Pathogenesis Of Diabetic Retinopathy Research Articles

The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in diabetic retinopathy.

In the working-age population worldwide, diabetic retinopathy (DR), a prevalent complication of diabetes, is the main cause of vision impairment. Chronic low-grade inflammation plays an essential role in DR development. Recently, concerning the pathogenesis of DR, the Nod-Like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome in retinal cells has been determined as a causal factor. In the diabetic eye, the NLRP3 inflammasome is activated by several pathways (such as ROS and ATP). The activation of NPRP3 leads to the secretion of inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18), and leads to pyroptosis, a rapid inflammatory form of lytic programmed cell death (PCD). Cells that undergo pyroptosis swell and rapture, releasing more inflammatory factors and accelerating DR progression. This review focuses on the mechanisms that activate NLRP3 inflammasome and pyroptosis leading to DR. The present research highlighted some inhibitors of NLRP3/pyroptosis pathways and novel therapeutic measures concerning DR treatment.

The role of aldosterone in the pathogenesis of diabetic retinopathy.

Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways, aldosterone may play an effect in the pathogenesis of diabetic retinopathy (DR) through the regulation of oxidative stress, vascular regulation, and inflammatory mechanisms. This implies that mineralocorticoids, including aldosterone, have great potential and value for the diagnosis and treatment of DR. Because early studies did not focus on the intrinsic association between mineralocorticoids and DR, targeted research is still in its infancy and there are still many obstacles to its application in the clinical setting. Recent studies have improved the understanding of the effects of aldosterone on DR, and we review them with the aim of exploring possible mechanisms for the treatment and prevention of DR.

Disorders of neurovascular unit in the pathogenesis of diabetic retinopathy

糖尿病视网膜病变（DR）是中老年人群致盲的主要原因之一。目前研究认为DR不仅是微血管疾病，同时也是神经退行性疾病。视网膜神经血管单元（NVU）是视网膜中血管细胞、神经元和胶质细胞功能耦合构成的细胞复合体，在DR的发病过程中NVU各组分发生进行性破坏以及功能障碍。本文就NVU相关研究进展进行阐述，为DR预防与治疗提供新思路。.

An Association Between the Intestinal Permeability Biomarker Zonulin and the Development of Diabetic Retinopathy in Type II Diabetes Mellitus.

Increased intestinal permeability (IP) and gut microbiota dysbiosis have been implicated in low-grade chronic inflammation, which is an important factor in the pathogenesis of diabetic retinopathy (DR). This study aims to demonstrate the relationship between the IP biomarker zonulin and DR in patients with type 2 diabetes mellitus (T2DM). This study was conducted with a total of 89 T2DM patients, including 33 non-DR, 28 with non-proliferative DR (NPDR), and 28 with proliferative DR (PDR), and 32 healthy controls. Zonulin levels were determined from blood samples using an enzyme-linked immunosorbent assay kit. There was no difference between the four groups in terms of age (p=0.236), gender (p=0.952), and body mass index (p=0.134) of the participants. Zonulin levels were significantly higher in the PDR group compared to the other three groups, as well as in the non-DR and NPDR groups compared to the control group. In multivariate logistic regression analysis, zonulin was found to be an independent predictor of DR (odds ratio: 1,781, 95% confidence interval: 1,122-2,829, p=0.014). Our study showed that elevated zonulin levels may play a significant role in the development of DR, particularly during the transition to the proliferative stage. This suggests that regulation of IP could be one of the targets of DR treatment. More studies are needed to determine whether a eubiotic gut microbiota and IP have a direct relationship with DR.

Serum glial fibrillary acidic protein and neurofilament light chain as biomarkers of retinal neurodysfunction in early diabetic retinopathy: results of the EUROCONDOR study.

