Investigative ophthalmology & visual science最新文献

{"title":"Modeling Neuropathic Corneal Pain: Pulled Nerve Approach With Elevated Krt16 Gene Expression.","authors":"Mohd Afzal Khan, Gehan Fatima, Acquah Emmanuel, Sang Seong Kim, Hyuk Sang Kwon, Kyung Chul Yoon, Young Ro Kim, Euiheon Chung","doi":"10.1167/iovs.66.2.35","DOIUrl":"10.1167/iovs.66.2.35","url":null,"abstract":"<p><strong>Purpose: </strong>Neuropathic corneal pain (NCP) is a debilitating condition affecting millions of people worldwide. Despite their critical importance, currently available animal models for NCP research are limited by complex surgeries with high-risk strategy. To advance fundamental understanding of NCP, we developed a novel rodent model that explores both structural and functional mechanisms of the disease, offering a comprehensive approach.</p><p><strong>Methods: </strong>By uplifting (2-3 mm transversely) the long ciliary nerve (LCN) with gentle force (0.09 ± 0.02 newton [N]) and pressure (0.18 ± 0.05 MPa), our pulled nerve model mimics human NCP conditions and was investigated alongside normal control, sham control, and full transection groups. Specifically, we quantified the NCP status by establishing a relationship between pain perception and chemical sensitivity, using Stevens' Power Law concept.</p><p><strong>Results: </strong>Following surgery, the temporal patterns of heightened pain perception showed consistent trends across different stimulus methods, suggesting that von Frey and chemical tests could effectively evaluate pain progression. The discernable differences in Alpha values (exponent) of the pain-perception curves across the normal control, pulled nerve, and full transection groups (0.175 ± 0.035, 0.235 ± 0.015, and 0.275 ± 0.005, respectively) demonstrate the model's sensitivity to changes in NCP status. Histological analysis revealed LCN elongation, thickening, and corneal alterations in pulled nerve models, with reduced satellite glial cells (SGCs) in trigeminal ganglion compared to the normal control models. Krt16 gene expression was significantly upregulated following pulled nerve surgery.</p><p><strong>Conclusions: </strong>Our model not only delineates the pathological landscape of NCP but also promises to accelerate the development of targeted therapies.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"35"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399230","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":"OCT-Based Retina Assessment Reflects Visual Impairment in Multiple Sclerosis.","authors":"Natacha Stolowy, Lilija Gutmann, Margareta Lüpke, Thierry David, Michael Dorr, Christina Mayer, Christoph Heesen, Frederike Cosima Oertel, Ting-Yi Lin, Friedemann Paul, Hanna Gwendolyn Zimmermann, Jan-Patrick Stellmann","doi":"10.1167/iovs.66.2.39","DOIUrl":"10.1167/iovs.66.2.39","url":null,"abstract":"<p><strong>Purpose: </strong>To explore the relationship between visual performance and retinal morphology as assessed by optical coherence tomography (OCT), and the ability of OCT to reflect visual impairment in people with multiple sclerosis (PwMS) compared with healthy controls (HC).</p><p><strong>Methods: </strong>We gathered data from two neurology referral centers on PwMS and HC. Neurological and ophthalmological assessments, including OCT, high-contrast visual acuity (HCVA) and low-contrast visual acuity (LCVA), area under the log contrast sensitivity function (AULCSF), and vision-related quality of life (National Eye Institute Visual Function Questionnaire), were conducted between 2018 and 2020, with follow-up at 1 year.</p><p><strong>Results: </strong>A total of 137 PwMS (271 eyes) and 118 HC (236 eyes) were available for analysis. The peripapillary retinal nerve fiber layer (pRNFL) and the macular ganglion cell layer and inner plexiform layer volume (mGCIPL) volume were both reduced in PwMS (92 µm in PwMS vs 98 µm in HC [P < 0.001], 0.55 mm3 vs 0.62 mm3 [P < 0.001], respectively). A cutoff effect for visual impairment was observed in PwMS when pRNFL fell below 68.8 µm (HCVA), 71.4 µm (LCVA), and 72.6 µm (AULCSF). Using mixed effects models, the mGCIPL volume emerged as the variable most strongly associated with the AULCSF (P < 0.001). The AULCSF showed the strongest correlation with both pRNFL and mGCIPL (P < 0.001), with optic neuritis being a significant contributing factor (P < 0.001).