scholarly journals Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets

2014 ◽  
Vol 2014 ◽  
pp. 1-18 ◽  
Author(s):  
Sher Zaman Safi ◽  
Rajes Qvist ◽  
Selva Kumar ◽  
Kalaivani Batumalaie ◽  
Ikram Shah Bin Ismail
Keyword(s):  
Diabetic Retinopathy ◽  
Structural Damage ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Therapeutic Targets ◽  
Polyol Pathway ◽  
Preventive Strategies ◽  
Retinal Cells ◽  
Hexosamine Pathway ◽  
Pathway Flux

The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors.

scholarly journals In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kolja Becker ◽  
Holger Klein ◽  
Eric Simon ◽  
Coralie Viollet ◽  
Christian Haslinger ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Expression Profiles ◽  
Cell Types ◽  
Sequencing Data ◽  
Disease Stages ◽  
Post Transcriptional Regulation

AbstractDiabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP–PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.

scholarly journals Retinal Redox Stress and Remodeling in Cardiometabolic Syndrome and Diabetes

2010 ◽  
Vol 3 (6) ◽  
pp. 392-403 ◽  
Author(s):  
Ying Yang ◽  
Melvin R. Hayden ◽  
Susan Sowers ◽  
Sarika V. Bagree ◽  
James R. Sowers
Keyword(s):  
Metabolic Pathways ◽  
Tissue Injury ◽  
Disease Process ◽  
Polyol Pathway ◽  
The United States ◽  
Redox Stress ◽  
Blood Retinal Barrier ◽  
Cardiometabolic Syndrome ◽  
Hexosamine Pathway ◽  
Pathway Flux

Diabetic retinopathy (DR) is a significant cause of global blindness; a major cause of blindness in the United States in people aged between 20–74. There is emerging evidence that retinopathy is initiated and propagated by multiple metabolic toxicities associated with excess production of reactive oxygen species (ROS). The four traditional metabolic pathways involved in the development of DR include: increased polyol pathway flux, advanced glycation end-product formation, activation of protein kinase Cisoforms and hexosamine pathway flux. These pathways individually and synergisticallycontribute to redox stress with excess ROS resulting in retinal tissue injury resulting in significant microvascular blood retinal barrier remodeling. The toxicity of hyperinsulinemia, hyperglycemia, hypertension, dyslipidemia, increased cytokines and growth factors, in conjunction with redox stress, contribute to the development and progression of DR. Redox stress contributes to the development and progression of abnormalities of endothelial cells and pericytes in DR. This review focuses on the ultrastructural observations of the blood retinal barrier including the relationship between the endothelial cell and pericyte remodeling in young nine week old Zucker obese (fa/ fa) rat model of obesity; cardiometabolic syndrome, and the 20 week old alloxan induced diabetic porcine model. Preventing or delaying the blindness associated with these intersecting abnormal metabolic pathways may be approached through strategies targeted to reduction of tissue inflammation and oxidative—redox stress. Understanding these abnormal metabolic pathways and the accompanying redox stress and remodeling mayprovide both the clinician and researcher a new concept of approaching this complicated disease process

scholarly journals Diabetic Retinopathy. Morphofunctional State of the Retina in Pancreas Recipients

2021 ◽  
Vol 18 (3) ◽  
pp. 459-469
Author(s):  
I. V. Vorobyeva ◽  
L. K. Moshetova ◽  
A. V. Pinchuk ◽  
E. V. Bulava ◽  
K. E. Lazareva ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Retinopathy ◽  
Pancreas Transplantation ◽  
Patient Management ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Retinal Damage ◽  
Common Complication ◽  
Immunological Markers

Diabetes mellitus (DM) is one of the most common and rapidly progressing diseases worldwide. Diabetic retinopathy (DR) is a common complication of diabetes and the main cause of vision loss in middle-aged and elderly people. The development and progression of DR is closely related to the duration of diabetes, hyperglycemia, and arterial hypertension. There is growing evidence that inflammation is one of the key links in the pathogenesis of diabetic retinal damage, but the exact molecular mechanisms remain to be known. Pancreas transplantation (PT) is currently the only effective treatment for diabetes that restores normal physiological glucose metabolism. Due to the limited number of PT surgeries associated with the severity of intra- and postoperative complications and the acute issue of organ donation, studies on the assessment of DR after PT are few and contradictory. There is a need for further studies of the DR state after PT with the study of the influence of risk factors, determination of the level of immunological markers and the use of modern instrumental research methods to create effective patient management regimens in the postoperative period.

scholarly journals Unveiling the Nanotechnology-Based Drug Delivery Systems and Patent Literature for Diabetic Retinopathy

