Investigative ophthalmology & visual science最新文献

{"title":"Effects of Verteporfin on Interstitial Fluid Flow-Induced Fibrotic Transdifferentiation of Human Tenon Fibroblasts.","authors":"Janne Frömmichen, Emma Bungert, Jeanne Ströble, Moritz Gläser, Charlotte Gottwald, Kosovare Zeqiri, Thomas Reinhard, Jan Lübke, Günther Schlunck, Cornelius Jakob Wiedenmann","doi":"10.1167/iovs.66.4.17","DOIUrl":"10.1167/iovs.66.4.17","url":null,"abstract":"<p><strong>Purpose: </strong>Postoperative scarring remains the major challenge in achieving long-term success after glaucoma filtration surgery. In a previous study, we showed that slow continuous fluid flow is sufficient to induce fibrotic responses in human tenon fibroblasts (HTFs) in two-dimensional (2D) and three-dimensional (3D) in vitro models. In the present study, we investigated the role of the mechanosensitive Yes-associated protein (YAP) and transcriptional coactivator (TAZ) signaling pathway in flow-induced fibrosis.</p><p><strong>Methods: </strong>HTFs were exposed to continuous fluid flow for 48 or 72 hours in the presence or absence of the YAP/TAZ-transcriptional enhanced associated domain inhibitor verteporfin (VP). In a 2D model, the F-actin cytoskeleton, fibronectin 1 (FN1), YAP, and TAZ were visualized by confocal immunofluorescence microscopy. In a 3D model, mRNA was extracted, and the expression of fibrosis-associated genes was detected by quantitative PCR.</p><p><strong>Results: </strong>HTFs exposed to slow fluid flow showed increased staining intensities for YAP/TAZ. Inhibition of YAP/TAZ by VP slightly reduced flow-induced fibrotic changes in the 2D model. The flow-induced increase in the expression of the extracellular matrix (ECM) genes COL1A1, CTGF, and FN1 was significantly inhibited by VP in the 3D model.</p><p><strong>Conclusions: </strong>Slow interstitial fluid flow activates the YAP/TAZ pathway. VP exerts antifibrotic potential by reducing morphologic changes and suppressing the expression of ECM genes induced by flow. Therefore, YAP/TAZ inhibition may exhibit therapeutic potential after glaucoma filtration surgery by inhibiting fibrotic changes induced by mechanical stimuli.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 4","pages":"17"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nonperfused Retinal Capillaries-A New Method Developed on OCT and OCTA.","authors":"Min Gao, Yukun Guo, Tristan T Hormel, Jie Wang, Elizabeth White, Dong-Wouk Park, Thomas S Hwang, Steven T Bailey, Yali Jia","doi":"10.1167/iovs.66.4.22","DOIUrl":"https://doi.org/10.1167/iovs.66.4.22","url":null,"abstract":"<p><strong>Purpose: </strong>This study aims to develop a new method to quantify nonperfused retinal capillaries (NPCs) and evaluate NPCs in eyes with AMD and diabetic retinopathy (DR).</p><p><strong>Methods: </strong>We averaged multiple registered optical coherence tomography (OCT)/OCT angiography (OCTA) scans to create high-definition volumes. The deep capillary plexus slab was defined and segmented. A developed deep learning denoising algorithm removed tissue background noise from capillaries in en face OCT/OCTA. The algorithm segmented NPCs by identifying capillaries from OCT without corresponding flow signals in OCTA. We then investigated the relationships between NPCs and known features in AMD and DR.</p><p><strong>Results: </strong>The segmented NPC achieved an accuracy of 88.2% compared to manual grading of NPCs in DR. Compared to healthy controls, both the mean number and total length (mm) of NPCs was significantly increased in AMD and DR eyes (P < 0.001, P < 0.001). Compared to early and intermediate AMD, the number and total length of NPCs were significantly higher in advanced AMD (number: P < 0.001, P < 0.001; total length: P = 0.002, P = 0.003). Geography atrophy, macular neovascularization, drusen volume, and extrafoveal avascular area (EAA) significantly correlated with increased NPCs (P < 0.05). In DR eyes, NPCs correlated with the number of microaneurysms and EAA (P < 0.05). The presence of fluid did not significantly correlate with NPCs in AMD and DR.</p><p><strong>Conclusions: </strong>A deep learning-based algorithm can segment and quantify retinal capillaries that lack flow using colocalized OCT/OCTA. This new biomarker may be useful in AMD and DR in predicting progression of these diseases.