</p><p><strong>Conclusions: </strong>AULCSF outperformed standard HCVA and LCVA, closely reflecting retinal atrophy. mGCIPL loss showed stronger associations with vision tests and detected neurodegeneration without the cutoff effect seen in pRNFL, making it the best marker for neuronal atrophy.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"39"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407913","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":"Transvitreal Retinochoroidal Biopsies of Primary Uveal Melanoma Reveal an Association of Low HLA Class I and High NK Cell Abundance in Low-Risk Disease.","authors":"Kalijn Fredrike Bol, Mark Wilhelmus Dirk Sweep, Michael Douglas Crowther, Mark Antonius Johannes Gorris, Pedro Aroca Lara, Arianna Draghi, Mette Marie Bagger, Carsten Faber, Johannes Textor, Marco Donia, Jens Folke Kiilgaard, Inge Marie Svane","doi":"10.1167/iovs.66.2.24","DOIUrl":"10.1167/iovs.66.2.24","url":null,"abstract":"<p><strong>Purpose: </strong>Immune cells in primary uveal melanoma (PUM) have mostly been studied in enucleated tissue, thereby precluding material from thinner, low-risk PUM tumors for research purposes. Here, we investigated the feasibility of using tumor tissue acquired by transvitreal retinochoroidal (TVRC) tumor biopsies to study the tumor immune microenvironment and relation to genetic risk class.</p><p><strong>Methods: </strong>Collected tumor biopsies of 41 patients were tested for genetic aberrations to determine high-risk (n = 19), medium-risk (n = 12), and low-risk (n = 9) tumors and were digested for flow cytometry analysis of immune cell and tumor markers. In addition, 13 patient-matched enucleated tumors were stained using multiplex immunohistochemistry.</p><p><strong>Results: </strong>Tumor biopsies showed a high variability in the degree of immune infiltration. The tumor-specific lymphocyte infiltration pattern correlated well with the infiltration pattern in patient-matched enucleations. High-risk tumors tended to have a higher abundance of CD8 T cells, which expressed activation markers CD39, CD69, and PD-1, with reduced CD127 expression. In general, low-risk tumors exhibited decreased human leukocyte antigen (HLA) class I expression, coinciding with a higher abundance of natural killer (NK) cells (P = 0.0049), indicating a different lymphocyte infiltration pattern between low-, medium- and high-risk tumors.</p><p><strong>Conclusions: </strong>TVRC biopsies are a suitable and valuable source of PUM tissue for research purposes. An abundance of CD8 T cells was found in high-risk PUM tumors. Further, medium- and low-risk PUM tumors are characterized by decreased HLA class I expression with a concomitant increase in NK cell infiltration as compared to high-risk PUM tumors, correlating with decreased risk of disease recurrence.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"24"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364861","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":"Comprehensive Visualization of Choroidal Alterations in Thyroid Eye Disease With Ultra-Widefield OCT Angiography.","authors":"Yi Wang, Tengbo Rao, Jichao Zhou, Debo You, Jiarui Yang, Lingge Suo","doi":"10.1167/iovs.66.2.25","DOIUrl":"10.1167/iovs.66.2.25","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate choroidal and optic disc alterations in eyes with thyroid eye disease (TED) compared with healthy eyes by using TowardPi widefield optical coherence tomography angiography (OCTA).</p><p><strong>Methods: </strong>This was a retrospective cross-sectional cohort study. A total of 112 participants (60 TED patients and 52 healthy controls) underwent TowardPi widefield OCTA, which provided detailed demographic and clinical data. Three-dimensional choroidal data, including thickness, vascular metrics, and optic disc measurements, were obtained from the built-in software.