Investigative ophthalmology & visual science最新文献

{"title":"A Novel Mouse Model of Granular Corneal Dystrophy Type II Reveals Impaired Autophagy and Recapitulates Human Pathogenesis.","authors":"Yanze Yu, Zhe Zhang, Zimeng Zhai, Bingqing Sun, Dongmei Yang, Zhanying Wang, Qinghong Lin, Xingtao Zhou, Jing Zhao","doi":"10.1167/iovs.66.12.7","DOIUrl":"10.1167/iovs.66.12.7","url":null,"abstract":"<p><strong>Purpose: </strong>To develop and characterize a novel mouse model of granular corneal dystrophy type II (GCD2) using CRISPR/Cas9 technology and explore the underlying pathogenesis of transforming growth factor-beta-induced protein (TGFBIp) aggregation.</p><p><strong>Methods: </strong>CRISPR/Cas9 technology was employed to introduce the R124H mutation in the TGFBI gene of mice. Genomic sequencing and polymerase chain reaction confirmed the mutation. Phenotypic characteristics were evaluated through slit-lamp examination, optical coherence tomography, histological analysis, electron microscopy, and immunofluorescence, comparing wild-type (WT), heterozygous (HE), and homozygous (HO) mice. Transcriptome sequencing was conducted to identify the pathogenesis of GCD2. The findings were further validated through western blotting and transmission electron microscopy.</p><p><strong>Results: </strong>The R124H mutation in TGFBI was successfully introduced, with breadcrumb-like deposits observed in the corneas of mutant mice, with HO mice displaying more severe phenotypes than HE mice. TGFBIp levels were elevated in HE and HO mice (both P < 0.001). Histological and electron microscopy analyses revealed abnormal collagen arrangement and TGFBIp deposits in the corneal stroma of the HE and HO mice. Transcriptome analysis indicated that the TGFBI-R124H mutation was associated with impaired autophagy, endocytosis, and extracellular matrix signaling. Additional experiments confirmed autophagy-related markers LC3 and SQSTM1 were upregulated in the corneas of mutant mice, accompanied by increased autophagosome formation in corneal keratocytes, indicating impaired autophagy flux in HE and HO mice.</p><p><strong>Conclusions: </strong>We established a GCD2 mouse model caused by the R124H mutation using CRISPR/Cas9, providing a reliable platform for understanding pathogenesis for GCD2.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"7"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel BEST1 Variant Characterization in a Large French Cohort in Light of Updated Bestrophin-1 Structure-Function Correlation.","authors":"Joan Bitan, Anaïs F Poncet, Claire Lecigne, Aurore Devos, Isabelle Meunier, Xavier Zanlonghi, Olivier Grunewald, Vasily Smirnov, Claire-Marie Dhaenens","doi":"10.1167/iovs.66.12.4","DOIUrl":"10.1167/iovs.66.12.4","url":null,"abstract":"<p><strong>Purpose: </strong>To update knowledge on bestrophin-1 structure and function with the aim of assessing the pathogenicity of variants reported in the Leiden Open Variation Database (LOVD) and in a large French cohort of bestrophinopathies.</p><p><strong>Methods: </strong>All unique variants reported in the latest version (October 2024) of the BEST1-LOVD database were uploaded and curated. We described all BEST1 variants identified in French patients analyzed at Lille University Hospital, between 2008 and 2024. A comprehensive analysis of each variant was performed based on in silico tools (at DNA, RNA, and protein levels), as well as a literature review providing clinical data and functional assays. All of these data were used to classify the variant pathogenicity according to the American College of Medical Genetics and Genomics (ACMG) criteria.</p><p><strong>Results: </strong>We detailed 488 variants from the LOVD. Among 450 French patients, we identified 150 different variants, 40 of which were novel. We classified only eight variants as variants of unknown significance, four of which were already in the LOVD. We identified specific recurrent variants in the French population: p.(Gly26Asp), p.(Val90Met), p.(Val137Met), and p.(Ile230del), the last of which was present in 17 patients (3.8%). All new variants cause changes in chemical interactions within the protein and are associated with clinical pictures of bestrophinopathy.</p><p><strong>Conclusions: </strong>The study and comparison of these two large cohorts highlight variants specific to the French population, as well as differences in protein distribution, which are undoubtedly influenced by several population-specific factors. Through multiple in silico analyses, we were able to reclassify 93.3% of variants as likely pathogenic or pathogenic, thereby strengthening clinical diagnoses.