RESUMO
Increased cellular senescence burden contributes in part to age-related organ dysfunction and pathologies. In our study, using mouse models of natural aging, we observed structural and functional decline in the aged retina, which was accompanied by the accumulation of senescent cells and senescence-associated secretory phenotype factors. We further validated the senolytic and senomorphic properties of procyanidin C1 (PCC1) both in vitro and in vivo, the long-term treatment of which ameliorated age-related retinal impairment. Through high-throughput single-cell RNA sequencing (scRNA-seq), we comprehensively characterized the retinal landscape after PCC1 administration and deciphered the molecular basis underlying the senescence burden increment and elimination. By exploring the scRNA-seq database of age-related retinal disorders, we revealed the role of cellular senescence and the therapeutic potential of PCC1 in these pathologies. Overall, these results indicate the therapeutic effects of PCC1 on the aged retina and its potential use for treating age-related retinal disorders.
Assuntos
Envelhecimento , Catequina , Senescência Celular , Proantocianidinas , Retina , Animais , Retina/metabolismo , Retina/efeitos dos fármacos , Camundongos , Proantocianidinas/farmacologia , Proantocianidinas/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Senescência Celular/efeitos dos fármacos , Catequina/farmacologia , Catequina/metabolismo , Catequina/química , Biflavonoides/farmacologia , Senoterapia/farmacologia , Camundongos Endogâmicos C57BL , Humanos , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/metabolismo , Doenças Retinianas/patologiaRESUMO
Given the widespread application of glucocorticoids in ophthalmology, the associated elevation of intraocular pressure (IOP) has long been a vexing concern for clinicians, yet the underlying mechanisms remain inconclusive. Much of the discussion focuses on the extracellular matrix (ECM) of trabecular meshwork (TM). It is widely agreed that glucocorticoids impact the expression of matrix metalloproteinases (MMPs), leading to ECM deposition. Since Zn2+ is vital for MMPs, we explored its role in ECM alterations induced by dexamethasone (DEX). Our study revealed that in human TM cells treated with DEX, the level of intracellular Zn2+ significantly decreased, accompanied by impaired extracellular Zn2+ uptake. This correlated with changes in several Zrt-, Irt-related proteins (ZIPs) and metallothionein. ZIP8 knockdown impaired extracellular Zn2+ uptake, but Zn2+ chelation did not affect ZIP8 expression. Resembling DEX's effects, chelation of Zn2+ decreased MMP2 expression, increased the deposition of ECM proteins, and induced structural disarray of ECM. Conversely, supplementation of exogenous Zn2+ in DEX-treated cells ameliorated these outcomes. Notably, dietary zinc supplementation in mice significantly reduced DEX-induced IOP elevation and collagen content in TM, thereby rescuing the visual function of the mice. These findings underscore zinc's pivotal role in ECM regulation, providing a novel perspective on the pathogenesis of glaucoma.NEW & NOTEWORTHY Our study explores zinc's pivotal role in mitigating extracellular matrix dysregulation in the trabecular meshwork and glucocorticoid-induced ocular hypertension. We found that in human trabecular meshwork cells treated with dexamethasone, intracellular Zn2+ significantly decreased, accompanied by impaired extracellular Zn2+ uptake. Zinc supplementation rescues visual function by modulating extracellular matrix proteins and lowering intraocular pressure, offering a direction for further exploration in glaucoma management.
Assuntos
Glaucoma , Malha Trabecular , Camundongos , Humanos , Animais , Malha Trabecular/metabolismo , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Glaucoma/patologia , Pressão Intraocular , Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Metaloproteinases da Matriz/metabolismo , Zinco/metabolismo , Células CultivadasRESUMO
Glaucoma is the leading cause of irreversible blindness worldwide. Previous observational studies have suggested a relationship between central corneal thickness (CCT) and glaucoma; however, the results are inconsistent. This study aimed to investigate whether CCT is associated with a risk for developing open-angle glaucoma (OAG). We employed two-sample Mendelian randomization to assess the relationship between CCT and OAG, namely, primary open-angle glaucoma (POAG) and suspected glaucoma. Genetic instruments composed of variants associated with CCT at genome-wide significance (P < 5 × 10-8) were obtained from published genome-wide association studies from Iglesias et al. for discovery and Bonnemaijer et al. for replication. Summary-level statistics for these instruments for the OAG were obtained from the FinnGen Project (Release 10). Inverse-variance-weighted regression of genetic susceptibility predicted that increased CCT was positively associated with an increased risk for POAG (odds ratio [OR], 1.005; 95% confidence interval [CI], 1.002-1.008; P = 0.001) and suspected glaucoma (OR, 1.006; 95% CI, 1.003-1.009; P < 0.001). In the replication sample of CCT, increased CCT was also positively associated with an increased risk for POAG (OR, 1.004; 95% CI, 1.000-1.008; P = 0.029) and suspected glaucoma (OR, 1.005; 95% CI, 1.001-1.008; P = 0.013). We found genetic evidence supporting a potential causal association between increased CCT and the risk of POAG and suspected glaucoma in the European population. This findings indicates the clinical significance of CCT in the diagnosis and treatment of glaucoma. Further studies are needed to elucidate the underlying mechanisms of this causal relationship.
