Deciphering Müller cell heterogeneity signatures in diabetic retinopathy across species: an integrative single-cell analysis.

Diabetic retinopathy (DR), a leading cause of visual impairment, demands a profound comprehension of its cellular mechanisms to formulate effective therapeutic strategies. Our study presentes a comprehensive single-cell analysis elucidating the intricate landscape of Müller cells within DR, emphasizing their nuanced involvement. Utilizing scRNA-seq data from both Sprague-Dawley rat models and human patients, we delineated distinct Müller cell clusters and their corresponding gene expression profiles. These findings were further validated through differential gene expression analysis utilizing human transcriptomic data. Notably, certain Müller cell clusters displayed upregulation of the Rho gene, implying a phagocytic response to damaged photoreceptors within the DR microenvironment. This phenomenon was consistently observed across species. Additionally, the co-expression patterns of RHO and PDE6G within Müller cell clusters provided compelling evidence supporting their potential role in maintaining retinal integrity during DR. Our results offer novel insights into the cellular dynamics of DR and underscore Müller cells as promising therapeutic targets for preserving vision in retinal disorders induced by diabetes.

IL-10-induced modulation of macrophage polarization suppresses outer-blood-retinal barrier disruption in the streptozotocin-induced early diabetic retinopathy mouse model.

Diabetic retinopathy (DR) is associated with ocular inflammation leading to retinal barrier breakdown, vascular leakage, macular edema, and vision loss. DR is not only a microvascular disease but also involves retinal neurodegeneration, demonstrating that pathological changes associated with neuroinflammation precede microvascular injury in early DR. Macrophage activation plays a central role in neuroinflammation. During DR, the inflammatory response depends on the polarization of retinal macrophages, triggering pro-inflammatory (M1) or anti-inflammatory (M2) activity. This study aimed to determine the role of macrophages in vascular leakage through the tight junction complexes of retinal pigment epithelium, which is the outer blood-retinal barrier (BRB). Furthermore, we aimed to assess whether interleukin-10 (IL-10), a representative M2-inducer, can decrease inflammatory macrophages and alleviate outer-BRB disruption. We found that modulation of macrophage polarization affects the structural and functional integrity of ARPE-19 cells in a co-culture system under high-glucose conditions. Furthermore, we demonstrated that intravitreal IL-10 injection induces an increase in the ratio of anti-inflammatory macrophages and effectively suppresses outer-BRB disruption and vascular leakage in a mouse model of early-stage streptozotocin-induced diabetes. Our results suggest that modulation of macrophage polarization by IL-10 administration during early-stage DR has a promising protective effect against outer-BRB disruption and vascular leakage. This finding provides valuable insights for early intervention in DR.

Association between biological aging and diabetic retinopathy.

The impact of aging on diabetic retinopathy (DR) remains underestimated. The current study aimed to investigate the association between biological aging and DR, in contrast to chronological age (CA). Using the National Health and Nutrition Survey data from 2005 to 2008. Biological aging was evaluated through the biological age (BA) and phenotypic age (PA), which were calculated from clinical markers. DR was identified in participants with diabetes mellitus (DM) when they exhibited one or more retinal microaneurysms or retinal blot hemorrhages under retinal imaging, with or without the presence of more severe lesions. Survey-weighted multivariable logistic regression was performed, and the regression model was further fitted using restricted cubic splines. The discriminatory capability and clinical utility of the model were evaluated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). Based on weighted analyses, of the 3100 participants included in this study, of which 162 had DR. In the adjusted model, BA (odds ratio [OR] = 1.12, 95% CI, 1.06-1.18) and PA (OR = 1.11, 95% CI, 1.07-1.14) were associated with DR, while CA was not significantly (OR = 1.01, 95% CI, 0.99-1.03). Narrowing the analysis to DM participants and adjusting for factors like insulin showed similar results. ROC and DCA analyses indicate that BA/PA predicted DR better than CA and offer greater clinical utility. The positive association between BA/PA and DR was consistent across subgroups despite potential interactions. Biological aging heightens DR risk, with BA/PA showing a stronger association than CA. Our findings underscored the importance of timely anti-aging interventions for preventing DR.