</p><p><strong>Results: </strong>The study included 24 eyes with dysthyroid optic neuropathy (DON), 24 eyes with active non-DON TED, 71 eyes with inactive TED, and 104 healthy eyes. Choroidal thickness significantly decreased in the optic disc region during the DON phase (148.71 ± 78.98 µm) compared to normal eyes (182.35 ± 51.98 µm) and inactive TED eyes (191.34 ± 58.86 µm) (P = 0.030). In DON, choroidal stromal volume was reduced (34,183.81 ± 10,649.01 × 106 µm3) compared to normal (46,339.53 ± 16,711.99 × 106 µm3) (P = 0.002), whereas the choroidal vascular index increased (42.67% ± 3.41%) compared to normal (38.53% ± 6.35%) (P = 0.002). Optic disc area increased in DON (1.99 ± 1.24 mm2) compared to inactive TED (1.39 ± 0.38 mm2) (P < 0.001), along with reduced retinal nerve fiber layer blood-flow density in DON (45.09% ± 3.07%,) compared to normal (47.84% ± 1.41%) (P < 0.001).</p><p><strong>Conclusions: </strong>This study highlights the critical role of choroidal and optic disc alterations in TED pathophysiology and underscore the utility of widefield OCTA in identifying these changes, particularly in DON-risk patients.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"25"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11812615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382011","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":"Photoreceptor Function and Structure in Retinal Areas With Intraretinal Hyperreflective Foci in Age-Related Macular Degeneration.","authors":"Xiaolin Wang, Sujin Hoshi, Ruixue Liu, Giulia Corradetti, Michael Ip, David Sarraf, SriniVas R Sadda, Yuhua Zhang","doi":"10.1167/iovs.66.2.27","DOIUrl":"10.1167/iovs.66.2.27","url":null,"abstract":"<p><strong>Purpose: </strong>To assess retinal light sensitivity in regions with intraretinal hyperreflective foci (IHRFs) in eyes with intermediate age-related macular degeneration (AMD) and examine the photoreceptor structure in these areas using adaptive optics scanning laser ophthalmoscopy (AOSLO) and optical coherence tomography (OCT).</p><p><strong>Methods: </strong>A retrospective analysis was conducted on 82 eyes of 57 subjects (age: 76.4 ± 7.0 years) with intermediate AMD. IHRFs were identified in OCT B-scans. Drusen and subretinal drusenoid deposits (SDDs) were evaluated using multimodal imaging. Photoreceptor structure was assessed with AOSLO, and choroidal and retinal thicknesses were measured in areas with IHRFs. In 16 eyes, mesopic and scotopic light sensitivities were compared in regions with and without IHRFs but with similar SDD/drusen load in the same eye.</p><p><strong>Results: </strong>Retinal areas with IHRFs had significantly reduced mesopic (17.19 ± 5.68 dB vs. 18.49 ± 5.35 dB, P = 0.0029) and scotopic (8.39 ± 5.67 dB vs. 9.72 ± 6.28 dB, P = 0.0096) light sensitivity compared to areas without IHRFs. AOSLO revealed disrupted cone photoreceptor structure in IHRF regions. Choroidal thickness beneath areas with IHRFs was thinner than in those without IHRFs (196.71 ± 73.31 µm vs. 202.37 ± 70.64 µm, P = 0.0211). Retinal thickness in regions with IHRFs was not significantly different from those without IHRFs (320.40 ± 31.16 µm vs. 316.92 ± 26.32 µm, P = 0.3537).</p><p><strong>Conclusions: </strong>IHRF presence is associated with localized reduced visual function and photoreceptor degeneration in intermediate AMD. Prospective studies are warranted to further investigate the mechanisms of photoreceptor and sensitivity loss in the context of IHRF.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"27"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11812613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382304","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":"Genotype-Phenotype Spectrum of eyeGENE Patients With Familial Exudative Vitreoretinopathy: Novel Variants in Norrin/β-Catenin Signaling Pathway Genes.","authors":"Fulya Yaylacioglu Tuncay, Melissa J Reeves, Sairah Yousaf, Ehsan Ullah, Bin Guan, Kerry E Goetz, Santa J Tumminia, Robert B Hufnagel","doi":"10.1167/iovs.66.2.9","DOIUrl":"10.1167/iovs.66.2.9","url":null,"abstract":"<p><strong>Purpose: </strong>To report the variants and genotype-phenotype correlations in patients with familial exudative vitreoretinopathy (FEVR) included in the eyeGENE database.