Assuntos
Córnea , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto , Análise da Randomização Mendeliana , Glaucoma de Ângulo Aberto/genética , Humanos , Córnea/patologia , Polimorfismo de Nucleotídeo Único , Pressão Intraocular/fisiologia , Fatores de Risco , Predisposição Genética para Doença , Paquimetria Corneana , Masculino , FemininoRESUMO
The purpose of the study was to determine the associations of self-perception, motor skills, and clinical features of young school-age children with glaucoma (CG). This is a cross-sectional observational study. Children from preschool to second grade, including CG (N = 19), children with amblyopia (CA, N = 28), and controls (N = 32), completed the Manual Dexterity and Aiming and Catching Scales of the Movement Assessment Battery for Children-2nd edition (MABC-2), including Manual Dexterity, Aiming and Catching, and Balance. CG, CA, and their parent completed the Pictorial Scale of Perceived Competence and Social Acceptance for Young Children, respectively, assessing the child's cognitive competence, peer acceptance, physical competence, and maternal acceptance. The Kruskal-Wallis H test and Bonferroni post hoc test compared motor skills among groups. Spearman's correlation analysis evaluated the correlations between motor skills, self-perception, and clinical features. The CG reported lower peer acceptance than CA (P = 0.040), and the parents of CG reported lower cognitive competence than CG reported (P = 0.046). Compared with controls, CG had worse performance of Aiming and Catching, and Balance (P = 0.018 and P = 0.001), and CA had worse performance of Balance (P = 0.009). The motor skills were comparable between CG and CA. For CG, older age correlated with worse competence of Aiming and Catching (r = - 0.620, P = 0.005), better best-corrected visual acuity of better-seeing eye correlated with higher competence of Manual Dexterity and Balance (r = - 0.494, P = 0.032, and r = - 0.516, P = 0.024), and longer duration of glaucoma correlated with worse competence of Manual Dexterity (r = - 0.487, P = 0.034). CONCLUSION: Glaucoma and amblyopia have significant negative impacts on children's daily motor skills. The acuity of a better-seeing eye is an important factor influencing motor movement. TRIAL REGISTRATION: ClinicalTrials.gov identifier, ChiCTR2100050415. WHAT IS KNOWN: ⢠The state of mental health in early childhood influences the development of their future personality and physical development. The prognosis and management of glaucoma may seriously impair the mental health development of the affected children. However, the exploration of psychological aspects and motor movement of childhood glaucoma was limited. WHAT IS NEW: ⢠Children with glaucoma have impaired motor skills and self-perception development, especially in terms of peer socialization.
Assuntos
Ambliopia , Glaucoma , Percepção de Movimento , Criança , Humanos , Pré-Escolar , Ambliopia/psicologia , Estudos Transversais , Destreza Motora , Autoimagem , Glaucoma/diagnósticoRESUMO
Retinopathy of prematurity (ROP) is an important cause of avoidable childhood visual impairment, and the increase in number and survival of premature infants may inflate its burden globally. We aimed to comprehensively assess the trends and inequalities in the burden of ROP-related visual impairment and to identify improvement gaps to facilitate appropriate actions in neonatal care systems. We obtained ROP data from the Global Burden of Disease 2019 study. We employed joinpoint regression analysis to assess the trends of the burden of ROP-related visual impairment, measured by age-standardised prevalence rates, health equity analysis methods to evaluate cross-country burden inequalities, and data envelopment and stochastic frontier analyses to identify improvement gaps based on the development status, i.e., sociodemographic index (SDI). Between 1990 and 2019, the age-standardised prevalence rates of ROP-related visual impairment significantly increased worldwide (average annual percentage change: 0.23 [95% confidence interval, 0.21-0.26] among males and 0.26 [0.25-0.27] among females), primarily in developed regions. Although significant SDI-related cross-country inequalities were identified, these reduced over time (slope index of inequality: -57.74 [-66.22 to -49.25] in 1990 to -29.68 [-38.39 to -20.97] in 2019; health concentration index: -0.11 [-0.13 to -0.09] in 1990 to -0.07 [-0.09 to -0.06] in 2019). Notably, some less-developed countries exhibited superior performance despite limited resources, whereas others with a higher SDI delivered lagging performance. Conclusion: The global burden of ROP-related visual impairment has steadily increased between 1990 and 2019, with disproportionate burden concentration among less-developed countries, requiring appropriate preventive and intervention measures. What is Known: ⢠Retinopathy of prematurity (ROP) is an important cause of avoidable childhood visual impairment. ⢠The prevalence of ROP is anticipated to increase due to the growing number of extremely premature infants. What is New: ⢠The prevalence of ROP-related visual impairment has increased worldwide, primarily in developed regions, with declining but persisting cross-country inequalities. ⢠The increasing burden of ROP-related visual impairment should be considered as part of global and national health agendas, requiring interventions with proven efficacy.
