Kota Sato

Précis: Plasma BDNF differed across glaucoma severity stages and was cross-sectionally associated with visual and structural parameters; in exploratory age-stratified analyses, the fitted csGCCT–BCVA relationship differed between younger and older patients. Purpose: To compare the plasma level of brain-derived neurotrophic factor (BDNF) in open-angle glaucoma (OAG) patients across disease stages and to examine its associations with visual and structural parameters. Patients and Methods: This cross-sectional study included 167 control (cataract) patients and 800 patients with OAG. Plasma BDNF level was measured using a bead-based immunoassay (Luminex). Clinical variables included best-corrected visual acuity (BCVA), Humphrey Field Analyzer 24-2 indices, and swept-source optical coherence tomography measurements of superior, central, and inferior papillomacular central-strip ganglion cell complex thickness (csGCCT). Glaucoma severity was classified with the Anderson-Patella criteria. Exploratory generalized additive models characterized the central csGCCT–BCVA relationship by age group and by lowest versus highest quartile. Results: Plasma BDNF was lower in early and moderate glaucoma patients than in controls ( P =0.006, 0.001) but higher in advanced than in early or moderate glaucoma patients ( P =0.040, 0.006). The highest-BDNF-quartile glaucoma patients had worse BCVA and mean deviation (MD) than the lowest-quartile patients, with significantly lower central csGCCT. Among patients aged <60 years, the fitted central csGCCT–BCVA relationship differed between the highest and lowest BDNF quartiles, with higher fitted logMAR in the highest-quartile group at lower csGCCT values. Conclusions: Plasma BDNF level differed across OAG disease stages and was associated with visual and structural parameters. Among younger patients, plasma BDNF quartile was associated with the fitted csGCCT–BCVA relationship. These cross-sectional findings do not establish temporal or causal relationships.

Transplantation of induced pluripotent stem cell-derived retinal ganglion cells (RGCs) is a promising strategy for optic nerve regeneration and vision restoration in glaucoma. However, injections of conventional single-cell suspensions have low engraftment rates, hindering the formation of the complex neural circuits essential for functional recovery. This study addresses this challenge by investigating an in vitro biomimetic tissue engineering approach designed for future translational objectives, such as RGC transplantation therapy. We systematically evaluated coating materials and culture supplements critical for the survival and morphological development of RGCs on biocompatible, aligned poly-ε-caprolactone (PCL) nanofiber membranes. Notably, we identified the xeno-free extracellular matrix (ECM) conditions that promote RGC neurite extension at levels comparable to animal-derived ECM, thereby overcoming a major barrier to clinical translation of this technique. Furthermore, while RGCs typically have compromised viability and limited outgrowth on nanofibers, enhancing cell-scaffold adhesion signaling via the integrin β1/focal adhesion kinase pathway significantly improved both survival and neurite development. Crucially, RGCs on aligned PCL nanofibers extended neurites along the longitudinal axes of the nanofibers, with both somata and neurites exhibiting functional calcium responses to depolarization. These findings represent a significant advancement in biomimetic in vitro tissue engineering aimed at recapitulating retinal neurite orientation, providing a scalable platform for future nanofiber-based neural regeneration therapies, with the ultimate goal of clinical applicability.

Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. While elevated intraocular pressure (IOP) remains the primary modifiable risk factor, a certain proportion of patients continue to deteriorate despite adequate IOP control, pointing to IOP-independent mechanisms of neurodegeneration. Oxidative stress—defined as an imbalance between the production of reactive oxygen species and the capacity of endogenous antioxidant defenses—has emerged as a central, multi-tiered contributor to glaucoma pathogenesis. In the anterior segment, chronic oxidative damage to the trabecular meshwork impairs aqueous humor outflow and drives IOP elevation. In addition, oxidative stress may impair ocular biomechanical integrity, including corneal hysteresis and lamina cribrosa, resulting in heightened susceptibility to IOP fluctuations. In the posterior segment, oxidative stress directly contributes to mitochondrial damage and vascular endothelial injury, leading to RGC apoptosis. The nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway coordinates the principal endogenous antioxidant response, while nicotinamide adenine dinucleotide (NAD⁺) depletion links redox imbalance to metabolic vulnerability of RGCs. This narrative review synthesizes evidence published up to March 2026 on the molecular mechanisms of oxidative stress in glaucoma, the role of biomarkers in aqueous humor and systemic circulation, and the translational landscape of antioxidant-based neuroprotection—including nicotinamide, coenzyme Q10, alpha-lipoic acid, and Nrf2-activating compounds. We highlight gaps between preclinical promise and clinical evidence, and outline priorities for future randomized controlled trials.