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"4"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting RPE Senescence Via Suppressing IL-6/IL-6R Signaling for Treating Retinal Degenerative Diseases.","authors":"Tian Zhou, Ziqi Yang, Biyan Ni, Hong Zhou, Yang Zhou, Huiyi Xu, Xiaojing Lin, Shiya Lin, Wei Yi, Chang He, Xialin Liu","doi":"10.1167/iovs.66.12.44","DOIUrl":"10.1167/iovs.66.12.44","url":null,"abstract":"<p><strong>Purpose: </strong>Progressive dysfunction of retinal pigment epithelium (RPE) cells is a crucial factor for retinal degeneration, leading to irreversible blindness with limited therapeutic options. Cellular senescence of RPE cells and inflammation are important hallmarks for retinal degeneration, but the underlying molecular mechanisms and potential interventions remain largely unexplored. This study aims to explore whether the IL-6/ IL-6R axis establishes a senescence-inducing circuit in RPE cells, and to evaluate the therapeutic efficacy of its inhibition in rescuing senescent RPE cells and degenerative retina.</p><p><strong>Methods: </strong>Sodium iodate (NaIO₃)-induced retinal degeneration mouse models were established and subjected to intravitreal injections of IL-6 neutralizing antibody, or an IL-6R inhibitor tocilizumab, respectively. Conditional deletion of Stat3 in RPE cells was achieved via subretinal delivery of AAV vectors. RPE cells were isolated for single-cell RNA sequencing (scRNA-seq), qPCR, Western blotting, and immunofluorescence staining. Retinal structure and function were assessed using optical coherence tomography (OCT), hematoxylin and eosin (H&E) staining, and electroretinography (ERG).</p><p><strong>Results: </strong>RPE underwent cellular senescence in NaIO3-induced degeneration, which was dependent on activation of the IL-6/IL-6R axis. IL-6 promoted the senescence of RPE and exacerbated retinal degeneration. In contrast, inhibition of IL-6 suppressed RPE senescence and facilitated recovery of retinal structure and function. Mechanistically, STAT3 activation was essential for IL-6-mediated cellular senescence. Notably, tocilizumab effectively blocked the IL-6/IL-6R/STAT3 signaling cascade, attenuated RPE senescence, and protected against retinal degeneration, expanding the indications of tocilizumab.</p><p><strong>Conclusions: </strong>IL-6 and IL-6R/STAT3 signaling played an essential role in RPE senescence, and tocilizumab presents a translational opportunity in treating retinal degenerative diseases.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"44"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enabling In Vivo Longitudinal Evaluation of Descemet's Membrane Thickness in Wild-type and FECD Mice Using Self-Referenced Optical Coherence Microscopy.","authors":"Hadiya Farhath Pattan, Subashree Murugan, Rajalekshmy Shyam, Patrice Tankam","doi":"10.1167/iovs.66.12.60","DOIUrl":"10.1167/iovs.66.12.60","url":null,"abstract":"<p><strong>Purpose: </strong>Descemet's membrane (DM) remodeling is a key factor in the etiology of early-onset Fuchs endothelial corneal dystrophy (FECD). Although various mouse models have been developed to replicate major FECD phenotypes, including DM thickening, there is currently no imaging technique capable of evaluating changes in mice DM thickness in vivo. This work proposed a novel self-referenced optical coherence microscope (OCM) to longitudinally evaluate age-dependent and FECD-dependent changes in DM thickness in mice.</p><p><strong>Methods: </strong>The self-referenced OCM used the mouse corneal surface as the reference to mitigate artifacts from breathing-induced motion, steep corneal curvature, and dispersion mismatch, that often compromise the delineation of the DM in vivo. The approach was validated by longitudinally evaluating the DM thickness in four wild-type (WT) and five FECD mice at two time points-5 weeks of age and 16 weeks of age.</p><p><strong>Results: </strong>Unlike standard OCM, the self-referenced approach enabled the delineation of the DM with an axial resolution of 1.6 µm in the living eyes of WT and FECD mice. A significant increase in DM thickness was observed in FECD mice (2.74 ± 0.12 µm) compared with WT mice (1.85 ± 0.22 µm) at 5 weeks of age. A similar trend was observed at 16 weeks of age (3.20 ± 0.20 µm in FECD mice vs 2.21 ± 0.32 µm in WT mice). No age-dependent increase in DM thickness was observed in either group between 5 weeks of age and 16 weeks of age.</p><p><strong>Conclusions: </strong>This study represents the first longitudinal in vivo evaluation of age-dependent changes in DM thickness in both WT and FECD mice using self-referenced OCM.