2021 ◽  
Vol 12 (5) ◽  
pp. 6651-6667
Keyword(s):  
Blood Pressure ◽  
Diabetic Retinopathy ◽  
Ganglion Cells ◽  
Polyol Pathway ◽  
Proliferative Retinopathy ◽  
Panretinal Photocoagulation ◽  
Arterial Blood ◽  
Hexosamine Pathway ◽  
Patent Literature ◽  
And Control

Diabetes mellitus is a principal reason for globally developing chronic microvascular disorders defined as diabetic retinopathy (DR). Proliferative retinopathy and non-proliferative retinopathy are the two types of DR. Long-term diabetes, and poor blood sugar and arterial blood pressure regulation are the key risk factors for the onset and advancement of DR. A variety of biochemical pathways are involved in the pathogenesis of DR, which includes increased polyol pathway fluxes, advanced glycation end product growth, protein kinase C isoform activation, and increased hexosamine pathway flux. The varieties of cells are involved in diabetic retinopathy, including glial cells, retinal ganglion cells, endothelial cells, and pericytes. Surgical treatment of DR includes laser treatment, panretinal photocoagulation, focal laser photocoagulation, and vitrectomy surgery. The systemic treatment of DR includes glycemic management and control of blood pressure and hyperlipidemia. Nanotechnology-based formulations like nanoparticles, polymeric nanomicelles, and nanocarrier composite, and various patented formulations have been investigated for the treatment of DR.

scholarly journals Molecular mechanisms of diabetic retinopathy: Potential therapeutic targets

2015 ◽  
Vol 22 (2) ◽  
pp. 135 ◽  
Author(s):  
AzzaB El-Remessy ◽  
Maha Coucha ◽  
SallyL Elshaer ◽  
WaelS Eldahshan ◽  
BarbaraA Mysona
Keyword(s):  
Diabetic Retinopathy ◽  
Molecular Mechanisms ◽  
Therapeutic Targets

scholarly journals Metabolic Dysregulation and Neurovascular Dysfunction in Diabetic Retinopathy

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1244
Author(s):  
Thangal Yumnamcha ◽  
Michael Guerra ◽  
Lalit Pukhrambam Singh ◽  
Ahmed S. Ibrahim
Keyword(s):  
Diabetic Retinopathy ◽  
Oxidative Phosphorylation ◽  
Glucose Homeostasis ◽  
Krebs Cycle ◽  
Polyol Pathway ◽  
Developed Countries ◽  
The United States ◽  
Glycolytic Flux ◽  
Obesity And Diabetes ◽  
Hexosamine Pathway

Diabetic retinopathy is a major cause of ocular complications in patients with type 1 and type 2 diabetes in developed countries. Due to the continued increase in the number of people with obesity and diabetes in the United States of America and globally, the incidence of diabetic retinopathy is expected to increase significantly in the coming years. Diabetic retinopathy is widely accepted as a combination of neurodegenerative and microvascular changes; however, which change occurs first is not yet understood. Although the pathogenesis of diabetic retinopathy is very complex, regulated by numerous signaling pathways and cellular processes, maintaining glucose homeostasis is still an essential component for normal physiological functioning of retinal cells. The maintenance of glucose homeostasis is finely regulated by coordinated interplay between glycolysis, Krebs cycle, and oxidative phosphorylation. Glycolysis is the most conserved metabolic pathway in biology and is tightly regulated to maintain a steady-state concentration of glycolytic intermediates; this regulation is called scheduled or regulated glycolysis. However, an abnormal increase in glycolytic flux generates large amounts of intermediate metabolites that can be shunted into different damaging pathways including the polyol pathway, hexosamine pathway, diacylglycerol-dependent activation of the protein kinase C pathway, and Amadori/advanced glycation end products (AGEs) pathway. In addition, disrupting the balance between glycolysis and oxidative phosphorylation leads to other biochemical and molecular changes observed in diabetic retinopathy including endoplasmic reticulum-mitochondria miscommunication and mitophagy dysregulation. This review will focus on how dysregulation of glycolysis contributes to diabetic retinopathy.

scholarly journals Emerging Roles of Dyslipidemia and Hyperglycemia in Diabetic Retinopathy: Molecular Mechanisms and Clinical Perspectives

2021 ◽  
Vol 12 ◽  
Author(s):  
Hussain Rao ◽  
Jonathan A. Jalali ◽  
Thomas P. Johnston ◽  
Peter Koulen
Keyword(s):  
Diabetic Retinopathy ◽  
Literature Review ◽  
Basic Science ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Vision Loss ◽  
Science Research ◽  
Therapeutic Interventions ◽  
Research Subject

