Experimental eye research最新文献

{"title":"Exploring the connection between HLA class I and class II genotypes and diabetic retinopathy: A comprehensive review of experimental evidence","authors":"Zahra Souri ,&nbsp;Hamid Ahmadieh","doi":"10.1016/j.exer.2024.110112","DOIUrl":"10.1016/j.exer.2024.110112","url":null,"abstract":"<div><div>Diabetic retinopathy (DR) is a microvascular complication associated with diabetes mellitus (DM). During the course of the disease, high blood glucose levels induce damage to the vasculature of the retina and promote neovascularization. Although numerous environmental risk factors have been associated with the emergence of DR, the role of genetics should not be underestimated. The human leukocyte antigen (HLA) plays a significant role in the regulation of the immune system. DR exhibits significant heterogeneity among patients, with differences in how the disease presents and progresses over time. The HLA gene, characterized by its extensive genetic variation, largely contributes to this diverse spectrum. Differences in HLA allele frequencies among healthy people, diabetic patients without retinopathy, and diabetic patients with different stages of retinopathy highlight the need for proper management of the disease. This comprehensive review outlines the current understanding of the relationship between HLA class I and class II variants and DR, shedding light on their potential significance as early onset indicators, prognostic indicators, and important risk factors for the development of this retinal condition.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110112"},"PeriodicalIF":3.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319822","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":"Current insights on mitochondria-associated endoplasmic reticulum membranes (MAMs) and their significance in the pathophysiology of ocular disorders","authors":"Xin-Yu Zhang ,&nbsp;Cheng Han ,&nbsp;Yong Yao ,&nbsp;Ting-Ting Wei","doi":"10.1016/j.exer.2024.110110","DOIUrl":"10.1016/j.exer.2024.110110","url":null,"abstract":"<div><div>The intricate interaction network necessary for essential physiological functions underscores the interdependence among eukaryotic cells. Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs), specialized junctions between mitochondria and the ER, were recently discovered. These junctions participate in various cellular processes, including calcium level regulation, lipid metabolism, mitochondrial integrity maintenance, autophagy, and inflammatory responses via modulating the structure and molecular composition of various cellular components. Therefore, MAMs contribute to the pathophysiology of numerous ocular disorders, including Diabetic Retinopathy (DR), Age-related Macular Degeneration (AMD) and glaucoma. In addition to providing a concise overview of the architectural and functional aspects of MAMs, this review explores the key pathogenetic pathways involving MAMs in the development of several ocular disorders.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110110"},"PeriodicalIF":3.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344369","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":"Trio-based whole-exome sequencing of 200 Chinese patients with keratoconus","authors":"Xingyong Li ,&nbsp;Yinghao Yao ,&nbsp;Shilai Xing ,&nbsp;Yi-Han Zheng ,&nbsp;Yang Zhou ,&nbsp;Xiaoguang Yu ,&nbsp;Jianzhong Su ,&nbsp;Shihao Chen ,&nbsp;Zi-Bing Jin","doi":"10.1016/j.exer.2024.110109","DOIUrl":"10.1016/j.exer.2024.110109","url":null,"abstract":"<div><div>Keratoconus (KC) is a complex corneal disorder with a well-recognized genetic component. In this study, we aimed to expand the genetic spectrum of 200 Chinese patients with keratoconus and their unaffected parents. Trio-based whole-exome sequencing was performed in 200 patients with sporadic keratoconus and their unaffected parents. The variants identified in candidate genes for keratoconus were analyzed using multiple bioinformatics tools. Finally, we identified 7 variants in 5 candidate genes for keratoconus in 5 patients. The c.T464C variant in the <em>IMPDH1</em> gene was defined as likely pathogenic according to the guidelines of the American College of Medical Genetics and Genomics, and the remaining variants in candidate genes (<em>TRANK1</em>, <em>SLC4A11</em>, <em>CERKL</em>, <em>IFT172</em>) were defined as uncertain significance. Our results expand the genetic spectrum in KC, highlight the genetic heterogeneity of this disease and provide important clues for future functional validation.