Search Results (115)

Ocular diseases, including glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD), remain major global causes of irreversible vision loss. Despite advances in clinical management, current therapies insufficiently address the shared metabolic, inflammatory, vascular, and neurodegenerative mechanisms underlying these conditions. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for type 2 diabetes and obesity, have emerged as multi-target candidates for ocular therapeutics due to their pleiotropic anti-inflammatory, antioxidant, vasculoprotective, and neuroprotective properties. Preclinical studies consistently demonstrate that GLP-1RAs preserve blood–retina barrier integrity, suppress pathological angiogenesis, mitigate oxidative and inflammatory stress, and protect retinal neurons from degeneration. Complementary clinical and real-world evidence shows a robust and reproducible reduction in glaucoma risk among GLP-1RA users across diabetic and non-diabetic populations. By contrast, findings for DR and AMD are more heterogeneous and appear context-dependent, with potential benefits most evident in early or non-exudative disease stages. Emerging safety considerations—including reports of nonarteritic anterior ischemic optic neuropathy and early DR worsening in the setting of rapid glycemic improvement—highlight the need for careful interpretation, individualized risk assessment, and appropriate ophthalmic monitoring. This review synthesizes molecular mechanisms, experimental data, clinical and pharmacoepidemiologic evidence, and safety signals to critically evaluate the therapeutic potential of GLP-1RAs in ocular disease. We also outline key translational challenges, including the need for ocular-targeted delivery strategies, prospective ophthalmology-specific trials, and precision-medicine approaches to determine when and how GLP-1RAs can be safely advanced as disease-modifying treatments in ophthalmology. Full article

Retinal astrocytes reside mainly in the nerve fiber layer and are central to shaping retinal vessels and maintaining neurovascular balance. Derived from the optic nerve head, they spread across the inner retina to form a meshwork that both supports and instructs the emerging superficial vascular plexus. Immature astrocytes supply vascular endothelial growth factor-A(VEGF-A) to guide endothelial sprouting, while signals from growing vessels promote astrocyte maturation and strengthen the blood–retinal barrier. In disorders such as diabetic retinopathy and neovascular age-related macular degeneration, these cells show marked plasticity. Reactive astrogliosis can sustain VEGF and inflammation, favoring fragile, leaky neovessels, whereas alternative astrocyte states help reinforce barrier function and release anti-angiogenic factors. Located at the core of the neurovascular unit, astrocytes communicate continuously with endothelial cells, pericytes and neurons. This review integrates data from single-cell profiling and advanced imaging to outline astrocyte development, morphology and key signaling pathways (VEGF, PDGF, Wnt/Norrin, Eph/ephrin), and considers how tuning astrocyte polarization might be exploited to preserve retinal vascular integrity. Full article

Background/Objectives: Vitamin B₁₂ deficiency is increasingly recognized as a contributor in both vascular and neurodegenerative aging-related disorders. Its deficiency disrupts one-carbon metabolism, leading to impaired homocysteine (Hcy) cycling. Elevated Hcy is a well-established risk factor for vascular dysfunction. Previously, we established that elevated Hcy contributes to aging retinal diseases and plays a central role in blood retinal barrier (BRB) dysfunction. Building on this foundation, the present study examines how B-vitamin deficiency disrupts one-carbon metabolism and whether restoring these vitamins can serve as a preventive or therapeutic strategy. Since B-vitamins (B₆, B₉, and B₁₂) are crucial cofactors in the metabolism of Hcy, we investigated how dietary changes in these vitamins affect serum Hcy levels and retinal vascular integrity in mice. Methods: C57BL/6- Wild-type (WT) and cbs^+/− mice (Cystathionine Beta-Synthase heterozygotes, common mouse model for elevated Hcy) were fed specially formulated diets, which contained different levels of B-vitamins (normal, deficient (B-Vit (−)) or enriched (B-Vit (+)). Initially, two groups of mice were placed on either a normal or a deficient diet. After 12–16 weeks, the success of the diet regimes was confirmed by observing serum B₁₂ deficiency in the B-Vit (−) group, along with elevated Hcy levels. Subsequently, a subgroup of the B-Vit (−) mice was switched to an enriched diet. The BRB integrity was evaluated in living mice using fluorescein angiography (FA), optical coherence tomography (OCT), and in the perfused mice retinas with Western blot analysis of leaked retinal albumin and tight junction proteins (occludin and ZO-1) levels. Results: The B-vitamin deficiency caused significant drop in serum vitamin B₁₂ and an increase in plasma Hcy, leading to vascular leakage, altered retinal thickness, choroidal neovascular changes, increased retinal albumin leak, and decreased tight junction protein expression, indicating BRB disruption, which was restored with B-vitamin supplementation. Conclusions: a long-term deficiency of vitamins B₆, B₉, and B₁₂ can lead to disruptions in the BRB. However, supplementation with these B-vitamins has the potential to reverse these effects and help maintain the integrity of BRB. This under-score the significance of one-carbon metabolism for retinal health and suggests that ensuring adequate levels of B-vitamins may aid in preventing aging retinal diseases with BRB disruption such as diabetic retinopathy and age-related macular degeneration. Full article

