Search Results (838)

Retinal neurovascular unit (RNVU) dysfunction underlies major blinding and neurodegenerative conditions including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal ischemia–reperfusion (RIR) injury, and Alzheimer’s disease (AD)-associated retinopathy. Within the RNVU, calcium ions coordinate neurotransmission, glial activation, vascular tone, and blood–retinal barrier maintenance, and calcium dysregulation is emerging as a unifying pathogenic hub across these conditions. Although upstream triggers differ, including mechanical stress in glaucoma, hyperglycemia in DR, oxidative damage in AMD, ischemic energy failure in RIR, and amyloid-β–driven endoplasmic reticulum stress in AD, all converge on disruption of intracellular calcium homeostasis, producing shared downstream consequences including excitotoxic injury of retinal ganglion cells (RGCs), Müller cell reactive gliosis, and pericyte hypercontraction. Broad-spectrum calcium channel blockade has shown limited clinical success, underscoring the need for cell-type-specific and pathway-selective approaches. This review therefore catalogs key interventional nodes, including transient receptor potential (TRP) channel antagonists, T-type calcium channel inhibitors, calcium/calmodulin-dependent protein kinase II (CaMKII) suppressors, and mitochondrial permeability transition pore (mPTP) inhibitors, and discusses how precision targeting of these pathways may restore RNVU homeostasis and open a therapeutic window into central nervous system (CNS) degenerative disorders. Full article

Background/Objectives: This retrospective cohort study compared hospitalization and follow-up rates in patients with newly diagnosed proliferative diabetic retinopathy (PDR) versus those without prior diabetic retinopathy (DR) screening. Methods: Using TriNetX, a global electronic health record database, 57,964 patients aged ≥ 40 years with type 2 diabetes and newly diagnosed PDR without diabetic macular edema (DME) requiring panretinal photocoagulation or intravitreal injection were included. Patients were stratified based on the presence or absence of prior DR screening in the last 5 years and balanced using propensity score matching (PSM). Primary outcomes included 30-, 60-, and 90-day hospitalization rates and repeat ophthalmic follow-up as estimated using repeat PDR diagnosis codes and repeat retinal imaging codes, including OCT, fundus photography, and fluorescein angiography. Results: Of 57,964 patients, 25,003 had no prior DR screening and 32,961 had prior DR screening. After matching, 19,316 patients were included per cohort. Patients without known DR screening had significantly higher hospitalization rates at 30 days (RR = 1.78, 95% CI 1.67–1.89), 60 days (RR = 1.59, 95% CI 1.51–1.67), and 90 days (RR = 1.51, 95% CI 1.44–1.58), and lower repeat ophthalmic visits by PDR codes at 30 days (RR = 0.458, 95% CI 0.440–0.476), 60 days (RR = 0.450, 95% CI 0.437–0.463) and 90 days (RR = 0.420, 95% CI 0.408–0.432) or by repeat retinal imaging codes at 30 days (RR = 0.450, 95% CI 0.423–0.478), 60 days (RR = 0.394, 95% CI 0.377–0.411), and 90 days (RR = 0.381, 95% CI 0.366–0.396) (all p < 0.0001). Conclusions: Absence of known prior DR screening in PDR patients is associated with higher hospitalization risk and reduced ophthalmic follow-up, suggesting that a lack of screening indicates broader gaps in healthcare engagement and disease control. Tailored strategies are needed to prevent vision loss as well as systemic complications. Full article

Ocular diseases like age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma and cataracts are major causes of visual impairment all over the world and are closely linked to oxidative stress, inflammation and mitochondrial dysfunction. This narrative review critically summarizes the available evidence on how various natural bioactive compounds, such as carotenoids, polyphenols, flavonoids, omega-3 fatty acids and botanical extracts, can affect important molecular pathways associated with ocular degeneration. Their antioxidant, anti-inflammatory, anti-angiogenic and neuroprotective properties are given particular emphasis, especially regarding the Nrf2, NF-κB and VEGF signaling pathways. This review is different from past reviews that simply discuss the potential of bioactives in the general nutritional context; rather, it unfolds the disease-specific mechanisms and compound-specific molecular actions and gives special attention to recent advances in nano-delivery systems and precision nutrition strategies to increase the bioavailability and therapeutic targeting of these nutrients in the eyes. Moreover, it offers a framework for a comparison of evidence between preclinical and clinical studies, as well as identifying current translational gaps, including limited bioavailability and a lack of long-term clinical trials, and suggesting future directions such as genotype-guided nutrition and microbiome-informed interventions. In general, this review provides a mechanistic and translational overview of how dietary bioactive compounds relate to eye health and offers the perspective of their possible use in prevention and complementary treatment for vision-related diseases. Full article