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110109"},"PeriodicalIF":3.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319823","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":"Bax expression impacts postnatal retinal vascular development and hyperoxia sensitivity","authors":"Nader Sheibani ,&nbsp;Yanzhi Sang ,&nbsp;Shoujian Wang ,&nbsp;Christine M. Sorenson","doi":"10.1016/j.exer.2024.110107","DOIUrl":"10.1016/j.exer.2024.110107","url":null,"abstract":"<div><div>Apoptosis plays prominent roles during organ development, maturation and homeostasis. In the retina, Bcl-2 family members function through the intrinsic cell death pathway with vital roles during vascular development and hyperoxia-mediated vessel obliteration during oxygen induced ischemic retinopathy (OIR). Bim, a BH3 only protein Bcl-2 family member, binds and activates Bax and/or Bak to facilitate apoptosis. In some systems deletion of both Bax and Bak are required to prevent cell loss, such as regression of ocular hyaloid vasculature. We previously showed Bim expression significantly impacts normal retinal vascular development and sensitivity to hyperoxia. Mice deficient in Bim (Bim^−/−) show increased retinal vascular density and are protected from hyperoxia mediated vessel obliteration. Since Bim activates Bax, here we determined the impact lack of Bax expression has on these processes. Compared to Bax^+/+ mice, retinas from Bax^−/− mice had significantly increased numbers of retinal endothelial cells and pericytes. We also demonstrated that hyperoxia-mediated vessel obliteration during OIR was significantly decreased in the absence of Bax. Although the increased endothelial cell numbers were comparable to that of Bim^−/− mice, the increased numbers of pericytes were not to the extent noted in Bim^−/− mice. These changes were supported by partial protection of retinal vessels from hyperoxia in Bax^−/− mice compared to that noted in Bim^−/− mice. Thus, Bim-Bax driven pathway is sufficient to remove excess endothelial cells but not pericytes during postnatal retinal vascularization and hyperoxia-mediated vessel obliteration. Thus, additional Bim-mediated pathway(s) are required for removal of pericytes and hyperoxia-mediated vessel obliteration.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110107"},"PeriodicalIF":3.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282671","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":"Controlled elevation of intraocular pressure in anesthetized mice","authors":"Diana C. Lozano,&nbsp;William O. Cepurna,&nbsp;Elaine C. Johnson,&nbsp;John C. Morrison","doi":"10.1016/j.exer.2024.110106","DOIUrl":"10.1016/j.exer.2024.110106","url":null,"abstract":"<div><div>Our purpose was to develop a protocol for prolonged anesthesia in mice and evaluate optic nerve axon injury in response to 4 h of controlled elevation of intraocular pressure (CEI). During CEI, C57BL/6 male mice (3–5 months old) were anesthetized with 1.5% isoflurane with 100% oxygen for 4 h and placed on a warm platform, with expired gas and anesthetic actively evacuated. Lactated ringers (0.5 ml) with 5% dextrose was administered subcutaneously at the start and end of CEI. Physiological parameters (oxygen saturation = O₂, heart rate = HR, systolic blood pressure = SBP, and temperature) were monitored throughout the 4-h CEI. One eye was cannulated with polyurethane tubing connected to a balanced salt solution reservoir and IOP