Pathogenesis Of Diabetic Retinopathy Research Articles

Dyslipidemia and reduced retinal layer thicknesses in mild to moderate non-proliferative diabetic retinopathy.

To investigate the changes in ganglion cell layer-inner plexiform layer (GCL-IPL) thickness and its association with peripheral blood indices in non-proliferative diabetic retinopathy (NPDR). In this cross-sectional study, 132 participants were categorized into three groups: 30 healthy volunteers (control group), 50 diabetic patients with non-diabetic retinopathy (NDR group), and 52 patients with NPDR. Optical coherence tomography (OCT) was used to measure the retinal nerve fiber layer (RNFL) and GCL-IPL thicknesses in the macula. The associations between RNFL loss and systemic risk factors for DR, such as diabetes duration, triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and hemoglobin A1c (HbA1c) were evaluated. The average, superior, and nasal thicknesses in the NDR and NPDR groups were significantly thinner compared to the control group (P=0.002, 0.020, 0.090, respectively). Similarly, GCL-IPL thicknesses in the 3 mm and 6 mm zones of the NDR and NPDR groups were thinner than those in the control group (P=0.040, 0.022, 0.037, respectively). Temporal thicknesses in the 3 mm range of the NDR and NPDR groups were also thinner than in the control group (P=0.010). Superior RNFL thickness was positively correlated with HbA1c (r=0.200, P=0.044), and negatively correlated with HDL (r=-0.198, P=0.047). The average inferior and nasal GCL-IPL thicknesses were negatively correlated with TC across the 3 mm zone (r=-0.211, P=0.033; r=-0.224, P=0.023; r=-0.227, P=0.022). Additionally, the average thickness of GCL-IPL in the 6-mm range were positively correlated with the duration of diabetes (r=0.196, P=0.048). This study demonstrates that dyslipidemia in diabetic patients correlates with reductions in RNFL and GCL-IPL thicknesses, suggesting a role in the pathogenesis of diabetic retinopathy.

Biomechanics of diabetic vitreopapillary traction syndrome

Diabetic vitreopapillary traction syndrome (VPT) is a variant of diabetic retinopathy (DR) that can lead to vision loss in advanced stages. This review reports on the biomechanics of the vitreous in the pathogenesis of proliferative DR, in particular diabetic VPT. The article analyzes and summarizes literature data, presents the views of different authors on this problem, and provides the results of Russian and foreign scientific research on this pathology. It is concluded that further research in this area can lead to a significant improvement in the results of therapy, timely diagnosis, and preservation of vision in patients with DR.

Towards the preclinical diagnosis of diabetic retinopathy and diabetic macular oedema using tear samples

Aims/Purpose: A wide spectrum of molecular‐genetic events, including inflammation (INF), angiogenesis (ANG), apoptosis (AP) and the concurrence of miRNAs and target genes, are involved in diabetic retinopathy (DR) and diabetic macular oedema (DMO). To unravel the complex pathogenesis of DR and DMO, we focus on the microvascular endothelial dysfunction (MVED) pathophysiologic pathways.Methods: Volunteers of both sexes, aged 35–80 years were enrolled and distributed into type 2 diabetics (T2DM), with DR (+DRG; n = 35), without DR (−DRG; n = 35), with DMO (DMOG; n = 28), and controls (CG; n = 40). Sociodemographic and comorbid data, ophthalmologic parameters, and molecular‐genetic variables related to INF, ANG, and AP, assayed in tear samples, were recorded. Statistics were performed by the R Core Team (2022) program.Results: Most of our participants were middle‐aged (mean age was 58 ± 11 years). Differential expression profile in tears was found statistically significant for SOCS6 gene (involved in INF) target of hsa‐miR‐155‐5p, VEGF‐A gene (implicated in ANG) target of hsa‐miR‐15b‐5p, and the BCL2L2 gene (AP effector) target of hsa‐miR‐10a‐5p, in both the +DRG and DMOG, as compared to the −DRG and CG.Conclusions: We confirm that INF, ANG, and AP, regulated by the hsa‐miR‐155‐5p, hsa‐miR‐15b‐5p and hsa‐miR‐10a‐5p, and its respective target genes SOCS6, VEGF‐A, and BCL2L2, expressed in tears, are key players in the development of structural and functional chorioretinal changes associated with MVED in DR/DMO patients. We may propose the above insights as potential diagnostic‐prognostic biomarkers for better managing the diabetic eyes and vision.