Unveiling the crucial role of intercellular adhesion molecule-1 in secondary diabetic complications.

Diabetes mellitus is associated with secondary complications such as diabetic retinopathy (DR), nephropathy (DN), and cardiomyopathy (DCM), all of which significantly impact patient health. Intercellular adhesion molecule-1 (ICAM-1) has been implicated in inflammatory responses and endothelial dysfunction, both crucial in the pathogenesis of these complications. The goal of this review is to investigate at potential therapy methods that target ICAM-1 pathways and to better understand the multifaceted role of ICAM-1 in secondary diabetic problems. A meticulous analysis of scholarly literature published globally was conducted to examine ICAM-1involvement in inflammatory processes, endothelial dysfunction, and oxidative stress related to diabetes and its complications. Elevated ICAM-1 levels are strongly associated with augmented leukocyte adhesion, compromised microvascular function, and heightened oxidative stress in diabetes. These pathways contribute significantly to DR, DN, and DCM pathogenesis, highlighting ICAM-1 as a key player in their progression. Understanding ICAM-1 role in secondary diabetic complications offers insights into novel therapeutic strategies. Targeting ICAM-1 pathways may mitigate inflammation, improve endothelial function, and ultimately attenuate diabetic complications, thereby enhancing patient health outcomes. Continued research in this area is crucial for developing effective targeted therapies.

MSC-derived small extracellular vesicles mitigate diabetic retinopathy by stabilizing Nrf2 through miR-143-3p-mediated inhibition of neddylation.

Diabetic retinopathy (DR) is a highly hazardous and widespread complication of diabetes mellitus (DM). The accumulated reactive oxygen species (ROS) play a central role in DR development. The aim of this research was to examine the impact and mechanisms of mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEV) on regulating ROS and retinal damage in DR. Intravitreal injection of sEV inhibited Cullin3 neddylation, stabilized Nrf2, decreased ROS, reduced retinal inflammation, suppressed Müller gliosis, and mitigated DR. Based on MSC-sEV miRNA sequencing, bioinformatics software, and dual-luciferase reporter assay, miR-143-3p was identified to be the key effector for MSC-sEV's role in regulating neural precursor cell expressed developmentally down-regulated 8 (NEDD8)-mediated neddylation. sEV were able to be internalized by Müller cells. Compared to advanced glycation end-products (AGEs)-induced Müller cells, sEV coculture decreased Cullin3 neddylation, activated Nrf2 signal pathway to combat ROS-induced inflammation. The barrier function of endothelial cells was impaired when endothelial cells were treated with the supernatant of AGEs-induced Müller cells, but was restored when treated with supernatant of AGEs-induced Müller cells cocultured with sEV. The protective effect of sEV was, however, compromised when miR-143-3p was inhibited in sEV. Moreover, the protective efficacy of sEV was diminished when NEDD8 was overexpressed in Müller cells. These findings showed MSC-sEV delivered miR-143-3p to inhibit Cullin3 neddylation, stabilizing Nrf2 to counteract ROS-induced inflammation and reducing vascular leakage. Our findings suggest that MSC-sEV may be a potential nanotherapeutic agent for DR, and that Cullin3 neddylation could be a new target for DR therapy.

Reduced light exposure mitigates streptozotocin-induced vascular changes and gliosis in diabetic retina by an anti-inflammatory effect and increased retinal cholesterol turnover.