Background/Objectives: Inflammation is a critical contributor to the development of diabetic retinopathy (DR). In the early stages of DR, the compromised permeability of the blood–retina barrier facilitates the infiltration of macrophages and the activation of microglia. These specific retinal immune cells can adopt morphologies M1 or M2, linked to pro- or anti-inflammatory responses, respectively. This dual response represents a new therapeutic target against DR progression. This study aimed to investigate the modulation of the response M1/M2 and the molecular mechanism of two algal diterpenoids, rugukadiol A (RK) and ruguloptone A (RL), in the early inflammatory events associated with DR. Methods: LPS-stimulated microglial (Bv.2) and macrophage (RAW264.7) cells and an ex vivo physiological model of DR were used to analyze the effects of RK and RL on M1 and M2 inflammatory markers. Results: Compounds RK and RL, besides decreasing the expression of the M1 pro-inflammatory factors iNOS, Il6 mRNA, and NLRP3 in LPS-stimulated Bv.2 cells, caused enhancements in Arg-1 mRNA and Il10 mRNA expression consistent with the induction of an M2 anti-inflammatory response. RK promoted p38α-MAPK phosphorylation, suggesting a non-classical activation of p38α related to the induction of anti-inflammatory responses. Consistently, treatment of retinal explants of BB rats in the early stages of DR with RL decreased M1 pro-inflammatory mediators and induced M2 anti-inflammatory markers, with a reduction in gliosis and a phenotype switch from activated to resting microglia. Conclusions: This study provides the first evidence of algal diterpenoids attenuating pro-inflammatory mediators and promoting the resolution of inflammation in a diabetic retinopathy context, thus opening the way to further explore this class of marine natural products and analogs for early DR management. Full article

Background/Objectives: Diabetic retinopathy (DR) is a major microvascular complication of type 1 diabetes mellitus (T1DM) and remains an important cause of preventable visual impairment. Region-specific data on the incidence and clinical predictors of DR among patients with T1DM in Saudi Arabia remain limited. This study aimed to determine the incidence of DR and identify associated demographic and systemic risk factors among patients with T1DM at a tertiary care center in Riyadh, Saudi Arabia. Methods: This retrospective cohort study included 449 patients with T1DM aged ≥9 years who were followed at King Abdulaziz Medical City, Riyadh, between 2015 and 2025. Patients were selected using a consecutive non-probability sampling technique. Data were extracted from the BESTCare 2.0A electronic medical record system and supplemented, when required, by phone-based interviews to verify selected clinical and demographic variables. Patients were classified as controls without DR or cases with DR, including non-vision-threatening DR and vision-threatening DR (VTDR), according to the International Clinical Diabetic Retinopathy Severity Scale. Multivariable logistic regression, Cox proportional hazards models, and temporal trend analysis were performed, with statistical significance set at p < 0.05. Results: The overall incidence rate of DR was 92.66 per 1000 person-years, with similar rates among males and females. In multivariable logistic regression, older age at T1DM diagnosis, longer diabetes duration, hypertension, hyperlipidemia, and albuminuria were independently associated with DR. Mean HbA1c and HbA1c variability were not independently associated with DR after adjustment. In Cox regression, older age at T1DM diagnosis was associated with higher hazards of both DR and VTDR, while hypertension was associated with VTDR. Among patients with DR, younger age at T1DM diagnosis was associated with higher odds of proliferative disease in exploratory severity analysis. Conclusions: DR was common among patients with T1DM in this tertiary-care cohort and was mainly associated with disease duration, age at diagnosis, and systemic vascular comorbidities. These findings support the importance of routine ophthalmologic screening and integrated management of systemic risk factors in patients with T1DM. Full article

