Investigative ophthalmology & visual science最新文献

{"title":"Ocular Surface Involvements in the Development of Sjögren's Syndrome-Associated Dry Eye in the IL14α Transgenic Mouse.","authors":"Minjie Zhang, Yichen Liang, Han Wu, Rongrong Zong, Xiaobo Zhang, Hui He, Peter Sol Reinach, Zuguo Liu, Long Shen, Wei Li","doi":"10.1167/iovs.66.3.2","DOIUrl":"10.1167/iovs.66.3.2","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the ocular surface changes during progress of the Sjögren's Syndrome (SS), using a previously described IL14α transgenic mice (IL14α TG) SS model.</p><p><strong>Methods: </strong>The ocular surface of IL14α TG and C57BL/6 wild-type (WT) female mice were evaluated at the age of six, nine, 12, 15, and 18 months. Slit lamp microscopy observation, Oregon green dextran staining, Schirmer test, and periodic-acid-Schiff staining were assessed. Immunohistochemistry, immunofluorescence, and associated gene expression analysis by qPCR and ELISA were performed in cornea, conjunctiva, and lacrimal grand at different ages of the mice. Masson's trichome staining was conducted on lacrimal gland cryosections.</p><p><strong>Results: </strong>Compared with C57BL/6 WT mice, IL14α TG mice showed corneal barrier function damage and losses in conjunctival goblet cell density starting at nine months, whereas decreases in tear secretion started at 18 months of age. Significant increases in CD4+ T cell infiltration in the conjunctiva of IL14α TG mice was first observed at 6 months. Higher expression levels of inflammatory cytokines IL-17A, IFN-γ, IL-1β, and TNF-α in the conjunctiva, whereas MUC5AC and MUC5B had lower expression levels at nine months in the IL14α TG mice. However, lacrimal gland function-associated gene expression levels mostly decreased in IL14α TG mice at 12 months of age.</p><p><strong>Conclusions: </strong>Ocular surface tissue changes were involved in SS-like dry eye in a time-dependent manner in IL14α TG mice, and conjunctival T-cell infiltration may contribute to ocular surface pathological changes in an early stage of SS-related dry eye.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"2"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541806","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":"Ameboid Microglia as a Scavenger Role in Phagocytosis of Photoreceptor Outer Segment in an Experimental Retinal Detachment Model.","authors":"Manjing Cao, Yahan Zhang, Yan Li, Xian Zhang, Mingming Ma","doi":"10.1167/iovs.66.3.4","DOIUrl":"10.1167/iovs.66.3.4","url":null,"abstract":"<p><strong>Purpose: </strong>Photoreceptor (PR) death is the ultimate cause of irreversible vision loss in retinal detachment (RD). Previous studies have shown that microglia may have a dual role in RD. Nevertheless, the potential protective effects of microglia on PR are largely unknown. We aimed to uncover the phagocytic role of microglia in RD and propose a new concept to regulate PR survival.</p><p><strong>Methods: </strong>An RD model was conducted by injecting sodium hyaluronate into the subretinal space (SRS) of C57BL/6J wild type mice. Bioinformatics analysis was used to evaluate the highly enriched pathways and terms relating to phagocytosis in human datasets and mouse transcriptomes of RD. The observation of microglial morphology was performed by immunofluorescence through cryosection and flat mount. PLX 3397 was used for microglial ablation. Phagocytosis of the outer segment (OS) by microglia was confirmed by immunofluorescence and hematoxylin and eosin staining. Expression of phagocytic markers in microglia was detected by immunofluorescence of cryosection. The PR survival was measured by TUNEL assay and hematoxylin and eosin staining. The optical coherence tomography (OCT) images through the center of the fovea in twelve patients were obtained to observe the clinic features of IS/OS dynamics after RD.</p><p><strong>Results: </strong>The results showed that OS went through an accumulation-clearance process after RD. Ameboid microglia accumulated in the SRS and engulfed OS. Upregulation of phagocytic markers was observed in subretinal microglia. Depletion of microglia led to failure of OS clearance and retinal ruffling, which had the same characteristics as outer retinal undulation (ORU) in some patients with RD. PR did not benefit from microglial depletion, as no morphology and thickness recovery of PR was observed in the long term.