Diabetic retinopathy is not cured efficiently and changes of lifestyle measures may delay early retinal injury in diabetes. The aim of our study was to investigate the effects of reduced daily light exposure on retinal vascular changes in streptozotocin (STZ)-induced model of DM with emphasis on inflammation, Aqp4 expression, visual cycle and cholesterol metabolism-related gene expression in rat retina and RPE. Male Wistar rats were divided into the following groups: 1. control; 2. diabetic group (DM) treated with streptozotocin (100 mg/kg); 3. group exposed to light/dark cycle 6/18 h (6/18); 4. diabetic group exposed to light/dark cycle 6/18 h (DM+6/18). Retinal vascular abnormalities were estimated based on lectin staining, while the expression of genes involved in the visual cycle, cholesterol metabolism, and inflammation was determined by qRT-PCR. Reduced light exposure alleviated vasculopathy, gliosis and the expression of IL-1 and TNF-α in the retina with increased perivascular Aqp4 expression. The expression of genes involved in visual cycle and cholesterol metabolism was significantly up-regulated in RPE in DM+6/18 vs. DM group. In the retina only the expression of APOE was significantly higher in DM+6/18 vs. DM group. Reduced light exposure mitigates vascular changes and gliosis in DM via its anti-inflammatory effect, increased retinal cholesterol turnover and perivascular Aqp4 expression.

The impact of sestrin2 on reactive oxygen species in diabetic retinopathy.

Diabetic retinopathy (DR) is a significant complication of diabetes that often leads to blindness, impacting Müller cells, the primary retinal macroglia involved in DR pathogenesis. Reactive oxygen species (ROS) play a crucial role in the development of DR. The objective of this study was to investigate the involvement of sestrin2 in DR using a high-glucose (HG)-induced Müller cell model and assessing cell proliferation with 5-ethynyl-2-deoxyuridine (EdU) labeling. Following this, sestrin2 was upregulated in Müller cells to investigate its effects on ROS, tube formation, and inflammation both in vitro and in vivo, as well as its interaction with the nuclear factor erythroid2-related factor 2 (Nrf2) signaling pathway. The findings demonstrated a gradual increase in the number of EdU-positive cells over time, with a subsequent decrease after 72 h of exposure to high glucose levels. Additionally, the expression of sestrin2 exhibited a progressive increase over time, followed by a decrease at 72 h. The rh-sestrin2 treatment suppressed the injury of Müller cells, decreased ROS level, and inhibited the tube formation. Rh-sestrin2 treatment enhanced the expression of sestrin2, Nrf2, heme oxygenase-1 (HO-1), and glutamine synthetase (GS); however, the ML385 treatment reversed the protective effect of rh-sestrin2. Finally, we evaluated the effect of sestrin2 in a DR rat model. Sestrin2 overexpression treatment improved the pathological injury of retina and attenuated the oxidative damage and inflammatory reaction. Our results highlighted the inhibitory effect of sestrin2 in the damage of retina, thus presenting a novel therapeutic sight for DR.

TIN2-mediated reduction of mitophagy induces RPE senescence under high glucose.

The telomere-associated protein TIN2 localizes to both telomeres and mitochondria. Nevertheless, the impact of TIN2 on retinal pigment epithelial (RPE) cells in diabetic retinopathy (DR) remains unclear. This research aims to examine the role of TIN2 in the senescence of RPE and its potential as a therapeutic target. Western blotting and immunofluorescence staining were utilized to identify TIN2 expression and mitophagy. RT-qPCR was employed to identify senescent associated secretory phenotype (SASP) in ARPE-19 cells infected with TIN2 overexpression. To examine mitochondria and the cellular senescence of RPE, TEM, SA-ß-gal staining, and cell cycle analysis were used. The impact of TIN2 was examined using OCT and immunohistochemistry in mice. DHE staining and ZO-1 immunofluorescence were applied to detect RPE oxidative stress and tight junctions. Our research revealed that increased mitochondria-localized TIN2 aggravated the cellular senescence of RPE cells both in vivo and in vitro under hyperglycemia. TIN2 overexpression stimulated the mTOR signaling pathway in ARPE-19 cells and exacerbated the inhibition of mitophagy levels under high glucose, which can be remedied through the mTOR inhibitor, rapamycin. Knockdown of TIN2 significantly reduced senescence and mitochondrial oxidative stress in ARPE-19 cells under high glucose and restored retinal thickness and RPE cell tight junctions in DR mice. Our study indicates that increased mitochondria-localized TIN2 induced cellular senescence in RPE via compromised mitophagy and activated mTOR signaling. These results propose that targeting TIN2 could potentially serve as a therapeutic strategy in the treatment of DR.