</p><p><strong>Methods: </strong>A retrospective study was conducted in a cohort of 122 eyeGENE patients from 114 families with FEVR. Clinical details and genetic test results were provided by referring clinicians and clinical laboratories in the eyeGENE network, respectively. Genotype and phenotype information was reviewed, and reported variants were reclassified.</p><p><strong>Results: </strong>Genetic test reports of 50 probands revealed 52 variants in the four genes of the Norrin/β-catenin signaling pathway: LRP5, FZD4, TSPAN12, and NDP. Following variant reclassification, 35 of the reported variants were interpreted as pathogenic or likely pathogenic (12 in LRP5, 11 in FZD4, seven in TSPAN12 and five in NDP), providing a conclusive test result for nearly one-third (32%) of the probands. Among the reported variants, 18 were novel (34.6%) and two-thirds were missense. Retinal detachment was reported less in patients with variants in TSPAN12 (P = 0.017). One-third of the patients (33.3%) with an FZD4 variant had asymmetric findings. In contrast, asymmetry was less pronounced in patients with variants in TSPAN12 (11.1%).</p><p><strong>Conclusions: </strong>This was one of the largest cohorts reviewed from North America, expanding the variant spectrum in FEVR. Among the eyeGENE FEVR patients, disease-associated variants in Norrin/β-catenin signaling pathway genes can explain one-third of the cohort. LRP5 and FZD4 variants were the most common. The genotype-phenotype correlations supported the phenotypic variability in FEVR.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"9"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11801387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189307","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":"Targeted Microperimetry Grids for Focal Lesions in Intermediate AMD: PINNACLE Study Report 7.","authors":"Stefan Futterknecht, Philipp Anders, Julia Mai, Sophie Riedl, Ursula Hall, Chrysoula Gabrani, Kristina Pfau, Martin J Menten, Daniel Rueckert, A Toby Prevost, Hrvoje Bogunovic, Lars G Fritsche, Ursula Schmidt-Erfurth, Sobha Sivaprasad, Andrew Lotery, Hendrik P N Scholl, Maximilian Pfau","doi":"10.1167/iovs.66.2.6","DOIUrl":"10.1167/iovs.66.2.6","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to evaluate the feasibility and utility of optical coherence tomography (OCT)-based, targeted microperimetry grids in assessing focal lesions in intermediate age-related macular degeneration (iAMD).</p><p><strong>Methods: </strong>The multicenter, prospective PINNACLE study enrolled 395 patients with iAMD aged 55 to 90 years across 12 international sites. Participants underwent imaging, including OCT and microperimetry, every 4 to 12 months over 3 years. Deep learning algorithms detected focal lesions and changes in OCT images, including drusen regression, EZ/IZ loss with hypertransmission, and subretinal fluid, guiding 5-point microperimetry targeted to lesion locations. Data were analyzed using linear mixed models to estimate differences between retinal sensitivity measured by the 5-point focal grids and sensitivity interpolated from the 24-point standard grids.</p><p><strong>Results: </strong>The final analysis included 93 eyes from 83 patients, assessing 605 of the 5-point targeted grids and standard grids across 235 focal lesions. The Pearson correlation between focally measured sensitivity and interpolated sensitivity was 0.76. However, interpolation from the standard grid could be erroneous, especially in central regions of lesions characterized by EZ/IZ loss with hypertransmission and subretinal fluid. Interpolation errors increased with distance to the nearest measurement point (slope = 2.20 dB per degree, 95% confidence interval [CI] = 1.52 to 2.87). A significant negative relationship was found between interpolation errors and retinal sensitivity, with the highest errors in areas of low sensitivity. Lesion size significantly impacted interpolation errors for EZ/IZ loss with hypertransmission (slope = -19.41 dB/mm², 95% CI = -29.63 to -9.18).