Neurovascular coupling reflex from contralateral stimulation: System setup

Aims/Purpose: Neurovascular coupling (NVC) is the blood flow modulation in response to stimuli and has been extensively studied in the brain. Concerning the human retina, this behaviour has been only measured in the ipsilateral eye, where stimuli and observed effects involve the same eye. This work aims to set up the hardware to assess NVC in the contralateral eye and demonstrate its feasibility in edifying human retina‐retina or cortico‐retinal connections.Methods: Adaptive optics (AO) is a cutting‐edge technology in retinal fundus imaging, offering exceptional spatial resolution. The NVC effect was successfully assessed using the RTX1, an AO retinal camera capable of ipsilateral stimulation. The possible effects of contralateral stimulation can be readily assessed by providing RTX1 with an external flickering device. Furthermore, connecting the thread between previous fMRI results and photic stimulation in the ipsi‐ and contralateral retina can offer valuable information on uncharted interocular or brain‐retina neural pathways and lead to cost‐effective and non‐invasive biomarkers for neurodegenerative diseases or early brain vasculature impairment diagnosis.Results: Even though further optimization of flicker‐related parameters is necessary to investigate the contralateral NVC response, preliminary tests showed the successful integration of a fully operational contralateral stimulation prototype with the RTX1. The entire procedure has been documented, and all components have been thoroughly evaluated.Conclusions: These preliminary assessments precede a clinical study involving patients with type 1 Diabetes Mellitus and a control group of healthy individuals. It follows previous fMRI studies that showed impaired NVC in type 2 diabetic patients by measuring the BOLD (Blood Oxygen Level‐Dependent) response using block and event‐related optical stimuli. A comparative analysis of the findings aims to demonstrate the potential role of neurovascular uncoupling in the early pathogenesis of diabetic retinopathy.

Okulistyczne aspekty terapii inhibitorami kotransportera sodowo-glukozowego 2. (SGLT-2) – nową grupą leków hipoglikemizujących

Sodium glucose cotransporter 2 is the major protein responsible for glucose reabsorption in the kidneys. Its inhibitors – gliflozins – constitute a new group of hypoglycaemic drugs. The aim of the study is a literature review of ophthalmic aspects of diabetes therapy with the use of this newly introduced group of drugs. Literature data report the expression of the sodium glucose cotransporter 2 not only in the kidneys, but also in non-renal tissues, e.g. in the retina and the lens. Moreover, they indicate its participation in the pathogenesis of diabetic retinopathy. In turn, sodium glucose cotransporter 2 inhibitors, according to the available literature, reduce edema and reduce the loss of pericytes of the retina, and thus may prevent pathological changes occurring in the retina in the course of diabetic retinopathy. The results of clinical trials provide evidence of their effectiveness in the treatment of ocular complications of diabetes, i.e. in preventing the development of diabetic retinopathy, reducing diabetic macular edema, and even inhibiting cataract progression. In addition, the literature provides evidence suggesting a beneficial effect of this new group of hypoglycemic drugs on diabetic retinopathy beyond the control of concentration of blood glucose per se, such as 1. improved energy metabolism, reduction of hypoxia, anti-inflammatory and anti-oxidant effects in the retina by inducing mild ketonemia, 2. as well as a reduction of production of reactive oxygen species via the ERK/1/2/cPLA2/AA/ROS cell pathway. Due to the innovativeness of the topic, the number of literature data in its scope is limited. Therefore, it should be keep in mind that the conclusions may not be complete.

