Age-related macular degeneration is a serious neurodegenerative disease of the retina that significantly impacts vision.Unfortunately,the specific pathogenesis remains unclear,and effective early treatment options are...Age-related macular degeneration is a serious neurodegenerative disease of the retina that significantly impacts vision.Unfortunately,the specific pathogenesis remains unclear,and effective early treatment options are consequently lacking.The microbiome is defined as a large ecosystem of microorganisms living within and coexisting with a host.The intestinal microbiome undergoes dynamic changes owing to age,diet,genetics,and other factors.Such dysregulation of the intestinal flora can disrupt the microecological balance,resulting in immunological and metabolic dysfunction in the host,and affecting the development of many diseases.In recent decades,significant evidence has indicated that the intestinal flora also influences systems outside of the digestive tract,including the brain.Indeed,several studies have demonstrated the critical role of the gut-brain axis in the development of brain neurodegenerative diseases,including Alzheimer’s disease and Parkinson’s disease.Similarly,the role of the“gut-eye axis”has been confirmed to play a role in the pathogenesis of many ocular disorders.Moreover,age-related macular degeneration and many brain neurodegenerative diseases have been shown to share several risk factors and to exhibit comparable etiologies.As such,the intestinal flora may play an important role in age-related macular degeneration.Given the above context,the present review aims to clarify the gut-brain and gut-eye connections,assess the effect of intestinal flora and metabolites on age-related macular degeneration,and identify potential diagnostic markers and therapeutic strategies.Currently,direct research on the role of intestinal flora in age-related macular degeneration is still relatively limited,while studies focusing solely on intestinal flora are insufficient to fully elucidate its functional role in age-related macular degeneration.Organ-on-a-chip technology has shown promise in clarifying the gut-eye interactions,while integrating analysis of the intestinal flora with research on metabolites through metabolomics and other techniques is crucial for understanding their potential mechanisms.展开更多
Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecu...Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.展开更多
Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central ...Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.展开更多
AIM:To elucidate causal pathways between oxidative biomarkers and age-related macular degeneration(AMD)phenotypes.METHODS:A bidirectional Mendelian randomization(MR)analytical protocol was implemented,which utilized g...AIM:To elucidate causal pathways between oxidative biomarkers and age-related macular degeneration(AMD)phenotypes.METHODS:A bidirectional Mendelian randomization(MR)analytical protocol was implemented,which utilized genome-wide association study(GWAS)summary statistics derived from the IEU OpenGWAS repositories.The investigation focused on 11 oxidative stress markers and AMD phenotypes,encompassing both wet and dry subtypes.The MR methodology incorporated inverse-variance weighted(IVW)calculations,MR-Egger statistical regression,weighted median approximation,and weighted mode assessments to estimate causative relationships.Sensitivity evaluations were conducted to verify result robustness and identify potential pleiotropy.RESULTS:Genetically predicted elevated catalase(CAT)concentrations demonstrated significant associations with heightened risks of overall AMD(IVW OR=1.084,95%CI:1.021-1.151,P=0.008)and wet AMD phenotype(IVW OR=1.113,95%CI:1.047-1.247,P=0.007).Higher genetically predicted albumin concentrations corresponded with reduced AMD risk(IVW OR=0.827,95%CI:0.715-0.957,P=0.013)but increased wet AMD risk(IVW OR=1.229,95%CI:1.036-1.458,P=0.018).Reverse MR analysis revealed that genetically predicted dry AMD exhibited significant association with reduced albumin levels(IVW OR=0.987,95%CI:0.979-0.996,P=0.004),while wet AMD corresponded with decreased total bilirubin(TBIL)and paraoxonase(PON)activity.CONCLUSION:The results offer strong support for a causal link between markers of oxidative stress and the development of AMD,indicating that oxidative processes play a role in driving the disease progression.展开更多
Age-related macular degeneration(AMD)is a disease that affects the vision of elderly individuals worldwide.Although current therapeutics have shown effectiveness against AMD,some patients may remain unresponsive and c...Age-related macular degeneration(AMD)is a disease that affects the vision of elderly individuals worldwide.Although current therapeutics have shown effectiveness against AMD,some patients may remain unresponsive and continue to experience disease progression.Therefore,in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment.Recently,studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species(ROS)and activation of the cyclic GMP-AMP synthase(cGAS)/stimulator of interferon genes(STING)innate immunity pathways,ultimately resulting in sterile inflammation and cell death in various cells,such as cardiomyocytes and macrophages.Therefore,combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management.Notably,emerging evidence indicates that natural products targeting mitochondrial quality control(MQC)and the cGAS/STING innate immunity pathways exhibit promise in treating AMD.Here,we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways,as well as their interconnected mediators,which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses,thereby hoping to offer new insights into therapeutic interventions for AMD treatment.展开更多
AIM:To conduct a comprehensive bibliometric analysis of age-related macular degeneration(AMD)research from 2002 to 2022,identifying key contributing countries,institutions,authors,journals,and research hotspots to inf...AIM:To conduct a comprehensive bibliometric analysis of age-related macular degeneration(AMD)research from 2002 to 2022,identifying key contributing countries,institutions,authors,journals,and research hotspots to inform future research directions.METHODS:Publications related to AMD were retrieved from the Web of Science Core Collection(WoSCC)database for the period January 1,2002,to December 31,2022.The search was limited to English-language articles and reviews.Bibliometric analysis was performed using Microsoft Excel 2021 for data management and annual publication analysis.Visualization and network analyses were conducted using VOSviewer,CiteSpace,and the Bibliometrix package in R.Collaboration networks among countries,institutions,authors,and journals were mapped.Keywords were analyzed for co-occurrence to identify research hotspots.Metrics such as H-index,total link strength(TLS),and citation counts were used to assess impact.RESULTS:A total of 16715 publications were analyzed,showing a consistent increase in AMD research output over the past 20y,peaking at 1445 publications in 2021.The United States was the leading contributor with 31.8%of total publications,followed by China and the United Kingdom.The University of Melbourne emerged as the most productive institution with the highest TLS,indicating strong international collaborations.Professor Frank G.Holz was identified as the most influential author based on H-index and publication count.Investigative Ophthalmology&Visual Science was the most prolific journal and had the highest citation impact.Keyword co-occurrence analysis revealed four main research clusters:pathogenesis,therapy,epidemiology,and diagnosis.Emerging research hotspots included anti-vascular endothelial growth factor(VEGF)therapies,optical coherence tomography angiography,and artificial intelligence(AI)applications in diagnosis.CONCLUSION:The bibliometric analysis highlights significant growth and collaborative efforts in AMD research globally.Key contributors have advanced understanding in pathogenesis,therapeutic strategies,epidemiology,and diagnostic technologies.Future research should focus on interdisciplinary collaborations,novel therapeutic targets,personalized medicine,and technological innovations such as AI to effectively address the challenges posed by AMD.展开更多