Diabetic retinopathy (DR) is a significant cause of vision loss and a research subject that is constantly being explored for new mechanisms of damage and potential therapeutic options. There are many mechanisms and pathways that provide numerous options for therapeutic interventions to halt disease progression. The purpose of the present literature review is to explore both basic science research and clinical research for proposed mechanisms of damage in diabetic retinopathy to understand the role of triglyceride and cholesterol dysmetabolism in DR progression. This review delineates mechanisms of damage secondary to triglyceride and cholesterol dysmetabolism vs. mechanisms secondary to diabetes to add clarity to the pathogenesis behind each proposed mechanism. We then analyze mechanisms utilized by both triglyceride and cholesterol dysmetabolism and diabetes to elucidate the synergistic, additive, and common mechanisms of damage in diabetic retinopathy. Gathering this research adds clarity to the role dyslipidemia has in DR and an evaluation of the current peer-reviewed basic science and clinical evidence provides a basis to discern new potential therapeutic targets.

scholarly journals The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury

2020 ◽  
Vol 31 (4) ◽  
pp. 716-730 ◽  
Author(s):  
Marc Johnsen ◽  
Torsten Kubacki ◽  
Assa Yeroslaviz ◽  
Martin Richard Späth ◽  
Jannis Mörsdorf ◽  
...  
Keyword(s):  
Gene Expression ◽  
Reperfusion Injury ◽  
Caloric Restriction ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxic Preconditioning ◽  
Preventive Strategies ◽  
Gene Expression Signatures

BackgroundAlthough AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance.MethodsTo identify genes and pathways shared by caloric restriction and hypoxic preconditioning, we used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning in mice before and after renal ischemia-reperfusion injury.ResultsThe gene expression signatures induced by both preconditioning strategies involve distinct common genes and pathways that overlap significantly with the transcriptional changes observed after ischemia-reperfusion injury. These changes primarily affect oxidation-reduction processes and have a major effect on mitochondrial processes. We found that 16 of the genes differentially regulated by both modes of preconditioning were strongly correlated with clinical outcome; most of these genes had not previously been directly linked to AKI.ConclusionsThis comparative analysis of the gene expression signatures in preconditioning strategies shows overlapping patterns in caloric restriction and hypoxic preconditioning, pointing toward common molecular mechanisms. Our analysis identified a limited set of target genes not previously known to be associated with AKI; further study of their potential to provide the basis for novel preventive strategies is warranted. To allow for optimal interactive usability of the data by the kidney research community, we provide an online interface for user-defined interrogation of the gene expression datasets (http://shiny.cecad.uni-koeln.de:3838/IRaP/).

scholarly journals Visual Cortex Transcranial Direct Current Stimulation for Proliferative Diabetic Retinopathy Patients: A Double-Blinded Randomized Exploratory Trial

2021 ◽  
Vol 11 (2) ◽  
pp. 270
Author(s):  
Angelito Braulio F. de Venecia ◽  
Shane M. Fresnoza
Keyword(s):  
Diabetic Retinopathy ◽  
Visual Cortex ◽  
Proliferative Diabetic Retinopathy ◽  
Direct Current ◽  
Transcranial Direct Current Stimulation ◽  
Vision Loss ◽  
Sham Stimulation ◽  
Direct Current Stimulation ◽  
Residual Vision ◽  
Cathodal Tdcs

Proliferative diabetic retinopathy (PDR) is a severe complication of diabetes. PDR-related retinal hemorrhages often lead to severe vision loss. The main goals of management are to prevent visual impairment progression and improve residual vision. We explored the potential of transcranial direct current stimulation (tDCS) to enhance residual vision. tDCS applied to the primary visual cortex (V1) may improve visual input processing from PDR patients’ retinas. Eleven PDR patients received cathodal tDCS stimulation of V1 (1 mA for 10 min), and another eleven patients received sham stimulation (1 mA for 30 s). Visual acuity (logarithm of the minimum angle of resolution (LogMAR) scores) and number acuity (reaction times (RTs) and accuracy rates (ARs)) were measured before and immediately after stimulation. The LogMAR scores and the RTs of patients who received cathodal tDCS decreased significantly after stimulation. Cathodal tDCS has no significant effect on ARs. There were no significant changes in the LogMAR scores, RTs, and ARs of PDR patients who received sham stimulation. The results are compatible with our proposal that neuronal noise aggravates impaired visual function in PDR. The therapeutic effect indicates the potential of tDCS as a safe and effective vision rehabilitation tool for PDR patients.

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