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 4","pages":"22"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocyte-Derived Extracellular Vesicles Alleviate Optic Nerve Injury Through Remodeling of Retinal Microenvironmental Homeostasis.","authors":"Lili Chen, Zhonghao Yu, Senmiao Zhu, Shihan Song, Guanwen He, Zai-Long Chi, Wencan Wu","doi":"10.1167/iovs.66.4.16","DOIUrl":"https://doi.org/10.1167/iovs.66.4.16","url":null,"abstract":"<p><strong>Purpose: </strong>Traumatic optic neuropathy (TON) leads to the loss of retinal ganglion cells (RGCs) and results in permanent visual impairment. Protecting and regenerating RGCs is crucial for the treatment of TON. Studies have demonstrated that astrocyte-derived extracellular vesicles (ADEVs) exhibit neuroprotective effects in models of central nervous system (CNS) injury. This study aimed to investigate whether ADEVs have a similar neuroprotective effect on RGCs in an optic nerve crush (ONC) rat model.</p><p><strong>Methods: </strong>ADEVs were collected from primary rat astrocytes, and an ONC model was established to evaluate the effects of ADEVs on retinal structure and visual function using optical coherence tomography (OCT), hematoxylin and eosin (H&E) staining, and flash visual evoked potential (f-VEP) analysis. Immunofluorescence was used to examine RGCs and investigate reactive gliotic changes. Additionally, miRNA sequencing of ADEVs and retinal mRNA sequencing were performed to identify the potential mechanisms involved.</p><p><strong>Results: </strong>ADEVs protected RGCs from progressive loss and improved visual function. ADEVs also significantly increased the expression of glial fibrillary acidic protein (GFAP) and modulated microglial activation. The miRNAs associated with ADEVs were targeted by neuroprotective signals, such as MAPK, PI3K-AKT, and TNF-α, and through the targeting network generated via retinal mRNA sequencing, we found that potential functional genes, such as THBS1, PAK3, and Gstm1, likely participate in microenvironmental regulation.</p><p><strong>Conclusions: </strong>We discovered that ADEVs play a neuroprotective role in optic nerve injury. Our findings provide a new cell-free therapeutic strategy for optic neuropathy.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 4","pages":"16"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotinamide Riboside Mitigates Retinal Degeneration by Suppressing Damaged DNA-Stimulated Microglial Activation and STING-Mediated Pyroptosis.","authors":"Shanshan Zhu, Lusi Zhang, Ping Tong, Jiawei Chen, Cong Wang, Zewei Wang, Jingyuan Liu, Peiyun Duan, Qian Jiang, Yubing Zhou, Guangshuang Tan, Xian Zhang, Bing Jiang","doi":"10.1167/iovs.66.4.14","DOIUrl":"https://doi.org/10.1167/iovs.66.4.14","url":null,"abstract":"<p><strong>Purpose: </strong>Microglial activation plays a pivotal role in the pathogenesis of retinal degeneration, contributing to neuroinflammation within the retina. Previous studies identified that nicotinamide riboside (NR) mitigated light-induced retinal degeneration (LIRD) and inhibited microglial activation. The cGAS-STING signaling pathway has been recognized as a key mediator of inflammation in response to cellular stress and tissue damage. This study further explores the regulatory impact of NR on microglial activation and STING-mediated pyroptosis in retinal degeneration.</p><p><strong>Methods: </strong>Balb/c mice were subjected to bright light exposure to induce retinal degeneration. Bioinformatics analysis was used to identify the upregulated key genes and signaling pathways involved in the progression of retinal degeneration, based on mouse transcriptomes from the LIRD model. Molecular biology techniques and immunofluorescence staining were used to assess cGAS-STING activation and expression of pyroptosis-associated molecules. Retinal function, photoreceptor apoptosis and inflammatory response were evaluated in the presence and absence of NR supplementation.</p><p><strong>Results: </strong>Exposure to bright light resulted in mitochondrial dysfunction and the release of dsDNA, significantly triggering the activation of cGAS-STING pathway and microglial pyroptosis. In contrast, NR treatment preserved mitochondrial biosynthesis, inhibited STING expression in reactive microglia, and dampened the pro-inflammatory response. Additionally, intraperitoneal administration of the STING inhibitor H151 reduced light-induced microglial activation and pyroptosis, while improving retinal function and promoting photoreceptor survival.</p><p><strong>Conclusions: </strong>These findings suggest that NR confers neuroprotection by attenuating damaged DNA-triggered STING-mediated microglial activation and pyroptosis. Targeting the cGAS-STING pathway presents a promising therapeutic avenue for retinal degeneration.