Immunomodulatory effects of Kaempferol on microglial and Macrophage cells during the progression of diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) stands as a prevalent secondary complication of diabetes, notably Type 1 Diabetes Mellitus (T1D), characterized by immune system involvement potentially impacting the retinal immune response mediated by microglia. Early stages of DR witness blood-retinal barrier permeabilization, facilitating peripheral immune cell interaction with the retinal immune system. Kaempferol (Kae), known for its potent anti-inflammatory activity, presents a promising avenue in DR treatment by targeting the immune mechanisms underlying its onset and progression. Our investigation delves into the molecular intricacies of innate immune cell interaction during DR progression and the attenuation of inflammatory processes pivotal to its pathology. METHODS: Employing in vitro studies, we exposed HAPI microglial and J774.A1 macrophage cells to pro-inflammatory stimuli in the presence or absence of Kae. Ex vivo and in vivo experiments utilized BB rats, a T1D animal model. Retinal explants from BB rats were cultured with Kae, while intraperitoneal Kae injections were administered to BB rats for 15 days. Quantitative PCR, Western blotting, immunofluorescence, and Spectral Domain - Optical Coherence Tomography (SD-OCT) facilitated survival assessment, cellular signaling analysis, and inflammatory marker determination. RESULTS: Results demonstrate Kae significantly mitigates inflammatory processes across in vitro, ex vivo, and in vivo DR models, primarily targeting immune cell responses. Kae administration notably inhibits proinflammatory responses during DR progression while promoting an anti-inflammatory milieu, chiefly through microglia-mediated synthesis of Arginase-1 and Hemeoxygenase-1(HO-1). In vivo, Kae administration effectively preserves retinal integrity amid DR progression. CONCLUSIONS: Our findings elucidate the interplay between retinal and systemic immune cells in DR progression, underscoring a differential treatment response predominantly orchestrated by microglia's anti-inflammatory action. Kae treatment induces a phenotypic and functional shift in immune cells, delaying DR progression, thereby spotlighting microglial cells as a promising therapeutic target in DR management.

Determinants of non-diabetic kidney diseases in type 2 diabetic patients: Twenty years of single center experience.