Assuntos
Doenças do Recém-Nascido , Retinopatia da Prematuridade , Recém-Nascido , Masculino , Lactente , Feminino , Humanos , Criança , Retinopatia da Prematuridade/complicações , Retinopatia da Prematuridade/epidemiologia , Países em Desenvolvimento , Lactente Extremamente Prematuro , Prevalência , Transtornos da Visão/epidemiologia , Transtornos da Visão/etiologia , Idade GestacionalRESUMO
BACKGROUND: The presence of sensory impairment among older age cohorts exerts a significant impact on both individuals and society generally. Although the impact of dietary patterns on health is vital across all stages of life, there still a paucity of comprehensive research on the association between dietary variety and sensory impairments. OBJECTIVE: To investigate the potential relationship between dietary diversity and the prevalence of visual and hearing impairment or dual sensory impairments (visual and hearing impairment) among the oldest old population. METHODS: This is a cross-sectional study relied on data obtained from the 2018 survey conducted by the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Subjects aged 80 and older with complete vision and hearing data were included in the study. Multivariate logistic regression models were developed to examine the association between dietary components and visual and hearing impairment while controlling for age, gender, socioeconomic demographic factors, living habits, other food habits, and general health status. RESULTS: The study included 10,093 participants, with an average age of 92.29 ± 7.75 years. Vision and hearing function were assessed based on the ability to distinguish the direction of the break in the circle and the requirement for hearing aids, respectively. Upon controlling for confounding variables, individuals with a greater Dietary Diversity Score (DDS, the number of food groups, range: 1-11) had a reduced likelihood of experiencing visual impairment (odds ratio [OR] = 0.944, 95% confidence interval [CI], 0.915-0.974) and dual sensory impairment (OR = 0.930, 95% CI, 0.905-0.955). In comparison to the low dietary variety group (insufficient dietary diversity, DDS < 4), the high dietary diversity group (sufficient dietary diversity, DDS ≥ 4) exhibited a decreased risk of visual impairment (OR = 0.820, 95% CI, 0.713-0.944) and dual sensory impairment (OR = 0.751, 95% CI, 0.667-0.846). However, no statistically significant correlation was observed between dietary diversity and the presence of only hearing impairment (OR = 0.924, 95% CI, 0.815-1.047) (P < 0.05). CONCLUSIONS AND IMPLICATIONS: The synthesis of research findings suggests that following diverse dietary patterns and healthy nutritional practices may be an effective and affordable way to prevent age-related decline in visual impairment and dual sensory impairment.
Assuntos
Dieta , Perda Auditiva , Transtornos da Visão , Humanos , Feminino , Masculino , China/epidemiologia , Estudos Transversais , Perda Auditiva/epidemiologia , Transtornos da Visão/epidemiologia , Idoso de 80 Anos ou mais , Estudos Longitudinais , Dieta/estatística & dados numéricos , Longevidade , Prevalência , População do Leste AsiáticoRESUMO
OBJECTIVE: This study aimed to profile ocular biometry parameters and predictors of spherical equivalent refraction (SER) among children with moderate to high hyperopia. METHODS: Individuals <18 years of age with moderate to high hyperopia were enrolled from November 2015 to November 2021. Participants underwent a series of comprehensive ocular examinations, and were classified as having low hyperopia, that is, SER +0.5 to < +2.0 D or moderate to high hyperopia, that is, SER ≥ +2.0 D. RESULTS: A total of 459 and 230 eyes with moderate to high hyperopia and low hyperopia, respectively, were included. Moderate to high hyperopic eyes had a shorter axial length, stronger lens power (24.78 ± 5.47 D vs. 18.74 ± 1.63 D, p < 0.001) and weaker corneal power (42.82 ± 1.75 D vs. 43.31 ± 1.55 D, p < 0.001) than low hyperopic eyes. When comparing values before and after 5 years of age, both lens power and axial length differed significantly in the moderate to high hyperopia group, whereas in the low hyperopia group, they only differed significantly after 9 years of age. Lens power was negatively associated with AL in eyes with axial lengths between 20 and 22 mm. A multiple linear regression model which included axial length (standardised ß = -0.80, p < 0.001), corneal power (standardised ß = -0.47, p < 0.001) and lens power (standardised ß = 0.23, p < 0.001) explained 81.2% of the variance in SER. CONCLUSIONS: Differences in lens power and axial length in moderate to high hyperopic eyes became significantly smaller after 5 years of age, at least 4 years earlier than for the low hyperopia. Lens power could offset the axial elongation in participants with axial lengths between 20 and 22 mm, suggesting that children with moderate to high hyperopia might have different ocular growth patterns. Axial length, corneal power and lens power were the main predictors of SER in moderate to high hyperopia.
