Search Results (192)

Objectives: To investigate the clinicopathologic characteristics and molecular biomarkers of atypical vasoproliferative retinal tumor (VPRT) with hemangioblastoma-like histopathologic features and concomitant von Willebrand factor (VWF) abnormalities. Methods: A 48-year-old woman undergoing phacoemulsification and 25-gauge pars plana vitrectomy with tumor resection was evaluated. Histopathological findings and immunohistochemical study of the resected tumor were performed using CD34, α-smooth muscle actin (αSMA), and glial fibrillary acidic protein (GFAP) markers. Preoperative plasma and intraoperative vitreous fluid VWF antigen levels, as well as ristocetin cofactor activity, were quantified using latex immunoturbidimetry. Results: Ultra-widefield imaging and angiography demonstrated a peripheral retinal tumor with intense vascular leakage and surrounding capillary nonperfusion. Histopathology showed hyalinized vascular components supportive of VPRT, along with abundant CD34/α-SMA-positive microvessels and scant GFAP-positive glial cells. Notably, numerous foamy vacuolated poorly differentiated cells suggested mixed hemangioblastoma-like features. Preoperative plasma VWF antigen (182.6%) and ristocetin cofactor activity (147.7%) were elevated, and vitreous VWF antigen was successfully detected at a low but distinct level (7.7%).and suggests that VWF abnormalities in the plasma and vitreous may reflect endothelial activation and/or blood–retinal barrier disruption in a subset of vascularized retinal tumors. Conclusions: Our findings demonstrate that VPRT may exhibit mixed clinicopathologic features, including hemangioblastoma-like components, which underscores the necessity of immunohistochemical assessment for definitive diagnosis. Furthermore, the quantification of VWF abnormalities in the plasma and vitreous suggests that VWF serves as a potential biomarker reflecting endothelial activation and/or blood–retinal barrier disruption in vascularized retinal tumors. Full article

Studies employing animal models play a pivotal role in advancing our understanding of the pathophysiology of retinal diseases. These models enable the investigation of molecular and cellular mechanisms underlying retinal structural damage, as well as the assessment of genetic and environmental factors contributing to disease development. The application of appropriate experimental models provides essential insights into the progression of degenerative processes and tissue responses to therapeutic interventions. The advancement of modern molecular biology and genetic engineering techniques has facilitated the development of increasingly precise animal models, which have proven crucial for identifying pathological alterations occurring in the course of retinal diseases. In recent years, research has demonstrated that, depending on the model employed, the observed changes may involve inflammatory processes, oxidative stress, photoreceptor dysfunction, extracellular matrix remodeling, and aberrant glial cell responses. It has also been shown that the nature and dynamics of these alterations vary according to the specific disease entity and the animal species used. The aim of this review is to compile and systematize current knowledge regarding the most commonly used animal models in retinal disease research and to discuss their utility in analyzing potential pathogenetic mechanisms and therapeutic targets. The review also highlights emerging complementary research strategies associated with New Approach Methodologies (NAMs), including retinal progenitor and iPSC-derived cell-based approaches, advanced retinal imaging techniques, and alternative experimental platforms such as the chorioallantoic membrane (CAM) assay, which may support translational retinal research and reduce reliance on traditional animal models. The authors hope that this work will contribute to the refinement of preclinical research methodologies and, through an improved understanding of the processes underlying the development of retinal diseases, facilitate the advancement of more effective diagnostic and therapeutic strategies in the future. Full article