BACKGROUND: Diabetic nephropathy is one of the most common complications associated with diabetes. However, non-diabetic kidney disease has been reported in patients with type 2 diabetes at varying incidence rates. The objective of our study is to investigate the occurrence, clinicopathological characteristics, and inflammatory markers linked to diabetic and non-diabetic nephropathy (NDN) in patients with type 2 diabetes mellitus (DM). Additionally, we aimed to explore the possibility of identifying non-diabetic pathology using different biopsy indications. MATERIALS AND METHODS: A total of 159 patients with type 2 DM who underwent renal biopsy at a tertiary care nephrology clinic between January 2000 and January 2022 were enrolled in the study. We collected comprehensive data, including patient demographics, co-morbidities, diabetes duration, renal biopsy indications and results, serological markers, renal function, diabetic retinopathy (DRP), full blood count, blood biochemistry, urinalysis, and inflammatory markers. Patients were categorized based on their biopsy indications, and their biopsy results were classified into three groups: isolated NDN, isolated diabetic nephropathy (DN), and mixed nephropathy with concurrent NDN. We evaluated the relationship between biopsy indications and accompanying pathologies and statistically assessed the likelihood of each biopsy indication detecting non-diabetic renal pathology. Additionally, differences in other data, including demographic and laboratory results and medical histories, among the three groups were investigated. RESULTS: The most frequent indication of renal biopsy was atypical presentations of nephrotic syndrome or nephrotic range proteinuria (ANS/ANP) in 25.1% of patients. Other indications included unexplained renal failure (URF) in 22.6%, atypical presentations of non-nephrotic range proteinuria (ANNP) in 18.2%, acute kidney injury or rapidly progressive kidney dysfunction (AKI/RPKD) in 16.9%, microscopic hematuria in 15.7%, URF with ANNP in 11.3%, and severe nephrotic range proteinuria (SNP) in 9.4%. Renal biopsy revealed isolated NDN in 64.8%, DN in 25.1%, and mixed nephropathy in 10.1% of patients. Primary glomerular diseases were the main non-diabetic renal pathology, predominantly focal segmental glomerulosclerosis (FSGS) (36.4%) followed by MN (10.6%) and IgA nephropathy (7.5%). In comparison with the isolated DN and mixed nephropathy groups, patients in the isolated NDN group had significantly shorter diabetes duration, fewer DRP, as well as lower serum creatinine and neutrophil-to-lymphocyte ratio (NLR). Multivariate logistic regression analysis revealed that presence of hematuria (OR 4.40; 95% CI 1.34 - 14.46, p = 0.014), acute nephrotic range proteinuria (OR 11.93; 95% CI 1.56 - 90.77, p = 0.017), and AKI/APKD (OR 41.08; 95% CI 3.40 - 495.39, p = 0.003) were strong predictors of NDN. Lower NLR (OR 0.77; 95% CI 0.60 - 0.98, p = 0.035), shorter duration of diabetes (OR 0.90; 95% CI 0.84 - 0.97, p = 0.010), and absence of DRP (OR 0.35; 95% CI 0.12 - 0.98, p = 0.046) were also found to be independent indicators of NDN. Receiver operating characteristic curve (ROC) analysis revealed a cut-off value of ≤ 3.01 for NLR (sensitivity of 63.1%, specificity of 63.5%) with regards to predicting non-diabetic renal pathology (p = 0.006). CONCLUSION: Renal biopsy findings in patients with type 2 DM highlight that the prevalence of NDN may be higher than assumed, as presented mainly in the form of primary glomerular disease. The presence of AKI/RPKD, hematuria, and ANS/ANP serves as a reliable indicator of non-diabetic renal pathology. In more ambiguous situations, factors such as a shorter duration of diabetes, absence of DRP, and a lower NLR value may assist clinicians in biopsy decision.

RNA-binding proteins potentially regulate the alternative splicing of cell cycle-associated genes in proliferative diabetic retinopathy.

RNA-binding proteins (RBPs) contribute to the pathogenesis of proliferative diabetic retinopathy (PDR) by regulating gene expression through alternative splicing events (ASEs). However, the RBPs differentially expressed in PDR and the underlying mechanisms remain unclear. Thus, this study aimed to identify the differentially expressed genes in the neovascular membranes (NVM) and retinas of patients with PDR. The public transcriptome dataset GSE102485 was downloaded from the Gene Expression Omnibus database, and samples of PDR and normal retinas were analyzed. A mouse model of oxygen-induced retinopathy was used to confirm the results. The top 20 RBPs were screened for co-expression with alternative splicing genes (ASGs). A total of 403 RBPs were abnormally expressed in the NVM and retina samples. Functional analysis demonstrated that the ASGs were enriched in cell cycle pathways. Cell cycle-associated ASEs and an RBP-AS regulatory network, including 15 RBPs and their regulated ASGs, were extracted. Splicing factor proline/glutamine rich (SFPQ), microtubule-associated protein 1 B (MAP1B), heat-shock protein 90-alpha (HSP90AA1), microtubule-actin crosslinking factor 1 (MACF1), and CyclinH (CCNH) expression remarkably differed in the mouse model. This study provides novel insights into the RBP-AS interaction network in PDR and for developing screening and treatment options to prevent diabetic retinopathy-related blindness.