Background and Objectives: Age-related macular degeneration (AMD) is an age-associated retinal disorder characterized by blood–retinal barrier (BRB) breakdown and pathological angiogenesis, leading to vascular leakage. The intravitreal administration of anti-VEGF agents remains the most effective treatment for neovascular AMD. However, repetitive intravitreal injections have risks, causing side effects such as cataracts, bleeding, retina damage, and, in severe cases, post-injection endophthalmitis. Hence, the development of innovative drug delivery systems is essential to minimize the risks and discomfort associated with intravitreal injections. Materials and Methods: We developed a microemulsion (ME)-based topical drug delivery system incorporating α-linolenic acid (ALA). In brief, pseudo-ternary phase diagrams were constructed by the water titration method using different combinations of surfactants and cosurfactants (S_mix-Cremophor RH 40: Span 80: Transcutol P in ratios of 1:1.05, 1:1:1, 1:1:1.5) containing ALA as the oil phase. Three blank microemulsions (ME1, ME2, and ME3) were prepared and characterized based on the optimized pseudo-ternary phase equilibrium with a S_mix ratio of 1:1:1. Results: ME3, with an average particle size of 38.59 nm, was selected as the optimized formulation for developing drug-loaded ME containing Fenofibrate, Axitinib, and Sirolimus. The drug-loaded ME showed particle size (46.94–56.39 nm) and in vitro release displayed sustained and longer time drug release for 240 h. The irritation and antiangiogenic activities were evaluated using the hen’s egg chorioallantoic membrane (HET-CAM) assay employing the optimized ME loaded with each drug. Among the three drug-loaded ME, the Sirolimus ME showed a reduction in blood vessel sprouting in the HET-CAM assay, indicating strong antiangiogenic activity. Treatment with the optimized blank ME and Sirolimus ME significantly (p < 0.05) reduced COX-2 protein expression in LPS-stimulated RAW 264.7 cells, suggesting their potential anti-inflammatory effects. Conclusions: Overall, we suggest that the α-linolenic acid-based Sirolimus microemulsion may serve as a promising topical therapeutic approach for managing AMD and offering a potential alternative to invasive intravitreal injections. Full article

Diabetic retinopathy (DR) is a leading cause of vision loss globally and represents one of the most common microvascular complications of diabetes. In addition to metabolic disturbances associated with hyperglycemia, oxidative stress has emerged as a critical contributor to the onset and progression of DR. Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defense mechanisms, leads to cellular injury, inflammation, and increased vascular permeability. In the diabetic retina, excessive ROS production promotes endothelial cell apoptosis, breakdown of the blood-retinal barrier (BRB), and induction of angiogenic factors such as vascular endothelial growth factor (VEGF). This review provides a comprehensive overview of the pathophysiology of DR, focusing on the molecular mechanisms of oxidative stress. Relevant studies were identified through a structured search of PubMed, Web of Science, and Scopus (2000–2025) using terms such as ‘diabetic retinopathy’, ‘oxidative stress’, and ‘antioxidants’. We explore current knowledge on oxidative stress-related biomarkers and therapeutic strategies targeting oxidative damage, including antioxidant compounds and mitochondrial protective agents. Recent findings from both experimental and clinical studies are summarized, highlighting the translational potential of oxidative stress modulation in DR management. Finally, future research directions are discussed, including biomarker standardization, personalized medicine approaches, and long-term clinical validation of antioxidant-based therapies. A deeper understanding of oxidative stress may offer valuable insights into novel diagnostic and therapeutic strategies for DR. Full article

