110
| | - Tommaso Torresin
- Department of Neuroscience—Ophthalmology, University of Padova, 35128 Padova, Italy; (T.T.); (E.L.); (E.P.); (L.F.)
| | - Evelyn Longhin
- Department of Neuroscience—Ophthalmology, University of Padova, 35128 Padova, Italy; (T.T.); (E.L.); (E.P.); (L.F.)
| | | | - Elisabetta Pilotto
- Department of Neuroscience—Ophthalmology, University of Padova, 35128 Padova, Italy; (T.T.); (E.L.); (E.P.); (L.F.)
| | - Luisa Frizziero
- Department of Neuroscience—Ophthalmology, University of Padova, 35128 Padova, Italy; (T.T.); (E.L.); (E.P.); (L.F.)
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Decreased MicroRNA-150 Exacerbates Neuronal Apoptosis in the Diabetic Retina. Biomedicines 2021; 9:biomedicines9091135. [PMID: 34572320 PMCID: PMC8469350 DOI: 10.3390/biomedicines9091135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 12/27/2022] Open
Abstract
Diabetic retinopathy (DR) is a chronic complication associated with diabetes and the number one cause of blindness in working adults in the US. More than 90% of diabetic patients have obesity-associated type 2 diabetes (T2D), and 60% of T2D patients will develop DR. Photoreceptors undergo apoptosis shortly after the onset of diabetes, which contributes to the retinal dysfunction and microvascular complications leading to vision impairment. However, how diabetic insults cause photoreceptor apoptosis remains unclear. In this study, obesity-associated T2D mice and cultured photoreceptors were used to investigate how decreased microRNA-150 (miR-150) and its downstream target were involved in photoreceptor apoptosis. In the T2D retina, miR-150 was decreased with its target ETS-domain transcription factor (ELK1) and phosphorylated ELK1 at threonine 417 (pELK1T417) upregulated. In cultured photoreceptors, treatments with palmitic acid (PA), to mimic a high-fat environment, decreased miR-150 but upregulated ELK1, pELK1T417, and the translocation of pELK1T417 from the cytoplasm to the cell nucleus. Deletion of miR-150 (miR-150-/-) exacerbates T2D- or PA-induced photoreceptor apoptosis. Blocking the expression of ELK1 with small interfering RNA (siRNA) for Elk1 did not rescue PA-induced photoreceptor apoptosis. Translocation of pELK1T417 from cytoplasm-to-nucleus appears to be the key step of diabetic insult-elicited photoreceptor apoptosis.
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Early (5-Day) Onset of Diabetes Mellitus Causes Degeneration of Photoreceptor Cells, Overexpression of Incretins, and Increased Cellular Bioenergetics in Rat Retina. Cells 2021; 10:cells10081981. [PMID: 34440748 PMCID: PMC8394146 DOI: 10.3390/cells10081981] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/27/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023] Open
Abstract
The effects of early (5-day) onset of diabetes mellitus (DM) on retina ultrastructure and cellular bioenergetics were examined. The retinas of streptozotocin-induced diabetic rats were compared to those of non-diabetic rats using light and transmission electron microscopy. Tissue localization of glucagon-like-peptide-1 (GLP-1), exendin-4 (EXE-4), and catalase (CAT) in non-diabetic and diabetic rat retinas was conducted using immunohistochemistry, while the retinal and plasma concentration of GLP-1, EXE-4, and CAT were measured with ELISA. Lipid profiles and kidney and liver function markers were measured from the blood of non-diabetic and diabetic rats with an automated biochemical analyzer. Oxygen consumption was monitored using a phosphorescence analyzer, and the adenosine triphosphate (ATP) level was determined using the Enliten ATP assay kit. Blood glucose and cholesterol levels were significantly higher in diabetic rats compared to control. The number of degenerated photoreceptor cells was significantly higher in the diabetic rat retina. Tissue levels of EXE-4, GLP-1 and CAT were significantly (p = 0.002) higher in diabetic rat retina compared to non-diabetic controls. Retinal cellular respiration was 50% higher (p = 0.004) in diabetic (0.53 ± 0.16 µM O2 min−1 mg−1, n = 10) than in non-diabetic rats (0.35 ± 0.07 µM O2 min−1 mg−1, n = 11). Retinal cellular ATP was 76% higher (p = 0.077) in diabetic (205 ± 113 pmol mg−1, n = 10) than in non-diabetic rats (116 ± 99 pmol mg−1, n = 12). Thus, acute (5-day) or early onslaught of diabetes-induced hyperglycemia increased incretins and antioxidant levels and oxidative phosphorylation. All of these events could transiently preserve retinal function during the early phase of the progression of diabetes.
