Experimental eye research最新文献

{"title":"Pigment epithelium-derived factor exerts neuroprotection in oxygen-induced retinopathy by targeting endoplasmic reticulum stress and oxidative stress","authors":"Ya'nuo Wang ,&nbsp;Sha Gao ,&nbsp;Shuang Gao ,&nbsp;Na Li ,&nbsp;Hanwen Huang ,&nbsp;Xiaohong Liu ,&nbsp;Huiping Yao ,&nbsp;Xi Shen","doi":"10.1016/j.exer.2024.110147","DOIUrl":"10.1016/j.exer.2024.110147","url":null,"abstract":"<div><div>Endoplasmic reticulum (ER) stress and oxidative stress have been involved in the occurrence of neuronal apoptosis in ischemic retinopathy. Pigment epitheliu-derived factor (PEDF) is well known for its multifunctional properties, including neuroprotection, anti-inflammation and antioxidant. However, the association between PEDF and ER stress or oxidative stress in ischemic retinopathy remain incompletely understood. In this study, the concentration of the key factor of ER stress C/EBP homologous protein (CHOP) in aqueous humor (AqH) and vitreous samples of proliferative diabetic retinopathy (PDR) patients were measured by ELISA assays. Oxygen-induced retinopathy (OIR) mice model was established and PEDF intravitreal injections were conducted. Primary bone marrow derived macrophages (BMDMs) were isolated and cultured under hypoxic conditions in vitro. Western blotting, real-time RT-PCR, immunofluorescence, transmission electron microscopy (TEM), TUNEL assays were performed to explore roles of PEDF on ER stress and oxidative stress, as well as subsequently neuronal apoptosis under hypoxic conditions in vivo and in vitro. The results revealed that ER stress and oxidative stress were notably activated under hypoxic conditions. We also observed that hypoxia evoked ultrastructural damage of ER and mitochondrion in the retina. However, PEDF significantly prevented ER stress and oxidative stress, as well as the damage of ultrastructure, resulting in diminution of photoreceptor apoptosis in OIR retinas. These results indicate that PEDF may play its neuroprotection role through inhibiting ER stress and oxidative stress in ischemic retinopathy, which is a novel molecular mechanism of PEDF protecting photoreceptors from ischemic damage, thereby suggesting that PEDF is an effective therapeutic agent for the treatment of neuron damage in ischemic retinal diseases.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110147"},"PeriodicalIF":3.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602826","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":"Role of angiopoietin-like 4 in neovascularization associated with retinopathy of prematurity","authors":"Xiaofeng Lu ,&nbsp;Zixin Fan ,&nbsp;Shuo Yang,&nbsp;Lei Zheng,&nbsp;Zhen Yu,&nbsp;Yuhang Yang,&nbsp;Mianying Zheng,&nbsp;Jian Zeng,&nbsp;Guoming Zhang","doi":"10.1016/j.exer.2024.110145","DOIUrl":"10.1016/j.exer.2024.110145","url":null,"abstract":"<div><div>To elucidate the mechanisms of angiopoietin-like 4 (ANGTPL4) in neovascularization (NV) in retinopathy of prematurity (ROP). We compared ANGPTL4 expression levels of aqueous humour and vitreous fluid samples in infants with acute-phase ROP and control group. ANGPTL4^−/− mice and WT mice were used to constructed oxygen-induced retinopathy (OIR) mouse models, with retinal tissues collected on postnatal days 12 (P12), 15 (P15) and 17 (P17). Analysis of retinal vessels and transcriptomics were performed to explore the role of ANGTPL4 in NV. The results showed ANGPTL4 level was significantly higher in the aqueous humour and vitreous fluid of children with ROP than that of control group. At P15 and P17, the vascular indices in the ANGPTL4^−/−-CON group were lower than those in the WT-CON group. The central non-perfused area of the retina and number of neovascular nuclei were also smaller in the ANGPTL4^−/−-OIR group than in the WT-OIR group. Immunofluorescence results showed the overexpression of ANGPTL4 protein in the WT-OIR group than in the WT-CON group, especially at P17. Furthermore, extracellular matrix (ECM) organisation was one of the key involved pathways based on gene ontology (GO) enrichment analyses. ANGPTL4 was one of the core genes involved in ECM organization, and neuralized E3 ubiquitin protein ligase 1B (NEURL1B), cd36 Molecule (CD36), matrix metallopeptidase 3 (MMP3) and collagen type III alpha 1 chain (COL3A1) were the first nodes interacting with ANGPTL4.In conclusion, ANGPTL4 is involved in the pathological NV by regulating NEURL1B, CD36, MMP3, and COL3A1. Thus, ANGPTL4 is a potential therapeutic target for ROP.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110145"},"PeriodicalIF":3.