Патогенез, ангиогенез диабетического макулярного отека и общая характеристика его лечения (Обзор литературы. Часть I)

Currently, the increase in the prevalence of diabetes mellitus is in the nature of a pandemic. Diabetic macular edema is a vision-threatening complication of diabetic retinopathy, the pathogenesis of which is multifactorial and includes hyperglycemia, endothelial dysfunction, leukostasis and inflammation, vasoconstriction and occlusion, oxidative stress and ischemia, neovascularization, which leads to the accumulation of exudative fluid, thickening of the central zone of the retina and irreversible processes of photoreceptors neurodegeneration with a significant decrease in visual functions. The article presents up-to-date information on the epidemiology, patho- and angiogenesis of this condition as well as the general characteristics of the DMO therapy. It consists of primary treatment of diabetes, laser photocoagulation and anti-angiogenic therapy. Intravitreal drug therapy based on VEGF inhibitors is currently the standard first-line treatment for DMO. The authors emphasize the necessity for further study of trigger points in the pathogenesis of diabetic retinopathy and the development of diabetic macular edema in order to find new drugs and work out a more individualized approach to patients. Key words:: diabetic retinopathy, diabetic macular edema, vascular endothelial growth factor, VEGF-therapy

Imaging the Retinal Vascular Mural Cells In Vivo: Elucidating the Timeline of Their Loss in Diabetic Retinopathy.

Vascular mural cells (VMCs) are integral components of the retinal vasculature with critical homeostatic functions such as maintaining the inner blood-retinal barrier and vascular tone, as well as supporting the endothelial cells. Histopathologic donor eye studies have shown widespread loss of pericytes and smooth muscle cells, the 2 main VMC types, suggesting these cells are critical to the pathogenesis of diabetic retinopathy (DR). There remain, however, critical gaps in our knowledge regarding the timeline of VMC demise in human DR. In this study, we address this gap using adaptive optics scanning laser ophthalmoscopy to quantify retinal VMC density in eyes with no retinal disease (healthy), subjects with diabetes without diabetic retinopathy, and those with clinical DR and diabetic macular edema. We also used optical coherence tomography angiography to quantify capillary density of the superficial and deep capillary plexuses in these eyes. Our results indicate significant VMC loss in retinal arterioles before the appearance of classic clinical signs of DR (diabetes without diabetic retinopathy versus healthy, 5.0±2.0 versus 6.5±2.0 smooth muscle cells per 100 µm; P<0.05), while a significant reduction in capillary VMC density (5.1±2.3 in diabetic macular edema versus 14.9±6.0 pericytes per 100 µm in diabetes without diabetic retinopathy; P=0.01) and capillary density (superficial capillary plexus vessel density, 37.6±3.8 in diabetic macular edema versus 45.5±2.4 in diabetes without diabetic retinopathy; P<0.0001) is associated with more advanced stages of clinical DR, particularly diabetic macular edema. Our results offer a new framework for understanding the pathophysiologic course of VMC compromise in DR, which may facilitate the development and monitoring of therapeutic strategies aimed at VMC preservation and potentially the prevention of clinical DR and its associated morbidity. Imaging retinal VMCs provides an unparalleled opportunity to visualize these cells in vivo and may have wider implications in a range of diseases where these cells are disrupted.

Tear and serum levels of the neuromarker BDNF in type 2 diabetes mellitus patients with and without diabetic retinopathy

Background: Numerous studies have been conducted to examine the growth factors capable of exerting simultaneous effects on the vascular and metabolic components of the pathogenesis of diabetic retinopathy (DR).Purpose: To examine tear and serum brain-derived neurotrophic factor (BDNF) levels in type 2 diabetes mellitus (DM2) patients with and without DR.Material and Methods: One hundred and seventy patients with DM2 and 84 practically healthy individuals without any eye disease (totally, 254 individuals and 504 eyes) were included in the study. Of the total individuals included in the study, 49.2% were males and 50.8% were females. The mean age plus or minus standard deviation was 67 ± 4.2 years for men and 64 ± 5.6 years for women.Results: It was found that tear BDNF levels lower than 97.5 pg/ml and serum BDNF levels lower than 23.8 ng/ml indicate the transition to DR, whereas tear BDNF levels lower than 62.0 pg/ml and serum BDNF levels lower than 12.0 ng/ml indicate the development of proliferative DR.Conclusion: Mean serum BDNF levels as low as below 23.8 ± 1.33 ng/ml and mean tear BDNF levels as low as below 97.5 ± 5.57 pg/ml are an early sign of DR.