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 4","pages":"14"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the Volume of Eyes With Pathologic Myopia Using 3D MRI.","authors":"Tomonari Takahashi, Tae Yokoi-Igarashi, Hiroyuki Takahashi, Noriko Nakao, Kengo Uramoto, Takeshi Yoshida, Muka Moriyama, Koju Kamoi, Koichiro Kimura, Ukihide Tateishi, Kyoko Ohno-Matsui","doi":"10.1167/iovs.66.4.13","DOIUrl":"https://doi.org/10.1167/iovs.66.4.13","url":null,"abstract":"<p><strong>Purpose: </strong>To determine the volume of eyes and its relationship to the shape and the presence of posterior staphylomas in patients with high myopia (HM).</p><p><strong>Methods: </strong>We studied 370 eyes of 199 patients with HM (refractive error >8.00 diopters [D] or an axial length ≥26.5 mm) and 44 eyes of 35 control patients without HM (refractive error from -7.50 to +2.50 D). Magnetic resonance imaging (MRI) of the ocular orbit was used to measure the volume of the eye using three-dimensional (3D) MRI. Reconstructed 3D images of eye were classified according to symmetry and steepness of the posterior curvature.</p><p><strong>Results: </strong>The mean volume was 12.42 ± 2.40 mL of the 370 HM eyes and 9.67 ± 1.41 mL of the 44 non-HM eyes. Thus, the volume of the HM eyes was 1.3 times larger than the mean volume of the non-HM eyes. The mean volume of the eye was significantly smaller in the cylindrically shaped and larger in barrel-shaped eyes than the eyes with other shapes. The mean eye volume in the HM eyes with a posterior staphyloma was not significantly different from that of HM eyes without a posterior staphyloma.</p><p><strong>Conclusions: </strong>The volume of HM eyes is larger than non-HM eyes and is associated with steepness of posterior curvature but not with the presence of a posterior staphyloma, suggesting that local outward protrusion of the posterior eye wall is not directly caused by global expansion of eyes and should be monitored specifically in HM eyes.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 4","pages":"13"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enlarged Blind Spot Linked to Gamma Zone and Peripapillary Hyperreflective Ovoid Mass-Like Structures in Non-Pathological Highly Myopic Eyes.","authors":"Qiuyan Wu, Ruihan Hu, Qihong Liu, Fang Li, Yuanyuan Wang, Zuohuizi Yi, Jiajia Yuan, Yilei Shao, Meixiao Shen, Hongmei Zheng, Changzheng Chen","doi":"10.1167/iovs.66.4.5","DOIUrl":"10.1167/iovs.66.4.5","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the prevalence and risk factors of enlarged blind spots in non-pathological highly myopic eyes.</p><p><strong>Methods: </strong>Visual field conditions of 313 eyes in 172 individuals with high myopia were evaluated. Clinical characteristics of 116 eyes with enlarged blind spots and 116 eyes with normal visual fields were compared. Generalized-estimating equation (GEE) regression model were used to assess the factors associated with enlarged blind spots.</p><p><strong>Results: </strong>The frequency of enlarged blind spots in non-pathological highly myopic eyes was 37.06% in this sample. Eyes with enlarged blind spots had larger gamma zone (P = 0.038), larger PHOMS area (P < 0.001), increased peripapillary retinal nerve fiber layer thickness (P = 0.006), and decreased macular ganglion cell-inner plexiform layer thickness (P = 0.016) compared with eyes with normal visual fields. In multivariate regression analysis, an expanded gamma zone (OR = 2.004; P = 0.022) and a larger PHOMS area (OR = 4.414; P = 0.009) were associated with an enlarged blind spot.</p><p><strong>Conclusions: </strong>An expanded gamma zone and a larger PHOMS area are associated with an enlarged blind spot, indicating that these two parameters may suggest a possibility of functional damage in early nonpathological, highly myopic eyes. This pattern of impairment might provide clues for the differential diagnosis between high myopia and glaucoma.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 4","pages":"5"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763090","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":"Phenotypic and Genotypic Characterization of RP1L1-Associated Retinopathy.","authors":"Alessio Antropoli, Lorenzo Bianco, Xavier Zanlonghi, Amine Benadji, Christel Condroyer, Aline Antonio, Julien Navarro, Claire-Marie Dhaenens, José-Alain Sahel, Christina Zeitz, Isabelle Audo","doi":"10.1167/iovs.66.4.7","DOIUrl":"10.1167/iovs.66.4.7","url":null,"abstract":"<p><strong>Purpose: </strong>Pathogenic variants in RP1L1 are associated with autosomal dominant occult macular dystrophy (OMD) and autosomal recessive retinitis pigmentosa (RP). In this study, we investigated the phenotypic and genotypic landscape of RP1L1-associated retinopathy in an ethnically heterogeneous cohort.