elevated to 20 (N = 18), 30 (N = 13), 50 (N = 14), and 60 mmHg (N = 16). An additional group of 22 female mice was exposed to CEI of 60 mmHg. Fourteen days after CEI, optic nerves were assessed for axonal injury by masked observers that assigned a grade on a scale from 1 (normal) to 5 (&gt;50% of axons degenerating). CEI optic nerve injury was compared to injury assessed in contralateral optic nerves (N = 84) and naïve optic nerves (N = 18) using a one-way ANOVA followed by Kruskal-Wallis test for multiple comparisons. The relationship between optic nerve injury, physiological parameters, and IOP were assessed by linear regression analyses. Physiologic parameters remained stable throughout CEI (O₂ = 95 ± 9%; HR = 450 ± 39; SBP = 102 ± 15 mmHg, and temperature = 38 ± 0.7 °C) and were not statistically different between groups (all comparisons had P &gt; 0.5). Mean optic nerve injury grades (±SD) for naïve optic nerves (1.01 ± 0.02) were not significantly different from fellow/contralateral optic nerves (1.03 ± 0.07, P &gt; 0.99), or from CEI of 20 mmHg (1.04 ± 0.08, P &gt; 0.99) or 30 mmHg (1.05 ± 0.06, P = 0.6). However, animals exposed to CEI of 50 mmHg (2.09 ± 1.43, P = 0.0005) and 60 mmHg (male: 2.86 ± 1.30, P &lt; 0.0001, female: 1.63 ± 1.00, P = 0.0006) developed significant optic nerve injury relative to their fellow/contralateral optic nerves. Axonal injury grades following a CEI of 60 mmHg were not significantly different between male and female mice (P = 0.19). Optic nerve injury positively correlated (P &lt; 0.0001) with IOP and not with physiological parameters, indicating that the optic nerve injury is IOP-related. In conclusion, prolonged anesthesia in mice requires careful attention to animal physiology. With this, a 4-h exposure to elevated IOP can produce significant optic nerve injury with IOPs equal to or greater than 50 mmHg. We provide detailed descriptions of methods and materials for producing prolonged elevations of IOP in mice while maintaining and monitoring their physiology, as well as a unique, cost-effective transducer system for monitoring pressure delivery.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110106"},"PeriodicalIF":3.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282672","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":"Increased susceptibility of human limbal aniridia fibroblasts to oxidative stress","authors":"Simon Trusen ,&nbsp;Julia Sarah Alexandra Zimmermann ,&nbsp;Fabian Norbert Fries ,&nbsp;Zhen Li ,&nbsp;Ning Chai ,&nbsp;Berthold Seitz ,&nbsp;Shweta Suiwal ,&nbsp;Maryam Amini ,&nbsp;Nóra Szentmáry ,&nbsp;Tanja Stachon","doi":"10.1016/j.exer.2024.110105","DOIUrl":"10.1016/j.exer.2024.110105","url":null,"abstract":"<div><div>Aniridia-associated keratopathy originates from a haploinsufficiency of the transcription factor PAX6 (PAX6^+/−). In the corneal epithelium of PAX6^+/− mice, a significant increase in oxidized proteins was observed, accompanied by impaired compensation for elevated oxidative stress (OS). The extent to which limbal fibroblast cells (LFCs) are affected by an increased susceptibility to OS in cases of congenital aniridia (AN) has not been determined, yet. Our aim was to examine the impact of OS on antioxidant enzyme expression in normal and AN-LFCs. Following isolation and culture of primary LFCs (n = 8) and AN-LFCs (n = 8), cells were treated with cobalt chloride for 48 h to chemically induce hypoxic conditions and OS. Subsequently, HIF-1α/-2α, PHD1/2, Nrf2, CAT, SOD1, PRDX6, and GPX1 gene expression was examined by qPCR. SOD1, PRDX6, and GPX1 protein levels were assessed from the cell lysate by Western blot. The induction of hypoxia led to reduced HIF-1α gene expression in both fibroblast groups (<em>p</em><em>≤</em> <em>0.