Neurodegeneration and glial activation are primary events in the pathogenesis of diabetic retinopathy. Serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are biomarkers of underlying neuroinflammatory and neurodegenerative disease processes. The aim of the present study was to assess the usefulness of these serum biomarkers for the identification and monitoring of retinal neurodysfunction in subjects with type 2 diabetes. A case-control study was designed including 38 patients from the placebo arm of the EUROCONDOR clinical trial: 19 with and 19 without retinal neurodysfunction assessed by multifocal electroretinography. GFAP and NfL were measuredby Simoa. Serum levels of GFAP and NfL directly correlated with age (r = 0.37, p = 0.023 and r = 0.54, p < 0.001, respectively). In addition, a direct correlation between GFAP and NfL was observed (r = 0.495, p = 0.002). Serum levels of GFAPwere significantly higher at baseline in those subjects in whom neurodysfunction progressed after the 2years of follow-up (139.1 ± 52.5pg/mL vs. 100.2 ± 54.6pg/mL; p = 0.04). GFAP could be a useful serumbiomarker for retinal neurodysfunction. Monitoring retinal neurodysfunction using blood samples would be of benefit in clinical decision-making. However, further research is needed to validate this result as well as to establish the best cutoff values.

Aberration in myeloid-derived pro-angiogenic cells in type-2 diabetes mellitus; implication for diabetic retinopathy?

Diabetic retinopathy (DR) is a major microvascular complication of type 2 diabetes mellitus (T2DM). Myelomonocytic proangiogenic cells (PAC) have been implicated in DR pathogenesis, but their functional and developmental abnormalities are unclear. In this study we assessed PAC characteristics from healthy controls, T2DM patients with DR (DR) and without (NoDR) in order to determine the consequence of the diabetic condition on PAC phenotype and function, and whether these differ between DR and NoDR patients. PAC were generated by culturing PBMC on fibronectin coating and then immunophenotyped using flow cytometry. Furthermore, cells were sorted based on CD14, CD105, and CD133 expression and added to an in vitro 3-D endothelial tubule formation assay, containing GFP-expressing human retinal endothelial cells (REC), pericytes, and pro-angiogenic growth factors. Tubule formation was quantified by fluorescence microscopy and image analysis. Moreover, sorted populations were analyzed for angiogenic mediator production using a multiplex assay. The expression of CD16, CD105 and CD31, but not CD133, was lower in PAC from T2DM patients with or without DR. Myeloid and non-myeloid T2DM-derived sorted populations increased REC angiogenesis in vitro as compared to control cultures. They also showed increased S100A8 secretion, decreased VEGF-A secretion, and similar levels of IL-8, HGF, and IL-3 as compared to healthy control (HC)-derived cell populations. T2DM PAC are phenotypically and functionally altered compared to PAC from HC. Differences between DR and NoDR PAC are limited. We propose that impaired T2DM PAC provide inadequate vascular support and promote compensatory, albeit pathological, retinal neovascularization.

Safety and Efficacy of Brolucizumab Injection among Patients with Diabetic Retinopathy &amp; DME in a Tertiary Care Hospital– A Prospective Study

Introduction: Diabetic Retinopathy (DR) is the leading cause of vision loss in adults aged 20–74 years. From 1990–2010, DR ranked as the fifth most common cause of preventable blindness and fifth most common cause of moderate to severe visual impairment. Previous research has implicated vascular endothelial growth factor (VEGF) in the pathogenesis of diabetic retinopathy (DR). Antivascular endothelial growth factor (anti-VEGF) therapy has become the treatment of choice for retinal vascular disorders such as diabetic macular edema (DME). Aim of the Study: The aim of this study was to evaluate the safety and efficacy of brolucizumab injection in patients with diabetic retinopathy. Methods: This was a prospective observational study and was conducted in the Department of Ophthalmology of Bangladesh Eye Hospital &amp; Institute Ltd, Dhaka, Bangladesh during the period from February, 2022 to February, 2023. In our study we took 300 patients with diabetic retinopathy &amp; DME. All of them were given 6mg IVI brolucizumab injection. Result: In our study we found majority (35%) of our patients were aged 55-64 years and most of our patients were male (60%).We found the mean age was 56.53± 9.74 years and mean blood glucose was 98.8 ± 1.4 mg/dL. All patients had Type 2 diabetes. We found 20% NPDR, 47.33% PDR &amp; 32.67% DME patients. The mean eye vision of our patients was 66.02± 4.02 and the mean kept reducing significantly till 18th week. Before treatment the mean of OCT was 427.04 ± 18.07 and after treatment we found 413.21 ± 11.12, 384.03 ± 14.02 &amp; 254.19 ± 9.02 at 6th, 12th &amp; 18th week respectively. Conclusion: In our study, we found a few complications of brolucizumab like no improvement of vision, nephropathy, cardiovascular disease was present among our patients. Although there were more adverse effects of brolucizumab but in our study we only found mild uveitis. The administration of anti-VEGF medicines in PDR is an emerging field. Although PRP is considered the first line .....