</p><p><strong>Methods: </strong>This multicenter cohort study retrospectively collected the following data: best-corrected visual acuity (BCVA), color fundus photograph (CFP), optical coherence tomography (OCT), short-wavelength fundus autofluorescence (SW-AF), and full-field electroretinography (ffERG). Patients were classified based on their clinical phenotype in OMD or RP. Atypical cases were analyzed separately and reappraised according to their clinical and genetic findings.</p><p><strong>Results: </strong>This study included 20 patients (40 eyes) from 19 families: 12 (60%) with OMD, 4 (20%) with RP, and 4 (20%) atypical cases (3 \"non-occult\" macular dystrophy, 1 rod-cone dystrophy with vitelliform maculopathy). Autosomal dominant OMD was the most common phenotype, with one autosomal recessive OMD case identified. Autosomal recessive RP had the latest onset, best visual acuity, and highest refractive error. OMD BCVA declined by ∼0.5 lines/year over a median follow-up of 3.2 years.</p><p><strong>Conclusions: </strong>Mutations in RP1L1 cause a spectrum of diseases, including autosomal dominant OMD, autosomal recessive OMD, and autosomal recessive rod-cone dystrophies, occasionally presenting with pseudovitelliform maculopathy.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 4","pages":"7"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763445","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":"Deep Corneal Nerve Plexus Selective Damage in Persistent Neurotrophic Corneal Epithelial Defects Detected by In Vivo Multiphoton Confocal Microscopy.","authors":"Seitaro Komai, Manuel E Quiroga-Garza, Raul E Ruiz-Lozano, Nadim S Azar, Hazem M Mousa, Sofia Murillo, Symon Ma, Ali Khodor, Sejiro Littleton, Daniel R Saban, Alain Chédotal, Victor L Perez","doi":"10.1167/iovs.66.4.1","DOIUrl":"10.1167/iovs.66.4.1","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the corneal nerve damage in neurotrophic corneal persistent epithelial defects by an in vivo imaging system using in vivo multiphoton confocal microscopy (MCM) and calcitonin gene-related peptide (CGRP):GFP Tg mice.</p><p><strong>Methods: </strong>Corneal epithelium was scraped, followed by administering a single dose of benzalkonium chloride (BAK) to develop a neurotrophic persistent epithelial defect. The defect was imaged with fluorescein staining for up to 24 hours, and wound closure percentage (%, WCP) was calculated. CGRP:GFP Tg mice were used in combination with in vivo MCM to acquire in vivo images of corneal nerve before and 24 hours after the creation of a corneal epithelial defect. GFP signals from CGRP-positive nerves were reconstructed into three-dimensional (3D) images, and nerve volume was analyzed. Additionally, corneal mechanosensation was evaluated using Cochet-Bonnet esthesiometry.</p><p><strong>Results: </strong>BAK-treated eyes showed a significant delay in WCP at 24 hours. In CGRP:GFP Tg mice, CGRP-positive nerves were successfully captured by in vivo MCM and reconstructed into 3D images. BAK-treated eyes showed a significant decrease in both stromal nerve volume and corneal mechanosensation compared to no BAK eyes at 24 hours after corneal scraping, suggesting that BAK impaired the stromal nerves in both structural and functional asides.</p><p><strong>Conclusions: </strong>Our in vivo corneal nerve imaging system using the combination of in vivo MCM and CGRP:GFP Tg mice demonstrated a longitudinal observation of murine corneal nerves. This system revealed that corneal stromal nerves were selectively damaged in persistent neurotrophic corneal epithelial defects and offered outstanding potential for various applications.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 4","pages":"1"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763953","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":"Histopathological Evaluation of Corneal Tissues in Microsporidia Stromal Keratitis.","authors":"Sohini Mandal, Soumya Sucharita, Vishwajeet Deshmukh, Smruti Rekha Priyadarshini, Srikant Kumar Sahu, Sujata Das","doi":"10.1167/iovs.66.4.9","DOIUrl":"10.1167/iovs.66.4.9","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to evaluate the histopathological factors in non-resolving cases of microsporidia stromal keratitis (MSK) through the study of corneal buttons obtained during therapeutic penetrating keratoplasty (TPK).