AIM:To quantitatively assess central macular thickness(CMT),macular neovascularization(MNV)area,vascular tortuosity(VT),and vascular dispersion(VDisp)in neovascular age-related macular degeneration(nAMD),type 1 and ty...AIM:To quantitatively assess central macular thickness(CMT),macular neovascularization(MNV)area,vascular tortuosity(VT),and vascular dispersion(VDisp)in neovascular age-related macular degeneration(nAMD),type 1 and type 2 MNV,by means of optical coherence tomography(OCT)and OCT angiography(OCTA)techniques.METHODS:In this retrospective and observational case series,patients were classified into type 1 or type 2 MNV groups.A comprehensive panel of OCT and OCTA metrics was evaluated,including CMT,MNV area,VT,and VDisp.All subjects underwent a standardized intravitreal conbercept(IVC)regimen[3+pro re nata(PRN)]with a 12-month follow-up.MNV area was obtained by manual measurements with OCTA software,and VT and VDisp were calculated by automated analysis with Image J software.RESULTS:A total of 101 participants were included,with 51 patients in the type 1 MNV group(mean age 67.32±9.12y)and 50 patients in the type 2 MNV group(mean age 64.74±5.21y).The mean number of IVC injections was 3.98±1.53 for type 1 MNV and 3.73±0.81 for type 2 MNV.Both subtypes exhibited significant improvements in visual acuity,accompanied by marked reductions in CMT and MNV area(P<0.05)at 12mo after treatment.In type 2 MNV,VT significantly decreased(P<0.05),whereas no significant change was observed in VT for type 1 MNV.VDisp did not significantly changed in either sybtypes.Moreover,in type 1 MNV,final best-corrected visual acuity(BCVA)using logMAR correlated positively with both pre-and post-treatment CMT,while in type 2 MNV,a significant positive correlation was found between the number of injections and final CMT.CONCLUSION:This study shows that conbercept treatment significantly improves visual acuity and macular structure in both type 1 and type 2 MNV with reductions in CMT and MNV area.The significant reduction in VT in type 2 MNV suggests its potential as a biomarker for disease activity.The findings imply the quantitative assessment useful for the stratification,prognostication,and personalized management of MNV in nAMD.展开更多
AIM:To investigate the associations between urinary dialkyl phosphate(DAP)metabolites of organophosphorus pesticides(OPPs)exposure and age-related macular degeneration(AMD)risk.METHODS:Participants were drawn from the...AIM:To investigate the associations between urinary dialkyl phosphate(DAP)metabolites of organophosphorus pesticides(OPPs)exposure and age-related macular degeneration(AMD)risk.METHODS:Participants were drawn from the National Health and Nutrition Examination Survey(NHANES)between 2005 and 2008.Urinary DAP metabolites were used to construct a machine learning(ML)model for AMD prediction.Several interpretability pipelines,including permutation feature importance(PFI),partial dependence plot(PDP),and SHapley Additive exPlanations(SHAP)analyses were employed to analyze the influence from exposure features to prediction outcomes.RESULTS:A total of 1845 participants were included and 137 were diagnosed with AMD.Receiver operating characteristic curve(ROC)analysis evaluated Random Forests(RF)as the best ML model with its optimal predictive performance among eleven models.PFI and SHAP analyses illustrated that DAP metabolites were of significant contribution weights in AMD risk prediction,higher than most of the socio-demographic covariates.Shapley values and waterfall plots of randomly selected AMD individuals emphasized the predictive capacity of ML with high accuracy and sensitivity in each case.The relationships and interactions visualized by graphical plots and supported by statistical measures demonstrated the indispensable impacts from six DAP metabolites to the prediction of AMD risk.CONCLUSION:Urinary DAP metabolites of OPPs exposure are associated with AMD risk and ML algorithms show the excellent generalizability and differentiability in the course of AMD risk prediction.展开更多
AIM:To examine effects of switching intravitreal aflibercept to bevacizumab in neovascular age-related macular degeneration(nAMD).METHODS:Data from patients treated for nAMD with anti-vascular endothelial growth facto...AIM:To examine effects of switching intravitreal aflibercept to bevacizumab in neovascular age-related macular degeneration(nAMD).METHODS:Data from patients treated for nAMD with anti-vascular endothelial growth factor(VEGF)injections atÖrebro University Hospital between January 2014 and June 2020,were extracted from the Swedish macular register(SMR).A total of 230 eyes were included in the study:116 in the study/bevacizumab switch group and 114 in the control/aflibercept group.Central retinal thickness(CRT)was measured at baseline and after 2y.Primary outcome was mean change in best corrected visual acuity(BCVA)between baseline and 2y.Secondary outcome variables included proportion of patients with a clinically significant change in BCVA[increase or decrease of≥15 Early Treatment Diabetic Retinopathy Study(ETDRS)letters],mean change in CRT,number of anti-VEGF injections,number of visits assessing disease activity and number of visits with active disease.RESULTS:The mean difference in BCVA between baseline and 2y was 1.13±14.47 ETDRS letters in the bevacizumab switch group and 1.81±13.01 ETDRS letters in the aflibercept group.The lower bound of the 95%confidence interval of the difference in BCVA was-4.25,indicating non-inferiority within a 5 ETDRS letter limit.No significant differences in mean change of CRT between baseline and 2y were detected(study-185.9±167.0 versus control-149.4±193.1μm,P=0.127).The distribution of clinically significant improvement(P=0.598)or worsening(P=0.508)of BCVA during follow-up did not show statistically significant differences between groups.The number of anti-VEGF injections administered(study 12.76±2.20 versus control 13.10±4.20,P=0.442),the number of visits assessing disease activity(P=0.301),and the number of visits with active disease(P=0.065)did not show differences between subjects receiving bevacizumab and aflibercept treatment.No significant differences were detected in baseline characteristics between the study and control groups,including age,BCVA,CRT,neovascular membrane type or location,duration of symptoms or prior cataract surgery.CONCLUSION:Switching to off-label bevacizumab in patients responding to initial aflibercept treatment is noninferior to continued aflibercept treatment with respect to change in visual acuity at 2y.Switching anti-VEGF from aflibercept to bevacizumab may be a viable option in clinical settings with limited resources.展开更多
AIM:To investigate cuproptosis-related molecular and immune infiltration in age-related macular degeneration(AMD)development and establish a predictive model.METHODS:The expression profiles of cuproptosisrelated genes...AIM:To investigate cuproptosis-related molecular and immune infiltration in age-related macular degeneration(AMD)development and establish a predictive model.METHODS:The expression profiles of cuproptosisrelated genes and immune signature in AMD based on the microarray dataset GSE29801 were analyzed.A total of 142 AMD samples were used to identify the cuproptosisrelated differentially expressed genes(Cu-DEGs),together with the immune cell infiltration.To further refine the list of potential genes for AMD diagnosis,three machine learning techniques were used,and an external dataset were applied for confirming the accuracy of the predictive performance.Reverse transcription polymerase chain reaction(RT-PCR)were also performed to examine the level of mRNA of hub genes.The activated immune responses and Cu-DEGs were assessed between AMD and controls.RESULTS:Six genes,including ATP7A,DBT,VEGFA,UBE2D3,CP,SLC31A1,were screened as cuproptosissignature in AMD via three machine learning methods.Next,SLC31A1 and VEGFA was selected as hub genes by performance evaluation in an external dataset GSE160011,further analysis showed that SLC31A1 and VEGFA were associated with pathways related to immune signaling and immune function,which were then observed in relation to infiltrating immune cells.Finally,the mRNA expression levels of SLC31A1 and VEGFA were significantly higher in laser induced choroidal neovascularization(CNV)group than in control group detected by RT-PCR.CONCLUSION:In this study,the possible relationship between cuproptosis and AMD is expounded systematically.A predictive model is developed to assess the risk of cuproptosis-related genes and their clinical prognostic value in AMD patients.展开更多