</p><p><strong>Conclusions: </strong>These results elucidate that microglial phagocytosis of OS is a critical process after RD. Insufficient phagocytosis leads to the accumulation of OS in the SRS and PR abnormalities. Appropriate regulation of microglial phagocytosis to remove OS may be a new concept to regulate photoreceptor survival.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"4"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541293","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-Cell Multiomics Analysis of Early Wound Response Programs in the Mouse Corneal Epithelium.","authors":"Zhao-Jing Lu, Jin-Guo Ye, Jing-Ni Li, Jiang-Bo Liang, Ming Zhou, Qiu-Ling Hu, Qi-Kai Zhang, Yu-Heng Lin, Ying-Feng Zheng","doi":"10.1167/iovs.66.3.9","DOIUrl":"10.1167/iovs.66.3.9","url":null,"abstract":"<p><strong>Purpose: </strong>Wound healing is crucial for restoring homeostasis in living organisms. Although wound response mechanisms have been studied extensively, the gene regulatory programs involved remain to be elucidated. Here, we used single-cell RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) analysis to profile the regulatory landscape of mouse corneal epithelium in early wound response.</p><p><strong>Methods: </strong>We used our previously published single-cell data sets of homeostatic adult mouse corneal epithelium as the unwounded group. The wounded group data sets were obtained by sequencing the epithelium after an annular epithelial wound. Following the integration of the relevant data sets, the Seurat and ArchR packages were employed for single-cell RNA-seq and single-cell ATAC-seq data processing and downstream analysis, respectively. The Monocle 2 was used for pseudo-time analysis, CellChat for intercellular communication analysis, and pySCENIC for analyzing transcription factors. The expression of key genes was validated via immunofluorescence staining and quantitative real-time PCR.</p><p><strong>Results: </strong>Our data show that the number of cell type-specific genes decreases and the number of common transcriptional responses increases in early wound response. Concurrently, we find that the chromatin accessibility landscape undergoes significant changes across all epithelial cell types and that the wound-induced open regions are similarly distributed across the genome. Motif enrichment analysis shows that Fosl1/AP-1 binding site is highly enriched among the opened regions. However, by assessing the correlation between changes in chromatin accessibility and gene expression, we observe that only a small subset of wound-induced genes shows a high correlation with the accessibility of nearby chromatin.</p><p><strong>Conclusions: </strong>Our study provides a detailed single-cell landscape for transcriptomic and epigenetic changes in mouse corneal epithelium during early wound response, which improved our understanding of the mechanisms of wound healing.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"9"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556832","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":"STING Deficiency Promotes Th17-Like Tfh to Aggravate the Experimental Autoimmune Uveitis.","authors":"Zhuang Li, Xiuxing Liu, Zuoyi Li, Zhiqiang Xiao, Guanyu Chen, Yangyang Li, Jun Huang, Yunwei Hu, Haixiang Huang, Wenjie Zhu, Yuxun Shi, Minzhen Wang, Yanyan Xie, Wenru Su, Xiaoqing Chen, Dan Liang","doi":"10.1167/iovs.66.3.8","DOIUrl":"10.1167/iovs.66.3.8","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to explore the underlying mechanism that Th17-like T follicular helper cells (Tfh) orchestrated by STING signaling have a pathogenic role in experimental autoimmune uveitis (EAU).