</p><p><strong>Methods: </strong>This was a retrospective noncomparative consecutive case series. This case series included 22 corneal buttons (22 patients) of histologically diagnosed MSK between June 2015 and April 2023. Records of preoperative clinical and microbiological data, and postoperative microbiological and histopathologic data of the corneal buttons were evaluated.</p><p><strong>Results: </strong>Histologic evaluation was conducted of the buttons for morphologic changes, degree and distribution of inflammatory cells, presence of microsporidial spores, and their degree and distribution within the corneal buttons. This study evaluated 22 patients with MSK, highlighting clinical, microbiological, treatment, and histopathological findings. The mean patient age was 57.1 ± 13.4 years (range = 22-83 years). The median interval from symptom onset to presentation was 4 months, and the mean time from presentation to keratoplasty was 1 month. Microsporidia spores were detected in 59% of cases through smears, with 41% of cases showing no organisms on microbiological tests. Targeted therapy using polyhexamethylene biguanide (PHMB) 0.02% was given in 13 cases, whereas 9 cases were treated empirically. Histopathology showed no significant correlation between the distribution of inflammatory cells and that of microsporidia. Moderate microsporidia severity correlated with longer symptom duration (10.0 ± 6.36 months). These findings underscore the complexity of MSK management and the variable outcomes.</p><p><strong>Conclusions: </strong>The progression of MSK in advanced stages appears to be influenced by a combination of pathogen-related factors, such as high microsporidial load with deep stromal penetration, and host-related factors, including a pronounced inflammatory response. Additionally, the limited effectiveness of topical PHMB may contribute to disease progression.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 4","pages":"9"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron-Sulfur Clusters and Iron Responsive Element Binding Proteins Mediate Iron Accumulation in Corneal Endothelial Cells in Fuchs Dystrophy.","authors":"Emma M Hartness, Hanna Shevalye, Jessica M Skeie, Timothy Eggleston, Matthew G Field, Gregory A Schmidt, Pornpoj Phruttiwanichakun, Aliasger K Salem, Mark A Greiner","doi":"10.1167/iovs.66.4.23","DOIUrl":"https://doi.org/10.1167/iovs.66.4.23","url":null,"abstract":"<p><strong>Purpose: </strong>Evidence suggests that corneal endothelial cell (CEC) death in Fuchs endothelial corneal dystrophy (FECD) is due to ferroptosis, an iron-mediated cell death. Iron-sulfur cluster (ISC)-containing aconitases and the iron responsive element binding proteins IREBP1 and IREBP2 are known mediators of iron homeostasis. This study investigates mechanisms underlying iron dysregulation in CECs and proposes a role for ISCs and IREBPs in the context of FECD pathogenesis.</p><p><strong>Methods: </strong>We studied gene expression of proteins responsible for ISC synthesis and iron homeostasis in human and mouse CECs and analyzed published RNA sequencing datasets. We validated a subset of transcriptional changes between FECD and control tissues using microfluidic Western blotting with human CEC tissues. Finally, we silenced proteins involved in ISC synthesis or iron homeostasis in cell cultures and assessed ferroptosis susceptibility.</p><p><strong>Results: </strong>RNA-seq and qPCR data demonstrated significantly decreased transcription of genes required for ISC synthesis in FECD tissues (P < 0.05). Protein quantification revealed a significant decrease in mitochondrial aconitase (P < 0.05), ferredoxin 1 (P < 0.001), and mitofusin (P < 0.05), and a significant increase in cysteine desulfurase (P < 0.05), cytosolic aconitase/IREBP1, and IREBP2 (P < 0.05) in FECD tissues. Silencing studies revealed increased susceptibility to ferroptosis upon siRNA knockdown of ferredoxin 1 (P < 0.05).</p><p><strong>Conclusions: </strong>We identified differential gene expression of proteins responsible for ISC synthesis, ISC-containing proteins, IREBPs that mediate cellular iron homeostasis, and mitofusin, which promotes mitochondrial fusion in FECD. We also identified increased susceptibility to ferroptosis after ferredoxin 1 knockdown in CECs. These results advance an ISC- and IREBP-mediated mechanism of iron accumulation in FECD CECs.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 4","pages":"23"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}