AIM:To quantify and compare longitudinal thickness changes of the ganglion cell complex(GCC)and the choroid in patients with different patterns of age-related macular degeneration(AMD)progression.METHODS:Retrospective...AIM:To quantify and compare longitudinal thickness changes of the ganglion cell complex(GCC)and the choroid in patients with different patterns of age-related macular degeneration(AMD)progression.METHODS:Retrospective cohort analysis of anonymized data from participants aged 50y or more and diagnosed with early/intermediate AMD in at least one eye(with no evidence of advanced AMD).A total of 64 participants were included from the Instituto de Retina de Lisboa(IRL)study(IPL/2022/MetAllAMD_ESTeSL)and divided into 4 groups according to the Rotterdam classification for AMD.Spectral domain optical coherence tomography(SD-OCT)was used to assess and quantify GCC and choroid thickness at two time points(first visit vs last visit)with a minimum interval of 3y.RESULTS:In the GCC inner ring,a thinner thickness(P=0.001)was observed in the atrophic AMD group(51.3±21.4μm)compared to the early AMD(84.3±11.5μm),intermediate AMD(77.6±16.1μm)and neovascular AMD(88.9±16.3μm)groups.Choroidal thickness quantification showed a generalized reduction in the central circle(P=0.002)and inner ring(P=0.001).Slight reductions in retinal thickness were more accentuated in the inner ring in the atrophic AMD(-13%;P<0.01).CONCLUSION:The variation of the analyzed structures could be an indicator of risk of progression with neurodegenerative(GCC)or vascular(choroid)pattern in the intermediate and atrophic AMD.The quantification of both structures can provide important information about the risk of disease progression in the early and intermediate stages but also for the evolution pattern into late stages(atrophic or neovascular).展开更多
Background: Exudative, or “wet” age-related macular degeneration (wAMD), characterized by choroidal neovascularization and consequent accumulation of subretinal fluid, is the leading cause of visual loss in elderly ...Background: Exudative, or “wet” age-related macular degeneration (wAMD), characterized by choroidal neovascularization and consequent accumulation of subretinal fluid, is the leading cause of visual loss in elderly patients in Western countries. Objective: To compare the effectiveness of aflibercept vs. ranibizumab for treatment-naive wAMD patients in the real world. Methods: PubMed, Web of Science and Cochrane Library were searched to compare aflibercept with ranibizumab. 21 studies with a total of 13,004 eyes were selected and assessed in this meta-analysis. Results: Compared to ranibizumab, aflibercept was more effective in improving best-corrected visual acuity (BCVA) at 12 months (WMD: −0.04;95% CI: −0.07 to 0.00;p = 0.04). At 3 months, aflibercept was superior to ranibizumab in reducing central retinal thickness in patients with worse baseline BCVA (WMD: −36.19;95% CI: −71.47 to −0.92;p = 0.04), reducing subfoveal choroidal thickness in patients with better baseline BCVA (WMD: −12.67;95% CI: −21.33 to −4.02;p = 0.004), reducing height of subfoveal pigment epithelial detachment (WMD: −43.88;95% CI: −73.88 to −13.87;p = 0.004) and improving the incidence of “dry macula” occurrence (OR: 2.26;95% CI: 1.33 to 3.82;p = 0.003). Conclusions: Compared with ranibizumab, aflibercept showed better efficacy in improving morphological changes at 3 months and visual acuity at 12 months post treatment initiation in community clinical setting.展开更多
AIM:To use two-sample Mendelian randomization(MR)method to study uveitis causal association with wet age-related macular degeneration(wAMD)risk from the genetic level.METHODS:Two-sample MR analysis was used to assess ...AIM:To use two-sample Mendelian randomization(MR)method to study uveitis causal association with wet age-related macular degeneration(wAMD)risk from the genetic level.METHODS:Two-sample MR analysis was used to assess the causal role of uveitis on wAMD risk,using the 8 genetic variants associated strongly with uveitis as instrumental variables.Besides,eight MR methods[inverse variance weighted(IVW),weighted median,MR-Egger regression,weighted mode,simple mode,robust adjusted profile score(RAPS),contamination inverse-variance weighted method,and debiased inverse-variance weighted method]were used to get the whole causal estimate for multiple instrumental single nucleotide polymorphism(SNPs).The MR analysis was based on Europeans.RESULTS:Uveitis was related to a higher risk of wAMD[odds ratio(OR):1.08,95%confidence interval(CI)1.03–1.12;P=1.03×10^(-3)]with the IVW method.No heterogeneity and directional pleiotropy were detected.On the contrary,no significant results were detected in reverse MR analysis.CONCLUSION:Uveitis is related to an increased risk of wAMD.Due to the high blindness rate of wAMD,understanding and controlling the risk factors of AMD is of great significance for reducing its incidence and early diagnosis and treatment.展开更多
Introduction Late age-related macular degeneration(AMD)is one of the leading causes of blindness globally(1).In their recent study published in JAMA Ophthalmology,Hallak et al.explore the potential of an emerging ther...Introduction Late age-related macular degeneration(AMD)is one of the leading causes of blindness globally(1).In their recent study published in JAMA Ophthalmology,Hallak et al.explore the potential of an emerging therapeutic opportunity of Janus kinase inhibitor(JAKi)in the role of systemic inflammation in AMD pathogenesis(2).This study offers a real-world examination of the relationship between JAKi and AMD,comparing the incidence of AMD in patients treated with JAKi and those receiving other immunotherapies for existing autoimmune diseases.展开更多
Dry age-related macular degeneration(AMD)is a progressive blinding disease that currently affects millions of people worldwide with no successful treatment available.Significant research efforts are currently underway...Dry age-related macular degeneration(AMD)is a progressive blinding disease that currently affects millions of people worldwide with no successful treatment available.Significant research efforts are currently underway to develop therapies aimed at slowing the progression of this disease or,more notably,reversing it.Here the therapies which have reached clinical trial for treatment of dry AMD were reviewed.A thorough search of Pub Med,Embase,and Clinicaltrials.gov has led to a comprehensive collection of the most recent strategies being evaluated.This review also endeavors to assess the status and future directions of therapeutics for this debilitating condition.展开更多
AIM： To systematically review the association between complement factors I （CFI） polymorphisms and age- related macular degeneration （AMD） and to explore whether CFI polymorphisms are associated with AMD, METHODS...AIM： To systematically review the association between complement factors I （CFI） polymorphisms and age- related macular degeneration （AMD） and to explore whether CFI polymorphisms are associated with AMD, METHODS： Meta-analysis of articles published from 1995 to January 2015 of articles involved with AMD and polymorphisms of the CFI gene. Eligible data were pooled in a Meta-analysis, analyzing using STATA software （version 12.0）, Review Manager （version 5.2） and different models based on the heterogeneity of effect sizes. Egger＇s test, Begg＇s rank correlation methods were used to evaluate for publication bias.~ RESULTS： Thirteen articles were eligible, describing two loci polymorphisms of the CFI gene （of which 12 articles focus on rs10033900T〉C and 3 articles focus on rs2285714C〉T）. For rs10033900T〉C, the results of our study revealed that having a mutant allele C, TC, CC and TC＋CC was associated with a decreased risk of AMD in all population groups studied （C versus T models, OR=0.84, 95%Ch 0.72-0.99, P=0.04; TC versus TT models OR= 0.89, 95%Ch 0.88-0.99, P=0.04;CC versus ＂1-1＂ models, OR=0.76, 95%Ch 0.60-0.98, P=-0.03; TC＋CC versus TT models, OR=0.81, 95%Ch0.65-0.99, P=0.04）. We found that C allele were related to lower AMD risk in the Caucasian population by subgroup analysis, but there was no association with AMD under the allele and genotypes comparison in Asian studies. For rs2285714 C〉T, the TC, TT genotypes contributed to a higher risk of AMD, compared with the CC carriers and CT＋CC （OR=1.34, 95%Ch 1.09-1.63, P=0.004; OR=1.50, 95%Ch 1.25-1.80, P〈0.0001）. CONCLUSION： This Meta-analysis suggests that CFI rs10033900T〉C and rs2285714C〉T polymorphisms may contribute to AMD.展开更多