Interphotoreceptor retinoid-binding protein (IRBP), an extracellular glycoprotein, supports cone-mediated vision through unclear molecular mechanisms. Over 30 different mutations in the IRBP gene have been found in patients with retinitis pigmentosa (RP), childhood-onset retinal dystrophy with high myopia, and cone-rod dystrophy, yet their pathogenicity and underlying pathogenic mechanisms have not been studied in animal models. Here, we found that extracellular IRBP significantly increased the quantities of the extracellular, but not intracellular, 11- cis -retinol and 11- cis -retinal synthesized by retinal G-protein–coupled receptor (RGR) in coordination with retinol dehydrogenases and GL stimuli. Retinoid trafficking in the retina and recovery of S-cone and rod maximum photoresponses were substantially delayed in male and female mice of a new RP model linked to the human D1080N-IRBP. The mutant IRBP was unstable, not secreted, and retained in the endoplasmic reticulum of photoreceptors due to formation of insoluble high molecular complexes via disulfide bonds. Young mutant mice exhibited profound reduction in photoresponses to ultraviolet stimuli without a significant S-opsin reduction and S-cone structural degeneration. In contrast, M-cones exhibited early and progressive degeneration, accompanied by mislocalization of M-opsin to the soma and synaptic region of M-cones. Rods also underwent early and progressive degeneration. Oxidative and inflammatory stresses as well as proapoptotic proteins such as activated caspase-3, BAX, and apoptosis-inducing factor were markedly increased in the mutant mouse retina. These findings identify both a role of IRBP in the RGR-mediated photopic visual cycle supporting daytime color vision and the molecular mechanism by which D1080N-IRBP causes vision impairment and photoreceptor degeneration.

Objectives: Glaucoma is an age-related neurodegenerative disease, characterized by retinal ganglion cell loss and progressive visual field deterioration. Beyond intraocular pressure (IOP), vascular and metabolic dysregulation contributes to optic nerve head (ONH) ischemia and neuronal vulnerability. Nutritional factors with antioxidative and vasodilatory properties may help preserve ocular perfusion. This study investigated the acute and subacute effects of a single dose of a dietary supplement containing red ginger extract (Zingiber officinale var. rubra), lutein, and vitamin B6 on ONH blood flow in patients with open-angle glaucoma (OAG). Methods: A retrospective self-controlled study was conducted at Tohoku University Hospital between August 2023 and March 2025. ONH blood flow was quantified using a laser speckle flowgraphy (LSFG) baseline one hour after and one month after continuous oral supplementation in patients with OAG. Systemic parameters, ocular biometry, and concomitant glaucoma medications were recorded in medical charts. Relative mean blur rate (MBR) changes were analyzed using a linear mixed-effects model, accounting for repeated measures and inter-eye correlations. Results: Nineteen glaucoma patients (38 eyes) were included in the acute phase and 13 patients (26 eyes) completed the one-month follow-up. After adjusting for age and sex, a single oral dose of red ginger extract significantly increased the relative MBR at 1 h (106.9 ± 3.1%; p < 0.05), and this enhancement increased after 1 month of continuous intake (115.4 ± 6.7%; p < 0.05). Greater ONH perfusion was particularly prominent in eyes with shorter axial length. Conclusions: Oral supplementation was associated with acute and short-term increases in ONH blood flow in glaucomatous eyes. Although this study was a retrospective study without a placebo-controlled comparison group, our findings offer hypothesis-generating evidence that nutritional interventions may support ocular perfusion alongside conventional glaucoma management. Future prospective randomized controlled trials are required to confirm these associations.

Objectives: Previously, we identified four open-angle glaucoma (OAG)-associated autoantibodies (anti-ETNK1, anti-VMAC, anti-NEXN, and anti-SUN1) using proteome-wide autoantibody screening by wet protein arrays. The objective of this exploratory study was to evaluate the diagnostic performance of these four glaucoma-associated autoantibodies using automated machine learning. Methods: Plasma samples from 119 patients with OAG and 35 patients with cataracts as controls were enrolled for the study. All machine-learning analyses were performed in Python 3.9.16 (GCC 11.2.0) using scikit-learn 1.2.2 and PyCaret 3.0.1. Variables included plasma levels of the autoantibodies, age, sex, and intra-ocular pressure (IOP). Probability calibration (Platt/sigmoid and isotonic) was assessed with reliability curves and Brier scores. Model explainability was examined with permutation importance, SHAP values, and an ablation analysis removing one autoantibody at a time. Results: The tuned random forest achieved an out-of-fold (OOF) area under the receiver-operating characteristic curve (ROC–AUC) of 0.852 (±0.040), an average precision (AP) of 0.950, and an F1 score of 0.865. Isotonic mapping improved agreement between predicted and empirical probabilities. Among these four autoantibodies, VMAC was the most important factor for the model’s prediction. Conclusions: A machine learning model using four autoantibodies from blood samples showed potential for diagnosing OAG.