Assuntos
Oftalmopatias Hereditárias , Hiperopia , Cristalino , Erros de Refração , Criança , Humanos , Pré-Escolar , Refração Ocular , Córnea , BiometriaRESUMO
INTRODUCTION: Non-ophthalmologists often lack sufficient operational training to use a direct ophthalmoscope proficiently, resulting in a global deficit of basic ophthalmological skills among general practitioners. This deficiency hampers the timely diagnosis, referral, and intervention of patients. Consequently, the optimization of teaching tools and methods to enhance teaching efficiency is imperative. This study explores the effectiveness of the Eyesi Direct Ophthalmoscope Simulator (Eyesi) as an innovative tool for fundus examination training. METHODS: Medical undergraduates were randomly assigned to Group A or B (n = 168). All participants completed a pre-training questionnaire. Group A received Eyesi training, while Group B underwent traditional direct ophthalmoscope (TDO) training. Subsequently, participants answered questionnaires relevant to their respective training methods. Both groups exchanged training tools and completed a summary questionnaire. RESULTS: After training, 54.17% of participants believed that images presented by the Eyesi were consistent with the real fundus. Group A scored significantly higher than Group B in fundus structure recognition and self-confidence in examination. The degree of mastery over fundus theory score increased from 6.10 ± 0.13 to 7.74 ± 0.16 (P < 0.001) in Group A, but Group B did not demonstrate a significant difference. We also compared undergraduates' tendencies for different learning purposes, 75.59% of participants preferred the Eyesi to TDO as a training tool, and 88.41% of participants were receptive to introducing the Eyesi in training. CONCLUSION: According to subjective participant feedback, Eyesi outperformed TDO in fundus observation, operational practice, and theoretical learning. It effectively equips undergraduates with fundus examination skills, potentially promoting the use of direct ophthalmoscopes in primary medical institutions.
Assuntos
Competência Clínica , Educação de Graduação em Medicina , Oftalmoscópios , Treinamento por Simulação , Humanos , Educação de Graduação em Medicina/métodos , Masculino , Feminino , Inquéritos e Questionários , Oftalmologia/educação , Adulto Jovem , Estudantes de Medicina , Avaliação Educacional , Oftalmoscopia/métodosRESUMO
BACKGROUND: Neuroinflammation and mitochondrial dysfunction play crucial roles in retinal ischemia and reperfusion (IR) injury. Recent studies have identified mitochondrial function as a promising target for immunomodulation. Empagliflozin (EMPA), an anti-diabetic drug, has exhibited great potential as both an anti-inflammatory agent and a protector of mitochondrial health. This study aimed to assess the therapeutic efficacy of EMPA in retinal IR injury. METHODS: To evaluate the protective effects of EMPA, the drug was injected into the vitreous body of mice post-retinal IR. Single-cell RNA sequencing (scRNA-seq) analysis was conducted to uncover the underlying mechanisms, and the results were further validated through in vivo and in vitro experiments. RESULTS: EMPA effectively protected retinal ganglion cells (RGCs) from IR injury by attenuating local retinal inflammation. The scRNA-seq analysis revealed that EMPA downregulated the nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) signaling pathway and restored mitochondrial dynamics by upregulating the expression of mitochondrial fusion-related genes, Mitofusin 1 (Mfn1) and optic atrophy 1 (Opa1). These findings were further corroborated by Western blotting. In vitro experiments provided additional insights, demonstrating that EMPA suppressed lipopolysaccharide (LPS)-induced cell inflammation and NLRP3 inflammasome activation. Moreover, EMPA enhanced mitochondrial fusion, neutralized mitochondrial reactive oxygen species (mtROS), and restored mitochondrial membrane potential (MMP) in BV2 microglia. Notably, genetic ablation of Mfn1 or Opa1 abolished the anti-inflammatory effects of EMPA. CONCLUSIONS: Our findings highlight the positive contribution of Mfn1 and Opa1 to the anti-inflammatory therapeutic effect of EMPA. By restoring mitochondrial dynamics, EMPA effectively mitigates microglia-mediated neuroinflammation and prevents RGC loss in retinal IR injury.