Claudin 5 (Cldn5) is a critical tight junction protein essential for maintaining paracellular barrier integrity across endothelial and epithelial cells in barrier-forming tissues, including the blood–brain barrier and blood–retinal barrier. Cldn5 plays a central role in regulating vascular permeability, immune responses, and tissue homeostasis. The complex distribution and organ-specific regulation of Cldn5 underscore its potential as a promising therapeutic target. This review comprehensively analyzes the role of Cldn5 in endothelial and epithelial barrier function, its regulation of vascular permeability, and the discrepancies in the literature regarding its expression, regulation, and function in both physiological and pathological conditions across multiple organ systems, including the retina, brain, lung, heart, gut, kidney, liver, skin, and peripheral nerves, while emphasizing its tissue-specific expression patterns. We discuss how both reduced and excessive expressions of Cldn5 can disrupt barrier integrity and contribute to the pathogenesis of ischemic retinopathies, neuroinflammation, cardiovascular injury, and other forms of barrier dysfunction. Furthermore, we explore the dual role of Cldn5 as both a biomarker and a therapeutic target, highlighting emerging strategies such as RNA silencing, pharmacological stabilizers, and transcriptional modulators in controlling barrier leakage in disease conditions. Full article

Background/Objectives: Methamphetamine (METH), a potent psychostimulant, exerts harmful effects on the vascular system by promoting oxidative stress, inflammation, and endothelial injury. While its impact on the blood–brain barrier is well documented, its influence on the retinal microvasculature remains less understood. This study investigated the effects of METH on syndecan-1 expression and endothelial function in primary rat retinal microvascular endothelial cells (RRMECs) and isolated ophthalmic arteries. Methods: We assessed METH-induced changes in mRNA and protein expression levels of syndecan-1, matrix metalloproteinase (MMP)-2, and MMP-9. Endothelial function was evaluated using scratch migration assays and trans-endothelial electrical resistance (TEER) measurements. The mechanistic involvement of MMP-9 and trace amine-associated receptor 1 (TAAR-1), a known receptor for METH, was examined using selective pharmacological inhibitors. Results: METH exposure significantly decreased syndecan-1 expression and increased MMP-9 levels. These changes were accompanied by impaired endothelial migration and reduced TEER in RRMECs. Similar findings were confirmed in cultured ophthalmic arteries, reinforcing the translational relevance of our in vitro results. Inhibition of MMPs restored syndecan-1 expression and rescued endothelial function. Furthermore, TAAR-1 antagonism protected against syndecan-1 degradation, reduced MMP-9 upregulation, and improved endothelial migration and barrier resistance. Conclusions: Our findings suggest that METH induces loss of syndecan-1 and retinal vascular integrity by promoting TAAR-1–mediated MMP-9 upregulation. Targeting the TAAR-1/MMP-9 axis may offer a promising therapeutic strategy for preventing METH-induced microvascular damage in the retina. Full article

The retina is highly sensitive to oxygen and blood supply, and hypoxia plays a key role in retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Müller glial cells, which are essential for retinal homeostasis, respond to injury and hypoxia with reactive gliosis, characterized by the upregulation of the glial fibrillary acidic protein (GFAP) and vimentin, cellular hypertrophy, and extracellular matrix changes, which can impair retinal function and repair. The retinal pigment epithelium (RPE) supports photoreceptors, forms part of the blood–retinal barrier, and protects against oxidative stress; its dysfunction contributes to retinal degenerative diseases such as AMD, retinitis pigmentosa (RP), and Stargardt disease (SD). Extracellular vesicles (EVs) play a crucial role in intercellular communication, protein homeostasis, and immune modulation, and have emerged as promising diagnostic and therapeutic tools. Understanding the role of extracellular vesicles’ (EVs’) signaling machinery of glial cells and the retinal pigment epithelium (RPE) is critical for developing effective treatments for retinal degeneration. In this study, we investigated the bidirectional EV-mediated crosstalk between RPE and Müller cells under hypoxic conditions and its impact on cellular metabolism and retinal cell integrity. Our findings demonstrate that RPE-derived extracellular vesicles (RPE EVs) induce time-dependent metabolic reprogramming in Müller cells. Short-term exposure (24 h) promotes pathways supporting neurotransmitter cycling, calcium and mineral absorption, and glutamate metabolism, while prolonged exposure (72 h) shifts Müller cell metabolism toward enhanced mitochondrial function and ATP production. Conversely, Müller cell-derived EVs under hypoxia influenced RPE metabolic pathways, enhancing fatty acid metabolism, intracellular vesicular trafficking, and the biosynthesis of mitochondrial co-factors such as ubiquinone. Proteomic analysis revealed significant modulation of key regulatory proteins. In Müller cells, hypoxic RPE-EV exposure led to reduced expression of Dyskerin Pseudouridine Synthase 1 (DKc1), Eukaryotic Translation Termination Factor 1 (ETF1), and Protein Ser/Thr phosphatases (PPP2R1B), suggesting alterations in RNA processing, translational fidelity, and signaling. RPE cells exposed to hypoxic Müller cell EVs exhibited elevated Ribosome-binding protein 1 (RRBP1), RAC1/2, and Guanine Nucleotide-Binding Protein G(i) Subunit Alpha-1 (GNAI1), supporting enhanced endoplasmic reticulum (ER) function and cytoskeletal remodeling. Functional assays also revealed the compromised barrier integrity of the outer blood–retinal barrier (oBRB) under hypoxic co-culture conditions. These results underscore the adaptive but time-sensitive nature of retinal cell communication via EVs in response to hypoxia. Targeting this crosstalk may offer novel therapeutic strategies to preserve retinal structure and function in ischemic retinopathies. Full article