Glaucoma is a major ocular neurodegenerative disease and a leading cause of irreversible blindness worldwide, with prevalence projected to exceed 110 million by 2040. Although lowering intraocular pressure (IOP) remains the only proven treatment, glaucoma arises from a complex interplay of genetic, local, and systemic factors—including oxidative stress, vascular dysregulation, mitochondrial dysfunction, and neuroinflammation. Emerging evidence suggests that modifiable lifestyle factors may influence these pathogenic pathways. In this review, higher dietary nitrate from leafy greens is consistently associated with lower primary open-angle glaucoma risk, aligning with nitric-oxide-mediated endothelial support and more stable ocular perfusion pressure. Flavonoids (anthocyanins and flavanols), carotenoids (lutein/zeaxanthin), and B vitamins have strong biological rationale for glaucoma prevention but have limited support from long-term, large population-based studies. The effect of polyunsaturated fats on glaucoma remains inconsistent and warrants source-(plant vs. animal) and substitution-based analyses. Consistent protective effects of aerobic exercise and high-quality sleep may be associated with favorable metabolic profiles and ocular perfusion, potentially mitigating retinal ganglion cell loss. Conversely, smoking and alcohol use are frequently coupled with poorer diet quality (e.g., lower vegetable intake) and heightened oxidative stress, which may exacerbate glaucomatous neurodegeneration. However, much of the current literature is constrained by cross-sectional designs, reliance on self-reported food frequency questionnaires, and insufficient use of structural endpoints such as retinal nerve fiber layer imaging. This review focuses on the potential of lifestyle modification and future directions in prevention and treatment strategies for glaucoma, highlighting the need for large-scale, multi-ethnic, genotype-stratified longitudinal studies and randomized controlled trials to establish causality and define optimal intervention strategies.

Purpose: We explored the role of oxytocin in glaucoma by measuring the blood levels of oxytocin in glaucoma patients, comparing them to normal control subjects, and examining its association with clinical parameters. Study design: Retrospective cross-sectional study. Material and Methods: After obtaining informed consent from 181 glaucoma patients and 44 age-matched control participants, we collected blood samples in ethylenediaminetetraacetic acid (EDTA) tubes and centrifuged them at 2000 g for 25 minutes at 4 °C. The resulting plasma was assayed for oxytocin concentration with an Enzyme Linked Immunosorbent Assay (ELISA) kit. We compared oxytocin concentrations in the control and glaucoma groups, and within the glaucoma group, we determined whether the oxytocin levels were correlated with mean deviation (MD) and sectoral total deviation (TD). Furthermore, in 33 patients who underwent at least five visual field tests over a two-year period following oxytocin measurements and received no surgical interventions during that time, we determined whether the oxytocin levels were correlated with MD slope and sectoral TD slopes. Results: Oxytocin levels in glaucoma patients were significantly lower than in age- and sex-matched normal controls (723.34 ± 303.44 vs. 557.59 ± 296.04 pg/ml, p=0.002). In glaucoma patients, oxytocin levels were significantly correlated with MD and inferior TD after adjustment for age and sex (β=0.149, p=0.041; β=0.156, p=0.034, respectively). There was a weak negative correlation between oxytocin concentration and MD slope (β=-0.334, p=0.084) and a weak negative correlation with central TD slope (β=-0.405, p=0.039), adjusted for age, sex, and history of additional eye drops. Conclusion: Oxytocin concentrations in glaucoma patients were significantly lower than in normal subjects and associated with the severity and progression of visual field defects. Given the wide variety of the pharmacological actions of oxytocin, it may be involved in the pathogenesis of glaucoma. Our results suggest that plasma oxytocin measurements may open a new avenue for glaucoma care.

Background: An acute angle-closure attack (AAC) is an ocular emergency that results from a rapid increase in intraocular pressure (IOP). Sustained IOP elevation induces severe degeneration of retinal ganglion cells (RGCs) without treatment. Overactivated microglia, key participants in innate immune responses, have critical roles in the pathogenesis of IOP-induced RGC death, although precise mechanisms remain unclear. In the present study, we used a rat ex vivo acute glaucoma model to investigate the role of microglial signaling in RGC death and examined whether pharmacological depletion of microglia using a CSF-1R inhibitor, PLX5622, exerts neuroprotection against pressure-induced retinal injury. Methods: Ex vivo rat retinas were exposed to hydrostatic pressure (10 mmHg or 75 mmHg) for 24 h. Pressure-dependent changes in retinal microglia and RGCs were detected by immunofluorescence. Morphological changes in the retina and RGC apoptosis were examined using light microscopy and TUNEL staining, respectively. The expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β were examined using Western blotting. Effects of PLX5622, an agent that depletes microglia, were examined in morphology, apoptosis, and protein expression assays, while TAK-242, a TLR4 inhibitor, was examined against protein expression. Results: Pressure loading at 75 mmHg markedly increased activated microglia and apoptotic RGCs in the isolated retinas. Western blotting revealed increases in expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg compared to 10 mmHg. Inhibition of pressure-induced increases in NLRP3 by TAK-242 indicates that pressure elevation induces RGC death via activation of the TLR4–NLRP3 inflammasome cascade. PLX5622 depleted microglia at 75 mmHg and significantly decreased expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg, resulting in preservation of RGCs. Conclusions: These results indicate that pressure elevation induces proliferation of inflammatory microglia and promotes IL-1β production via activation of the TLR4–NLRP3 inflammasome cascade, resulting in RGC death. Pharmacological depletion of microglia with PLX5622 could be a potential neuroprotective approach to preserve RGCs from inflammatory cytokines in AAC eyes.