Oxidative Stress Mediates Epigenetic Modifications and the Expression of miRNAs and Genes Related to Apoptosis in Diabetic Retinopathy Patients.

Knowledge on the underlying mechanisms and molecular targets for managing the ocular complications of type 2 diabetes mellitus (T2DM) remains incomplete. Diabetic retinopathy (DR) is a major cause of irreversible visual disability worldwide. By using ophthalmological and molecular-genetic approaches, we gathered specific information to build a data network for deciphering the crosslink of oxidative stress (OS) and apoptosis (AP) processes, as well as to identify potential epigenetic modifications related to noncoding RNAs in the eyes of patients with T2DM. A total of 120 participants were recruited, being classified into two groups: individuals with T2MD (T2MDG, n = 67), divided into a group of individuals with (+DR, n = 49) and without (-DR, n = 18) DR, and a control group (CG, n = 53). Analyses of compiled data reflected significantly higher plasma levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) and significantly lower total antioxidant capacity (TAC) in the +DR patients compared with the -DR and the CG groups. Furthermore, the plasma caspase-3 (CAS3), highly involved in apoptosis (AP), showed significantly higher values in the +DR group than in the -DR patients. The microRNAs (miR) hsa-miR 10a-5p and hsa-miR 15b-5p, as well as the genes BCL2L2 and TP53 involved in these pathways, were identified in relation to DR clinical changes. Our data suggest an interaction between OS and the above players in DR pathogenesis. Furthermore, potential miRNA-regulated target genes were identified in relation to DR. In this concern, we may raise new diagnostic and therapeutic challenges that hold the potential to significantly improve managing the diabetic eye.

HAGLR, stabilized by m6A modification, triggers PTEN-Akt signaling cascade-mediated RPE cell pyroptosis via sponging miR-106b-5p.

Consistent hyperglycaemia on retinal microvascular tissues is recognized as a vital inducer of diabetic retinopathy (DR) pathogenesis. In view of the essential functionality of long noncoding RNAs (lncRNAs) in multiple human diseases, we aim to figure out the exact role and underlying mechanisms of lncRNA HOXD Cluster Antisense RNA 1 (HAGLR) in DR pathogenesis. Serum specimens from patients with proliferative DR and healthy volunteers were collected for measuring HAGLR levels. Human primary retinal pigment epithelium (HRPE) cells kept in high glucose (HG) condition were applied to simulating hyperglycaemia of DR pathology in vitro. Cell proliferation, apoptosis, either pyroptosis was assess using Cell Counting Kit-8 TUNEL, flow cytometry, and enzyme-linked immunoassay assays. Bioinformatics analysis was subjected to examine the interaction between HAGLR and N6-methyladenosine (m6A)-bind protein IGF2BP2, as determined using RNA immunoprecipitation and RNA pull-down. Luciferase reporter assay was performed to assess the HAGLR-miR-106b-5p-PTEN axis. Levels of pyroptosis-associated biomarkers were detected using western blotting. Aberrantly overexpressed HAGLR was uncovered in the serum samples of DR patients and HG-induced HRPE cells, of which knockdown attenuated HG-induced cytotoxic impacts on cell apoptosis and pyroptosis. Whereas, reinforced HAGLR further aggravated these effects. IGF2BP2 positively regulated HAGLR in a m6A-dependent manner. HAGLR served as a sponge for miR-106b-5p to upregulate PTEN, thereby activating Akt signaling cascade. Rescue assays demonstrated that PTEN overexpression abolished the inhibition of silenced HAGLR on pyroptosis in HRPE cells. HAGLR, epigenetically modified by IGF2BP2 in an m6A-dependent manner, functioned as a sponge for miR-106b-5p, thereby activating PTEN/Akt signaling cascade to accelerate DR pathology.

Diabetes Modulates Iodothyronine Deiodinase 2 Expression in the Mouse Retina: A Role for Thyroid Hormone in the Pathogenesis of Diabetic Retinopathy.