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Tonade D, Kern TS. Photoreceptor cells and RPE contribute to the development of diabetic retinopathy. Prog Retin Eye Res 2021; 83:100919. [PMID: 33188897 PMCID: PMC8113320 DOI: 10.1016/j.preteyeres.2020.100919] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/27/2020] [Accepted: 10/31/2020] [Indexed: 12/26/2022]
Abstract
Diabetic retinopathy (DR) is a leading cause of blindness. It has long been regarded as vascular disease, but work in the past years has shown abnormalities also in the neural retina. Unfortunately, research on the vascular and neural abnormalities have remained largely separate, instead of being integrated into a comprehensive view of DR that includes both the neural and vascular components. Recent evidence suggests that the most predominant neural cell in the retina (photoreceptors) and the adjacent retinal pigment epithelium (RPE) play an important role in the development of vascular lesions characteristic of DR. This review summarizes evidence that the outer retina is altered in diabetes, and that photoreceptors and RPE contribute to retinal vascular alterations in the early stages of the retinopathy. The possible molecular mechanisms by which cells of the outer retina might contribute to retinal vascular damage in diabetes also are discussed. Diabetes-induced alterations in the outer retina represent a novel therapeutic target to inhibit DR.
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Affiliation(s)
- Deoye Tonade
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA
| | - Timothy S Kern
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA; Veterans Administration Medical Center Research Service, Cleveland, OH, USA; Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA, USA; Veterans Administration Medical Center Research Service, Long Beach, CA, USA.
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GSH-Independent Induction of ER Stress during Hypoglycaemia in the Retinal Cells of Mice. J Clin Med 2021; 10:jcm10112529. [PMID: 34200353 PMCID: PMC8201117 DOI: 10.3390/jcm10112529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/31/2021] [Accepted: 06/04/2021] [Indexed: 11/17/2022] Open
Abstract
Glucose is one of the most important metabolic substrates of the retina, and glycaemic imbalances can lead to serious side effects, including retinopathy. We previously showed that hypoglycaemia induces retinal cell death in mice, as well as the implication of glutathione (GSH) in this process. This study aimed to analyse the role of low glucose-induced decrease in GSH levels in endoplasmic reticulum (ER) stress. We cultured 661W photoreceptor-like cells under various glucose conditions and analysed ER stress markers at the mRNA and protein levels. We used the ERAI (“ER stress-activated indicator”) mouse model to test ER stress in both ex vivo, on retinal explants, or in vivo, in mice subjected to hypoglycaemia. Moreover, we used buthionine sulfoximine (BSO) and glutamate cysteine ligase (Gclm)-KO mice as models of low GSH to test its effects on ER stress. We show that the unfolded protein response (UPR) is triggered in 661W cells and in ERAI mice under hypoglycaemic conditions. Low GSH levels promote cell death, but have no impact on ER stress. We concluded that low glucose levels induce ER stress independently of GSH levels. Inhibition of ER stress could prevent neurodegeneration, which seems to be an early event in the pathogenesis of diabetic retinopathy.