The retinal pigment epithelium (RPE), a monolayer of pigmented cells, is critical for visual function through its interaction with the neural retina. In healthy eyes, RPE cells exhibit a uniform hexagonal arrangement, but under stress or disease, such as age-related macular degeneration (AMD), dysmorphic traits like cell enlargement and apparent multinucleation emerge. Multinucleation has been hypothesized to result from cellular fusion, a compensatory mechanism to maintain cell-to-cell contact and barrier function, as well as conserve resources in unhealthy tissue. However, traditional two-dimensional (2D) imaging using apical border markers alone may misrepresent multinucleation due to the lack of lateral markers. We present high-resolution confocal images enabling three-dimensional (3D) visualization of apical (ZO-1) and lateral (α-catenin) markers alongside nuclei. In two RPE damage models, we find that seemingly multinucleated cells are often single cells with displaced neighboring nuclei and lateral membranes. This emphasizes the need for 3D analyses to avoid misidentifying multinucleation and underlying fusion mechanisms. Lastly, images from the NaIO₃ oxidative damage model reveal variability in RPE damage, with elongated, dysmorphic cells showing increased ZsGreen reporter protein expression driven by EMT-linked CAG promoter activity, while more regular RPE cells displayed somewhat reduced green signal more typical of epithelial phenotypes. Full article

Pericytes, specialized mural cells surrounding microvessels, play a crucial role in maintaining vascular homeostasis and function across various organs, including the eye. These versatile cells regulate blood flow, support the integrity of the blood–retinal barrier, and contribute to angiogenesis. Recent advancements in molecular and cellular biology have revealed the heterogeneity of pericytes and their critical involvement in ocular physiology and pathology. This review provides a comprehensive analysis of pericyte functions in ocular health and their implications in diseases such as diabetic retinopathy, age-related macular degeneration, glaucoma, and retinal vein occlusion. Pericyte dysfunction is implicated in vascular instability, neurovascular coupling failure, inflammation, and pathological neovascularization, contributing to vision-threatening disorders. The review further explores recent findings on pericyte-targeted therapies, including pharmacological agents, gene therapy, and cell-based approaches, aiming to restore pericyte function and preserve ocular health. Full article

Diabetic retinopathy is a sight-threatening complication of diabetes mellitus, affecting millions of people worldwide. From a vascular perspective, diabetic retinopathy compromises the structure and function of the blood–retinal barrier, leading to aberrant angiogenesis and vascular leakage, with consequent loss of vision. This review will delve into the vascular abnormalities caused by diabetic retinopathy in the inner blood–retinal barrier, focusing primarily on retinal endothelial cells. It will then discuss how calcium signalling regulates inner blood–retina barrier function and dysfunction, how calcium channels contribute to the development of diabetic retinopathy, and how studying the components of the calcium toolkit may identify new therapeutic targets. Full article