Background/Objectives: Cystatin C-based and combined creatinine–cystatin C estimated glomerular filtration rate (eGFR) equations improve early chronic kidney disease (CKD) detection and prediction of adverse outcomes compared to creatinine alone. However, their role in predicting microvascular complications such as diabetic retinopathy (DR) is less clear. We examined the association between diabetic kidney disease (DKD), defined using creatinine-, cystatin C-, and combined eGFR measures, as well as albuminuria, and the risk of incident DR among Asian adults in Singapore. Methods: We analysed 1135 Chinese and Indian adults with diabetes aged ≥40 years from a population-based cohort study with baseline (2007–2011) and 6-year follow-up (2013–2017) data. DR was graded from retinal photographs, and incident DR was defined as new-onset at follow-up. DKD was defined as eGFR < 60 mL/min/1.73 m² using eGFRcr, eGFRcys, combined eGFRcr-cys, and albuminuria (UACR ≥ 30 mg/g), assessed individually and jointly. Modified Poisson regression models adjusted for age, sex, ethnicity, diabetes duration, HbA1c, and systolic blood pressure were used to estimate relative risks (RRs). Results: Overall, incident DR occurred in 13.0% of participants. Among those with DKD, incidence was 18.2% (eGFRcr), 16.7% (eGFRcys), 23.7% (eGFRcr-cys), and 18.3% (albuminuria). eGFRcr-DKD (RR = 2.18, 95% CI 1.33–3.58), eGFRcys-DKD (2.38 [1.51–3.78]), and eGFRcr-cys-DKD (3.15 [1.94–5.12]) were independently associated with incident DR, whereas albuminuria alone was not. Risk increased with increasing number of markers,2.00 (1.02–3.92) by dual and 4.91 (2.50–9.65) by triple markers. Conclusions: DKD defined using multiple kidney markers, particularly combined creatinine–cystatin C, was strongly associated with incident DR. These findings support the use of multiple kidney function markers to improve risk stratification for developing DR. Full article

Background/Objectives: Using a well-established model of streptozotocin-induced diabetic retinopathy (DR), this study sought to evaluate the neuroprotective effect of intravitreal Forskolin (FSK) on retinal ganglion cell survival and glial activation and explore the association of circulating miR-200b with metabolic and oxidative stress in DR. Methods: A total of 18 male Wistar rats were divided into a control group (n = 6) and a streptozotocin-induced diabetic group (n = 12), which were further divided into diabetic control and FSK-treated groups (n = 6 each). Total antioxidant capacity (TAC), total peroxide (TP), triglycerides (TGs), total cholesterol, and high-density lipoprotein cholesterol (HDL-C) were measured. qRT-PCR analysis for miRNA-200b and immunohistochemistry were performed. Results: Diabetic rats showed oxidative stress and hyperlipidemia associated with increased circulating miR-200b levels. The retina showed reduced neuron numbers (Caspase-3), altered glial and astrocyte staining (IBA1, GFAP), and changes in microglia/macrophage morphology and distribution. Intravitreal FSK improved retinal ganglion cell survival and reduced glial activation, while systemic lipid profile and oxidative stress markers remained largely unchanged. Circulating miR-200b levels showed a positive correlation with oxidative stress markers across groups. Conclusions: Intravitreal FSK was able to limit the disease exacerbation via improved neuronal survival through inhibition of apoptosis. FSK did not produce observable qualitative changes in GFAP expression or IBA1+ cell morphology under the conditions tested. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the management of type 2 diabetes mellitus (T2DM) by providing robust glycemic control alongside significant cardioprotective and renoprotective benefits. This review synthesizes current mechanistic, preclinical, and clinical evidence regarding the impact of GLP-1RAs on retinal microvasculature and summarizes the current clinical evidence of GLP-1RA-induced retinal complications. GLP-1RAs exert pleiotropic effects on the retinal microvasculature, offering protection by amelioration of endothelial function, reduction in oxidative stress, inflammation, microvascular remodeling, and preservation of the blood–retinal barrier (BRB). Despite these mechanistic advantages, emerging clinical data have raised concerns regarding potential retinal adverse events associated with GLP-1RA therapy. Observational studies and pharmacovigilance analyses have suggested possible associations with non-arteritic anterior ischemic optic neuropathy (NAION), diabetic macular edema (DME), vitreous hemorrhage, retinal detachment, macular hole formation, and progression of diabetic retinopathy (DR), particularly in the context of semaglutide use. Most evidence comes from retrospective studies or secondary endpoints, limiting causal inference. Retinal complications associated with GLP-1RAs remain heterogeneous and inconclusive, requiring careful evaluation of potential risks across diverse patient populations. Future research should conduct large, randomized trials with standardized ocular endpoints, detailed imaging, and stratified analyses to clarify GLP-1RA retinal safety. Full article