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568271","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":"Optical and retinal changes influenced by different lighting conditions","authors":"Elvira Orduna-Hospital ,&nbsp;Juan J. Sanchez-Bautista ,&nbsp;Guisela Fernández-Espinosa ,&nbsp;María Arcas-Carbonell ,&nbsp;Ana Sanchez-Cano","doi":"10.1016/j.exer.2024.110146","DOIUrl":"10.1016/j.exer.2024.110146","url":null,"abstract":"<div><div>Retinal morphology, specifically in its curvature, and ocular aberrations change when the eye adapts to different lighting conditions, including photopic, scotopic, mesopic, blue light, and red light. Sixty healthy young subjects with refractive error less than ±4.00 D of sphere and 3.00 D of cylinder, not suffering from accommodative problems, ocular or systemic pathology, and not having used electronic devices half an hour before or having taken substances that alter the retina during the 2 h prior to the study were included. The subjects adapted to five lighting conditions, each for 5 min, in a controlled environment. Ocular aberrometry and Optical Coherence Tomography (OCT) were taken to capture images of the central and peripheral retina before (baseline measurements) and after adaptation to each lighting condition. The OCT images were exported and processed to analyze retinal curvature, obtaining parameters such as eccentricity, asphericity and shape factor. The results showed that the shape of the retina was hyperbolic prolate, becoming flatter in scotopic and blue light conditions, and more curved in mesopic conditions. Retinal curvature was closest to baseline under red light and photopic conditions. Aberrometric differences, particularly in the C(2,0) polynomial for defocus, showed higher values in mesopic, baseline, and scotopic conditions, and lower values in photopic, blue light, and red light. Significant differences were also observed in spherical aberrations C(4,0) and C(6,0), vertical coma C(3,-1), and trefoil C(3,-3). The spherical equivalent indicated more myopic values in mesopic, baseline, and scotopic conditions, and more hyperopic values in blue, photopic, and red light, suggesting a link between myopia and lower luminosity. This study concludes that illumination affects retinal curvature and ocular refraction, influencing myopia.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110146"},"PeriodicalIF":3.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568269","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":"The aryl hydrocarbon receptor: A crucial mediator in ocular disease pathogenesis and therapeutic target","authors":"Juanjuan Ji ,&nbsp;Chanyu Xiong ,&nbsp;Huining Yang ,&nbsp;Zhilin Jiang ,&nbsp;Yun Zhang ,&nbsp;Xiao Wang ,&nbsp;Tianshu Yu ,&nbsp;Qiong Li ,&nbsp;Shikai Zhu ,&nbsp;Yu Zhou","doi":"10.1016/j.exer.2024.110144","DOIUrl":"10.1016/j.exer.2024.110144","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AHR) is a pivotal nuclear receptor involved in mediating cellular responses to a wide range of environmental pollutants and endogenous ligands. AHR plays a central role in regulating essential physiological processes, including xenobiotic metabolism, immune response modulation, cell cycle control, tumorigenesis, and developmental events. Recent studies have identified AHR as a critical mediator and a potential therapeutic target in the pathogenesis of ocular diseases. This review provides a thorough analysis of the various functions of AHR signalling in the ocular environment, with a specific emphasis on its effects on the retina, retinal pigment epithelium (RPE), choroid, and cornea. We provide a detailed discussion on the molecular mechanisms through which AHR integrates environmental and endogenous signals, influencing the development and progression of age-related macular degeneration (AMD), retinitis pigmentosa, uveitis, and other major ocular disorders. Furthermore, we evaluate the therapeutic potential of modulating AHR activity through novel ligands and agonists as a strategy for treating eye diseases. Understanding the molecular mechanisms of AHR in ocular tissues may facilitate the development of AHR-targeted therapies, which is crucial for addressing the pressing clinical demand for novel treatment strategies in ocular diseases.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110144"},"PeriodicalIF":3.