Clinical investigations associate hypothyroidism with an increased risk for microvascular complications, yet the mechanism by which thyroid hormone regulates the development of diabetic retinopathy is not clearly understood. We investigated the role of iodothyronine deiodinase 2 (DIO2) in the pathogenesis of diabetic retinopathy. Retinas from streptozotocin-induced diabetic and nondiabetic mice were evaluated by RNA sequencing, RT-PCR, and immunostaining. Media and cell lysates from mouse retinal microvascular endothelial cells and retinal astrocytes exposed to physiologic (5mM) and high glucose (25 mM) containing media were assessed by liquid chromatography-tandem mass spectrometry to measure tetraiodothyronine (T4) and tri-iodothyronine (T3) concentrations and by Western blot analysis to determine the relationship of T4/T3 to oxidative stress and inflammatory mediators. Cell death was determined by Trypan Blue exclusion assay. At 12 weeks of diabetes duration, retinas from diabetic mice compared with nondiabetic mice demonstrated a significant decrease in Dio2 transcripts and Dio2 gene and protein (P < 0.05) expression. When cultured in the presence of high glucose, both mouse retinal astrocytes and microvascular endothelial cells demonstrated a significant reduction of DIO2 protein compared with cells cultured in physiologic glucose. High glucose inhibited generation of T3, leading to a significantly increased T4/T3 (P < 0.0079). Supplementation of cells with T3, but not T4, prevented the high glucose-induced rise in endothelial nitric oxide synthase, intercellular cell adhesion molecule 1, and endothelial cell death (P < 0.0079). Decreased intraretinal T3 owing to diabetes-induced loss of DIO2 may lead to dysfunction and death of cells in the retina, thereby contributing to the pathogenesis of early diabetic retinopathy.

Mechanical Regulation of Retinal Vascular Inflammation and Degeneration in Diabetes.

Vascular inflammation is known to cause degeneration of retinal capillaries in early diabetic retinopathy (DR), a major microvascular complication of diabetes. Past studies investigating these diabetes-induced retinal vascular abnormalities have focused primarily on the role of molecular or biochemical cues. Here we show that retinal vascular inflammation and degeneration in diabetes are also mechanically regulated by the increase in retinal vascular stiffness caused by overexpression of collagen-crosslinking enzyme lysyl oxidase (LOX). Treatment of diabetic mice with LOX inhibitor β-Aminopropionitrile (BAPN) prevented the increase in retinal capillary stiffness, vascular ICAM-1 overexpression, and leukostasis. Consistent with these anti-inflammatory effects, BAPN treatment of diabetic mice blocked the upregulation of proapoptotic caspase-3 in retinal vessels, which concomitantly reduced retinal capillary degeneration, pericyte ghost formation, and the diabetes-induced loss of contrast sensitivity in these mice. Finally, our in vitro studies indicate that retinal capillary stiffening is sufficient to increase the adhesiveness and neutrophil elastase-induced death of retinal endothelial cells. By uncovering a link between LOX-dependent capillary stiffening and the development of retinal vascular and functional defects in diabetes, these findings offer a new insight into DR pathogenesis that has important translational potential.

Blockade of interleukin-6 trans-signaling prevents mitochondrial dysfunction and cellular senescence in retinal endothelial cells

Interleukin-6 (IL-6) is a multifaceted cytokine implicated in the pathogenesis of diabetic retinopathy (DR). Its activity extends through cis- and trans-signaling (TS) pathways, with cis-signaling limited to specific cell types possessing the membrane-bound IL-6 receptor, while trans-signaling broadly activates various cells without the membrane bound IL-6 receptor, including retinal endothelial cells. In this study, we determined the effects of interleukin-6 trans-signaling on mitochondrial dysfunction and cellular senescence in human retinal endothelial cells (HRECs). HRECs were cultured and treated with IL-6 + soluble IL-6R or Hyper IL-6 to activate trans-signaling, along with sgp130Fc for inhibition. RT-PCR was used to analyze gene expression changes associated with inflammation and senescence. Cellular senescence was assessed using SA β-gal staining. Mitochondrial function was evaluated using Seahorse XFe24 Bioanalyzer. IL-6 trans-signaling induced inflammatory gene expression as indicated by the upregulation of ICAM1, MCP1, and SERPINA3 levels. Additionally, it reduced mitochondrial respiration and oxidative phosphorylation, and these effects were counteracted by sgp130Fc. Moreover, IL-6 trans-signaling led to altered expression of apoptosis-associated genes, including downregulation of FIS1, BCL2, and MCL1, while promoting cellular senescence, a phenomenon mitigated by sgp130Fc. These results not only deepen our understanding of IL-6 in DR but also carry broader implications for age-related diseases and the aging process itself. This study underscores the potential therapeutic value of targeting IL-6 trans-signaling with sgp130Fc as a promising anti-inflammatory approach for DR and potentially other inflammatory conditions. Further in-vivo investigations are warranted to elucidate the function of IL-6 trans-signaling in aging-related pathologies and overall organismal health.