</em>008), while the decrease in PHD1 was limited to AN-LFCs (<em>p</em> = 0.0007). On the other hand, under hypoxic conditions, PHD2 showed higher mRNA expression in AN-LFCs compared to normal LFCs (<em>p</em> = 0.013). As a result of OS, the mRNA levels of Nrf2 (<em>p</em><em>&lt;</em>0.0001) and the antioxidant enzymes CAT (<em>p</em> = 0.005), SOD1 (<em>p</em> = 0.005), GPX1 (<em>p</em> = 0.002) decreased in AN-LFCs. This was accompanied by an increased protein expression of SOD1 (<em>p</em> = 0.019) and PRDX6 (<em>p</em><em>=</em>0.0009). In the normal LFC group, the induced extent of OS had no impact on the gene (<em>p</em><em>≥</em>0.151) and protein expression (<em>p</em> ≥ 0.629) of antioxidant enzymes, except for the GPX1 mRNA level (<em>p</em> = 0.027). AN-LFCs exhibit higher susceptibility to OS than normal LFCs. Therefore, in AN-LFCs, there are sustained alterations in gene and protein expression of antioxidative enzymes even after 48 h of CoCl₂ treatment.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110105"},"PeriodicalIF":3.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282675","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":"Moringa oleifera hydroalcoholic leaf extracts mitigate valproate-induced oxidative status in the extraorbital lacrimal gland in a rat model","authors":"Burcin Alev-Tuzuner ,&nbsp;Sehkar Oktay ,&nbsp;Eda Cergel ,&nbsp;Gulsum Elik ,&nbsp;Umar Faruk Magaji ,&nbsp;Ozlem Sacan ,&nbsp;Refiye Yanardag ,&nbsp;Aysen Yarat","doi":"10.1016/j.exer.2024.110104","DOIUrl":"10.1016/j.exer.2024.110104","url":null,"abstract":"<div><div>Dysfunction of the extraorbital lacrimal gland (ELG) can lead to loss of vision due to damage to the epithelium of cornea. The broad-spectrum anti-epileptic drug sodium valproate (SV) has numerous side effects. <em>Moringa oleifera (M.oleifera)</em> is widely used as a food and in folk medicine. The effects of orally administered SV and <em>M. oleifera</em> hydroalcoholic leaf extract on rat ELG were investigated in this study by analysing both antioxidant and oxidant parameters. Additionally, boron level and tissue factor (TF) activity were determined. Protein changes were detected by sodium dodecyl sulfate gel electrophoresis (SDS-PAGE). Significantly lower values of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and total antioxidant status (TAS) were observed in the SV group compared to the control group. Treatment with Moringa extract significantly increased SOD, CAT and TAS values in the Moringa given SV group (SVM). While no significant differences were observed between the sialic acid values of the groups, lipid peroxidation (LPO), nitric oxide (NO) and total oxidant status (TOS) values were significantly elevated in the SV group compared to the control group. Due to the effect of Moringa extract, LPO, NO and TOS levels were significantly decreased in the SVM group compared to the SV group. TF activity was not meaningfully altered between groups. Compared to control rats, oxidative stress index (OSI) level significantly increased, whereas the boron level decreased in the SV group. Moringa extract treatment noticeably reduced OSI in the SVM group. According to SDS-PAGE, decreases in the density of protein bands with molecular weights of 51, 83, and 90 kDa were observed in SV given rats compared to the other groups. These decreases were reversed by the administration of Moringa extract. Moringa extract has shown protective properties arising from antioxidant potential, especially with its very low OSI value. Individuals undergoing SV treatment and having ELG complications might consider using Moringa extract to mitigate valproate induced damage.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110104"},"PeriodicalIF":3.