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564230","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":"Neuroprotective effect of Sigma-2 modulator CT2074 in a mouse model of ocular hypertension","authors":"Nina Donkor ,&nbsp;Charles C. Kiehlbauch ,&nbsp;Nathaniel Pappenhagen ,&nbsp;Gary C. Look ,&nbsp;Autumn B. Morgan ,&nbsp;Rick Shin ,&nbsp;Mary E. Hamby ,&nbsp;Denise M. Inman","doi":"10.1016/j.exer.2024.110143","DOIUrl":"10.1016/j.exer.2024.110143","url":null,"abstract":"<div><div>Ocular neurodegenerative diseases, particularly glaucoma, represent a significant global cause of blindness, with current therapies inadequately addressing the degeneration of the retina and optic nerve. Recent research has identified the sigma-2 receptors as a potential druggable target to offer neuroprotection in managing ocular neurodegenerative disorders. This study investigates the neuroprotective potential of CT2074, a sigma-2 receptor modulator, in a mouse model of primary open-angle glaucoma.</div><div>Male mice were subjected to unilateral magnetic bead-induced elevation of intraocular pressure (IOP) and received daily oral administration of CT2074, commencing three days prior to ocular hypertension (OHT) induction, and continuing for three weeks. Mice received bilateral intraocular injections of cholera toxin B-488 (CTB) to assess retinal ganglion cell (RGC) anterograde transport. Retina, optic nerve, and brain tissues were collected three weeks post OHT induction for quantification of RGC and axon number, with contralateral retinas and cerebelli preserved for assessment of drug exposure.</div><div>CT2074 was observed in the retina at levels exceeding the 95% receptor occupancy concentration. RGC quantification showed a significant reduction in the Vehicle group compared to Naïve and CT2074 groups. Notably, the CT2074 treatment group exhibited significantly higher RGC density than the Vehicle (p &lt; 0.0001) and was no different than Naïve. Analysis of RGC axons in optic nerve cross-sections revealed significant axonal loss in both the Vehicle and CT2074 groups compared to Naïve, though the CT2074-treated group had significantly higher axon number compared to the Vehicle. Anterograde transport in the Vehicle and CT2074 groups did not differ.</div><div>This study underscores the potential of CT2074 administered orally to protect RGCs exposed to elevated IOP, as evidenced by substantial preservation of RGCs and their axons compared to Vehicle-treated mice. These findings signify a promising avenue for the development of sigma-2 receptor-targeted therapeutics in glaucoma and related neurodegenerative diseases, addressing a critical unmet need in the field of ocular neuroprotection.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110143"},"PeriodicalIF":3.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557488","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":"A comprehensive review of experimental models for investigating blue light-induced ocular damage: Insights into parameters, limitations, and new opportunities","authors":"Wan-Ju Yeh ,&nbsp;Pin-Ting Chien ,&nbsp;Yao-Tseng Wen ,&nbsp;Chi-Hao Wu","doi":"10.1016/j.exer.2024.110142","DOIUrl":"10.1016/j.exer.2024.110142","url":null,"abstract":"<div><div>Light-emitting diodes (LEDs) are widely used in modern lighting and electronic devices, including smartphones, computer monitors, tablets, televisions, and vehicle lights. Blue light (BL) hazards to eye health have received increasing attention because white LED bulbs emit higher levels of BL than traditional lighting sources. At wavelengths of 400–500 nm, BL is characterized by its high energy and risks associated with prolonged exposure, which may lead to photochemical damage and morphological alterations in the retina. Recent research has revealed that the harmful effects of BL are intricately linked to light intensity and exposure frequency, with mechanisms involving the overproduction of reactive oxygen species through photooxidative processes. This growing body of knowledge deepens our understanding of photodamage and opens avenues for exploring protective strategies for our eyes. Although current clinical trials assessing the safety of BL exposure remain limited, the development of experimental models that mimic physiological conditions has revealed BL toxicity. This review categorizes and evaluates BL-induced retinopathy <em>in vivo</em>, providing a comprehensive overview of the associated experimental parameters, including photosensitive fluorophores, light wavelength, illuminance, irradiance, exposure duration, animal strains, and their unique lesion patterns. Moreover, this study underscores the need for further research to evaluate photoprotective agents, which may offer valuable insights to the ongoing discussion on preserving ocular health in our increasingly illuminated digital environments.