Macrophage activation contributes to diabetic retinopathy.

Diabetic retinopathy (DR) is recognized as a neurovascular complication of diabetes, and emerging evidence underscores the pivotal role of inflammation in its pathophysiology. Macrophage activation is increasingly acknowledged as a key contributor to the onset and progression of DR. Different populations of macrophages originating from distinct sources contribute to DR-associated inflammation. Retinal macrophages can be broadly categorized into two main groups based on their origin: intrinsic macrophages situated within the retina and vitreoretinal interface and macrophages derived from infiltrating monocytes. The former comprises microglia (MG), perivascular macrophages, and macrophage-like hyalocytes. Retinal MG, as the principal population of tissue-resident population of mononuclear phagocytes, exhibits high heterogeneity and plasticity while serving as a crucial connector between retinal capillaries and synapses. This makes MG actively involved in the pathological processes across various stages of DR. Activated hyalocytes also contribute to the pathological progression of advanced DR. Additionally, recruited monocytes, displaying rapid turnover in circulation, augment the population of retinal macrophages during DR pathogenesis, exerting pathogenic or protective effect based on different subtypes. In this review, we examine novel perspectives on macrophage biology based on recent studies elucidating the diversity of macrophage identity and function, as well as the mechanisms influencing macrophage behavior. These insights may pave the way for innovative therapeutic strategies in the management of DR.

The clinical evaluation of a widefield lens to expand the field of view in optical coherence tomography (OCT-A).

This study aimed to evaluate the clinical benefits of incorporating a widefield lens (WFL) in optical coherence tomography angiography (OCT-A) in patients with retinal vascular diseases in comparison to standard single-shot OCT-A scans. Sixty patients with retinal vascular diseases including diabetic retinopathy (DR) and retinal vein occlusion (RVO) were recruited. OCT-A imaging (PlexElite 9000) with and without WFL was performed in randomized order. The assessment included patient comfort, time, field of view (FoV), image quality and pathology detection. Statistical analysis included paired t-tests, Mann-Whitney U-tests and Bonferroni correction for multiple tests, with inter-grader agreement using the kappa coefficient. Using a WFL did not lead to statistically significant differences in DR and RVO group test times. Patient comfort remained high, with similar responses for WFL and non-WFL measurements. The WFL notably expanded the scan field (1.6× FoV increase), enhancing peripheral retinal visibility. However, image quality varied due to pathology and eye dominance, affecting the detection of peripheral issues in RVO and DR cases. The use of a WFL widens the scan field, aiding vascular retinal disease imaging with minor effects on comfort, time, and image quality. Further enhancements are needed for broader view angles, enabling improved quantification of non-perfused areas and more reliable peripheral proliferation detection.

Role of MST2/YAP1 signaling pathway in retinal cells apoptosis and diabetic retinopathy.

Diabetic retinopathy (DR) is a main factor affecting vision of patients, and its pathogenesis is not completely clear. The purpose of our study was to investigate correlations between MST2 and DR progression, and to study the possible mechanism of MST2 and its down pathway in high glucose (HG)-mediated RGC-5 apoptosis. The diabetic rat model was established by intraperitoneal injection of streptozotocin (STZ) 60 mg/kg. HE and TUNEL staining were used to evaluate the pathological changes and apoptosis of retinal cells in rats. Western blot, qRT-PCR and immunohistochemistry showed that levels of MST2 were increased in diabetic group (DM) than control. In addition, the differential expression of MST2 is related to HG-induced apoptosis of RGC-5 cells. CCK-8 and Hoechst 33,342 apoptosis experiments showed that MST2 was required in HG-induced apoptosis of RGC-5 cells. Further research revealed that MST2 regulated the protein expression of YAP1 at the level of phosphorylation in HG-induced apoptosis. Simultaneously, we found that Xmu-mp-1 acts as a MST2 inhibitor to alleviate HG-induced apoptosis. In summary, our study indicates that the MST2/YAP1 signaling pathway plays an important role in DR pathogenesis and RGC-5 apoptosis. This discovery provides new opportunities for future drug development targeting this pathway to prevent DR.