Assuntos
Proteína 3 que Contém Domínio de Pirina da Família NLR , Traumatismo por Reperfusão , Camundongos , Animais , Doenças Neuroinflamatórias , Microglia/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Isquemia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , GTP Fosfo-HidrolasesRESUMO
BACKGROUND: Retinal ischemia-reperfusion (RIR) injury refers to an obstruction in the retinal blood supply followed by reperfusion. Although the molecular mechanism underlying the ischemic pathological cascade is not fully understood, neuroinflammation plays a crucial part in the mortality of retinal ganglion cells. METHODS: Single-cell RNA sequencing (scRNA-seq), molecular docking, and transfection assay were used to explore the effectiveness and pathogenesis of N,N-dimethyl-3ß-hydroxycholenamide (DMHCA)-treated mice with RIR injury and DMHCA-treated microglia after oxygen and glucose deprivation/reoxygenation (OGD/R). RESULTS: DMHCA could suppress inflammatory gene expression and attenuate neuronal lesions, restoring the retinal structure in vivo. Using scRNA-seq on the retina of DMHCA-treated mice, we provided novel insights into RIR immunity and demonstrated nerve injury-induced protein 1 (Ninjurin1/Ninj 1) as a promising treatment target for RIR. Moreover, the expression of Ninj1, which was increased in RIR injury and OGD/R-treated microglia, was downregulated in the DMHCA-treated group. DMHCA suppressed the activation of the nuclear factor kappa B (NF-κB) pathways induced by OGD/R, which was undermined by the NF-κB pathway agonist betulinic acid. Overexpressed Ninj1 reversed the anti-inflammatory and anti-apoptotic function of DMHCA. Molecular docking indicated that for Ninj1, DMHCA had a low binding energy of - 6.6 kcal/mol, suggesting highly stable binding. CONCLUSION: Ninj1 may play a pivotal role in microglia-mediated inflammation, while DMHCA could be a potential treatment strategy against RIR injury.
Assuntos
NF-kappa B , Traumatismo por Reperfusão , Camundongos , Animais , NF-kappa B/metabolismo , Transdução de Sinais , Simulação de Acoplamento Molecular , Oxigênio , Células Ganglionares da Retina/patologia , Traumatismo por Reperfusão/metabolismo , Inflamação/tratamento farmacológico , Fatores de Crescimento Neural , Moléculas de Adesão Celular NeuronaisRESUMO
N6-methyladenosine (m6A) modification is one of the most common types of methylation modifications in eukaryotic mRNA. However, its role in the pathogenesis of pseudoexfoliation glaucoma (PXG) has not yet been reported. To enhance understanding in this regard, we assessed the m6A methylome in the aqueous humor of patients with PXG. MeRIP-Seq and RNA-Seq analyses were performed to compare the m6A methylomes and gene expression profiles of the aqueous humor of patients with PXG with those of patients with age-related cataract (ARC). Colorimetric m6A quantification was performed to detect global m6A levels. Quantitative reverse transcription PCR confirmed the expression of m6A-related enzymes and mRNAs in both groups. Results showed significantly higher aqueous humor m6A levels in the PXG group than in the ARC group. Five m6A-related enzymes, including METTL3, YTHDC2, HNRNPA2B1, HNRNPC, and LRPPRC, were significantly up-regulated in PXG specimens. We also observed 9728 m6A-modified peaks related to 6126 gene transcripts in the PXG group, with more than 250 genes containing one m6A peak (hypomethylated or hypermethylated). The distribution of the m6A peaks was enriched in coding sequences and 3'-untranslated regions for both groups. GGAC motif structures were also significantly enriched. Bioinformatics analysis further revealed that m6A plays a critical role in extracellular matrix formation and histone deacetylation. Additionally, MMP14, ADAMTSL1, FN1, and HDAC1 showed significant changes in m6A methylation and mRNA expression in the PXG group. Therefore, m6A methylation may regulate extracellular matrix composition in PXG and METTL3 may be a pivotal regulator of this process. In the future, it would be necessary to investigate MMP14, ADAMTSL1, FN1, and HDAC1, which are potential target genes.
Assuntos
Catarata , Síndrome de Exfoliação , Glaucoma , Humanos , Transcriptoma , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Metilação , Humor Aquoso/metabolismo , Síndrome de Exfoliação/metabolismo , Catarata/genética , Catarata/metabolismo , Glaucoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Metiltransferases/genéticaRESUMO
PURPOSE: To characterize the distribution of refractive and ocular biometry parameters and analyze the effect factors of the refractive status in cynomolgus monkey colonies. METHODS: A Population-based cross-sectional study was conducted in adult cynomolgus macaque colonies. Animals were anesthetized with Zoletil 50. Intraocular pressure was measured using the Icare tonometer. Cycloplegic refraction (three drops of 1% tropicamide) and corneal radius of curvature (CRC) were measured using an autorefractor. The spherical equivalent (SE) was calculated. Biometric measurements, including the anterior chamber depth (ACD), lens thickness (LT), and axial length (AL), were obtained by A-scan ultrasonography. The AL-to-CR ratio (AL/CRC) was calculated. Central corneal thickness (CCT) and choroidal thickness (ChT) were measured using the Heidelberg Spectralis HRA OCT. Multiple regression analysis was performed to explore the association between refraction and ocular biometry. RESULTS: Among 263 cynomolgus monkeys (aged 5-26 years), which consisted of 520 eyes, 29.42% had hyperopia, 27.12% had emmetropia, 33.27% had mild-to-moderate myopia and 10.19% had high myopia. The mean SE was -1.27 ± 3.44 Diopters (D). The mean CRC, CCT, AL, and ChT was 5.70 ± 0.22 mm, 454.30 ± 32.40 µm, 18.76 ± 0.89 mm and 188.96 ± 38.19 µm, respectively. The LT was the thickest in the hyperopic eyes. CRC was the lowest, and CCT was the thickest in high myopic eyes. AL increased, while ChT decreased as SE decreased. For the SE variance, AL alone explained 40.5%; age, AL, and CRC together explained 57.5%. CONCLUSIONS: The refractive characteristics and biometry parameters of cynomolgus monkeys are highly comparable to those of humans. AL, CRC, and ChT showed the similar variation tendency in cynomolguses when compared to humans. Cynomolgus monkeys with naturally-occurring refractive errors may be a good animal model for refractive studies.