AIM:Age-related macular degeneration(AMD)is a multifactorial disease and a prevalent cause of visual impairment in developed countries.Many studies suggest that age-related maculopathy susceptibility 2(ARMS2)is a seco...AIM:Age-related macular degeneration(AMD)is a multifactorial disease and a prevalent cause of visual impairment in developed countries.Many studies suggest that age-related maculopathy susceptibility 2(ARMS2)is a second major susceptibility gene for AMD.At present,there is no functional information on this gene.Therefore,the purpose of the present study was to detect the expression of ARMS2 in retinal pigment epithelium(RPE)cells and to investigate the effect of ARMS2 on the phagocytosis function of RPE cells.METHODS:Immunofluorescence and reverse transcriptase PCR were used to demonstrate the presence and location of ARMS2 in ARPE-19(human retinal pigment epithelial cell line,ATCC,catalog No.CRL-2302)cells.siRNA was used to knock down ARMS2 mRNA,and the effects of the knockdown on the phagocytosis function of the ARPE-19 cells were evaluated via Fluorescence Activated Cell Sorting(FACS).RESULTS:ARMS2 was present in ARPE-19 cells,localized in the cytosol of the perinuclear region.The expression of ARMS2 mRNA(messenger RNA)in ARPE-19 cells transfected with ARMS2-siRNA(small interfering RNA,0.73+/-0.08)was decreased compared with normal cells(1.00+/-0.00)or with cells transfected with scrambled siRNA(0.95+/-0.13)(P<0.05).After incubation of RPE cells with a latex beads medium for 12,18,or 24 hours,the fluorescence intensities were 38.04+/-1.02,68.92+/-0.92,and 78.00+/-0.12 in the ARMS2-siRNA-transfected groups,respectively,and 77.98+/-5.43,94.87+/-0.60,and 98.30+/-0.11 in the scrambled siRNA-transfected groups,respectively.The fluorescent intensities of the same time points in the two groups were compared using Student's t-test,and the p values were all less than 0.001 at the three different time points.CONCLUSION:There is endogenous expression of ARMS2 in ARPE-19 cells.ARMS2 plays a role in the phagocytosis function of RPE cells,and this role may be one of the mechanisms that participates in the development of AMD.展开更多
Age-related macular degeneration(AMD)is a leading cause of blindness worldwide.AMD most commonly affects older individuals and is characterized by irreversible degeneration of the retinal pigment epithelium and neuros...Age-related macular degeneration(AMD)is a leading cause of blindness worldwide.AMD most commonly affects older individuals and is characterized by irreversible degeneration of the retinal pigment epithelium and neurosensory retina.Currently,there are limited treatment options for dry AMD outside of lifestyle modification and nutrient supplementation.Risuteganib[Luminate(ALG-1001),Allegro Ophthalmics,CA,USA]is an intravitreally administered inhibitor of integrin heterodimersαVβ3,αVβ5,α5β1,andαMβ2.It is currently undergoing clinical trials for the treatment of dry AMD and diabetic macular edema(DME).Preclinical studies have shown that risuteganib has an effect on the pathways for angiogenesis,inflammation,and vascular permeability.Ongoing clinical trials have had promising results showing improvements in patient best corrected visual acuity(BCVA)and reduced central macular thickness measured by optical coherence tomography(OCT).There is a pressing need for treatments for dry AMD and while risuteganib appears to have a potential benefit for patients,more data are needed before one can truly evaluate its efficacy.This narrative review provides a concise summary of the most up to date data regarding the proposed mechanism of action of risuteganib in the treatment of nonexudative AMD and DME as well as the results from recent phase 1 and phase 2 clinical trials.展开更多
Advanced age is an independent risk factor for ageing-related complex diseases, such as coronary artery disease, stroke, and hypertension, which are common but life threatening and related to the ageing-associated vas...Advanced age is an independent risk factor for ageing-related complex diseases, such as coronary artery disease, stroke, and hypertension, which are common but life threatening and related to the ageing-associated vascular dysfunction. On the other hand, patients with progeria syndromes suffer from serious atherosclerosis, suggesting that the impaired vascular functions may be critical to organismal ageing, or vice versa. However, it remains largely unknown how vascular cells, particularly endothelial cell, become senescent and how the senescence impairs the vascular functions and contributes to the age-related vascular diseases over time. Here, we review the recent progress on the characteristics of vascular ageing and endothelial cell senescence in vitro and in vivo, evaluate how genetic and envi- ronmental factors as well as autophagy and stem cell influence endothelial cell senescence and how the senescence contributes to the age- related vascular phenotypes, such as atherosclerosis and increased vascular stiffness, and explore the possibility whether we can delay the age-related vascular diseases through the control of vascular ageing.展开更多
Age-related eye diseases,including cataract,glaucoma,diabetic retinopathy(DR),and age-related macular degeneration(AMD),are the leading causes of vision loss in the world.Several studies have shown that the occurrence...Age-related eye diseases,including cataract,glaucoma,diabetic retinopathy(DR),and age-related macular degeneration(AMD),are the leading causes of vision loss in the world.Several studies have shown that the occurrence and development of these diseases have an important relationship with oxidative stress in the eye.The Keap1-Nrf2-ARE pathway is a classical pathway that resists oxidative stress and inflammation in the body.This pathway is also active in the development of age-related eye diseases.A variety of drugs have been shown to treat agerelated eye diseases through the Keap1-Nrf2-ARE(Kelch-like ECH-Associating protein 1-nuclear factor erythroid 2 related factor 2-antioxidant response element)pathway.This review describes the role of oxidative stress in the development of age-related eye diseases,the function and regulation of the Keap1-Nrf2-ARE pathway,and the therapeutic effects of drugs associated with this pathway on age-related eye diseases.展开更多
基金supported by the National Natural Science Foundation of China,No.82171080Nanjing Medical Science and Technology Development Project,No.YKK23264Postgraduate Research&Practice Innovation Program of Jiangsu Province,Nos.JX10414151,JX10414152(all to KL)。
文摘Age-related macular degeneration is a serious neurodegenerative disease of the retina that significantly impacts vision.Unfortunately,the specific pathogenesis remains unclear,and effective early treatment options are consequently lacking.The microbiome is defined as a large ecosystem of microorganisms living within and coexisting with a host.The intestinal microbiome undergoes dynamic changes owing to age,diet,genetics,and other factors.Such dysregulation of the intestinal flora can disrupt the microecological balance,resulting in immunological and metabolic dysfunction in the host,and affecting the development of many diseases.In recent decades,significant evidence has indicated that the intestinal flora also influences systems outside of the digestive tract,including the brain.Indeed,several studies have demonstrated the critical role of the gut-brain axis in the development of brain neurodegenerative diseases,including Alzheimer’s disease and Parkinson’s disease.Similarly,the role of the“gut-eye axis”has been confirmed to play a role in the pathogenesis of many ocular disorders.Moreover,age-related macular degeneration and many brain neurodegenerative diseases have been shown to share several risk factors and to exhibit comparable etiologies.As such,the intestinal flora may play an important role in age-related macular degeneration.Given the above context,the present review aims to clarify the gut-brain and gut-eye connections,assess the effect of intestinal flora and metabolites on age-related macular degeneration,and identify potential diagnostic markers and therapeutic strategies.Currently,direct research on the role of intestinal flora in age-related macular degeneration is still relatively limited,while studies focusing solely on intestinal flora are insufficient to fully elucidate its functional role in age-related macular degeneration.Organ-on-a-chip technology has shown promise in clarifying the gut-eye interactions,while integrating analysis of the intestinal flora with research on metabolites through metabolomics and other techniques is crucial for understanding their potential mechanisms.