USP14 Regulates ATF2/PIK3CD Axis to Promote Microvascular Endothelial Cell Proliferation, Migration, and Angiogenesis in Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the leading causes of blindness in diabetic patients. However, the pathogenesis of DR is complex, and no firm conclusions have been drawn so far. It has become a hot spot in ophthalmology research to deeply study the mechanism of DR pathological changes and find effective treatment options. Human retinal microvascular endothelial cells (HRMECs) were induced by high glucose (HG) to construct DR cell model. CCK-8 assay was used to detect the viability of HRMECs. Transwell assay was used to detect the migration ability of HRMECs. Tube formation assay was used to identify the tube formation ability of HRMECs. The expressions of USP14, ATF2 and PIK3CD were detected by Western blot analysis and qRT-PCR assay. Immunoprecipitation (IP) was used to ascertain the relationship of USP14 and ATF2. To explore the regulatory relationship between ATF2 and PIK3CD by dual-luciferase reporter gene assay and Chromatin immunoprecipitation (ChIP) assay. High glucose treatment promoted the proliferation, migration, and tube formation of HRMEC, and the expressions of USP14, ATF2 and PIK3CD were significantly up-regulated. USP14 or ATF2 knockdown inhibited HG-induced HRMECs proliferation, migration, and tube formation. USP14 regulated the expression of ATF2, and ATF2 promoted PIK3CD expression. PIK3CD overexpression attenuated the inhibitory effectiveness of USP14 knockdown on proliferation, migration and tube formation of DR cell model. Here, we revealed that USP14 regulated the ATF2/PIK3CD axis to promote proliferation, migration, and tube formation in HG-induced HRMECs.

Transcriptomic Profiling Reveals Chemokine CXCL1 as a Mediator for Neutrophil Recruitment Associated With Blood-Retinal Barrier Alteration in Diabetic Retinopathy.

Intravitreal CXCL1 injection and diabetes result in increased retinal vascular permeability with neutrophil and monocyte recruitment. Ly6G antibody treatment for neutrophil depletion in both animal models showed decreased retinal permeability and decreased cytokine expression. CXCL1 is produced by retinal endothelial cells, pericytes, and astrocytes. CXCL1 level is significantly increased in serum samples of patients with diabetic retinopathy. CXCL1, through neutrophil recruitment, alters the blood-retinal barrier in diabetic retinopathy and, thus, may be used as a therapeutic target.

Genome-Wide Associations and Confirmatory Meta-Analyses in Diabetic Retinopathy.

The present study aimed to summarize and validate the genomic association signals for diabetic retinopathy (DR), proliferative DR, and diabetic macular edema/diabetic maculopathy. A systematic search of the genome-wide association study (GWAS) catalog and PubMed/MELINE databases was conducted to curate a comprehensive list of significant GWAS discoveries. The top signals were then subjected to meta-analysis using established protocols. The results indicate the need for improved consensus among DR GWASs, highlighting the importance of validation efforts. A subsequent meta-analysis confirmed the association of two SNPs, rs4462262 (ZWINT-MRPS35P3) (odds ratio = 1.38, p = 0.001) and rs7903146 (TCF7L2) (odd ratio = 1.30, p < 0.001), with DR in independent populations, strengthening the evidence of their true association. We also compiled a list of candidate SNPs for further validation. This study highlights the importance of consistent validation and replication efforts in the field of DR genetics. The two identified gene loci warrant further functional investigation to understand their role in DR pathogenesis.

Low serum dehydroepiandrosterone levels are associated with diabetic retinopathy in patients with type 2 diabetes mellitus.