Identification of miRNA-mRNA Regulatory Networks Associated with Diabetic Retinopathy using Bioinformatics Analysis.

Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of visual loss. This study aimed to explore biomarkers for DR that may provide additional reference to DR pathogenesis and development. The differentially expressed genes (DEGs) between the DR and control samples in the GSE53257 dataset were identified. Logistics analyses were performed to identify DR-associated miRNAs and genes, and correlation analysis was performed to determine the correlation between them in GSE160306. A total of 114 DEGs in DR were identified in GSE53257. Three genes, including ATP5A1 (down), DAUFV2 (down), and OXA1L (down), were differentially expressed between DR and control samples in GSE160306. Univariate logistics analysis identified that ATP5A1 (OR=0.007, p = 1.40E-02), NDUFV2 (OR = 0.003, p = 6.40E-03), and OXA1L (OR = 0.093, p = 3.08E-02) were DR-associated genes. ATP5A1 and OXA1L were regulated by multiple miRNAs, of which hsa-let- 7b-5p (OR = 26.071, p = 4.40E-03) and hsa-miR-31-5p (OR = 4.188, p = 5.09E-02) were related to DR. ATP5A1 and OXA1L were closely correlated with each other in DR. The hsa-miR-31-5p-ATP5A1 and hsa-let-7b-5p-OXA1L axes might play novel and important roles in the pathogenesis and development of DR.

Dysregulated CD200-CD200R signaling in early diabetes modulates microglia-mediated retinopathy.

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.

Association of inflammation-related markers and diabetic retinopathy severity in the aqueous humor, but not serum of type 2 diabetic patients.

Diabetic retinopathy (DR) is a frequent microvascular complication of diabetes mellitus, and inflammatory pathways have been linked to its pathogenesis. In this retrospective, observational pilot study, we aimed to compare the concentrations of four inflammation-related proteins, ZAG, Reg-3a, elafin and RBP-4, in the serum and aqueous humor of healthy controls and diabetic patients with different stages of DR. The concentrations of VEGF-A, IL-8, IL-6 were determined in parallel as internal controls. In the serum, we did not find significant differences in the concentrations of target proteins. In the aqueous humor, higher levels of ZAG, RBP-4, Reg-3a and elafin were observed in advanced nonproliferative DR (NPDR)/ proliferative DR (PDR) compared to controls. The levels of ZAG and RBP-4 were also higher in advanced NPDR/PDR than in nonapparent DR. Normalization of target protein concentrations to the aqueous humor total protein demonstrates that a spill-over from serum due to breakage of the blood-retina barrier only partially accounts for increased inflammation related markers in later stages. In conclusion, we found elevated levels of Reg-3a, RBP-4, elafin and ZAG in advanced stages of diabetic retinopathy. Higher levels of pro-inflammatory proteins, Reg-3a and RBP-4, might contribute to the pathogenesis of diabetic retinopathy, as the parallel increased concentrations of anti-inflammatory molecules elafin and ZAG might indicate a compensatory mechanism.

Highly-Expressed MiR-221-3p Distinctly Increases the Incidence of Diabetic Retinopathy in Patients With Type 2 Diabetes Mellitus.