Glaucoma is a chronic progressive optic neuropathy and one of the leading causes of irreversible blindness worldwide. Although elevated intraocular pressure remains the most important modifiable risk factor, increasing evidence suggests that immune dysregulation and autoimmune responses also contribute substantially to disease onset and progression. Clinical studies across different glaucoma subtypes have identified subtype-dependent immune abnormalities, including altered serum autoantibody profiles, dysregulated cytokine and chemokine expression, and changes in peripheral immune cell subsets. Experimental and translational studies further indicate that multiple immunopathogenic mechanisms are involved in glaucomatous neurodegeneration, including glial cell-mediated immune responses, activation of pattern recognition receptor signalling pathways, adaptive immune responses, and complement cascade dysregulation. These processes may interact to sustain chronic neuroinflammation, promote retinal ganglion cell injury, and accelerate optic nerve degeneration. Importantly, a better understanding of immune involvement in glaucoma has generated growing interest in immunomodulatory therapy as a potential strategy beyond intraocular pressure lowering. Targeting microglial activation, inflammatory signalling pathways, adaptive immune imbalance, and complement-mediated injury has shown neuroprotective potential in animal or in vitro models, whereas clinical evidence in glaucoma patients remains limited. These findings may provide preliminary directions for future therapeutic development. In this review, we summarise the current clinical evidence linking glaucoma with autoimmunity, discuss the major immune mechanisms implicated in disease pathogenesis, and highlight recent advances in immunomodulatory therapeutic strategies. Elucidating the immune basis of glaucoma may help pave the way for more precise and effective treatments for this complex optic neuropathy. We believe that immune dysregulation in glaucoma functions as a context-dependent amplifier of retinal ganglion cell injury rather than a uniform primary driver, with innate (microglia/astrocytes), adaptive (T/B cells, HSP-specific immunity), and complement pathways interacting to sustain neuroinflammation and neurodegeneration. This integrated immune response contributes to subtype- and stage-specific vulnerability, and targeting these maladaptive immune mechanisms represents a promising, precision-guided strategy for neuroprotection beyond intraocular pressure lowering. Full article

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: 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

Alzheimer’s disease (AD) is increasingly recognized as a multisystem neurodegenerative disorder in which sensory dysfunction accompanies cognitive decline. As an accessible extension of the central nervous system, the retina provides a valuable window for investigating early neurodegenerative processes; however, the cellular mechanisms underlying AD-associated retinal pathology remain incompletely understood. Here, using the APP/PS1 mouse model, we systematically examined structural, functional, and glial alterations in the retina across disease stages. Despite robust age-dependent amyloid plaque accumulation in visual-related brain regions, no plaque-like β-amyloid (Aβ) deposits were detected in the retina even at advanced ages. Nevertheless, young APP/PS1 mice exhibited early thinning of inner retinal layers, impaired retinal electrophysiological responses, and reduced excitatory synaptic inputs to retinal ganglion cells (RGCs), preceding overt neuronal loss. These neuronal changes were accompanied by pronounced Müller glial activation, characterized by upregulation of gliosis markers and extensive morphological remodeling. Functional analyses further revealed dynamic alterations in glial homeostasis, including early elevation followed by age-dependent decline of glutamine synthetase activity, together with increased expression and disrupted perivascular polarity of aquaporin-4. Consistently, transcriptomic profiling of young AD retinas identified coordinated dysregulation of genes involved in amino acid metabolism, transport, and oxidative stress responses. Together, our findings identify Müller glial remodeling as an early feature of AD-associated retinal pathology that coincides with synaptic vulnerability of RGCs and occurs independently of local Aβ plaque deposition, highlighting retinal glia as potential early indicators and modulators of neurodegeneration. Full article

The retina is a complex sensory neural tissue composed of six major types of neurons and one type of glial cell. The cell fate specification of retinal cells is tightly governed by intrinsic factors and extrinsic microenvironmental cues. Among the key regulators directing retinal cell fate differentiation is a group of bHLH family transcription factors (TFs). Our previous work demonstrated that the bHLH TF Ngn3 exhibits robust potential to induce retinogenesis in both distantly related fibroblasts in vitro and late retinal progenitor cells (RPCs) in vivo. However, the underlying molecular mechanisms remain largely elusive. In this study, we combined immunohistological examination and RNA-seq and ATAC-seq analyses to investigate the cellular and molecular mechanisms governing Ngn3-driven retinogenesis in late RPCs. Our results revealed that Ngn3 overexpression promotes premature cell cycle exit in late RPCs and remodels their transcriptomic and epigenomic landscape towards a state favoring rod photoreceptor and RGC differentiation. Furthermore, cross-comparison with Ngn3-overexpressing fibroblasts in vitro revealed cell-type-specific mechanisms underlying Ngn3-mediated neuronal fate reprogramming. These findings advance our understanding of Ngn family-mediated retinal cell fate regulation and provide a mechanistic framework for optimizing Ngn3-based retinal regeneration strategies for the treatment of retinal degeneration diseases. 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