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Énzsöly A, Hajdú RI, Turóczi Z, Szalai I, Tátrai E, Pálya F, Nagy ZZ, Mátyás C, Oláh A, Radovits T, Szabó K, Dékány B, Szabó A, Kusnyerik Á, Soltész P, Veres DS, Somogyi A, Somfai GM, Lukáts Á. The Predictive Role of Thyroid Hormone Levels for Early Diabetic Retinal Changes in Experimental Rat and Human Diabetes. Invest Ophthalmol Vis Sci 2021; 62:20. [PMID: 34010957 PMCID: PMC8142702 DOI: 10.1167/iovs.62.6.20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose In diabetic subjects, early visual functional alterations such as color vision deficiencies (CVDs) are known to precede clinically apparent diabetic retinopathy. Prominent photoreceptor outer segment degeneration and an increase in the number of retinal dual cones (co-expressing S- and M-opsins simultaneously) have been described in diabetic rat models, suggesting a connection with the development of CVDs. As cone opsin expression is controlled by thyroid hormones, we investigated the diabetic retina in association with thyroid hormone alterations. Methods In rat models of type 1 and 2 diabetes, dual cones were labeled by immunohistochemistry, and their numbers were analyzed in relation to free triiodothyronine (fT3) and free thyroxine (fT4) levels. Quantification of dual cones was also performed in human postmortem retinas. Additionally, a cross-sectional case–control study was performed where thyroid hormone levels were measured and color vision was assessed with Lanthony desaturated D15 discs. Results A higher number of dual cones was detectable in diabetic rats, correlating with fT4 levels. Dual cones were also present in postmortem human retinas, with higher numbers in the three diabetic retinas. As expected, age was strongly associated with CVDs in human patients, and the presence of diabetes also increased the risk. However, the current study failed to detect any effect of thyroid hormones on the development of CVDs. Conclusions Our results point toward the involvement of thyroid homeostasis in the opsin expression changes in diabetic rats and human samples. The evaluation of the possible clinical consequences warrants further research.
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Affiliation(s)
- Anna Énzsöly
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Rozina I Hajdú
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary.,Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
| | - Zsolt Turóczi
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Irén Szalai
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Erika Tátrai
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Fanni Pálya
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Zoltán Z Nagy
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Csaba Mátyás
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Attila Oláh
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Tamás Radovits
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Klaudia Szabó
- Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
| | - Bulcsú Dékány
- Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
| | - Arnold Szabó
- Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
| | - Ákos Kusnyerik
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Petra Soltész
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Dániel S Veres
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - Anikó Somogyi
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Gábor M Somfai
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary.,Eye Clinic, Stadtspital Waid and Triemli, Zürich, Switzerland.,Werner H. Spross Foundation for the Advancement of Research and Teaching in Ophthalmology, Zürich, Switzerland
| | - Ákos Lukáts
- Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
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Diabetic retinal neurodegeneration as a form of diabetic retinopathy. Int Ophthalmol 2021; 41:3223-3248. [PMID: 33954860 DOI: 10.1007/s10792-021-01864-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 04/08/2021] [Indexed: 12/11/2022]
Abstract
PURPOSE To review the evidence supporting diabetic retinal neurodegeneration (DRN) as a form of diabetic retinopathy. METHOD Review of literature. RESULTS DRN is recognized to be a part of retinopathy in patients with diabetes mellitus (DM), in addition to the well-established diabetic retinal vasculopathy (DRV). DRN has been noted in the early stages of DM, before the onset of clinically evident diabetic retinopathy. The occurrence of DRN has been confirmed in animal models of DM, histopathological examination of donor's eyes from diabetic individuals and assessment of neural structure and function in humans. DRN involves alterations in retinal ganglion cells, photoreceptors, amacrine cells and bipolar cells, and is thought to be driven by glutamate, oxidative stress and dysregulation of neuroprotective factors in the retina. Potential therapeutic options for DRN are under evaluation. CONCLUSIONS Literature is divided on the temporal relation between DRN and DRV, with evidence of both precedence and simultaneous occurrence. The relationship between DRN and multi-system neuropathy in DM is yet to be evaluated critically.
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Fletcher EL, Phipps JA, Wilkinson-Berka JL. Dysfunction of retinal neurons and glia during diabetes. Clin Exp Optom 2021; 88:132-45. [PMID: 15926876 DOI: 10.1111/j.1444-0938.2005.tb06686.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2004] [Revised: 04/15/2005] [Accepted: 04/23/2005] [Indexed: 12/27/2022] Open
Abstract
Diabetic retinopathy is the leading cause of blindness in those of working age. It is well known that the retinal vasculature is altered during diabetes. More recently, it has emerged that neuronal and glial dysfunction occurs in those with diabetes. Current research is directed at understanding these neuronal and glial changes because they may be an early manifestation of disease processes that ultimately lead to vascular abnormality. This review will highlight the recent advances in our understanding of the neuronal and glial changes that occur during diabetes.
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Affiliation(s)
- Erica L Fletcher
- Department of Anatomy and Cell Biology, The University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia
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