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110142"},"PeriodicalIF":3.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568305","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":"Integrative multiomic analysis unveils the molecular nexus of mitochondrial dysfunction in the pathogenesis of age-related macular degeneration","authors":"Jianqi Chen ,&nbsp;Zhe Liu ,&nbsp;Yingting Zhu ,&nbsp;Zhidong Li ,&nbsp;Yuwen Wen ,&nbsp;Danna Chen ,&nbsp;Jingying Liang ,&nbsp;Yue Xiao ,&nbsp;Yunxia Leng ,&nbsp;Yehong Zhuo","doi":"10.1016/j.exer.2024.110141","DOIUrl":"10.1016/j.exer.2024.110141","url":null,"abstract":"<div><div>Mitochondrial dysfunction is linked to age-related macular degeneration (AMD), but its mechanisms and related molecular networks remain unclear. We explored the association between mitochondrial-related genes and AMD by integrating multiomic data. We acquired summary-level data on mitochondrial-related protein abundance, gene expression, and gene methylation from quantitative trait locus studies. Genetic associations with AMD were sourced from the International Age-related Macular Degeneration Genomics Consortium (discovery), FinnGen (replication), and UK Biobank (replication) studies. We used summary-data-based Mendelian randomization to assess the correlations between mitochondrial-related gene molecular characteristics and AMD. Furthermore, colocalization analysis was performed to ascertain if the detected signal pairings had a common causative genetic variation. Mitochondrial-related gene <em>NFKB1</em> demonstrated a protective role in AMD (tier 1 evidence), whereas <em>HSPA1A</em> and <em>HSPA1B</em> genes were also associated with decreased AMD risk (tier 2 evidence). The methylation of cg09390974 and cg15409712 in <em>NFKB1</em> was associated with increased NFKB1 expression, consistent with the protective effect on AMD risk, whereas inverse associations were observed between gene methylation and gene expression for HSPA1B (cg04835051 and cg16372051), supporting the risk roles of methylation in AMD. At circulating protein level, genetically predicted higher levels of HSPA1A (odds ratio [OR] 0.28, 95% confidence interval [CI] 0.19−0.41, <em>P</em> &lt; 0.001), HSPA1B (OR 0.13, 95% CI 0.06−0.27, <em>P</em> &lt; 0.001), and NFKB1 (OR 0.43, 95% CI 0.27−0.68, <em>P</em> &lt; 0.001) were inversely associated with AMD risk. These associations were corroborated in the colocalization analysis. We identified AMD-linked mitochondrial-related genes, potentially improving the understanding of its pathophysiological mechanisms and aiding the identification of novel pharmaceutical targets.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110141"},"PeriodicalIF":3.0,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568308","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":"Paquinimod attenuates retinal injuries by suppressing the S100A9/TLR4 signaling in an experimental model of diabetic retinopathy","authors":"Can Deng ,&nbsp;Xiaomeng Li ,&nbsp;Mingxin Ren,&nbsp;Ziyang Ye,&nbsp;Feiyu Jin,&nbsp;Bochen Yao,&nbsp;Yuewei Peng,&nbsp;Li Lu,&nbsp;Kai Dong","doi":"10.1016/j.exer.2024.110131","DOIUrl":"10.1016/j.exer.2024.110131","url":null,"abstract":"<div><div>Diabetic retinopathy (DR), the most common ocular complication of diabetes mellitus (DM), has exhibited an increase in incidence over the past decade. S100 calcium-binding protein A9 (S100A9) plays a significant role in inflammation and cancer. Toll-like receptor 4 (TLR4), a transmembrane receptor, initiates signaling cascades upon ligand binding. S100A9 activates TLR4, and their involvement in various diseases is well-established. We found elevated S100A9/TLR4 pathway proteins in the vitreous of DR patients. Bioinformatics analysis revealed differential gene expression related to this pathway. These proteins were also detected in diabetic rat retinas and induced structural damage. Paquinimod, an S100A9 inhibitor, decreased pathway protein expression and reduced retinal damage. Our study validates the S100A9/TLR4 pathway in diabetic retinas and suggests its potential as a therapeutic target for DR. Targeting S100A9 could offer a novel approach to prevention and treatment.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110131"},"PeriodicalIF":3.