Pericytes (PCs), a heterogeneous population of perivascular supporting cells, are critical regulators of vascular stability, angiogenesis, and blood–tissue barrier integrity. Increasing evidence highlights their active role in the pathophysiology of diabetic microangiopathies, including those affecting the retina, kidney, brain, heart, and peripheral nerves. In diabetes, hyperglycemia-induced PC dysfunction is a major contributor to vascular degeneration, impaired tissue repair, and disease progression across multiple organs. Pericytes also share many characteristics with mesenchymal stem cells (MSCs). They exhibit regenerative capacity, immunomodulatory activities, and multipotent capacities. This review explores the emerging role of PCs as tissue resident MSCs, emphasizing their pathophysiological involvement in diabetes complications, and their potential for utilization in regenerative medicine. We also discuss advances in PC-based therapies, tissue engineering strategies, and clinical applications. Thus, PCs are positioned as promising targets for therapeutic intervention and vascular tissue regeneration. Full article

Traumatic brain injury (TBI) induces complex molecular and cellular responses, often leading to vision deterioration and potential mortality. Current objective diagnostic methods are limited, necessitating the development of novel tools to assess disease severity. This review focuses on the retina, a readily approachable part of the central nervous system (CNS), as a potential indicator of TBI. We conduct a targeted database search and employ a blinded scoring system, incorporating both human and artificial intelligence (AI) assessments, to identify relevant articles. We then perform a detailed analysis to elucidate the molecular pathways and cellular changes in the retina following TBI. Recent findings highlight the involvement of key molecular markers, such as ionized calcium-binding adapter molecule 1 (IBA1), phosphorylated tau, glial fibrillary acidic protein (GFAP), and various cytokines (IL-1β, IL-6, and TNF). Additionally, the roles of oxidative stress, reactive oxygen species (ROS), and blood–retina barrier (BRB) disruption are explored. Based on these findings, we hypothesize that alterations in these molecular pathways and cellular components, particularly microglia, can serve as direct indicators of brain health and TBI severity. Recent technological advancements in retinal imaging now allow for a direct assessment of retinal cells, including microglia, and related inflammatory processes, facilitating the translation of these molecular findings into clinical practice. This review underscores the retina’s potential as a non-invasive window into the molecular pathophysiology of TBI. Full article

Upregulation of leucine-rich alpha-2-glycoprotein-1 (LRG1) contributes to aberrant neovascularization in many different diseases. In contrast, LRG1 is not involved in developmental angiogenesis. Here, we investigated the vasculopathic properties of LRG1 by examining its effect on developing retinal blood vessels. By injecting recombinant protein or an expression vector into the mouse retina during vascular development, we showed that exogenous LRG1 reduces pericyte coverage and NG2 expression. It leads to diminished collagen IV sheathing, fewer adhesion and gap junctions, and reduced vessel calibre and vascular density. Moreover, in mouse retinae containing exogenous LRG1, the developing blood–retinal barrier remains more permeable with significantly higher numbers of transcytotic vesicles present in microvascular endothelial cells. These results reveal that exogeneous LRG1 is sufficient to interfere with the maturation of developing retinal vessels and drive vessel development towards a dysfunctional phenotype. These observations deliver further evidence that LRG1 is an angiopathic factor and highlight the therapeutic potential of blocking LRG1 in diseases characterized by pathogenic angiogenesis or vascular remodelling. Full article

Diabetic retinopathy (DR) is a major complication of diabetes, leading to vision impairment and blindness. The pathogenesis of DR involves multiple factors, including hyperglycemia-induced vascular damage, hypertension, obesity, anemia, immune dysregulation, and disruption of the blood–retinal barrier (BRB). Th17 and Treg cells, two types of CD4+ T cells, play opposing roles in inflammation. Th17 cells are pro-inflammatory, producing cytokines such as IL-17A, while Treg cells help suppress immune responses and promote anti-inflammatory effects. Recent studies highlight the importance of the Th17/Treg balance in retinal inflammation and disease progression in DR. Our literature review reveals an imbalance in DR, with increased Th17 activity and reduced Treg function. This shift creates a pro-inflammatory environment in the retina, worsening vascular leakage, neovascularization, and vision loss. The limited infiltration of Treg cells suggests that Th17 cells may uniquely infiltrate the retina by overwhelming or outnumbering Tregs or increasing the expression of recruiting chemokines, rather than only taking advantage of a damaged BRB. Therapeutic strategies, such as neutralizing IL-17A and enhancing Treg function with compounds like IL-35 or curcumin, may reduce inflammation and retinal damage. Restoring the balance between Th17 and Treg cells could provide new approaches for treating DR by controlling inflammation and preventing further retinal damage. Full article