</p><p><strong>Methods: </strong>The differences of transcriptome and gene ontology (GO) pathway of Tfh between EAU and control mice were analyzed by single-cell RNA sequence (scRNA-seq) and bulk RNA sequence. Additionally, draining lymph nodes (DLNs) were extracted to verify the expression of IL-17A and IFN-γ in Tfh from EAU and control mice by flow cytometry. Then, the scRNA-seq and flow cytometry were used to explore the different proportion of Tfh between STING deficiency (Sting-/-) mice and wild type (WT) mice. In vitro, naïve CD4+ T cells were isolated from Sting-/- mice and WT mice to induce the Tfh under the induction condition. In addition, flow cytometry was used to detect the different induction ratio and the IL-17A expression between 2 groups of naïve CD4+ T cells.</p><p><strong>Results: </strong>Compared with control mice, marked increase of Tfh was observed in EAU, accompanied by elevated levels of Th1 and Th17 cells. Moreover, Th17-related genes, such as Rorc, Il22, Il23r, Il17a, and Il17f, and the corresponding GO pathways were upregulated in Tfh from EAU. The scRNA-seq showed that a higher proportion of Tfh was observed in the DLNs from Sting-/- mice than WT mice, which was verified by flow cytometry. When STING was knocked out, the Tfh was characterized with upregulated Th17-related phenotype in vivo, and there was a higher induction ratio of Tfh whose IL-17A expression was significantly increased in vitro. Notably, the STING expression of CD4+ T cells was downregulated in the EAU. STING-deficient EAU mice displayed more severe retinal inflammation, characterized by massive infiltration of CD4+ T cells, including Th1 and Th17 subsets. Importantly, treatment with a STING agonist alleviated inflammation of EAU.</p><p><strong>Conclusions: </strong>Th17-like Tfh cells play a pathogenic role in the EAU. STING deficiency promotes the differentiation and phenotypic transformation of Th17-like Tfh cells, exacerbating the inflammatory response in EAU. These findings highlight the potential of targeting STING to modulate Tfh cells as a therapeutic strategy for uveitis.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"8"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556834","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":"Porcine Sub-Retinal Pigment Epithelium Deposits: A Model for Dry Age-Related Macular Degeneration With Comparison to Human Drusen.","authors":"Erika M Shaw, David M Anderson, Ramesh Periasamy, Kevin L Schey, Christine A Curcio, Daniel M Lipinski","doi":"10.1167/iovs.66.3.18","DOIUrl":"10.1167/iovs.66.3.18","url":null,"abstract":"<p><strong>Purpose: </strong>Due to the slowly progressing nature of age-related macular degeneration (AMD) and critical differences in ocular anatomy between humans and animals, it has been difficult to model disease progression, hampering the development of novel therapeutics aimed at impacting drusen biogenesis. To determine whether \"drusen-in-a-dish\" model systems are of utility in screening potential therapeutics aimed at early-intermediate dry AMD, we developed a detailed characterization of the protein, glycoprotein, and lipid composition of sub-retinal pigment epithelium (RPE) deposits grown by monolayers of ex vivo porcine RPE with human drusen in AMD globes.</p><p><strong>Methods: </strong>Immunohistochemistry and imaging mass spectrometry (IMS) were performed on 20-week aged monolayers of porcine RPE and human donor globes recovered from an 81-year-old non-transplant donor with confirmed diagnosis of bilateral dry AMD. The presence of major protein, glycoprotein, and lipid species was compared between porcine sub-RPE deposits and human drusen with reference to macular/peripheral eccentricity.</p><p><strong>Results: </strong>The protein and glycoprotein composition of porcine sub-RPE deposits closely mimics human drusen identified in donor globes with dry AMD, including the presence of major complement components (C9, CFH, CHI), apolipoproteins (ApoE, ApoJ), extracellular matrix proteins (vitronectin, collagen VI), and calcification (hydroxyapatite). Sub-RPE deposits were additionally rich in long-chain ceramide species (Cer, CerPE, PI), which have only recently been described in human drusen.