Assuntos
Hiperopia , Miopia , Adulto , Humanos , Animais , Macaca fascicularis , Estudos Transversais , Refração Ocular , Córnea/diagnóstico por imagem , BiometriaRESUMO
BACKGROUND: Age-related macular degeneration (AMD), characterized by the degeneration of retinal pigment epithelium (RPE) and photoreceptors, is the leading cause of irreversible vision impairment among the elderly. RPE senescence is an important contributor to AMD and has become a potential target for AMD therapy. HTRA1 is one of the most significant susceptibility genes in AMD, however, the correlation between HTRA1 and RPE senescence hasn't been investigated in the pathogenesis of AMD. METHODS: Western blotting and immunohistochemistry were used to detect HTRA1 expression in WT and transgenic mice overexpressing human HTRA1 (hHTRA1-Tg mice). RT-qPCR was used to detect the SASP in hHTRA1-Tg mice and ARPE-19 cells infected with HTRA1. TEM, SA-ß-gal was used to detect the mitochondria and senescence in RPE. Retinal degeneration of mice was investigated by fundus photography, FFA, SD-OCT and ERG. The RNA-Seq dataset of ARPE-19 cells treated with adv-HTRA1 versus adv-NC were analyzed. Mitochondrial respiration and glycolytic capacity in ARPE-19 cells were measured using OCR and ECAR. Hypoxia of ARPE-19 cells was detected using EF5 Hypoxia Detection Kit. KC7F2 was used to reduce the HIF1α expression both in vitro and in vivo. RESULTS: In our study, we found that RPE senescence was facilitated in hHTRA1-Tg mice. And hHTRA1-Tg mice became more susceptible to NaIO3 in the development of oxidative stress-induced retinal degeneration. Similarly, overexpression of HTRA1 in ARPE-19 cells accelerated cellular senescence. Our RNA-seq revealed an overlap between HTRA1-induced differentially expressed genes associated with aging and those involved in mitochondrial function and hypoxia response in ARPE-19 cells. HTRA1 overexpression in ARPE-19 cells impaired mitochondrial function and augmented glycolytic capacity. Importantly, upregulation of HTRA1 remarkably activated HIF-1 signaling, shown as promoting HIF1α expression which mainly located in the nucleus. HIF1α translation inhibitor KC7F2 significantly prevented HTRA1-induced cellular senescence in ARPE-19 cells, as well as improved the visual function in hHTRA1-Tg mice treated with NaIO3. CONCLUSIONS: Our study showed elevated HTRA1 contributes to the pathogenesis of AMD by promoting cellular senescence in RPE through damaging mitochondrial function and activating HIF-1 signaling. It also pointed out that inhibition of HIF-1 signaling might serve as a potential therapeutic strategy for AMD. Video Abstract.
Assuntos
Degeneração Retiniana , Idoso , Humanos , Animais , Camundongos , Epitélio Pigmentado da Retina , Transdução de Sinais , Mitocôndrias , Núcleo CelularRESUMO
Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Glaucoma de Ângulo Aberto/metabolismo , Proteínas de Homeodomínio/fisiologia , Células Ganglionares da Retina/fisiologia , Transativadores/fisiologia , Sequência de Aminoácidos , Animais , Estudos de Casos e Controles , Morte Celular , Linhagem Celular , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/patologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Regulação para CimaRESUMO
PURPOSE: To describe the normative profile of ophthalmic parameters in a healthy cynomolgus monkey colony, and to identify the characteristic of the spontaneous ocular disease non-human primates (NHP) models. METHODS: The NHP eye study was a cross-sectional on-site ocular examination with about 1,000 macaques held in Guangdong Province, southeastern China. The NHPs (Macaca fascicularis, cynomolgus) in this study included middle-aged individuals with a high prevalence of the ocular disease. The NHP eye study (NHPES) performed the information including systematic data and ocular data. Ocular examination included measurement of intraocular pressure (IOP), anterior segment- optical coherence tomography (OCT), slit-lamp examination, fundus photography, autorefraction, electroretinography, etc. Ocular diseases included measurement of refractive error, anisometropia, cataract, pterygium, etc. RESULTS: A total of 1148 subjects were included and completed the ocular examination. The average age was 16.4 ± 4.93 years. Compared to the male participants, the females in the NHPES had shorter axial length and the mean Average retinal nerve fiber layer (RNFL) thickness (except for the nasal quadrants). The mean IOP, anterior chamber depth, lens thickness, axial length, central corneal thickness, choroid thickness and other parameters were similar in each group. CONCLUSION: The NHPES is a unique and high-quality study, this is the first large macaque monkey cohort study focusing on ocular assessment along with comprehensive evaluation. Results from the NHPES will provide important information about the normal range of ophthalmic measurements in NHP.