基金supported by the Start-up Fund for new faculty from the Hong Kong Polytechnic University(PolyU)(A0043215)(to SA)the General Research Fund and Research Impact Fund from the Hong Kong Research Grants Council(15106018,R5032-18)(to DYT)+1 种基金the Research Center for SHARP Vision in PolyU(P0045843)(to SA)the InnoHK scheme from the Hong Kong Special Administrative Region Government(to DYT).
文摘Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.
基金supported by grants from National Key R&D Program of China,No.2023YFC2506100(to JZ)the National Natural Science Foundation of China,No.82171062(to JZ).
文摘Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.
基金Supported by National Natural Science Foundation of China(No.82371033)Tianjin Health Bureau Fund(No.ZC20030)+4 种基金Tianjin Eye Hospital Fund Project(No.YKYB1911)Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-016A)Nankai University Institute of Optometry Science Research Open Fund(No.YKPY2208)Tianjin Eye Hospital Science and Technology Fund(No.NKSGY202405)Xianyang Science and Technology Plan Project(No.L2022ZDYFSF038).
文摘AIM:To elucidate causal pathways between oxidative biomarkers and age-related macular degeneration(AMD)phenotypes.METHODS:A bidirectional Mendelian randomization(MR)analytical protocol was implemented,which utilized genome-wide association study(GWAS)summary statistics derived from the IEU OpenGWAS repositories.The investigation focused on 11 oxidative stress markers and AMD phenotypes,encompassing both wet and dry subtypes.The MR methodology incorporated inverse-variance weighted(IVW)calculations,MR-Egger statistical regression,weighted median approximation,and weighted mode assessments to estimate causative relationships.Sensitivity evaluations were conducted to verify result robustness and identify potential pleiotropy.RESULTS:Genetically predicted elevated catalase(CAT)concentrations demonstrated significant associations with heightened risks of overall AMD(IVW OR=1.084,95%CI:1.021-1.151,P=0.008)and wet AMD phenotype(IVW OR=1.113,95%CI:1.047-1.247,P=0.007).Higher genetically predicted albumin concentrations corresponded with reduced AMD risk(IVW OR=0.827,95%CI:0.715-0.957,P=0.013)but increased wet AMD risk(IVW OR=1.229,95%CI:1.036-1.458,P=0.018).Reverse MR analysis revealed that genetically predicted dry AMD exhibited significant association with reduced albumin levels(IVW OR=0.987,95%CI:0.979-0.996,P=0.004),while wet AMD corresponded with decreased total bilirubin(TBIL)and paraoxonase(PON)activity.CONCLUSION:The results offer strong support for a causal link between markers of oxidative stress and the development of AMD,indicating that oxidative processes play a role in driving the disease progression.
基金funded by Chinese NSFC(Grant Nos.:82373336,82303238,and U22A20311,Sichuan Science and Technology Department,China(GrantNos.:2024NSFSC1945,,and 2023NSFSC0667)the Third People's Hospital of Chengdu Clinical Research Program,China(Grant Nos.:CSY-YN-01-2023-013,CSYYN-01-2023-005,and CSY-YN-03-2024-003)+1 种基金Sichuan University“From O to 1”Innovative Research Project,China(Project No.:2023SCUH0024)Health Commission of Chengdu,China(Grant No.:2024291).
文摘Age-related macular degeneration(AMD)is a disease that affects the vision of elderly individuals worldwide.Although current therapeutics have shown effectiveness against AMD,some patients may remain unresponsive and continue to experience disease progression.Therefore,in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment.Recently,studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species(ROS)and activation of the cyclic GMP-AMP synthase(cGAS)/stimulator of interferon genes(STING)innate immunity pathways,ultimately resulting in sterile inflammation and cell death in various cells,such as cardiomyocytes and macrophages.Therefore,combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management.Notably,emerging evidence indicates that natural products targeting mitochondrial quality control(MQC)and the cGAS/STING innate immunity pathways exhibit promise in treating AMD.Here,we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways,as well as their interconnected mediators,which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses,thereby hoping to offer new insights into therapeutic interventions for AMD treatment.
基金Supported by the National Natural Science Foundation of China(No.82371033)the Tianjin Natural Science Foundation(No.21JCZDJC01250)the Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-016A).
文摘AIM:To conduct a comprehensive bibliometric analysis of age-related macular degeneration(AMD)research from 2002 to 2022,identifying key contributing countries,institutions,authors,journals,and research hotspots to inform future research directions.METHODS:Publications related to AMD were retrieved from the Web of Science Core Collection(WoSCC)database for the period January 1,2002,to December 31,2022.The search was limited to English-language articles and reviews.Bibliometric analysis was performed using Microsoft Excel 2021 for data management and annual publication analysis.Visualization and network analyses were conducted using VOSviewer,CiteSpace,and the Bibliometrix package in R.Collaboration networks among countries,institutions,authors,and journals were mapped.Keywords were analyzed for co-occurrence to identify research hotspots.Metrics such as H-index,total link strength(TLS),and citation counts were used to assess impact.RESULTS:A total of 16715 publications were analyzed,showing a consistent increase in AMD research output over the past 20y,peaking at 1445 publications in 2021.The United States was the leading contributor with 31.8%of total publications,followed by China and the United Kingdom.The University of Melbourne emerged as the most productive institution with the highest TLS,indicating strong international collaborations.Professor Frank G.Holz was identified as the most influential author based on H-index and publication count.Investigative Ophthalmology&Visual Science was the most prolific journal and had the highest citation impact.Keyword co-occurrence analysis revealed four main research clusters:pathogenesis,therapy,epidemiology,and diagnosis.Emerging research hotspots included anti-vascular endothelial growth factor(VEGF)therapies,optical coherence tomography angiography,and artificial intelligence(AI)applications in diagnosis.CONCLUSION:The bibliometric analysis highlights significant growth and collaborative efforts in AMD research globally.Key contributors have advanced understanding in pathogenesis,therapeutic strategies,epidemiology,and diagnostic technologies.Future research should focus on interdisciplinary collaborations,novel therapeutic targets,personalized medicine,and technological innovations such as AI to effectively address the challenges posed by AMD.