</p><p><strong>Conclusions: </strong>Due to their compositional similarity to human drusen, ex vivo \"drusen-in-a-dish\" systems represent a potentially robust and cost-effective model for both studying the pathobiology of drusen biogenesis and screening novel therapeutics aimed at limiting drusen formation.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"18"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567088","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 siRNA Delivery Against RUNX1 Via tFNA: Inhibiting Retinal Neovascularization and Restoring Vessels Through Dll4/Notch1 Signaling.","authors":"Xiaodi Zhou, Xiaoxiao Xu, Qiong Wang, Yanting Lai, Linyan Zhang, Yunfeng Lin, Xiaoyan Ding, Limei Sun","doi":"10.1167/iovs.66.3.39","DOIUrl":"10.1167/iovs.66.3.39","url":null,"abstract":"<p><strong>Purpose: </strong>To assess the efficacy of tetrahedral framework nucleic acids (tFNAs) as a delivery system for small interfering RNA (siRNA) targeting RUNX1 (siRUNX1) in inhibiting retinal neovascularization (RNV) and restoring vascular integrity via the Dll4/Notch1 signaling pathway.</p><p><strong>Methods: </strong>tFNAs and tFNAs-siRUNX1 were synthesized using annealing of single-stranded DNAs and characterized by PAGE and high-performance capillary electrophoresis. Human umbilical vein endothelial cells were treated under hypoxic conditions with tFNAs-siRUNX1, and cellular uptake was evaluated using fluorescence microscopy and flow cytometry. Angiogenesis was assessed through EdU proliferation, tube formation, and wound-healing assays. In vivo experiments used oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models in mice, with subsequent imaging by optical coherence tomography (OCT) and fundus fluorescence angiography. Gene and protein expression were analyzed by RT-PCR and Western blotting, focusing on the Dll4/Notch1 pathway and apoptosis markers.</p><p><strong>Results: </strong>tFNAs-siRUNX1 effectively inhibited endothelial cell proliferation, migration, and tube formation in vitro. In OIR and CNV models, it reduced neovascularization, nonperfusion areas, and vascular leakage. The mechanism involved modulation of the Dll4/Notch1 pathway, with decreased Dll4, Notch1, and Hes1 and increased Nts expression. tFNAs-siRUNX1 also reduced endothelial cell apoptosis via the Bcl-2/Bax pathway.</p><p><strong>Conclusions: </strong>tFNAs-siRUNX1 is a promising delivery system for targeting RNV, inhibiting neovascularization, and restoring retinal vascular integrity, providing a potential therapeutic alternative to anti-VEGF treatments.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"39"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656994","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":"A Novel Model for Cornea Power Shift in Eyes Wearing Orthokeratology Lenses With Different Back Optic Zone Diameters for Myopia Control.","authors":"Ting Wang, Xiaoqin Chen, Mengdi Li, Hua Bi, Xiaoyan Yang, Muhan Sun, Yue Liu, Lihua Li, Bin Zhang","doi":"10.1167/iovs.66.3.29","DOIUrl":"10.1167/iovs.66.3.29","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to quantify the corneal power changes after wearing orthokeratology lenses of different back optic zone diameters (BOZDs) and to propose a novel 4-parameter model capable of revealing the associations between each parameter and axial length growth (ALG).</p><p><strong>Methods: </strong>A prospective self-controlled study was conducted between June 2022 and December 2023. One eye in each subject (N = 33) was randomly assigned to wear a lens with a BOZD of either 5 mm (5 oz) or 6 mm (6 oz). Axial lengths were measured at 6 and 12 months and ALG was calculated from those measurements. Corneal topography obtained at baseline, 6 months, and 12 months after lens-wearing was analyzed, and the central flatten region is considered as the treatment zone (TZ). The power change profile was fitted with a riverbank model with parameters describing the amplitude, location shift, slope, and base. A linear mixed model was used to evaluate the association between ALG and model parameters.