This cross-sectional study assessed the association of serum dehydroepiandrosterone levels with the risk of diabetic retinopathy in patients with type 2 diabetes mellitus in China. Patients with type 2 diabetes mellitus were included in a multivariate logistic regression analysis to assess the association of dehydroepiandrosterone with diabetic retinopathy after adjusting for confounding factors. A restricted cubic spline was also used to model the association of serum dehydroepiandrosterone level with the risk of diabetic retinopathy and to describe the overall dose-response correlation. Additionally, an interaction test was conducted in the multivariate logistic regression analysis to compare the effects of dehydroepiandrosterone on diabetic retinopathy among age, sex, obesity status, hypertension, dyslipidemia, and glycosylated hemoglobin level subgroups. In total, 1,519 patients were included in the final analysis. Low serum dehydroepiandrosterone was significantly associated with diabetic retinopathy in patients with type 2 diabetes mellitus after adjustment for confounding factors (odds ratio [quartile 4 vs quartile 1]: 0.51; 95% confidence interval: 0.32-0.81; P=0.012 for the trend). Additionally, the restricted cubic spline indicated that the odds of diabetic retinopathy decreased linearly as the dehydroepiandrosterone concentration increased (P-overall=0.044; P-nonlinear=0.364). Finally, the subgroup analyses showed that the dehydroepiandrosterone level stably affected diabetic retinopathy (all P for interaction >0.05). Low serum dehydroepiandrosterone levels were significantly associated with diabetic retinopathy in patients with type 2 diabetes mellitus, suggesting that dehydroepiandrosterone contributes to the pathogenesis of diabetic retinopathy.

Aldose reductase gene polymorphism rs752010122 and retinopathy in type 2 diabetics.

To investigate the association of polymorphism in rs752010122 in aldose reductase gene with the pathogenesis of diabetic retinopathy, and to determine the association and allelic frequency between the variant and the disease. The cross-sectional study was conducted from June 2021 to March 2022 at Centre for Research in Experimental and Applied Medicine (CREAM) Laboratory, Department of Biochemistry and Molecular Biology, Army Medical College, in collaboration with the Armed Forces Institute of Ophthalmology, Rawalpindi, Pakistan, and comprised blood samples from subjects of either gender aged 40-70 years. The samples were divided into group I having diabetic retinopathy patients, group II having diabetics without retinopathy, and group III having healthy controls matched for age and gender. The samples were subjected to molecular analysis. Gene sequence was downloaded from the Human Genome Database and Ensemble. Data was analysed using SPSS 22. Of the 150 subjects, there were 50(33.3%) in each of the 3 groups. Variants of aldose reductase rs752010122 polymorphism were significantly associated with a lower risk of diabetic retinopathy (p<0.05). An odds ratio of 1 was noted for both heterozygous and homozygous genotypes (95% confidence interval: 1). Aldose reductase was associated with lower risk of the disease.

Dysregulation of circulating CD4 + CXCR5 + PD-1+ T cells in diabetic retinopathy

AimsWe aimed to determine an association between follicular helper T (Tfh) cells and Bcl-6 and CXCL13 levels and determine the role of Tfh cells, Bcl-6, and CXCL13 serum levels in the pathogenesis of diabetic retinopathy (DR) since Tfh cells have an important role in type 1 diabetes; however, their role in type 2 diabetes-related DR requires exploration. MethodsBlood samples were collected from 24 patients with non-proliferative diabetic retinopathy (NPDR), 20 with proliferative diabetic retinopathy (PDR), and 18 age- and sex-matched healthy volunteers. Flow cytometry detected CD4 + CXCR5 + PD1+ Tfh cells. Serum Bcl-6 and CXCL13 levels were determined using enzyme-linked immunosorbent assay. ResultsCD4 + CXCR5 + PD-1+ Tfh cell percentages in peripheral blood and serum levels of Bcl-6 and CXCL13 in the non-proliferative DR (NPDR) and proliferative DR (PDR) groups' were significantly higher than those in healthy individuals. The proportion of Tfh cells in DR patients' peripheral blood positively correlated with Bcl-6 and CXCL13 serum levels, DR course severity, Fasting blood glucose, glycosylated hemoglobin and body mass index. ConclusionsThe increased circulating Tfh cells, serum Bcl-6 levels, and CXCL13 levels of DR patients with type 2 diabetes suggested that circulating Tfh cells and the germinal center response may have a role in the occurrence and development of DR.