Diabetic retinopathy (DR) is a leading cause of vision impairment and permanent blindness worldwide, requiring accurate and automated systems for multi-grade severity classification. However, standard Convolutional Neural Networks (CNNs) often struggle to capture fine, high-frequency microvascular patterns critical for diagnosis. This study proposes a Robust Intelligent CNN Model (RICNN) that integrates Gabor-based feature extraction with deep learning to improve DR classification. Specifically, Gabor filters are applied during preprocessing to extract orientation- and frequency-sensitive texture features, which are transformed into feature maps and concatenated with CNN feature representations at the fully connected layer (feature-level fusion). The model also incorporates the Synthetic Minority Oversampling Technique (SMOTE) for data balancing and the Adam optimizer for efficient convergence. This integration enhances sensitivity to microvascular structures such as microaneurysms and hemorrhages. The proposed RICNN was evaluated on the Messidor dataset (1200 images) across four severity levels: Mild, Moderate, Severe, and Proliferative DR. The model achieved an accuracy of 89%, a precision of 88.75%, a recall of 89%, and an F1-score of 89%, with AUCs of 97% for Severe DR and 99% for Proliferative DR. Comparative analysis confirms that the proposed texture-aware Gabor enhancement significantly outperforms LBP and Color Histogram approaches, indicating its potential for reliable clinical decision support. Full article

Purpose: Neuroinflammation and oxidative stress are increasingly recognized as central, interconnected drivers of neurodegeneration in the visual system. This review examines the pathogenic mechanisms shared across glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and Alzheimer’s disease (AD), and evaluates the therapeutic rationale for targeting both pathways simultaneously. Methods: A narrative review of peer-reviewed literature was conducted using PubMed. Searches combined the following MeSH terms: neuroinflammation, oxidative stress, retinal neurodegeneration, microglia, Müller glia, mitochondrial dysfunction, glaucoma, age-related macular degeneration, diabetic retinopathy, and Alzheimer’s disease. Priority was given to original research, systematic reviews, and high-impact publications from 2000 through 2025. However, seminal foundational works were included regardless of publication date. Studies were selected based on relevance to glial activation, mitochondrial dysfunction, reactive oxygen and nitrogen species, and disease-specific neuronal outcomes. Results: Across all four diseases, persistent microglial and Müller glial activation, mitochondrial electron transport chain dysfunction, and excess reactive oxygen species (ROS) and reactive nitrogen species (RNS) production form a self-amplifying feed-forward loop that accelerates neuronal injury. In glaucoma, these mechanisms drive intraocular pressure-independent retinal ganglion cell loss. In AMD and DR, lipid dysregulation, complement activation, and chronic hyperglycemia sustain oxidative-inflammatory injury to the retinal pigment epithelium, photoreceptors, and neurovasculature. In AD, retinal amyloid deposition and oxidative stress mirror cortical pathology, positioning the retina as a noninvasive biomarker site. Conclusions: Neuroinflammation and oxidative stress constitute unifying upstream mechanisms across major vision-threatening neurodegenerative diseases. Combination therapeutic strategies that simultaneously modulate glial activation and restore redox homeostasis may offer superior neuroprotective efficacy compared to approaches targeting isolated downstream mediators. Full article