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"60"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12476163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the Effects of Customized Corneal Cross-Linking on Corneal Geometry.","authors":"Matteo Frigelli, Miguel A Ariza Gracia, M Enes Aydemir, Emilio A Torres-Netto, Farhad Hafezi, Jos Rozema, Philippe Büchler, Sabine Kling","doi":"10.1167/iovs.66.12.51","DOIUrl":"10.1167/iovs.66.12.51","url":null,"abstract":"<p><strong>Purpose: </strong>To validate an existing finite element model (FEM) for predicting the flattening effect of corneal cross-linking (CXL) in a clinical scenario and to use this model to investigate the parameters that most influence CXL-induced flattening effects.</p><p><strong>Methods: </strong>Retrospective data were collected from two clinical cohorts, each with 20 patients receiving either standard or customized CXL. Data were collected before surgery and at the six-month follow-up. Both CXL treatments were simulated with a FEM calibrated on experimental data. Standard anterior corneal geometry indexes (e.g., sphere, cylinder), as well as the curvature changes observed at follow-up were compared to those predicted by FEM simulations.</p><p><strong>Results: </strong>At follow-up, patients who underwent customized CXL exhibited more corneal flattening compared to those who received standard CXL (Kmax-t: -2.28 ± 1.4 D vs. -0.81 ± 1.5 D; P < 0.001). The FEM-predicted curvature reduction in the central CXL regions showed a significant correlation with the follow-up data for both standard (R2 = 0.48, P < 0.01) and customized CXL (R2 = 0.59, P < 0.01). Compared to follow-up data, standard CXL model showed concordance correlation coefficients > 0.9 for nine corneal geometry parameters and customized CXL model for three. Sensitivity analysis demonstrated that a 3 mm Hg increase in intraocular pressure (IOP) combined with a 10% weaker keratoconus region alters flattening outcomes by up to 20%.</p><p><strong>Conclusions: </strong>Customized CXL induces a flattening of about 2 diopters in the cone region six months after surgery. The model adequately captured the curvature corrections induced by the treatment in the keratoconus cone region, but showed reduced accuracy in predicting global corneal metrics, particularly for customized CXL. The induced flattening effects depend on the IOP, keratoconus-induced biomechanical weakening, and the fluence delivered to the cone.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"51"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Bcl3/NF-κB p50 Pathway for Neuroinflammation Attenuation and RGCs Protection in Retinal Ischemia/Reperfusion Injury.","authors":"Meini Chen, Xuan Zhang, Zhou Zeng, Cong Fan, Si Chen, Chao Quan, Jiachang Chen, Mengling You, Xiaobo Xia","doi":"10.1167/iovs.66.12.63","DOIUrl":"10.1167/iovs.66.12.63","url":null,"abstract":"<p><strong>Purpose: </strong>Retinal ischemia/reperfusion (IR) injury caused by pathologically high intraocular pressure (ph-IOP) induces excessive inflammation, contributing to retinal ganglion cell (RGC) death in glaucoma. Lowering IOP alone is insufficient, highlighting the need for neuroprotective strategies. Resveratrol (RSV) exhibits anti-inflammatory and neuroprotective effects, but its molecular mechanisms remain unclear. This study aims to evaluate RSV's neuroprotective role and underlying mechanisms in retinal IR injury.</p><p><strong>Methods: </strong>Retinal morphology and RGC survival were assessed via immunofluorescence and hematoxylin and eosin (H&E) staining. Retinal function was evaluated using flash visual evoked potential (F-VEP) and flash electroretinogram (F-ERG). Inflammation and microglial activation were analyzed by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Pyroptosis and apoptosis were examined using Western blotting, TUNEL staining, and electron microscopy. RNA sequencing, qRT-PCR, and Western blotting identified molecular pathways.</p><p><strong>Results: </strong>RSV significantly protected RGCs and preserved retinal function. It reduced inflammation by inhibiting microglial activation and redistribution. Electron microscopy confirmed its protective effects against apoptosis and pyroptosis. Most importantly, we identified the Bcl3/NF-κB p50 pathway as a key target of RSV. Using the Bcl3-NF-κB p50-specific inhibitor JS-6, we validated this pathway's role in reducing neuroinflammation, pyroptosis, and apoptosis.</p><p><strong>Conclusions: </strong>This study provides insights into RSV's molecular mechanisms and identifies new therapeutic targets for glaucoma.