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282676","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 genotype-phenotype study in 203 individuals with retinoblastoma","authors":"Yoo Jin Lee ,&nbsp;Jeong Hun Kim ,&nbsp;Sang-Yeon Lee ,&nbsp;Dong Hyun Jo","doi":"10.1016/j.exer.2024.110102","DOIUrl":"10.1016/j.exer.2024.110102","url":null,"abstract":"<div><p>Retinoblastoma is the most common intraocular tumor in children and is caused by biallelic inactivation of the <em>RB1</em> gene. The identification of <em>RB1</em> germline variants in patients with retinoblastoma and their families is critical for early diagnosis and prevention. In this study, genetic testing was conducted on the genomic DNA of 203 patients with retinoblastoma using a combined approach of direct sequencing and multiplex ligation-dependent probe amplification (MLPA) assays for genotype-phenotype correlation studies. Sixty-five germline variants were identified in 80 of the 203 patients, with 67 bilateral and 13 unilateral retinoblastoma cases. The variant detection rates in the bilateral and unilateral cases were 88% and 10%, respectively. Eighteen novel variants were identified. Variants were classified according to their presence, mutation pattern, location, molecular consequences, and pathogenicity. Subsequently, the genotypes and phenotypes of the 203 patients were evaluated. Variants were associated with age at diagnosis (<em>p</em> &lt; 0.001), laterality (<em>p</em> &lt; 0.001), and tumor size (<em>p</em> = 0.010). The molecular consequences of the variants were related to laterality (<em>p</em> &lt; 0.001) and tumor size (<em>p</em> = 0.001). The pathogenicity of the variants was associated with age at diagnosis (<em>p</em> = 0.001), laterality (<em>p</em> = 0.0212), treatment response (<em>p</em> = 0.0470), and tumor size (<em>p</em> = 0.002). These results suggest that patient phenotypes are associated with the inherent characteristics of germline <em>RB1</em> variants. These findings indicate the potential application of genetic testing results in clinical practice.</p></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110102"},"PeriodicalIF":3.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142270643","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":"Comparative analysis of In vivo endothelial cell translatomes across central nervous system vascular beds","authors":"Ana J. Chucair-Elliott ,&nbsp;Kevin Pham ,&nbsp;Audrey C.A. Cleuren ,&nbsp;Christopher M. Schafer ,&nbsp;Courtney T. Griffin ,&nbsp;Sarah R. Ocanas ,&nbsp;Willard M. Freeman ,&nbsp;Michael H. Elliott","doi":"10.1016/j.exer.2024.110101","DOIUrl":"10.1016/j.exer.2024.110101","url":null,"abstract":"<div><p>Endothelial cells (ECs) display organ- and tissue-specific heterogeneity. In the eye, the retinal and choroidal vascular beds are distinct networks with different molecular and morphological properties that serve location-specific functions, i.e., the former maintaining a tight barrier and the latter, a permeable fenestrated vasculature. Given that retinal health critically relies on the function of these vascular beds and that their dysfunction is implicated in a variety of retinal diseases, a molecular understanding of both physiological and pathophysiological characteristics of these distinct vasculatures is critical. Given their interspersed anatomic distribution among parenchymal cells, the study of EC gene expression, <em>in vivo</em>, has been hampered by the challenge of isolating pure populations of ocular ECs in sufficient quantities for large-scale transcriptomics. To address this challenge, we present a methodological and analytical workflow to facilitate inter-tissue comparisons of the <em>in vivo</em> EC translatome isolated from choroid, retina, and brain using the Cre-inducible NuTRAP flox construct and two widely-used endothelial Cre mouse lines: constitutive Tie2-Cre and tamoxifen-inducible Cdh5-CreERT2. For each Cre line, inter-tissue comparison of TRAP-RNAseq enrichment (TRAP-isolated translatome vs input transcriptome) showed tissue-specific gene enrichments with differential pathway representation. For each mouse model, inter-tissue comparison of the EC translatome (choroid vs brain, choroid vs retina, and brain vs retina) showed over 50% overlap of differentially expressed genes (DEGs) between the three paired comparisons, with differential pathway representation for each tissue. Pathway analysis of DEGs in the Cdh5-NuTRAP vs Tie2-NuTRAP comparison for retina, choroid, and brain predicted inhibition of processes related to myeloid cell function and activation, consistent with more specific targeting of ECs in the Cdh5-NuTRAP than in the Tie2-NuTRAP model which also targets hematopoietic progenitors giving rise to immune cells. Indeed, while TRAP enriches for EC transcripts in both models, myeloid transcripts were also captured in the Tie2-NuTRAP model which was confirmed using cell sorting. We suggest experimental/analytical considerations should be taken when selecting Cre-lines to target ECs.