Diabetic retinopathy (DR) is a common cause of vision loss in diabetes, and it often progresses without early symptoms. DR reflects injury of the retinal neurovascular unit (NVU), which includes neurons, Müller glia, astrocytes, endothelial cells, pericytes, and immune cells. Chronic hyperglycemia drives oxidative stress, advanced glycation end products–receptor for advanced glycation end products (AGE–RAGE) signaling, mitochondrial injury, and low-grade inflammation. These changes disrupt endothelial junctions, promote leukostasis, weaken pericyte support, increase basement membrane thickening, and lead to capillary dropout and hypoxia. Hypoxia-related signaling increases anti-vascular endothelial growth factor (VEGF) activity, which raises vascular leakage and supports neovascular disease. Glial stress and microglial activation add cytokines and reactive oxygen species, and neural dysfunction can appear early and can weaken neurovascular coupling. Modern diabetes care changes the short-term risk landscape because potent therapies can lower HbA1c quickly. Large and rapid HbA1c reductions can trigger early worsening of diabetic retinopathy (EWDR), mainly in patients with high baseline HbA1c and moderate-to-severe baseline DR. Semaglutide’s retinopathy complication signal in SUSTAIN-6 fits an EWDR-like pattern that tracks with rapid glycemic improvement in vulnerable eyes. In parallel, surgery adds acute stress, inflammation, glucose swings, hemodynamic shifts, and medication interruptions. These factors can worsen microvascular instability during recovery. Current perioperative guidelines and regulatory recommendations describe glucose targets and medication safety considerations, including preoperative interruption of SGLT2 inhibitors to reduce euglycemic ketoacidosis risk; however, the retina-specific implications of these measures remain indirect. This review summarizes current evidence linking NVU biology, EWDR risk, and perioperative diabetes-related factors. It discusses how these factors may interact in patients with diabetes and how they may influence retinal outcomes. The review is intended to synthesize current evidence and mechanistic interpretations rather than to provide formal clinical practice recommendations. Full article

The purpose of this project was to define gene expression changes associated with the acquisition and loss of resilience to diabetic retinopathy (RDR) in individual retinal cell types. A non-immune form of type 1 diabetes mellitus (DM) was induced by injecting male C57Bl6J mice with streptozotocin. Single-cell RNA sequencing was performed on retinas from mice that experienced DM for 5 or 15 days, along with retinas from age-matched, non-DM mice. The resulting data sets were analyzed to identify DM-associated differentially expressed genes and pathway enrichments after each duration of DM. We observed that acquisition of RDR, previously shown to arise after 5 days of DM was linked to altered expression of genes in a subset of retinal cells, mainly Müller cells. Pathway analysis indicated enhancement of numerous modes of protection, including reinforced neurovascular and structural homeostasis through phagocytosis, integrin signaling, and interferon-mediated defense. After 15 days of DM, when we previously showed that RDR is waning this pro-protection surge in gene expression subsided. We conclude that a duration of DM that is too short to cause diabetic retinopathy (DR) nonetheless evoked a profound change in the gene expression profile within a subset of retinal cell types. The nature and timing of this molecular shift indicated that it was not the preamble to DM-related damage that eventually develops. Rather, DM engaged numerous defense programs within Müller cells. The temporal alignment between RDR and activation of Müller cell-based defense provides a molecular foundation for the retina’s transient ability to remain healthy in the face of DM. Full article