基金Supported by Natural Science Foundation of Shandong Province(No.ZR2023MH363)Bethune Langmu Young Scholars Research Fund Project(No.BJ-LM2021007J).
文摘AIM:To quantitatively assess central macular thickness(CMT),macular neovascularization(MNV)area,vascular tortuosity(VT),and vascular dispersion(VDisp)in neovascular age-related macular degeneration(nAMD),type 1 and type 2 MNV,by means of optical coherence tomography(OCT)and OCT angiography(OCTA)techniques.METHODS:In this retrospective and observational case series,patients were classified into type 1 or type 2 MNV groups.A comprehensive panel of OCT and OCTA metrics was evaluated,including CMT,MNV area,VT,and VDisp.All subjects underwent a standardized intravitreal conbercept(IVC)regimen[3+pro re nata(PRN)]with a 12-month follow-up.MNV area was obtained by manual measurements with OCTA software,and VT and VDisp were calculated by automated analysis with Image J software.RESULTS:A total of 101 participants were included,with 51 patients in the type 1 MNV group(mean age 67.32±9.12y)and 50 patients in the type 2 MNV group(mean age 64.74±5.21y).The mean number of IVC injections was 3.98±1.53 for type 1 MNV and 3.73±0.81 for type 2 MNV.Both subtypes exhibited significant improvements in visual acuity,accompanied by marked reductions in CMT and MNV area(P<0.05)at 12mo after treatment.In type 2 MNV,VT significantly decreased(P<0.05),whereas no significant change was observed in VT for type 1 MNV.VDisp did not significantly changed in either sybtypes.Moreover,in type 1 MNV,final best-corrected visual acuity(BCVA)using logMAR correlated positively with both pre-and post-treatment CMT,while in type 2 MNV,a significant positive correlation was found between the number of injections and final CMT.CONCLUSION:This study shows that conbercept treatment significantly improves visual acuity and macular structure in both type 1 and type 2 MNV with reductions in CMT and MNV area.The significant reduction in VT in type 2 MNV suggests its potential as a biomarker for disease activity.The findings imply the quantitative assessment useful for the stratification,prognostication,and personalized management of MNV in nAMD.
基金Supported by the National Key Research and Development Program of China(No.2022YFC2502800)the National Natural Science Foundation of China(No.82171076)the Shanghai Municipal Education Commission(No.2023KJ05-67).
文摘AIM:To investigate the associations between urinary dialkyl phosphate(DAP)metabolites of organophosphorus pesticides(OPPs)exposure and age-related macular degeneration(AMD)risk.METHODS:Participants were drawn from the National Health and Nutrition Examination Survey(NHANES)between 2005 and 2008.Urinary DAP metabolites were used to construct a machine learning(ML)model for AMD prediction.Several interpretability pipelines,including permutation feature importance(PFI),partial dependence plot(PDP),and SHapley Additive exPlanations(SHAP)analyses were employed to analyze the influence from exposure features to prediction outcomes.RESULTS:A total of 1845 participants were included and 137 were diagnosed with AMD.Receiver operating characteristic curve(ROC)analysis evaluated Random Forests(RF)as the best ML model with its optimal predictive performance among eleven models.PFI and SHAP analyses illustrated that DAP metabolites were of significant contribution weights in AMD risk prediction,higher than most of the socio-demographic covariates.Shapley values and waterfall plots of randomly selected AMD individuals emphasized the predictive capacity of ML with high accuracy and sensitivity in each case.The relationships and interactions visualized by graphical plots and supported by statistical measures demonstrated the indispensable impacts from six DAP metabolites to the prediction of AMD risk.CONCLUSION:Urinary DAP metabolites of OPPs exposure are associated with AMD risk and ML algorithms show the excellent generalizability and differentiability in the course of AMD risk prediction.
文摘AIM:To examine effects of switching intravitreal aflibercept to bevacizumab in neovascular age-related macular degeneration(nAMD).METHODS:Data from patients treated for nAMD with anti-vascular endothelial growth factor(VEGF)injections atÖrebro University Hospital between January 2014 and June 2020,were extracted from the Swedish macular register(SMR).A total of 230 eyes were included in the study:116 in the study/bevacizumab switch group and 114 in the control/aflibercept group.Central retinal thickness(CRT)was measured at baseline and after 2y.Primary outcome was mean change in best corrected visual acuity(BCVA)between baseline and 2y.Secondary outcome variables included proportion of patients with a clinically significant change in BCVA[increase or decrease of≥15 Early Treatment Diabetic Retinopathy Study(ETDRS)letters],mean change in CRT,number of anti-VEGF injections,number of visits assessing disease activity and number of visits with active disease.RESULTS:The mean difference in BCVA between baseline and 2y was 1.13±14.47 ETDRS letters in the bevacizumab switch group and 1.81±13.01 ETDRS letters in the aflibercept group.The lower bound of the 95%confidence interval of the difference in BCVA was-4.25,indicating non-inferiority within a 5 ETDRS letter limit.No significant differences in mean change of CRT between baseline and 2y were detected(study-185.9±167.0 versus control-149.4±193.1μm,P=0.127).The distribution of clinically significant improvement(P=0.598)or worsening(P=0.508)of BCVA during follow-up did not show statistically significant differences between groups.The number of anti-VEGF injections administered(study 12.76±2.20 versus control 13.10±4.20,P=0.442),the number of visits assessing disease activity(P=0.301),and the number of visits with active disease(P=0.065)did not show differences between subjects receiving bevacizumab and aflibercept treatment.No significant differences were detected in baseline characteristics between the study and control groups,including age,BCVA,CRT,neovascular membrane type or location,duration of symptoms or prior cataract surgery.CONCLUSION:Switching to off-label bevacizumab in patients responding to initial aflibercept treatment is noninferior to continued aflibercept treatment with respect to change in visual acuity at 2y.Switching anti-VEGF from aflibercept to bevacizumab may be a viable option in clinical settings with limited resources.