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497718","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":"TGF-β1-mediated upregulation of LMCD1 drives corneal myofibroblast differentiation and corneal fibrosis","authors":"Yunlan Tang ,&nbsp;Liyan Xu ,&nbsp;Yiran Yang ,&nbsp;Fangyuan Qin ,&nbsp;Feiying Meng ,&nbsp;Lijuan Dai ,&nbsp;Zhihong Meng ,&nbsp;Shengwei Ren","doi":"10.1016/j.exer.2024.110130","DOIUrl":"10.1016/j.exer.2024.110130","url":null,"abstract":"<div><div>Transforming growth factor β1 (TGF-β1) drives corneal fibroblasts to differentiate into corneal myofibroblasts and plays a key role in corneal fibrosis. However, the role of LIM and cysteine-rich domains-1 (LMCD1) in TGF-β1-induced corneal myofibroblast differentiation and corneal fibrosis remains elusive. Thus, this study aimed to investigate the expression, regulatory mechanism, and role of LMCD1 in TGF-β1-induced corneal myofibroblast differentiation and corneal fibrosis. The expression of LMCD1 in TGF-β1-stimulated corneal fibroblasts was found to be upregulated through mRNA sequencing, quantitative PCR (qPCR), and Western blotting. Moreover, LMCD1 was identified to be upregulated in a mouse model of corneal fibrosis via qPCR and Western blotting. Additionally, our results demonstrated that the increase in LMCD1 expression induced by TGF-β1 in corneal fibroblasts was primarily regulated by the SMAD3 signaling pathway. Furthermore, LMCD1 knockdown significantly inhibited TGF-β1-induced corneal fibroblast-to-myofibroblast differentiation and simultaneously activated SMAD3, JNK, and p38 by promoting <em>TGF-β1</em> transcription. These findings collectively suggest that LMCD1 could upregulate alpha-smooth muscle actin (α-SMA) expression and downregulate TGF-β1 expression in corneal myofibroblast differentiation. Consequently, upregulation of LMCD1 expression could potentially serve as a strategy to mediate the TGF-β1 signaling pathway in corneal myofibroblast differentiation and corneal fibrosis, laying a theoretical reference for corneal fibrosis and contributing to the development of effective therapeutic strategies for corneal fibrosis.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110130"},"PeriodicalIF":3.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461425","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":"Regulation of LAMTOR1 by oxidative stress in retinal pigment epithelium: Implications for age-related macular degeneration pathogenesis","authors":"Jingjing Cai ,&nbsp;Fei Liao ,&nbsp;Yandie Mao ,&nbsp;Shuyi Liu ,&nbsp;Xiong Wu ,&nbsp;Shiqi Tang ,&nbsp;Simin Wang ,&nbsp;Ge Shan ,&nbsp;Shengzhou Wu","doi":"10.1016/j.exer.2024.110129","DOIUrl":"10.1016/j.exer.2024.110129","url":null,"abstract":"<div><div>Oxidative stress is a critical pathogenic factor for age-related macular degeneration (AMD). Autophagy serves as a mechanism to counteract oxidative stress. LAMTOR1 regulates mTORC1 activity by recruiting or disassembling it on the lysosome under the addition or deprivation of amino acids. This regulation inhibits or enhances autophagy. Our study investigates whether oxidative stress impacts LAMTOR1, thereby adapting to oxidative conditions. We employed oxidative stressors, menadione (VK3) and 4-hydroxynonenal (4-HNE), and observed a reduction of LAMTOR1 in both human and mouse retinal pigment epithelium (RPE) following short-term (1h) and prolonged exposures (24h). Nrf2 overexpression increased both <em>lamtor1</em> mRNA and LAMTOR1 protein in the RPE. To determine if Nrf2 regulates <em>lamtor1</em> transcription, we cloned the deletion mutants of the <em>lamtor1</em> promoter into a luciferase reporter. Although the promoter contained antioxidant response elements, transcriptional activity depended on the interaction between Nrf2 and the constructs containing the transcriptional start site. Moreover, Nrf2-driven transcription was significantly reduced by an inhibitor of histone acetyltransferase, p300. Correspondingly, Nrf2 overexpression increased levels of acetylated histone 3 and p300. The reduction in LAMTOR1 by 4-HNE was reversed by pepstatin A and NH₄Cl which block lysosomal degradation. 4-HNE increased TFEB nuclear translocation which was reversed by LAMTOR1 overexpression. <em>In vivo</em>, LAMTOR1 levels decreased in the photoreceptor and RPE layers of NaIO₃-injected mice, compared to PBS-injected controls. In conclusion, oxidative injury reduces LAMTOR1, predominantly through lysosomal degradation although Nrf2-mediated histone acetylation enhances <em>lamtor1</em> transcription. This study reveals a previously unrecognized regulatory mechanism of <em>lamtor1</em> by oxidative stress, suggesting a novel role for LAMTOR1 in the pathogenesis of AMD.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110129"},"PeriodicalIF":3.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461423","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}