Diabetic retinopathy (DR) remains a major cause of vision loss in patients with diabetes, and earlier recognition of retinal vascular abnormalities may improve risk stratification and clinical follow-up. Optical coherence tomography angiography (OCTA) provides a noninvasive way to visualize the retinal microvasculature and may detect DR-related changes before they are evident on routine clinical assessment. In this work, we investigated whether dividing OCTA images into anatomically defined retinal regions could improve DR classification and clarify which regions carry the greatest discriminative information. The study included 188 OCTA images: 67 from normal eyes, 57 from eyes with mild DR, and 64 from eyes with moderate DR. Each image was divided into seven concentric regions centered on the fovea, and vessel-density features were extracted from each region. Ten machine learning classifiers were trained and compared at the regional level. For each region, the best-performing classifier was retained, and the final prediction was obtained with a majority-voting ensemble. To examine model behavior, Local Interpretable Model-Agnostic Explanations (LIME) were applied. Performance was also compared with that of a transfer-learning MobileNet model trained on whole OCTA images. On the held-out patient-level test set, the ensemble model achieved 97% accuracy, 98% precision, 97% recall, and a 97% F1-score for three-class classification. These results were higher than those obtained with the tested whole-image transfer-learning baselines. The interpretability analysis consistently identified the parafoveal regions as the most informative for classification. Among the seven regions, Region 3 showed the highest overall contribution, followed by Regions 2 and 5, whereas Region 5 became more influential in moderate DR. These results suggest that regional analysis of OCTA-derived vessel density can improve both classification performance and interpretability in DR assessment. The findings also indicate that parafoveal vascular alterations carry substantial discriminative value in distinguishing normal, mild DR, and moderate DR cases. Validation in larger, independent cohorts from multiple centers will be necessary to confirm the generalizability of these findings. Full article

Diabetic retinopathy (DR), recognized as a progressive neurovascular and microvascular complication of diabetes, remains one of the leading causes of visual disability worldwide, within the context of a sustained increase in ophthalmic diseases and retinal vascular disorders that compromise vision. This study aimed to characterize the progression of diabetic retinopathy in a streptozotocin (STZ)-induced Wistar rat model. A single dose of 65 mg/kg body weight was administered, with follow-up periods at 2, 4, 8, and 10 weeks, compared to healthy controls. STZ-induced rats exhibited reduced weight gain compared to the control group. They also showed markedly variable hyperglycemia, with glucose concentrations ranging from 250 to 530 mg/dL. Histological analysis of retinal tissue at week 4 revealed early signs of vascular compromise, including early indications of a microenvironment conducive to neovascularization and edema. By week 8, retinal damage had progressed to hemorrhage, persistent edema, and layer-specific vascular disruption. At week 10, intensified neovascularization and exacerbated edema indicated advanced microvascular deterioration. Immunofluorescence analysis demonstrated a temporal accumulation of CD8⁺ T cells in the retina, correlating with photoreceptor degeneration. The coordinated dynamics of CD4⁺ and CD8⁺ T cells suggested transient immune activation during STZ-induced retinal degeneration. Gene expression profiling revealed a proinflammatory and pro-oxidative retinal microenvironment, characterized by the overexpression of angiogenic pathways and proliferative signals. Simultaneously, the antioxidant response appeared partially impaired. Collectively, these findings provide mechanistic perspective on the multifactorial nature of diabetic retinopathy. Oxidative stress, inflammation, and angiogenesis converge to disrupt retinal homeostasis. This experimental model may serve as a reliable platform for future studies aimed at elucidating disease pathophysiology, identifying novel therapeutic targets, and evaluating emerging ophthalmic antidiabetic interventions. Full article

Diabetic retinopathy (DR) is a major cause of adult blindness and is characterized by progressive retinal vascular dysfunction and pathological angiogenesis. To establish a DR model, streptozotocin (STZ) was intraperitoneally injected into rats. After 8 weeks, naïve placenta-derived mesenchymal stem cells (PD-MSCs) or PEDF-overexpressing PD-MSCs (PD-MSCs^PEDF) were intravitreally transplanted into the right eye for 4 weeks. Pathological neovascularization in DR is regulated by the balance between vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). In diabetic retinas, increased VEGF and decreased PEDF expression were reversed following PD-MSC transplantation. Notably, PD-MSCs^PEDF treatment resulted in higher PEDF, and lower VEGF expression compared with naïve PD-MSCs, with similar expression patterns observed in the contralateral non-transplanted eyes. These findings indicate that engineering PD-MSCs^PEDF enhances anti-angiogenic activity by modulating VEGF and PEDF balance, thereby alleviating vascular damage in STZ-induced diabetic retinas. Full article