文摘AIM:To investigate cuproptosis-related molecular and immune infiltration in age-related macular degeneration(AMD)development and establish a predictive model.METHODS:The expression profiles of cuproptosisrelated genes and immune signature in AMD based on the microarray dataset GSE29801 were analyzed.A total of 142 AMD samples were used to identify the cuproptosisrelated differentially expressed genes(Cu-DEGs),together with the immune cell infiltration.To further refine the list of potential genes for AMD diagnosis,three machine learning techniques were used,and an external dataset were applied for confirming the accuracy of the predictive performance.Reverse transcription polymerase chain reaction(RT-PCR)were also performed to examine the level of mRNA of hub genes.The activated immune responses and Cu-DEGs were assessed between AMD and controls.RESULTS:Six genes,including ATP7A,DBT,VEGFA,UBE2D3,CP,SLC31A1,were screened as cuproptosissignature in AMD via three machine learning methods.Next,SLC31A1 and VEGFA was selected as hub genes by performance evaluation in an external dataset GSE160011,further analysis showed that SLC31A1 and VEGFA were associated with pathways related to immune signaling and immune function,which were then observed in relation to infiltrating immune cells.Finally,the mRNA expression levels of SLC31A1 and VEGFA were significantly higher in laser induced choroidal neovascularization(CNV)group than in control group detected by RT-PCR.CONCLUSION:In this study,the possible relationship between cuproptosis and AMD is expounded systematically.A predictive model is developed to assess the risk of cuproptosis-related genes and their clinical prognostic value in AMD patients.
基金Supported by FCT/MCTES UIDB/05608/2020(https://doi.org/10.54499/UIDB/05608/2020)UIDP/05608/2020(https://doi.org/10.54499/UIDP/05608/2020)+1 种基金IDI&CA grant IPL/2022/MetAllAMD_ESTeSL by H&TRC-Health&Technology Research Center,ESTeSL-Escola Superior de Tecnologia da Saúde,Instituto Politécnico de Lisboaby Retina Institute of Lisbon(IRL).
文摘AIM:To quantify and compare longitudinal thickness changes of the ganglion cell complex(GCC)and the choroid in patients with different patterns of age-related macular degeneration(AMD)progression.METHODS:Retrospective cohort analysis of anonymized data from participants aged 50y or more and diagnosed with early/intermediate AMD in at least one eye(with no evidence of advanced AMD).A total of 64 participants were included from the Instituto de Retina de Lisboa(IRL)study(IPL/2022/MetAllAMD_ESTeSL)and divided into 4 groups according to the Rotterdam classification for AMD.Spectral domain optical coherence tomography(SD-OCT)was used to assess and quantify GCC and choroid thickness at two time points(first visit vs last visit)with a minimum interval of 3y.RESULTS:In the GCC inner ring,a thinner thickness(P=0.001)was observed in the atrophic AMD group(51.3±21.4μm)compared to the early AMD(84.3±11.5μm),intermediate AMD(77.6±16.1μm)and neovascular AMD(88.9±16.3μm)groups.Choroidal thickness quantification showed a generalized reduction in the central circle(P=0.002)and inner ring(P=0.001).Slight reductions in retinal thickness were more accentuated in the inner ring in the atrophic AMD(-13%;P<0.01).CONCLUSION:The variation of the analyzed structures could be an indicator of risk of progression with neurodegenerative(GCC)or vascular(choroid)pattern in the intermediate and atrophic AMD.The quantification of both structures can provide important information about the risk of disease progression in the early and intermediate stages but also for the evolution pattern into late stages(atrophic or neovascular).
文摘Background: Exudative, or “wet” age-related macular degeneration (wAMD), characterized by choroidal neovascularization and consequent accumulation of subretinal fluid, is the leading cause of visual loss in elderly patients in Western countries. Objective: To compare the effectiveness of aflibercept vs. ranibizumab for treatment-naive wAMD patients in the real world. Methods: PubMed, Web of Science and Cochrane Library were searched to compare aflibercept with ranibizumab. 21 studies with a total of 13,004 eyes were selected and assessed in this meta-analysis. Results: Compared to ranibizumab, aflibercept was more effective in improving best-corrected visual acuity (BCVA) at 12 months (WMD: −0.04;95% CI: −0.07 to 0.00;p = 0.04). At 3 months, aflibercept was superior to ranibizumab in reducing central retinal thickness in patients with worse baseline BCVA (WMD: −36.19;95% CI: −71.47 to −0.92;p = 0.04), reducing subfoveal choroidal thickness in patients with better baseline BCVA (WMD: −12.67;95% CI: −21.33 to −4.02;p = 0.004), reducing height of subfoveal pigment epithelial detachment (WMD: −43.88;95% CI: −73.88 to −13.87;p = 0.004) and improving the incidence of “dry macula” occurrence (OR: 2.26;95% CI: 1.33 to 3.82;p = 0.003). Conclusions: Compared with ranibizumab, aflibercept showed better efficacy in improving morphological changes at 3 months and visual acuity at 12 months post treatment initiation in community clinical setting.
基金Supported by the National Natural Science Foundation of China(No.82201163)Natural Science Foundation Youth Foundation of Shaanxi Province(No.2023-JC-QN-0861)Shaanxi Province Key Research and Development Program(No.2021SF-332).
文摘AIM:To use two-sample Mendelian randomization(MR)method to study uveitis causal association with wet age-related macular degeneration(wAMD)risk from the genetic level.METHODS:Two-sample MR analysis was used to assess the causal role of uveitis on wAMD risk,using the 8 genetic variants associated strongly with uveitis as instrumental variables.Besides,eight MR methods[inverse variance weighted(IVW),weighted median,MR-Egger regression,weighted mode,simple mode,robust adjusted profile score(RAPS),contamination inverse-variance weighted method,and debiased inverse-variance weighted method]were used to get the whole causal estimate for multiple instrumental single nucleotide polymorphism(SNPs).The MR analysis was based on Europeans.RESULTS:Uveitis was related to a higher risk of wAMD[odds ratio(OR):1.08,95%confidence interval(CI)1.03–1.12;P=1.03×10^(-3)]with the IVW method.No heterogeneity and directional pleiotropy were detected.On the contrary,no significant results were detected in reverse MR analysis.CONCLUSION:Uveitis is related to an increased risk of wAMD.Due to the high blindness rate of wAMD,understanding and controlling the risk factors of AMD is of great significance for reducing its incidence and early diagnosis and treatment.
基金supported by Health Education England/National Institute for Health Research(NIHR)(Clinical Lectureship CL-2020-18-009 for C.H.).
文摘Introduction Late age-related macular degeneration(AMD)is one of the leading causes of blindness globally(1).In their recent study published in JAMA Ophthalmology,Hallak et al.explore the potential of an emerging therapeutic opportunity of Janus kinase inhibitor(JAKi)in the role of systemic inflammation in AMD pathogenesis(2).This study offers a real-world examination of the relationship between JAKi and AMD,comparing the incidence of AMD in patients treated with JAKi and those receiving other immunotherapies for existing autoimmune diseases.
基金Supported by the Gates Family Fundthe Doni Solich Family Chair in Ocular Stem Cell Research,the Cell Sight Fundan Unrestricted Research Award from Research to Prevent Blindness to the Department of Ophthalmology at the University of Colorado。
文摘Dry age-related macular degeneration(AMD)is a progressive blinding disease that currently affects millions of people worldwide with no successful treatment available.Significant research efforts are currently underway to develop therapies aimed at slowing the progression of this disease or,more notably,reversing it.Here the therapies which have reached clinical trial for treatment of dry AMD were reviewed.A thorough search of Pub Med,Embase,and Clinicaltrials.gov has led to a comprehensive collection of the most recent strategies being evaluated.This review also endeavors to assess the status and future directions of therapeutics for this debilitating condition.