Background/Objectives: Vascular inflammation and impaired endothelial regeneration contribute to chronic degenerative disorders, including ocular neovascularization and retinal degeneration. Nutritional bioactives that modulate molecular pathways governing angiogenesis and tissue remodeling represent promising adjunct strategies for vascular health. This study investigated whether cocoa powder (CP) regulates hypoxia-driven molecular signaling and attenuates vascular inflammation and degeneration. Methods: The vascular-modulatory effects of CP were examined in human umbilical vein endothelial cells (HUVECs) and in murine models of alkali-induced corneal neovascularization and N-methyl-N-nitrosourea (MNU)-induced retinal degeneration. Hypoxia-inducible factor-1α (HIF-1α) signaling and downstream angiogenic targets were assessed by Western blotting and quantitative PCR. Endothelial migration, tube formation, and transwell assays were performed to evaluate angiogenic responses. In vivo, oral CP (50 or 200 mg/kg) was administered, and vascular growth, inflammatory and remodeling markers, and retinal structural integrity were analyzed by histology, immunofluorescence, and protein expression. Results: At non-cytotoxic concentrations (0.1–1.0 μg/mL), CP suppressed hypoxia-induced HIF-1α protein stabilization without altering HIF-1α mRNA levels and reduced expression of VEGFA, EPO, and GLUT1. CP significantly inhibited VEGF-A-induced endothelial migration, network formation, and chemotactic invasion. In alkali-injured corneas, CP reduced the neovascularized area and downregulated VEGF, MMP2, MMP9, α-smooth muscle actin, and Ninj1, indicating attenuation of vascular inflammation and fibrotic remodeling. In the MNU model, CP preserved outer nuclear layer thickness, reduced glial activation (GFAP), maintained rhodopsin expression, and decreased MMP9 induction. Conclusions: CP functions as a nutritional modulator of hypoxia-responsive and inflammatory pathways, suppressing pathological angiogenesis while supporting structural preservation in degenerative vascular conditions. These findings highlight the translational potential of dietary polyphenol-rich interventions in regulating vascular inflammation and regeneration. Full article

The dystrophin gene encodes multiple dystrophin isoforms with tissue-specific functions, including several shorter isoforms expressed in the central nervous system and retina. While Duchenne muscular dystrophy (DMD) has historically been characterized as a primary myopathy resulting from loss of the full-length dystrophin Dp427, increasing clinical evidence indicates that dysfunction of shorter dystrophin isoforms contributes to significant extramuscular pathology, including retinal disease. In particular, loss of the Dp71 isoform has been implicated in retinal inflammation, blood–retinal barrier breakdown, and pathological angiogenesis. In this study, we investigated whether low-level residual expression of Dp71 is sufficient to mitigate retinal inflammation in the mdx3Cv mouse model, which displays reduced—but not absent—expression of multiple dystrophin isoforms. Western blot analysis revealed that mdx3Cv retinas express approximately 4% of wild-type Dp71 protein levels. Despite this marked reduction, mdx3Cv mice did not exhibit the inflammatory phenotype previously observed in Dp71-null mice. Retinal VEGF protein levels and VEGF receptor (FLT-1 and KDR) mRNA expression were preserved, while VEGF mRNA levels were modestly reduced. Furthermore, expression of inflammatory markers ICAM-1 and ALOX5AP, leukocyte adhesion to retinal vasculature, Aquaporin-4 expression, and BRB permeability to albumin were all comparable to wild-type littermates. Together, these findings demonstrate that minimal residual expression of Dp71 is sufficient to preserve retinal vascular homeostasis and prevent inflammatory and permeability defects in the mdx3Cv retina. These results further suggest that partial dystrophin restoration—at levels achievable with current exon-skipping or gene-based therapies—may be adequate to prevent or attenuate retinal pathology in DMD, providing a realistic and clinically relevant therapeutic target. Full article

Background/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors—including pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF), rod-derived cone viability factor (RdCVF), brain-derived neurotrophic factor (BDNF), fibroblast growth factors (FGFs), glial cell line-derived neurotrophic factor (GDNF), and proinsulin—have demonstrated photoreceptor preservation across multiple preclinical IRD models regardless of the underlying genetic mutation. The recent FDA approval of CNTF cell-based gene therapy (Encelto) for macular telangiectasia type 2 validates this therapeutic paradigm. Complement system inhibition represents another gene-agnostic strategy, with intravitreal complement inhibitors approved for geographic atrophy secondary to age-related macular degeneration and gene therapy approaches targeting C3, C5, or delivering soluble complement regulators under investigation for IRDs. Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Conclusions: Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable. Full article