Drp1-dependent mitochondrial fragmentation mediates photoreceptor abnormalities in type 1 diabetic retina.

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.

An interpretable dual attention network for diabetic retinopathy grading: IDANet.

Diabetic retinopathy (DR) is the most prevalent cause of visual impairment in adults worldwide. Typically, patients with DR do not show symptoms until later stages, by which time it may be too late to receive effective treatment. DR Grading is challenging because of the small size and variation in lesion patterns. The key to fine-grained DR grading is to discover more discriminating elements such as cotton wool, hard exudates, hemorrhages, microaneurysms etc. Although deep learning models like convolutional neural networks (CNN) seem ideal for the automated detection of abnormalities in advanced clinical imaging, small-size lesions are very hard to distinguish by using traditional networks. This work proposes a bi-directional spatial and channel-wise parallel attention based network to learn discriminative features for diabetic retinopathy grading. The proposed attention block plugged with a backbone network helps to extract features specific to fine-grained DR-grading. This scheme boosts classification performance along with the detection of small-sized lesion parts. Extensive experiments are performed on four widely used benchmark datasets for DR grading, and performance is evaluated on different quality metrics. Also, for model interpretability, activation maps are generated using the LIME method to visualize the predicted lesion parts. In comparison with state-of-the-art methods, the proposed IDANet exhibits better performance for DR grading and lesion detection.

Parallelism and non-parallelism in diabetic nephropathy and diabetic retinopathy.

Diabetic nephropathy (DN) and diabetic retinopathy (DR), as microvascular complications of diabetes mellitus, are currently the leading causes of end-stage renal disease (ESRD) and blindness, respectively, in the adult working population, and they are major public health problems with social and economic burdens. The parallelism between the two in the process of occurrence and development manifests in the high overlap of disease-causing risk factors and pathogenesis, high rates of comorbidity, mutually predictive effects, and partial concordance in the clinical use of medications. However, since the two organs, the eye and the kidney, have their unique internal environment and physiological processes, each with specific influencing molecules, and the target organs have non-parallelism due to different pathological changes and responses to various influencing factors, this article provides an overview of the parallelism and non-parallelism between DN and DR to further recognize the commonalities and differences between the two diseases and provide references for early diagnosis, clinical guidance on the use of medication, and the development of new drugs.

Quantitative assessment of retinal vasculature changes in systemic lupus erythematosus using wide-field OCTA and the correlation with disease activity.

Purpose: To assess the retinal vasculature changes quantitatively using wide-field optical coherence tomography angiography (OCTA) in systemic lupus erythematosus (SLE), and explore its correlation with systemic clinical features. Design: Prospective, cross-sectional, observational study. Participants and controls: Patients with SLE who presented to the Ophthalmology Department of Peking Union Medical College Hospital from November 2022 to April 2023 were collected. The subjects were divided into retinopathy and without retinopathy groups. Age and gender-matched healthy subjects were selected as controls. Methods: Patients with SLE and control subjects were imaged with 24×20 mm OCTA scans centered on the fovea and 6×6 mm OCTA scans centered on the optic disc. The sub-layers of OCTA images were stratified by the built-in software of the device and then the retinal thickness and vessel density were measured automatically. The characteristics of retinal OCTA parameters of SLE and its correlation with systemic clinical indicators of patients without retinopathy were analyzed. Main outcome measures: OCTA parameters, visual acuity, intraocular pressure, and systemic clinical indicators of patients such as disease activity index, autoimmune antibodies, and inflammatory marker levels were collected. Results: A total of 102 SLE patients were included, 24 of which had retinopathy, and 78 had unaffected retina. Wide-field OCTA could effectively detect retinal vascular obstruction, non-perfusion area, and morphological abnormalities in patients with lupus retinopathy. SLE patients without retinopathy had significantly higher retinal superficial vessel density (SVD) in foveal (P=0.02), para-foveal temporal (P=0.01), nasal (P=0.01), peripheral foveal temporal (P=0.02), and inferior areas (P=0.02), as well as subregion temporal (P=0.01) and inferior areas (P=0.03) when compared with healthy controls (n=65 eyes from 65 participants). The area under curve (AUC) value of subregion inferior SVD combined parafoveal temporal SVD was up to 0.70. There was a significantly positive correlation between SVD and disease activity in SLE without retinopathy group. Patients with severe activity had the most significant increase in SVD. Conclusion: Wide-field OCTA can provide a relatively comprehensive assessment of the retinal vasculature in SLE. In the absence of pathological changes of the retina, the SVD was significantly increased and was positively correlated with the disease activity of SLE.