</p><p><strong>Conclusions: </strong>Targeted grids improved the detection and understanding of how focal retinal changes affect visual function in patients with iAMD, supporting the development of therapeutic interventions.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"6"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11801386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189326","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":"Single and Multiple Visual Function Impairments and Associated- Vision-Related Quality of Life Impact in Older Adults Aged 60 to 100 Years.","authors":"Preeti Gupta, Tai Anh Vu, Chiew Meng Johnny Wong, Sahil Thakur, Alex A Black, Joanne M Wood, Ryan E K Man, Eva K Fenwick, Ecosse L Lamoureux","doi":"10.1167/iovs.66.2.18","DOIUrl":"10.1167/iovs.66.2.18","url":null,"abstract":"<p><strong>Purpose: </strong>Determine the prevalence and vision-related quality of life (VRQoL) effects of single and multiple visual function impairments (VFIs) in multi-ethnic older Asians.</p><p><strong>Methods: </strong>A total of 2380 participants from a population-based cohort study were included. Visual function comprised presenting visual acuity (VA), contrast sensitivity (CS), depth perception (DP), and color vision (CV). Rasch-transformed VRQoL was obtained using the Brief Impact of Visual Impairment questionnaire. Multiple linear regression explored the independent (mutually adjusting for each VFI) impact of bilateral single (VAI, CSI, CVI and DPI) and multiple (i.e., the co-occurrence of any two, three, or four bilateral VFI) VFIs on VRQoL. Dominance analysis estimated the relative contribution for each of the single VFI on VRQoL.</p><p><strong>Results: </strong>The prevalence of bilateral VAI, CSI, CVI, or DPI alone was 15.3%, 20.7%, 8.1%, and 23.5%, respectively, whereas for concurrent two, three and four bilateral VFIs was 11%, 4.1% and 1.6%, respectively. Participants with single bilateral VFI (except CVI) experienced poorer overall VRQoL (β -0.25 to -0.34; all p < 0.05) compared to those without. CSI had the largest contribution (25%), to the decline in overall VRQoL. As the number of concurrent bilateral VFIs increased, VRQoL progressively worsened (% decrements -12.26% to -25.61%; all P < 0.001) compared to no VFI.</p><p><strong>Conclusions: </strong>Bilateral single and multiple VFIs are prevalent in older Asians. CSI had the largest contribution to VRQoL decrements. There was a systematic worsening in VRQoL scores with an increase in concurrent bilateral VFI. Comprehensive visual function testing may be warranted to prevent the debilitating consequences of VFIs on healthy aging.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"18"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255703","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":"Lamp2 Deficiency Enhances Susceptibility to Oxidative Stress-Induced RPE Degeneration.","authors":"Guannan Wu, Shoji Notomi, Ziming Xu, Yosuke Fukuda, Yusuke Maehara, Yan Tao, Huanyu Zhao, Keijiro Ishikawa, Yusuke Murakami, Toshio Hisatomi, Koh-Hei Sonoda","doi":"10.1167/iovs.66.2.2","DOIUrl":"10.1167/iovs.66.2.2","url":null,"abstract":"<p><strong>Purpose: </strong>Autophagy and lysosomal degradation are vital processes that protect cells from oxidative stress. This study investigated the role of lysosome-associated membrane protein 2 (Lamp2), a lysosomal protein essential for autophagosome maturation and lysosome biogenesis, in maintaining retinal health under oxidative stress.</p><p><strong>Methods: </strong>To induce oxidative stress, young Lamp2 knockout (KO) and wild-type mice received an intravenous injection of a low dose (10 mg/kg) of sodium iodate (NaIO3). We examined retinal histopathology and morphological changes in the RPE. The involvement of resident microglia or infiltrating macrophages was assessed using immunostaining, flow cytometry, and real-time PCR for chemokines and cytokines.