</p><p><strong>Results: </strong>ALG was significantly slower in eyes wearing 5 oz lenses (0.19 ± 0.15 vs. 0.26 ± 0.15 mm, P < 0.01). TZ sizes were smaller in the 5 oz group (6.76 ± 2.21 vs. 8.07 ± 2.01 mm2, P < 0.01). For relative corneal refractive powers shift (RCRPS) profiles averaged across 360 degrees, greater amplitudes (4.70 ± 1.05 vs. 4.33 ± 0.99 diopter [D], P = 0.04) and smaller location shifts (1.97 ± 0.32 vs. 2.11 ± 0.27 mm, P < 0.01) were found in the 5 oz group. For RCRPS profiles calculated in eight different meridians, strong meridional modulations were found in the parameters in each group. Moreover, significant inter-group parameter differences (P < 0.01) were only found on the temporal side. Multiple regression showed that only location shift was significantly associated with ALG (P = 0.01).</p><p><strong>Conclusions: </strong>Eyes wearing a 5 oz lens had significantly slower ALG, compared with the eyes wearing 6 oz lens. Such difference may be attributed to the smaller location shift on the temporal side.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"29"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11918062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604804","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":"Long Non-Coding RNA Osr2 Promotes Fusarium solani Keratitis Inflammation via the miR-30a-3p/ Xcr1 Axis.","authors":"Hanfeng Tang, Yi Lin, Jianzhang Hu","doi":"10.1167/iovs.66.3.27","DOIUrl":"10.1167/iovs.66.3.27","url":null,"abstract":"<p><strong>Purpose: </strong>Fungal keratitis (FK) is a challenging and sight-threatening corneal disease caused by fungal infections. Although long noncoding RNAs (lncRNAs) have been explored in various infectious diseases, their specific roles in FK remain largely unexplored.</p><p><strong>Methods: </strong>A mouse model of FK was created by infecting corneal stromal cells with Fusarium solani. High-throughput lncRNA expression profiling was conducted on FK-affected corneal tissues to identify differentially expressed lncRNAs. Reverse transcription quantitative PCR (RT-qPCR) was used to validate the results. A competing endogenous RNA (ceRNA) network was constructed. Additionally, a specific antisense oligonucleotide (ASO) targeting lncRNA ENSMUST00000226838/Osr2 (Osr2) was developed for therapeutic evaluation. Inflammatory markers IL-1β, IL-6, and TNF-α were measured, and corneal inflammation was assessed through histological analysis and slit-lamp examination. Fluorescent in situ hybridization (FISH) was used to confirm Osr2 localization, whereas a dual-luciferase reporter assay verified interactions between Osr2 and miR-30a-3p.</p><p><strong>Results: </strong>We identified 1143 differentially expressed lncRNAs in FK, with 701 upregulated and 442 downregulated. The ceRNA network analysis indicated that lncRNA Osr2 regulates Xcr1 expression through miR-30a-3p. Treatment with ASO-Osr2 significantly reduced corneal inflammation, and FISH confirmed lncRNA Osr2 distribution in both the nucleus and cytoplasm. Dual-luciferase assays demonstrated the interaction between Osr2 and miR-30a-3p, highlighting their potential roles in the progression of FK.</p><p><strong>Conclusions: </strong>This study outlined the lncRNA expression profile in FK and established a ceRNA regulatory network, identifying lncRNA Osr2 as a crucial modulator of FK pathogenesis through its interaction with miR-30a-3p. These findings highlighted lncRNA Osr2 as a promising therapeutic target for the treatment of FK.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"27"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11918059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604806","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":"Silicone Oil Affects Fibrosis of Human Trabecular Meshwork Cells by Upregulating Ferroptosis Through a ROS/NOX4/Smad3 Axis.","authors":"Jing Wang, Yang Zhang, Huimin Zhong, Yumeng Zhang, Ruiqi Han, Yanzhi Guo, Shouyue Huang, Huan Yu, Yisheng Zhong","doi":"10.1167/iovs.66.3.25","DOIUrl":"10.1167/iovs.66.3.25","url":null,"abstract":"<p><strong>Purpose: </strong>Silicone oil (SiO) is commonly employed as an intravitreal tamponade to manage complex retinal detachments associated with proliferative diabetic retinopathy, trauma, or severe myopia and to facilitate retinal reattachment. Nevertheless, SiO usage is linked to several complications, notably secondary glaucoma, which constitutes a significant proportion of adverse effects. This study investigated the impact of SiO on trabecular meshwork cells, given their pivotal role in regulating aqueous humor outflow.