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"63"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Visceral Obesity Indicators and Associated Metabolic Fingerprint in Incident Diabetic Retinopathy.","authors":"Yingcheng He, Jingxin Zhou, Jiawei Wang, Shenyu Huang, Huimin Li, Jing Cao, Juan Ye","doi":"10.1167/iovs.66.12.17","DOIUrl":"10.1167/iovs.66.12.17","url":null,"abstract":"<p><strong>Purpose: </strong>Evidence on the association between visceral obesity and diabetic retinopathy (DR) remains sparse and debatable. We aimed to use three novel indicators, body roundness index (BRI), lipid accumulation product (LAP), and visceral adiposity index (VAI), to investigate the longitudinal relationship between visceral obesity and DR, and explore the potential metabolic mechanisms.</p><p><strong>Methods: </strong>In this prospective study based on the UK Biobank (UKB), 14,738 individuals with diabetes free of DR at baseline were included. Cox proportional hazards regression models were adopted to explore the association among the three indices and DR. Based on nuclear magnetic resonance (NMR) metabolomics of 168 plasma metabolites, we performed elastic net regression to select metabolites associated with visceral obesity and DR. Enrichment and pathway analyses were used to investigate biological pathways and network analysis was performed to discover the metabolic interactions.</p><p><strong>Results: </strong>Over a 10-year follow-up, 1594 subjects developed DR. In the fully adjusted models, the three indices were significantly correlated with a high risk of DR, especially in Caucasians. Furthermore, we identified a metabolic fingerprint comprising 12 biomarkers associated with visceral obesity and DR, including 3-hydroxybutyrate, acetone, alanine, albumin, citrate, intermediate-density lipoprotein particles, creatinine, glucose, glycine, glycoprotein acetyls, pyruvate, and tyrosine. These metabolites were mainly enriched in alanine metabolism and their interaction was partly through succinic acid.</p><p><strong>Conclusions: </strong>Visceral obesity indices (BRI, LAP, and VAI) were positively associated with DR onset in patients with DM, and the potential mechanism involves alanine and energy metabolism. Our findings may promote early detection and precision prevention of DR.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"17"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Na-Cl Cotransporter (SLC12A3) Inhibition Exacerbates Age-Related Macular Degeneration Via the Nrf2/HO-1 Ferroptosis Pathway.","authors":"Chengming Chen, Tingke Xie, Huan Zhang, Lifu Chang, Yanyan Lan, Chao Fan, Dongyu Wei, Xiaolan Wang, Sida Liu, Yixuan Chen, Yuhao Chen, Xuejiao Wang, Xiaolong Yan, Lei Shang, Liyuan Tao, Jing Han","doi":"10.1167/iovs.66.12.24","DOIUrl":"10.1167/iovs.66.12.24","url":null,"abstract":"<p><strong>Purpose: </strong>To explore the causal links between antihypertension drugs usage and age-related macular degeneration (AMD).</p><p><strong>Methods: </strong>Multiple genetic analyses, including summary data-based Mendelian randomization (SMR), traditional MR, and colocalization analysis, were used to explore the causal associations between antihypertension drugs and AMD. Clinical data from the UK Biobank and the National Health and Nutrition Examination Survey (NHANES) was applied to refined risk assessment of specific antihypertensive medications in the context of AMD development. In vitro and in vivo oxidative stress models, mediated by NaIO3, were utilized to study the impact of specific antihypertensive drugs and target genes on AMD pathogenesis.</p><p><strong>Results: </strong>Genetic analyses substantiated the causal relationship between increased SLC12A3 expression and a lowered AMD risk. Colocalization analysis supported the shared causal attributes between SLC12A3 expression and AMD. Cross-sectional analysis results based on UK Biobank indicated that AMD risk was significantly lower in participants taking thiazide diuretics with other antihypertensives or not on antihypertensives compared to those on thiazides alone. The results based on NHANES support the above results. In vivo and in vitro experiments showed that thiazide diuretics worsened retinal damage in AMD mouse models, and SLC12A3 knockdown disrupted the balance of oxidative stress in retinal pigment epithelium (RPE) cells. Further molecular mechanism experiments showed that SLC12A3 knockdown promoted retinal degeneration by regulating RPE ferroptosis through activation of the Nrf2/HO-1 pathway.</p><p><strong>Conclusions: </strong>Our study underscores a notable causal association between thiazide diuretic use and AMD risk and reveals a potential mechanism by which inhibition or downregulation of SLC12A3 (sodium-chloride cotransporter [NCC]) contributes to AMD progression. However, deeper exploration is needed to enhance the accuracy and validity of our findings.