Experimental eye research最新文献

{"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}

{"title":"Binding with HSP90β, cimifugin ameliorates fibrotic cataracts in vitro and in vivo by inhibiting TGFβ signaling pathways","authors":"Xuefei Ding ,&nbsp;Zhaochuan Liu ,&nbsp;Hailong Li ,&nbsp;Peilin Yue ,&nbsp;Yuxuan Jia ,&nbsp;Enjie Li ,&nbsp;Ningxin Lv ,&nbsp;Ting Chen ,&nbsp;Rui Fang ,&nbsp;Honggang Zhou ,&nbsp;Xudong Song","doi":"10.1016/j.exer.2024.110127","DOIUrl":"10.1016/j.exer.2024.110127","url":null,"abstract":"<div><div>Fibrotic cataracts, the most frequent complications after phacoemulsification, cannot be cured by drugs in clinic. The primary mechanism underlying the disease is the epithelial-mesenchymal transition (EMT). Cimifugin is a natural monomer component of traditional Chinese medicines. Previous researches have demonstrated the effect of cimifugin inhibiting EMT in the lung. The purpose of this work is to evaluate the impact of cimifugin on EMT in the lens and elucidate its precise mechanism. The pathogenesis of fibrotic cataracts was simulated using TGFβ2-induced cell model of EMT and the injury-induced anterior subcapsular cataract animal model. Through H&amp;E staining and immunofluorescence of mice eyeballs, we discovered that cimifugin can inhibit the expansion of fibrotic lesions in vivo. Furthermore, at mRNA and protein levels, we confirmed that cimifugin can allay EMT of lens epithelial cells (LECs) in vitro and in vivo. Additionally, the inhibition of cimifugin on the activation of TGFβ-related signaling pathways was certified by immunoblot. HSP90β, the target of cimifugin, was predicted by network pharmacology and verified by drug affinity responsive target stability, the cellular thermal shift assay, and microscale thermophoresis. Moreover, co-immunoprecipitation revealed the interaction between HSP90β and TGFβ receptor (TGFβR) II. Together, our findings showed that by weakening the binding of HSP90β and TGFβRII, cimifugin suppressed the TGFβ signaling pathways to alleviate fibrotic cataracts. Cimifugin is a promising medication for the treatment of fibrotic cataracts.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"249 ","pages":"Article 110127"},"PeriodicalIF":3.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461420","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":"Ghost vessels in the eye: Cell free choriocapillaris domains in atrophic age-related macular degeneration","authors":"Robert F. Mullins ,&nbsp;Miles J. Flamme-Wiese ,&nbsp;Emma M. Navratil ,&nbsp;Erin A. Boese ,&nbsp;Katayoun Varzavand ,&nbsp;Megan J. Riker ,&nbsp;Kai Wang ,&nbsp;Edwin M. Stone ,&nbsp;Budd A. Tucker","doi":"10.1016/j.exer.2024.110128","DOIUrl":"10.1016/j.exer.2024.110128","url":null,"abstract":"<div><div>The choriocapillaris is a dense vascular bed in the inner choroid that supplies the photoreceptor cells and retinal pigment epithelium (RPE). While loss of choriocapillaris density has been described in association with age-related macular degeneration (AMD), whether these changes are primary or secondary to RPE degenerative changes in AMD has been debated. In this study we characterized choriocapillaris loss by quantifying “ghost” vessels in a series of 99 human donor maculae labeled with the UEA-I lectin, and found significant increases in early-intermediate AMD and a greater difference in geographic atrophy in areas with intact RPE. Eyes were genotyped at the <em>CFH</em> Tyr402His locus, and those homozygous for the His allele showed significantly more ghost vessels than those with other genotypes. When only non-AMD eyes were evaluated, His homozygotes had increased ghost vessel density but this trend did not reach statistical significance. These results support the notion that choriocapillaris death often precedes RPE degeneration in AMD and that this loss is an important therapeutic consideration for AMD.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110128"},"PeriodicalIF":3.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446562","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":"The role of nicotinamide riboside in the preservation of retinal ganglion cells using an in vitro glutamate-induced excitotoxicity model","authors":"Nan Zhang ,&nbsp;Dongxiao Ji ,&nbsp;Yixin Hu ,&nbsp;Pengyu Zhang ,&nbsp;Xizhi Deng ,&nbsp;Min Zhu ,&nbsp;Wen Zeng ,&nbsp;Min Ke","doi":"10.1016/j.exer.2024.110126","DOIUrl":"10.1016/j.exer.2024.110126","url":null,"abstract":"<div><div>Delaying or preventing the loss of retinal ganglion cells (RGCs) in glaucoma is needed for vision preservation. Glutamate-mediated neurotoxicity arises from the excessive stimulation of N-methyl-D-aspartate membrane receptors by glutamate. This overstimulation, occurring specifically in RGCs, triggers a progressive deterioration of the optic nerve that ultimately leads to the vision loss in glaucoma. Our previous investigation demonstrated that nicotinamide riboside (NR) effectively preserved RGCs in multiple mouse models of glaucoma. To investigate the precise role of NR concerning RGCs which remains uncertain, a glutamate-induced excitotoxicity RGCs damage model was established using R28 cells in this study. Results showed that NR treatment could not only prevent the decrease in cell viability but also effectively inhibit the apoptosis of R28 cells induced by glutamate, as proven by flow cytometry and expression of key pro-apoptotic proteins. Additionally, it significantly attenuated oxidative stress induced by glutamate, as evaluated by the production of inflammatory factors, reactive oxygen species (ROS) and mitochondrial ROS (mtROS). Furthermore, NR elevated the intracellular nicotinamide adenine dinucleotide (NAD+) levels in R28 cells. Lastly, we used RNA-seq to reveal the underlying mechanism of NR protection. Combining the results of RNA-seq and Western blot, we found that NR also restored the decreased protein expression of sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) induced by glutamate. These findings strongly indicated that NR exhibits a protective effect against R28 cell apoptosis in a glutamate-induced excitotoxicity RGCs damage model. This protective effect is likely mediated through the activation of the SIRT1/PGC1α pathway, achieved by increasing intracellular NAD + levels.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110126"},"PeriodicalIF":3.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446561","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}