Diabetic retinopathy (DR) is the leading cause of blindness in patients with diabetes mellitus (DM). MiR-221-3p is implicated in microvascular dysfunction in DR, and we explored their relationship. Patients with type 2 diabetes mellitus (T2DM) were allocated to the non-DR (NDR)/nonproliferative DR (NPDR)/proliferative DR (PDR) groups, with their clinical baseline and pathological data collected. The miR-221-3p and VEGF levels were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and ELISA, respectively. Peripheral blood endothelial progenitor cell (EPC) and endothelial cell (EC) ratios were ascertained by flow cytometry. The correlations between miR-221-3p levels and VEGF/EPCs/ECs, the predictive value of serum miR-221-3p levels in DR, and the independent risk factors for DR occurrence in T2DM were analyzed by Pearson's correlation analysis, receiver operating characteristic (ROC) curve, and multifactorial logistic regression analysis. Serum miR-221-3p was highly expressed in DR. Clinical severity of DR was positively correlated with miR-221-3p levels. Endothelial function was impaired in DR. Serum miR-221-3p levels in DR were favorably correlated with VEGF and ECs and negatively associated with EPCs. The area under the curve of serum miR-221-3p in evaluating DR occurrence in patients with T2DM was 0.8178 (1.235 cutoff value, 69.62% sensitivity, and 82.35% specificity). High expression of miR-221-3p increased DR incidence in patients with T2DM. Diabetes course, VEGF, EPCs, ECs, and miR-221-3p levels were independent risk factors for DR development in patients with T2DM. Serum miR-221-3p levels in patients with DR were positively correlated with VEGF and ECs and negatively linked with EPCs. Highly expressed miR-221-3p distinctly increased DR incidence in patients with T2DM and was an independent risk factor for DR development in patients with T2DM. This study assessed serum miR-221-3p level and endothelial function indicators (VEGF, EPCs, and ECs) in patients with DR and analyzed the correlation between each indicator. We found that high serum miR-221-3p expression prominently increased the incidence of DR in patients with T2DM and was an independent risk factor for the development of DR in patients with T2DM. This study provided a scientific basis for further clarification of the pathogenesis of DR, and also provided new ideas for clinical prediction and management of DR.

NEDD4L Promotes IκBα Ubiquitination and Degradation in the Pathogenesis of Diabetic Retinopathy

Purpose The dysregulation of NF-κB signaling activity plays an important role in the pathogenesis of diabetic retinopathy (DR). This study explored the association between NEDD4L and IκBα in DR. Methods The rat model of diabetes was established and altered retinal vascular permeability in these rats was examined through an Evans blue dye assay. A range of glucose concentrations were used to treat retinal vascular endothelial cells (RVECs). The cells viability and apoptosis were assessed through MTT and flow cytometry, while shifts in cell permeability were examined by transendothelial resistance (TEER) and FITC dextran assay. The interaction of NEDD4L and IκBα was tested by Co-IP, while mRNA and protein levels were assessed via qPCR and Western blotting, respectively. Results High glucose suppressed proliferative activity of RVECs, and promoted apoptosis and the protein level of NEDD4L and NF-κB p65, but decreased IκBα. NEDD4L knockdown reversed the changes in inflammation, oxidative stress, and permeability in RVECs exposed to high glucose. Similarly, NEDD4L silencing reverted observed TEER decreases, increased monolayer permeability to FITC dextran, and ZO-1 and Claudin-5 downregulation in response to high glucose. Conversely, the impact of NEDD4L overexpression was reversed by the NF-κB inhibitor PDTC treatment. NEDD4L induced the ubiquitination of IκBα in an IKK-2-dependent manner. Moreover, siNEDD4L treatment alleviated the symptoms of DR through the inactivation of NF-κB signaling in vivo. Conclusions NEDD4L could enhance inflammation, oxidative stress, and permeability in the retinal vascular endothelium by facilitating the ubiquitination of IκBα in an IKK-2-dependent manner. Our results support a role for NEDD4L in the pathogenesis of DR.