</p><p><strong>Results: </strong>After administering a low-dose NaIO3, Lamp2 KO mice showed significant RPE degeneration, whereas wild-type mice had minimal damage. Histological analysis and electron microscopy revealed significant thinning of the outer nuclear layer and loss of RPE epithelial polarity in Lamp2 KO mice. Additionally, there was a significant increase in ionized calcium-binding adaptor molecule 1-positive microglia and macrophages in the outer retina. Early proliferation of CD45lowMHC-IIlow resident microglia was followed by the infiltration of CD45highLy6Chigh monocytes and the engraftment of CD11b+CD45high monocyte-derived macrophages. Transcript levels of monocyte chemoattractant protein 1, macrophage inflammatory protein 1β, Il- 1β, and Il-6 also increased in the retinas of Lamp2 KO mice. Furthermore, pretreatment with the macrophage-depleting agent clodronate prevented NaIO3-induced RPE degeneration and macrophage infiltration in Lamp2 KO mice.</p><p><strong>Conclusions: </strong>Lamp2 deficiency, when combined with oxidative stress, leads to RPE degeneration in vivo. Lysosomal dysfunction also promotes macrophage engraftment and triggers neurotoxic inflammation.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"2"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079757","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":"Molecular Subtype Identification and Potential Drug Prediction Based on Anoikis-Related Genes Expression in Keratoconus.","authors":"Zhixin Jiang, Boyang Zhang, Shichong Jia, Xiaoyong Yuan","doi":"10.1167/iovs.66.2.3","DOIUrl":"10.1167/iovs.66.2.3","url":null,"abstract":"<p><strong>Purpose: </strong>Anoikis is a special apoptosis accompanied by the loss of extracellular matrix (ECM) environment and the decomposition of ECM is an important process in the occurrence of keratoconus (KC). This study aims to describe the expression profile of anoikis-related genes (ARGs) in KC samples, identify differentially expressed genes (DEGs), characterize the biological functions and immune characteristics of different molecular subtypes of KC and predict potential drugs based on the construction of a co-expression network.</p><p><strong>Methods: </strong>First, we identified molecular subtypes by optimal clustering K based on the expression profile of ARGs in the KC dataset and analyzed the differences of functional and immune characteristics. Then a weighted gene co-expression network was constructed based on cluster analysis to obtain hub genes and protein-protein interaction network was constructed to analyze hub nodes and predict potential node-targeting drugs.</p><p><strong>Results: </strong>By comparing the expression profile between disease and normal samples, we found that there were significant differences in ARGs such as BCL2, CAV1, and CEACAM5. Consistent cluster analysis identified two definite clusters on the basis of ARGs expression difference. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis showed that DEGs were enriched significantly in pathways like ECM receptor interaction, chemokine signal, notch signal, focal adhesion, and functional sets like proteolysis, anoikis, regulation of natural killer and T-cell proliferation. CIBERSORT calculation showed that there were significant differences between the two subtypes on immune cell infiltration (monocytes and plasma) and immune molecules (CCL11, CCL14, HLA-A, HLA-B, and so on). Then, co-expression network was constructed based on cluster phenotype, 5202 genes were selected as hub genes, and 321 HubDEGs were obtained after intersection with significant DEGs. Seven hub nodes, EIF4G1, KHSRP, PABPC1, POLR2A, PTBP1, RPS19, and SMARCA4, were identified and matched drugs or small molecular compounds. Insulin and dexamethasone were identified as potential target drugs.</p><p><strong>Conclusions: </strong>We revealed the differential expression of ARGs in KC samples, and identified two distinct subtypes that showed significant differences in biological function and immune infiltration. The identification of hub gene nodes elucidated their therapeutic value on predicted potential drugs.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"3"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079872","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}