Advances in Research Related to MicroRNA for Diabetic Retinopathy.

Diabetic retinopathy (DR) is a severe microvascular complication of diabetes and is one of the primary causes of blindness in the working-age population in Europe and the United States. At present, no cure is available for DR, but early detection and timely intervention can prevent the rapid progression of the disease. Several treatments for DR are known, primarily ophthalmic treatment based on glycemia, blood pressure, and lipid control, which includes laser photocoagulation, glucocorticoids, vitrectomy, and antivascular endothelial growth factor (anti-VEGF) medications. Despite the clinical efficacy of the aforementioned therapies, none of them can entirely shorten the clinical course of DR or reverse retinopathy. MicroRNAs (miRNAs) are vital regulators of gene expression and participate in cell growth, differentiation, development, and apoptosis. MicroRNAs have been shown to play a significant role in DR, particularly in the molecular mechanisms of inflammation, oxidative stress, and neurodegeneration. The aim of this review is to systematically summarize the signaling pathways and molecular mechanisms of miRNAs involved in the occurrence and development of DR, mainly from the pathogenesis of oxidative stress, inflammation, and neovascularization. Meanwhile, this article also discusses the research progress and application of miRNA-specific therapies for DR.

Transthyretin-Regulated Diabetic Retinopathy Through the VEGFA/PI3K/AKT Pathway.

Purpose: Transthyretin (TTR) plays a regulatory role in a variety of diabetes-related diseases. The objective of this work was to probe whether TTR affects diabetic retinopathy (DR) through the VEGFA/PI3K/AKT pathway. Methods: High glucose (HG, 25 mM) was used to treat human retinal microvascular endothelial cells (hRMECs) and C57BL/6J mice were intraperitoneally injected with STZ (50 mg/kg) to construct a DR model. In vitro, the effect of TTR on DR was evaluated by measuring hRMEC proliferation, migration, and angiogenesis. The changes in retinal tissue were observed by hematoxylin and eosin staining in vivo. ELISA, immunohistochemistry, and immunofluorescence staining were used to measure VEGFA or CD31 levels. The levels of all proteins were evaluated through Western blot. Results: The increase of proliferation, migration, and angiogenesis and decrease of apoptosis in hRMECs caused by HG were notably reversed by TTR. TTR greatly impeded HG-raised VEGFA, PI3K p-p85, and p-AKT in hRMECs. Inhibition of TTR further exacerbated the effect of HG-induced hRMECs. Inhibition of VEGFA reversed the effect of HG-induced hRMECs. VEGFA neutralized the function of TTR on cell proliferation, apoptosis, migration, and angiogenesis in HG-triggered hRMECs. It was further confirmed in vivo that TTR can alleviate the occurrence of DR in diabetic mice models. Conclusions: TTR significantly restrained the progression of DR via molecular modulation of the VEGFA/PI3K/AKT axis.