Hyperlipidemia and lipid-lowering therapy in diabetic retinopathy (DR): A bibliometric study and visualization analysis in 1993–2023

BackgroundDiabetic retinopathy (DR) is a common complication in diabetic patients. DR is also a neurodegenerative disease. Patients with hyperglycemia, hyperlipidemia, and hypertension are vulnerable to retinopathy development. While the roles of blood glucose and blood pressure in the development of retinopathy have been extensively studied, the relationship between body fat and DR pathogenesis and the impact of lipid-reducing drugs on DR has just emerged as a research hotspot in DR study. We aim to visualize the contributions and cooperation of reporters, organizations, and nations, in addition to the research hotspots and trends in DR-related lipid research from 1993 to 2023, by bibliometric analysis. MethodsWe extracted all publications about DR-related lipid research from 1993 to 2023 from the Web of Science Core Collection, and bibliometric features were studied using VOSviewer and the CiteSpace program. Results1402 documents were retrieved. The number of studies has risen consistently for three decades, from an average of 16.8/year in the 1990s to 28.8/year in the 2000s, 64.5/year in 2010s, and reached 112/year in 2020–2022, confirming they are hot research topic in the field. These reports were from 93 nations/regions, with the USA, China, Japan, Australia, and England taking the leading positions. Diabetes Research and Clinical Practice was the journal that published the most studies, and Diabetes Care was the most quoted. We identified 6979 authors, with Wong TY having the most papers and being the most commonly co-cited. The most popular keyword, according to our research, is diabetic retinopathy. Oxidative stress, diabetic macular edema (DME), lipid peroxidation, and other topics have often been investigated. ConclusionDR-related lipid research is conducted mainly in North America, Asia, Oceania, and Europe. Much study has centered on the relationship between lipid-lowering therapy and DR pathogenesis. These studies strongly support using lipid-reducing medications (fenofibrate, statins, and omega-3 PUFAs), combined with hyperglycemia and hypertension therapy, to prevent and treat DR. However, the impact of fenofibrate or statin on retinopathy is not correlated with their action on blood lipid profiles. Thus, more randomized clinical trials with primary endpoints related to DR in T1D or T2D are merited. In addition, the lipid biomarker for DR (lipid aldehydes, ALEs, and cholesterol crystals), the action of lipid-reducing medicines on retinopathy, the mechanism of lipid-lowering medications preventing or curing DR, and ocular delivery of lipid-lowering drugs to diabetic patients are predicted as the research focus in the future in the DR-related lipid research field.

Associations of levels of high-molecular-weight adiponectin, secreted frizzled-related protein 5 and vascular endothelial growth factor-165 with diabetic retinopathy

Abstract Background: The pathogenesis of diabetic retinopathy (DR) remains unclear. The aim of the study was to explore the associations of DR with the levels of high-molecular-weight adiponectin (HMW-ADP), secreted frizzled-related protein 5 (SFRP-5) as well as vascular endothelial growth factor-165 (VEGF165). Methods: Based on the diagnostic criteria for DR, non-DR (NDR), proliferative DR (PDR) plus non-proliferative DR (NPDR) groups were set up for type 2 diabetes mellitus (T2DM) patients (n=180) treated from January 2020 to March 2021. The control group consisted of another 60 healthy subjects undergoing physical examinations. Their clinical data were compared. Receiver operating characteristic curves were plotted to assess the predictive values of HMW-ADP, VEGF165 and SFRP-5 for DR. The predictive efficiency of the established nomogram model was assessed. Results: The differences in age, fasting plasma glucose (FPG), T2DM duration, triglyceride (TG), hypertension history, high-density lipoprotein cholesterol (HDL-C), glycosylated haemoglobin (HbA1c), serum creatinine (Scr), homeostasis model assessment of insulin resistance (HOMA-IR), urine acid (UA), SFRP-5 HMW-ADP, and VEGF165 were significant between control and DR groups (P&lt;0.05). HMW-ADP, VEGF165 and SFRP-5 had predictive values for DR (AUC&gt;0.7), and the predictive efficiency of their combination was highest. The duration of T2DM, Scr, UA and VEGF165 were independent risk factors for DR, while HMW-ADP and SFRP-5 were protective factors (P&lt;0.05). Preferable discrimination and accuracy together with clinical applicability were obtained for the nomogram prediction model. Conclusions: The three indicators as a whole have a high predictive value for DR, as potential indicators for the clinical screening of high-risk groups.