</p></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110101"},"PeriodicalIF":3.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014483524003233/pdfft?md5=e65d6a1b03aa1ed7f8ca3ab69fa4bbe9&pid=1-s2.0-S0014483524003233-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142270645","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":"Estrogen, via ESR2 receptor, prevents oxidative stress-induced Müller cell death and stimulates FGF2 production independently of NRF2, attenuating retinal degeneration","authors":"Hiroshi Tawarayama ,&nbsp;Keiko Uchida ,&nbsp;Hirokazu Hasegawa ,&nbsp;Masaaki Yoshida ,&nbsp;Maki Inoue-Yanagimachi ,&nbsp;Wataru Sato ,&nbsp;Noriko Himori ,&nbsp;Masayuki Yamamoto ,&nbsp;Toru Nakazawa","doi":"10.1016/j.exer.2024.110103","DOIUrl":"10.1016/j.exer.2024.110103","url":null,"abstract":"<div><div>In this study, we aimed to investigate the effects of the deficient antioxidative gene, nuclear factor-erythroid 2-related factor 2 (<em>Nrf2</em>), on 17β-estradiol (E₂)-mediated oxidative stress response, with a specific focus on growth factor production and cell death in Müller cells and retinal tissue. Administration of hydrogen peroxide (H₂O₂) reduced the viability of Müller cells derived from <em>Nrf2</em> wild-type (WT) and knockout (KO) mice. However, this effect was more significant in the KO cells than in the WT cells. Pretreatment with E₂ inhibited H₂O₂-induced cell death in both <em>Nrf2</em> WT and KO Müller cell genotypes. Small interfering RNA-mediated gene silencing of estrogen receptor 2 (<em>Esr2</em>) attenuated the cell survival-promoting activity of E₂ in <em>Nrf2</em> KO Müller cells, while other identified estrogen receptors, <em>Esr1</em> or G protein-coupled estrogen receptor 1 (<em>Gper1</em>), had no effect. Western blotting revealed higher ESR2 expression levels in <em>Nrf2</em> KO cells than in WT Müller cells. Conditioned media from E₂-and H₂O₂-treated <em>Nrf2</em> WT or KO Müller cells enhanced the dissociated retinal cell viability compared with H₂O₂-treated cells. Both quantitative reverse-transcription polymerase chain reaction assay (qRT-PCR) and enzyme-linked immunosorbent assay exhibited a significant increase in fibroblast growth factor 2 (FGF2) expression levels in E₂-and H₂O₂-treated <em>Nrf2</em> WT and KO Müller cells compared to those in E₂-treated cells. <em>In vivo,</em> administration of N-methyl-N-nitrosourea (MNU) reduced the thickness and cell density of the outer nuclear layer (ONL) in <em>Nrf2</em> KO mice and enhanced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells in the ONL. However, E₂ administration attenuated these defects in MNU-treated mice. Concomitant administration of MNU and E₂ enhanced FGF2 protein levels in retinal lysates of <em>Nrf2</em> KO mice. In conclusion, E₂ demonstrated a significant role in preventing oxidative stress-induced retinal cell death by stimulating FGF2 production in Müller cells, independent of the <em>Nrf2</em> gene. Based on these findings, we anticipate that exogenous administration of estrogens or ESR2-selective agonists could aid in treating patients with oxidative stress-related retinal degenerative diseases such as age-related macular degeneration and retinitis pigmentosa.</div></div>","PeriodicalId":12177,"journal":{"name":"Experimental eye research","volume":"248 ","pages":"Article 110103"},"PeriodicalIF":3.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282673","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}