Assuntos
Retina , Células Ganglionares da Retina , Feminino , Animais , Masculino , Macaca fascicularis , Estudos de Coortes , Estudos Transversais , Tomografia de Coerência Óptica/métodosRESUMO
INTRODUCTION: The primary aim of this study was to assess the longitudinal changes in retinal nerve fiber layer (RNFL) thickness and relative ONH parameters using spectral-domain optical coherence tomography (SD-OCT) in the living eyes of nonhuman primates with spontaneous glaucoma. METHODS: Totally 9 macaque subjects underwent a standard fundus photo and OCT examination, including 3 adult monkeys with stable elevated intraocular pressure (IOP) as the glaucoma suspect group and 6 normal IOP monkeys as the control group. Each eye of primates with IOP measurement was repeated three times. OCT measurements recorded RNFL, Bruch's membrane opening (BMO) minimum rim width (MRW). The follow-up scan of glaucomatous subjects was undergone in 10 months. RESULTS: The mean ages of glaucoma and healthy subjects are 19.33 ± 0.33 and 20.5 ± 1.46 years. Elevated IOP was achieved in three nonhuman primate eyes with an average increase of 10 mm Hg over the study period. Elevated IOP was associated with decreased RNFL thickness in all the regions and decreased RNFL phase retardation in the superior and inferior regions. When averaged over the entire retinal area, only the whole RNFL and temporal regions showed a significant decrease. The mean IPL thicknesses are 87.17 ± 2.15 µm in glaucomatous and 93.33 ± 1.51 µm in healthy eyes (p = 0.03). Lamina cribrosa parameters are measured from the OCT images and showed significant differences between glaucoma primates and normal primates. CONCLUSIONS: Of the measured parameters, decreased RNFL and MRW were correlated with glaucomatous damage. Natural glaucoma primate can be a natural glaucoma model which is closer to glaucoma in humans.
Assuntos
Glaucoma , Hipertensão Ocular , Disco Óptico , Adulto , Animais , Humanos , Adolescente , Adulto Jovem , Pressão Intraocular , Células Ganglionares da Retina , Glaucoma/diagnóstico , Hipertensão Ocular/diagnóstico , Tomografia de Coerência Óptica/métodos , PrimatasRESUMO
Amacrine cells are a diverse population of interneurons in the retina that play a critical role in extracting complex features of the visual world and shaping the receptive fields of retinal output neurons (ganglion cells). While much of the computational power of amacrine cells is believed to arise from the immense mutual interactions among amacrine cells themselves, the intricate circuitry and functions of amacrine-amacrine interactions are poorly understood in general. Here we report a specific interamacrine pathway from a small-field, glutamate-glycine dual-transmitter amacrine cell (vGluT3) to a wide-field polyaxonal amacrine cell (PAS4/5). Distal tips of vGluT3 cell dendrites made selective glycinergic (but not glutamatergic) synapses onto PAS4/5 dendrites to provide a center-inhibitory, surround-disinhibitory drive that helps PAS4/5 cells build a suppressed-by-contrast (sbc) receptive field, which is a unique and fundamental trigger feature previously found only in a small population of ganglion cells. The finding of this trigger feature in a circuit upstream to ganglion cells suggests that the sbc form of visual computation occurs more widely in the retina than previously believed and shapes visual processing in multiple downstream circuits in multiple ways. We also identified two different subpopulations of PAS4/5 cells based on their differential connectivity with vGluT3 cells and their distinct receptive-field and luminance-encoding characteristics. Moreover, our results revealed a form of crosstalk between small-field and large-field amacrine cell circuits, which provides a mechanism for feature-specific local (<150 µm) control of global (>1 mm) retinal activity.