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"24"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12429710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nkx3.2 Inhibits Retinal Degeneration by Modulating Inflammation and Cell Death in RPE.","authors":"Minsun Park, Seung-Won Choi, Da-Un Jeong, Hae-Sol Shin, Jiyeon Han, Hye-Kyoung Oh, Jun-Ho Jang, Nari Ryu, Hyunjin Jeong, Young-Do Song, Kyoung Yul Seo, Sanghyuk Lee, Dae-Won Kim","doi":"10.1167/iovs.66.12.2","DOIUrl":"10.1167/iovs.66.12.2","url":null,"abstract":"<p><strong>Purpose: </strong>To identify the expression of Nkx3.2 in retinal pigment epithelium (RPE) and evaluate its physiological role in association with retinal degeneration.</p><p><strong>Methods: </strong>Nkx3.2 expression in RPE was examined by biochemical and histological analyses. Various in vitro and in vivo assays were employed to reveal the molecular mechanisms by which Nkx3.2 regulates inflammatory responses and cell survival in RPE. In addition, by investigating multiple animal models, the biological significance of Nkx3.2 in retinal degeneration was assessed.</p><p><strong>Results: </strong>Nkx3.2 expression was verified in human cadaveric and mouse eye tissues and shown to be regulated by aging and oxidative stress. Mouse model analyses demonstrated retina protection activity of Nkx3.2 against aging, oxidative stress, vascular endothelial growth factor (VEGF) hyperactivation, and laser-induced damage. In vitro studies showed that Nkx3.2 downregulates pro-inflammatory cytokines and chemokines, but it upregulates anti-inflammatory factors. In addition, Nkx3.2 induced proteasomal degradation of receptor-interacting protein kinase 3 (RIP3), which, in turn, inhibited necroptosis. Consistent with these results, transcriptome analysis of mouse retina tissues indicated that Nkx3.2 can modulate gene expression profiles related to inflammatory responses, cell death, and visual function under oxidative stress.</p><p><strong>Conclusions: </strong>Nkx3.2 can suppress inflammatory responses and necroptic cell death in RPE. By employing these mechanisms, Nkx3.2 may play a significant role in inhibiting retinal degeneration caused by aging and oxidative stress.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"2"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antagonizing Viral MicroRNAs Reduces Ocular HSV-1 Pathogenesis and Enhances Mucosal Immune Homeostasis.","authors":"Chandrashekhar D Patil, Raza Ali Naqvi, Hemant Borase, Araceli Valverde, Afsar R Naqvi, Deepak Shukla","doi":"10.1167/iovs.66.12.16","DOIUrl":"10.1167/iovs.66.12.16","url":null,"abstract":"<p><strong>Purpose: </strong>Herpes simplex virus 1 (HSV-1) is a globally prevalent pathogen that causes recurrent lesions at mucosal and cutaneous sites, including the cornea, leading to herpetic keratitis, a major cause of infectious blindness. While HSV-1-encoded microRNAs (v-miRs) are known to regulate viral latency and immune evasion, their role in acute mucosal infection remains unclear. This study investigates the function of v-miRs during acute HSV-1 infection of the cornea.</p><p><strong>Methods: </strong>Using a murine model of corneal HSV-1 infection, we performed RNA sequencing and in situ hybridization to identify v-miRs enriched in the cornea during acute infection. Topical locked nucleic acid (LNA)-modified inhibitors targeting individual v-miRs (miR-H1-5p, miR-H3-3p, miR-H6-3p, and miR-H27) were administered, and effects on disease severity, viral replication, immune response, and lymphoid cell activation were assessed.</p><p><strong>Results: </strong>Inhibition of select v-miRs significantly attenuated corneal keratitis, reduced viral titers, and suppressed Th1/Th17-mediated inflammation. v-miR inhibition also decreased immune cell infiltration in draining lymph nodes and enhanced the frequency of IL-10-producing CD4⁺ T cells. Expression of immunoregulatory genes, including Arg1 and CD25, was increased, and T-cell proliferation was reduced ex vivo, indicating the establishment of a tissue-protective immune environment.</p><p><strong>Conclusions: </strong>HSV-1 v-miRs act as key immunoregulatory effectors during acute corneal infection. Their targeted inhibition using LNA-based therapy mitigates inflammation and promotes immune regulation, highlighting a novel therapeutic strategy for ocular HSV-1 disease.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"16"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}