</p><p><strong>Methods: </strong>Human trabecular meshwork cells (HTMCs) were co-cultured with SiO. The impact on proliferation, fibrosis-related markers, and ferroptosis levels on these cells was evaluated using 5-ethynyl-2'-deoxyuridine (EdU), western blot, and immunofluorescence assays. Further gene knockdown experiments with NOX4 and Smad3 were conducted to elucidate the underlying mechanisms of SiO-induced changes.</p><p><strong>Results: </strong>SiO intervention inhibited HTMC proliferation, upregulated fibrosis-related markers, and elevated ferroptosis levels. Gene knockdown experiments revealed that SiO-induced ferroptosis and reactive oxygen species (ROS) increase were mediated through NOX4 upregulation and Smad3 activation.</p><p><strong>Conclusions: </strong>These findings highlight the significance of ferroptosis and the ROS/NOX4/Smad3 axis in the mechanism of SiO-induced intraocular pressure elevation. The insights gained from this study identify potential therapeutic targets to mitigate postoperative complications associated with SiO tamponade in ophthalmic surgery.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"25"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11918095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604819","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":"Topical Administration of Novel FKBP12 Ligand MP-004 Improves Retinal Function and Structure in Retinitis Pigmentosa Models.","authors":"Araceli Lara-López, Klaudia Gonzalez-Imaz, María Rodríguez-Hidalgo, Miren Sarasola-Gastesi, Leire Escudero-Arrarás, Santiago Milla-Navarro, Pedro de la Villa, Maialen Sagartzazu-Aizpurua, José Ignacio Miranda, Jesús María Aizpurua, Adolfo López de Munain, Ainara Vallejo-Illarramendi, Javier Ruiz-Ederra","doi":"10.1167/iovs.66.3.56","DOIUrl":"10.1167/iovs.66.3.56","url":null,"abstract":"<p><strong>Purpose: </strong>This study evaluates the therapeutic potential of MP-004, a novel FKBP12 ligand, in the treatment of inherited retinal dystrophies (IRDs). MP-004 targets the FKBP12/RyR interaction, which is disrupted in several neurologic disorders with underlying oxidative stress.</p><p><strong>Methods: </strong>The toxicity and efficacy of MP-004 were examined in vitro in 661W cells. Efficacy was evaluated in phototoxic and H2O2-induced damage using impedance assays, calcium imaging, and in situ PLA. In vivo, MP-004 efficacy was evaluated in the rd10 mouse model of retinitis pigmentosa (RP) by topical ocular instillation. Retinal function was assessed by electroretinography (ERG), visual acuity was measured using a water maze test, and retinal structure was analyzed morphometrically.</p><p><strong>Results: </strong>MP-004 exhibited low toxicity (LD50: 1.22 mM) and effectively protected 661W cells from phototoxicity (EC50: 30.6 nM). Under oxidative stress conditions, MP-004 preserved the FKBP12.6/RyR2 interaction, restored cytosolic and endoplasmic reticulum calcium levels, and prevented cell death. In vivo, MP-004 significantly preserved retinal function in rd10 mice, with ERG wave amplitude increases of up to 50% in scotopic and 71% in photopic conditions, corresponding to rod and cone functions, respectively. Additionally, MP-004 improved visual acuity for low spatial frequency patterns and preserved retinal structure, with a 23% increase in outer nuclear layer thickness and preservation in the number of rods and cones and their segment length.</p><p><strong>Conclusions: </strong>MP-004 shows promise as a therapeutic agent for RP, preserving retinal structure and function, likely through modulation of the FKBP12.6/RyR2 interaction. Further studies are needed to explore its pharmacokinetics and efficacy in other IRD models.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 3","pages":"56"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709808","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}