Assuntos
Células Amácrinas/fisiologia , Fenômenos Eletrofisiológicos , Retina/fisiologia , Animais , Camundongos , Camundongos TransgênicosRESUMO
BACKGROUND: Patients with high myopia have an increased lifetime risk of complications. The prevalence patterns of high myopia in children and adolescents in southern China are unclear. Early identification of high-risk individuals is critical for reducing the occurrence and development of high myopia and avoiding the resulting complications. OBJECTIVE: This study aimed to determine the prevalence of high myopia in children and adolescents in southern China via real-world screening data and to predict its onset by studying the risk factors for high myopia based on machine learning. METHODS: This retrospective school-based study was conducted in 13 cities with different gross domestic products in southern China. Through data acquisition and filtering, we analyzed the prevalence of high myopia and its association with age, school stage, gross domestic product, and risk factors. A random forest algorithm was used to predict high myopia among schoolchildren and then assessed in an independent hold-out group. RESULTS: There were 1,285,609 participants (mean age 11.80, SD 3.07, range 6-20 years), of whom 658,516 (51.2%) were male. The overall prevalence of high myopia was 4.48% (2019), 4.88% (2020), and 3.17% (2021), with an increasing trend from the age of 11 to 17 years. The rates of high myopia increased from elementary schools to high schools but decreased at all school stages from 2019 to 2021. The coastal and southern cities had a higher proportion of high myopia, with an overall prevalence between 2.60% and 5.83%. Age, uncorrected distance visual acuity, and spherical equivalents were predictive factors for high myopia onset in schoolchildren. The random forest algorithm achieved a high accuracy of 0.948. The area under the receiver operator characteristic curve (AUC) was 0.975. Both indicated sufficient model efficacy. The performance of the model was validated in an external test with high accuracy (0.971) and a high AUC (0.957). CONCLUSIONS: High myopia had a high incidence in Guangdong Province. Its onset in children and adolescents was well predicted with the random forest algorithm. Efficient use of real-world data can contribute to the prevention and early diagnosis of high myopia.
Assuntos
Miopia , Humanos , Adolescente , Criança , Masculino , Adulto Jovem , Adulto , Feminino , Prevalência , Estudos Retrospectivos , China , CidadesRESUMO
BACKGROUND: National standardized training for resident doctors (STRD) in mainland China has been formally established since 2014 as a kind of postgraduate education. The purpose of this survey was to assess the satisfaction of the training residents in Guangdong Province on the ophthalmology STRD program after a duration of 5 years. METHOD: A 48-item survey was sent to all postgraduate ophthalmology residents from bases in Guangdong Province to inquire about their attitude towards the program. The survey contained questions about demographic and work-related information, job satisfaction, psychological resilience, and job performance. All responses were verified, and invalid questionnaires were excluded. Statistical analyses were performed using SPSS software version 22.0 (SPSS, Inc., Chicago, IL). Multiple logistic regression analysis was used to evaluate the factors (demographic information, working environment, clinical exposure, supervision and hands-on training opportunities, and involvement in academic activities) impacting the overall satisfaction. P < 0.05 was considered statistically significant. RESULTS: A total of 471/635 (74.17%) valid questionnaires were returned from all the STRD bases of Guangdong Province, which included 38 hospitals. 60.3% of the respondents reported overall satisfaction with their training. The satisfaction with operative teaching (60.7%) was slightly lower than the other settings of teaching experience (above 65%). Meanwhile, the satisfaction on different secessions of operative experience was all below 70%, of which in the areas of cornea and orbit were 55.42% and 57.53%, respectively. Some potential factors were found to affect general satisfaction, including the training grade, marriage, working time, income level, the doctor-patient relationship, family members working as doctors, the time proportion spent on writing medical documents during clinical work, and the frequency of attending academic meetings. Improvement was observed in both performing and reporting clinical examinations in the last year of training in comparison to the first year. Finally, 82.8% of the residents acknowledged this training was helpful for future clinical work. The first five career preferences for residents were cataract (67.1%), refractive surgery (42.3%), vitreo-retina (36.5%), optometry (28.7%), and oculoplastic (27.2%). CONCLUSION: Ophthalmology residents in Guangdong Province expressed comparable satisfaction with the STRD program. To further improve satisfaction, factors such as resident subsidy, harmonious marriage, the patient-doctor relationship, and chances of attending academic conferences should be emphasized.
Assuntos
Internato e Residência , Oftalmologia , Humanos , Oftalmologia/educação , Relações Médico-Paciente , China , Satisfação Pessoal , Inquéritos e Questionários , Satisfação no EmpregoRESUMO
BACKGROUND: The aim of this study was to establish a complete retinal cell atlas of ischemia-reperfusion injury by single-cell RNA sequencing, and to explore the underlying mechanism of retinal ischemia-reperfusion injury in mice. METHODS: Single-cell RNA sequencing was used to evaluate changes in the mouse retinal ischemia reperfusion model. In vivo and in vitro experiments were performed to verify the protective effect of inhibiting ferroptosis in retinal ischemia-reperfusion injury. RESULTS: After ischemia-reperfusion injury, retinal cells were significantly reduced, accompanied by the activation of myeloid and a large amount of blood-derived immune cell infiltration. The IFNG, MAPK and NFKB signaling pathways in retinal neuronal cells, together with the TNF signaling pathway in myeloid give rise to a strong inflammatory response in the I/R state. Besides, the expression of genes implicating iron metabolism, oxidative stress and multiple programed cell death pathways have changed in cell subtypes described above. Especially the ferroptosis-related genes and blocking this process could apparently alleviate the inflammatory immune responses and enhance retinal ganglion cells survival. CONCLUSIONS: We established a comprehensive landscape of mouse retinal ischemia-reperfusion injury at the single-cell level, revealing the important role of ferroptosis during this injury, and targeted inhibition of ferroptosis can effectively protect retinal structure and function.