Diabetic retinopathy (DR) is more than a capillary disorder. Diabetes affects neurons, glial cells, vascular cells, and immune signals within the retinal neurovascular unit (NVU). Retinal neurovascular coupling (NVC) is a useful functional marker of NVU integrity because it reflects the rise in local blood flow that follows neural activity. Many human flicker-light studies report smaller vessel dilation or weaker flow responses in diabetes. This finding can appear even in patients without clear fundus lesions. When NVC is reduced, retinal tissue may receive less oxygen. Lower oxygen delivery can raise oxidative stress and promote inflammation. These changes can then worsen vascular injury. This review describes key NVC pathways and diabetes-related NVU changes in Müller glia, astrocytes, microglia, pericytes, and endothelial cells. The review highlights sympathetic activation as a common stress signal. Pain, anxiety, perioperative stress, and sleep loss can increase sympathetic activity and circulating catecholamines. In the diabetic retina, vascular reserve is often limited. Under these conditions, catecholamines can increase mural cell constriction, reduce nitric oxide (NO)-dependent relaxation, and increase endothelial activation and barrier strain. These effects can shift the baseline state of glial and immune cells and further weaken NVC. The review also summarizes translational tools that can test these links. These tools include heart rate variability, standardized NVC protocols with diameter and flow measures, and retinal organoid and organ-on-a-chip platforms with controlled adrenergic exposure. The review discusses perioperative care packages that reduce stress responses, protect sleep, and manage glucose as practical ways to support retinal microcirculation. More longitudinal human studies are still needed. Retina-specific perioperative endpoints are also needed to clarify causality and to guide intervention trials. Full article

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and can lead to severe visual impairment. Based on disease severity, DR is classified into no clinically apparent diabetic retinopathy (NDR), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR). Although nearly all retinal cell types are involved in DR progression, the dominant cell populations and their pathophysiological changes at each stage remain unclear. By integrating bulk and single-cell transcriptomic data from human and mouse retinas, this study revealed the following: (1) In the NDR stage, photoreceptors exhibit significant changes in ribosomal pathways. (2) In the NPDR stage, endothelial cells and pericytes show marked transcriptional alterations, accompanied by enhanced LAMININ signaling in cell-cell communication. (3) At the PDR stage, neural and glial cells are extensively involved in disease progression, with notable changes in ANGPTL signaling. Additionally, this study observed DR-specific subtypes of endothelial cells and pericytes and potentially identifies gene signatures in macroglia cells that correlate with disease duration. The altered expression of several key genes in early diabetic retina was confirmed by qPCR. These findings may offer a comprehensive view of the cellular and molecular landscape underlying DR and may suggest potential targets. Full article

Background: The principal glial cells of the retina, Müller glia, play a central role in retinal regeneration in teleost fish and have recently attracted attention as potential sources of neuronal regeneration in mammals. Objectives: In this study, we examined whether SV40-immortalized rat Müller glia could be directed toward neuronal differentiation using a non-genetic approach with defined culture conditions. Methods: Comprehensive transcriptomic profiling by RNA sequencing indicated that changes in culture medium alone could induce transcriptional reprogramming toward a neuronal lineage. Results: Specifically, expression of Müller glia-related genes decreased, while a subset of photoreceptor-related transcription factors and specific genes showed altered expression, suggesting early-stage induction toward a photoreceptor-like fate. This finding suggests that even immortalized cells may exhibit activation of neuronal genes through non-genetic culture interventions. Gene set enrichment analysis further revealed upregulation of pathways related to the synaptic vesicle cycle, metabolic activation, oxidative stress defense, and lysosomal function, consistent with initiation of neuronal differentiation. Conversely, pathways associated with cell cycle regulation and stemness signaling were downregulated, reflecting a transition from a proliferative to a differentiation-prone state. Collectively, these results provide preliminary molecular markers for early neuronal induction and potential targets for chemical screening. Conclusions: Importantly, this strategy enables neuronal-like differentiation of Müller glia without genetic manipulation, offering a safe and cost-effective platform. Overall, our findings may support the development of in vitro models for retinal neuroregeneration and facilitate research toward regenerative therapies for retinal disorders. Full article