A REVIEW OF ANTI-VEGF AGENTS FOR PROLIFERATIVE DIABETIC RETINOPATHY

Diabetic retinopathy (DR) is commonly known among diabetic patients, which causes blindness. Proliferative diabetic retinopathy (PDR) and macular edema are the most common complications of DR that adversely impact the vision. Many observational and preclinical studies have implicated vascular endothelial growth factor (VEGF) in the pathogenesis of DR, and recent successes with anti-VEGF therapy for age-related macular degeneration (AMD) have prompted research into the application of anti-VEGF drugs to DR. Here we review the numerous early studies that suggest an important potential role for anti-VEGF agents in the management of diabetic retinopathy.

Peripheral Blood Mononuclear Cells from Patients with Type 1 Diabetes and Diabetic Retinopathy Produce Higher Levels of IL-17A, IL-10 and IL-6 and Lower Levels of IFN-γ-A Pilot Study.

Inflammation is key to the pathogenesis of diabetic retinopathy (DR). This prospective study investigated alterations in inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) in 41 people with type 1 diabetes (T1D), sub-grouped into mild non-proliferative DR (mNPDR; n = 13) and active and inactive (each n = 14) PDR. Age/gender-matched healthy controls (n = 13) were included. PBMCs were isolated from blood samples. Intracellular cytokine expression by PBMCs after 16-h stimulation (either E. coli lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate plus ionomycin, D-glucose or D-mannitol) were assessed by flow cytometry. Cytokine production in plasma, non-stimulated and LPS-stimulated PBMC supernatant was also assessed. Increased BMC IL-10 secretion and reduced expression of IL-6 and IFN-γ in CD3+ cells were observed in mNPDR. Reduced IL-6 and IL-10 secretion, and higher levels of intracellular IL-6 expression, especially in CD11b+ PBMCs, was detected in aPDR; levels were positively correlated with DR duration. Patients with T1D demonstrated increased intracellular expression of IL-17A in myeloid cells and reduced IFN-γ expression in CD3+ cells. Plasma levels of IL-1R1 were increased in mNPDR compared with controls. Results suggest that elevated PBMC-released IL-10, IL-6, in particular myeloid-produced IL-17A, may be involved in early stages of DR. IL-6-producing myeloid cells may play a role in PDR development.

Cross Talks between Oxidative Stress, Inflammation and Epigenetics in Diabetic Retinopathy.

Diabetic retinopathy, one of the most devastating complications of diabetes, is a multifactorial progressing disease with a very complex etiology. Although many metabolic, molecular, functional and structural changes have been identified in the retina and its vasculature, the exact molecular mechanism of its pathogenesis still remains elusive. Sustained high-circulating glucose increases oxidative stress in the retina and also activates the inflammatory cascade. Free radicals increase inflammatory mediators, and inflammation can increase production of free radicals, suggesting a positive loop between them. In addition, diabetes also facilitates many epigenetic modifications that can influence transcription of a gene without changing the DNA sequence. Several genes associated with oxidative stress and inflammation in the pathogenesis of diabetic retinopathy are also influenced by epigenetic modifications. This review discusses cross-talks between oxidative stress, inflammation and epigenetics in diabetic retinopathy. Since epigenetic changes are influenced by external factors such as environment and lifestyle, and they can also be reversed, this opens up possibilities for new strategies to inhibit the development/progression of this sight-threatening disease.

Bioinformatics Tools for Bulk Gene Expression Deconvolution in Diabetic Retinopathy.

Retinal neovascularization is one of the leading causes of vision loss and a hallmark of proliferative diabetic retinopathy (PDR). The immune system is observed to be involved in the pathogenesis of diabetic retinopathy (DR). The specific immune cell type that contributes to retinal neovascularization can be identified via a bioinformatics analysis of RNA sequencing (RNA-seq) data, known as deconvolution analysis. Previous study has identified the infiltration of macrophages in the retina of rats with hypoxia-induced retinal neovascularization and patients with PDR through a deconvolution algorithm, known as CIBERSORTx. Here, we describe the protocols of using CIBERSORTx to perform the deconvolution analysis and downstream analysis of RNA-seq data.

Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy.

Diabetic retinopathy, characterized as a microangiopathy and neurodegenerative disease, is the leading cause of visual impairment in diabetic patients. Many clinical features observed in diabetic retinopathy, such as capillary occlusion, acellular capillaries and retinal non-perfusion, aggregate retinal ischemia and represent relatively late events in diabetic retinopathy. In fact, retinal microvascular injury is an early event in diabetic retinopathy involving multiple biochemical alterations, and is manifested by changes to the retinal neurovascular unit and its cellular components. Currently, intravitreal anti-vascular endothelial growth factor therapy is the first-line treatment for diabetic macular edema, and benefits the patient by decreasing the edema and improving visual acuity. However, a significant proportion of patients respond poorly to anti-vascular endothelial growth factor treatments, indicating that factors other than vascular endothelial growth factor are involved in the pathogenesis of diabetic macular edema. Accumulating evidence confirms that low-grade inflammation plays a critical role in the pathogenesis and development of diabetic retinopathy as multiple inflammatory factors, such as interleukin-1β, monocyte chemotactic protein-1 and tumor necrosis factor -α, are increased in the vitreous and retina of diabetic retinopathy patients. These inflammatory factors, together with growth factors such as vascular endothelial growth factor, contribute to blood-retinal barrier breakdown, vascular damage and neuroinflammation, as well as pathological angiogenesis in diabetic retinopathy, complicated by diabetic macular edema and proliferative diabetic retinopathy. In addition, retinal cell types including microglia, Müller glia, astrocytes, retinal pigment epithelial cells, and others are activated, to secrete inflammatory mediators, aggravating cell apoptosis and subsequent vascular leakage. New therapies, targeting these inflammatory molecules or related signaling pathways, have the potential to inhibit retinal inflammation and prevent diabetic retinopathy progression. Here, we review the relevant literature to date, summarize the inflammatory mechanisms underlying the pathogenesis of diabetic retinopathy, and propose inflammation-based treatments for diabetic retinopathy and diabetic macular edema.

Retracted: Identification of lncRNAs Associated with the Pathogenesis of Diabetic Retinopathy: From Sequencing Analysis to Validation via In Vivo and In Vitro Experiments

Retracted: Identification of lncRNAs Associated with the Pathogenesis of Diabetic Retinopathy: From Sequencing Analysis to Validation via <i>In Vivo</i> and <i>In Vitro</i> Experiments

The rs1800469 T/T and rs1800470 C/C genotypes of the TGFB1 gene confer protection against diabetic retinopathy in a Southern Brazilian population.

The transforming growth factor beta 1 (TGFB1) is a pro-inflammatory cytokine that plays a key role in the mechanisms of angiogenesis and breakdown of the blood-retina barrier, which are implicated in the pathogenesis of diabetic retinopathy (DR). Polymorphisms in the TGFB1 gene have been associated with DR; however, results are still contradictory. Therefore, the aim of this study was to investigate the potential association between two TGFB1 polymorphisms and DR. This study included 992 patients with diabetes mellitus (DM): 546 patients with DR (cases) and 446 patients without DR and with ≥10 years of DM (controls). The TGFB1 rs1800469 and rs1800470 polymorphisms were genotyped by real-time PCR. Frequency of rs1800469 T/T genotype was higher in controls compared to DR cases (18.3% vs. 12.7%, P= 0.022). This genotype remained associated with protection for DR, adjusting for covariables (OR= 0.604; 95% CI 0.395 - 0.923; P= 0.020, recessive model). The rs1800470 C/C genotype was observed in 25.4% of the controls and 18.0% of the cases (P= 0.015); thus, being associated with protection against DR under the recessive model (OR= 0.589; 95% CI 0.405 - 0.857; P= 0.006), adjusting for covariables. In conclusion, the TGFB1 rs1800469 and rs1800470 polymorphisms are associated with protection against DR in DM patients from Southern Brazil.