基金Supported by the Scientific Research Project of Traditional Chinese Medicine of Health and Family Planning Commission of Chongqing (ZY20150243)
文摘AIM： To systematically review the association between complement factors I （CFI） polymorphisms and age- related macular degeneration （AMD） and to explore whether CFI polymorphisms are associated with AMD, METHODS： Meta-analysis of articles published from 1995 to January 2015 of articles involved with AMD and polymorphisms of the CFI gene. Eligible data were pooled in a Meta-analysis, analyzing using STATA software （version 12.0）, Review Manager （version 5.2） and different models based on the heterogeneity of effect sizes. Egger＇s test, Begg＇s rank correlation methods were used to evaluate for publication bias.~ RESULTS： Thirteen articles were eligible, describing two loci polymorphisms of the CFI gene （of which 12 articles focus on rs10033900T〉C and 3 articles focus on rs2285714C〉T）. For rs10033900T〉C, the results of our study revealed that having a mutant allele C, TC, CC and TC＋CC was associated with a decreased risk of AMD in all population groups studied （C versus T models, OR=0.84, 95%Ch 0.72-0.99, P=0.04; TC versus TT models OR= 0.89, 95%Ch 0.88-0.99, P=0.04;CC versus ＂1-1＂ models, OR=0.76, 95%Ch 0.60-0.98, P=-0.03; TC＋CC versus TT models, OR=0.81, 95%Ch0.65-0.99, P=0.04）. We found that C allele were related to lower AMD risk in the Caucasian population by subgroup analysis, but there was no association with AMD under the allele and genotypes comparison in Asian studies. For rs2285714 C〉T, the TC, TT genotypes contributed to a higher risk of AMD, compared with the CC carriers and CT＋CC （OR=1.34, 95%Ch 1.09-1.63, P=0.004; OR=1.50, 95%Ch 1.25-1.80, P〈0.0001）. CONCLUSION： This Meta-analysis suggests that CFI rs10033900T〉C and rs2285714C〉T polymorphisms may contribute to AMD.
基金Supported by National Natural Science Foundation of China(No.30901637)Qingdao Sci-Tec Bureau,China(No.08-2-1-3-nsh)
文摘AIM:Age-related macular degeneration(AMD)is a multifactorial disease and a prevalent cause of visual impairment in developed countries.Many studies suggest that age-related maculopathy susceptibility 2(ARMS2)is a second major susceptibility gene for AMD.At present,there is no functional information on this gene.Therefore,the purpose of the present study was to detect the expression of ARMS2 in retinal pigment epithelium(RPE)cells and to investigate the effect of ARMS2 on the phagocytosis function of RPE cells.METHODS:Immunofluorescence and reverse transcriptase PCR were used to demonstrate the presence and location of ARMS2 in ARPE-19(human retinal pigment epithelial cell line,ATCC,catalog No.CRL-2302)cells.siRNA was used to knock down ARMS2 mRNA,and the effects of the knockdown on the phagocytosis function of the ARPE-19 cells were evaluated via Fluorescence Activated Cell Sorting(FACS).RESULTS:ARMS2 was present in ARPE-19 cells,localized in the cytosol of the perinuclear region.The expression of ARMS2 mRNA(messenger RNA)in ARPE-19 cells transfected with ARMS2-siRNA(small interfering RNA,0.73+/-0.08)was decreased compared with normal cells(1.00+/-0.00)or with cells transfected with scrambled siRNA(0.95+/-0.13)(P<0.05).After incubation of RPE cells with a latex beads medium for 12,18,or 24 hours,the fluorescence intensities were 38.04+/-1.02,68.92+/-0.92,and 78.00+/-0.12 in the ARMS2-siRNA-transfected groups,respectively,and 77.98+/-5.43,94.87+/-0.60,and 98.30+/-0.11 in the scrambled siRNA-transfected groups,respectively.The fluorescent intensities of the same time points in the two groups were compared using Student's t-test,and the p values were all less than 0.001 at the three different time points.CONCLUSION:There is endogenous expression of ARMS2 in ARPE-19 cells.ARMS2 plays a role in the phagocytosis function of RPE cells,and this role may be one of the mechanisms that participates in the development of AMD.
文摘Age-related macular degeneration(AMD)is a leading cause of blindness worldwide.AMD most commonly affects older individuals and is characterized by irreversible degeneration of the retinal pigment epithelium and neurosensory retina.Currently,there are limited treatment options for dry AMD outside of lifestyle modification and nutrient supplementation.Risuteganib[Luminate(ALG-1001),Allegro Ophthalmics,CA,USA]is an intravitreally administered inhibitor of integrin heterodimersαVβ3,αVβ5,α5β1,andαMβ2.It is currently undergoing clinical trials for the treatment of dry AMD and diabetic macular edema(DME).Preclinical studies have shown that risuteganib has an effect on the pathways for angiogenesis,inflammation,and vascular permeability.Ongoing clinical trials have had promising results showing improvements in patient best corrected visual acuity(BCVA)and reduced central macular thickness measured by optical coherence tomography(OCT).There is a pressing need for treatments for dry AMD and while risuteganib appears to have a potential benefit for patients,more data are needed before one can truly evaluate its efficacy.This narrative review provides a concise summary of the most up to date data regarding the proposed mechanism of action of risuteganib in the treatment of nonexudative AMD and DME as well as the results from recent phase 1 and phase 2 clinical trials.
基金supported by the National Basic Research Program of the Chinese Ministry of Science and Technology to XLT(No.2013CB530700)
文摘Advanced age is an independent risk factor for ageing-related complex diseases, such as coronary artery disease, stroke, and hypertension, which are common but life threatening and related to the ageing-associated vascular dysfunction. On the other hand, patients with progeria syndromes suffer from serious atherosclerosis, suggesting that the impaired vascular functions may be critical to organismal ageing, or vice versa. However, it remains largely unknown how vascular cells, particularly endothelial cell, become senescent and how the senescence impairs the vascular functions and contributes to the age-related vascular diseases over time. Here, we review the recent progress on the characteristics of vascular ageing and endothelial cell senescence in vitro and in vivo, evaluate how genetic and envi- ronmental factors as well as autophagy and stem cell influence endothelial cell senescence and how the senescence contributes to the age- related vascular phenotypes, such as atherosclerosis and increased vascular stiffness, and explore the possibility whether we can delay the age-related vascular diseases through the control of vascular ageing.
基金Supported by National Natural Science Foundation of China(No.81970801No.81670859)+1 种基金Natural Science Foundation of Hunan Province(No.2019JJ40001)Key Project of Changsha Science and Technology Bureau(No.kh1801229)。
文摘Age-related eye diseases,including cataract,glaucoma,diabetic retinopathy(DR),and age-related macular degeneration(AMD),are the leading causes of vision loss in the world.Several studies have shown that the occurrence and development of these diseases have an important relationship with oxidative stress in the eye.The Keap1-Nrf2-ARE pathway is a classical pathway that resists oxidative stress and inflammation in the body.This pathway is also active in the development of age-related eye diseases.A variety of drugs have been shown to treat agerelated eye diseases through the Keap1-Nrf2-ARE(Kelch-like ECH-Associating protein 1-nuclear factor erythroid 2 related factor 2-antioxidant response element)pathway.This review describes the role of oxidative stress in the development of age-related eye diseases,the function and regulation of the Keap1-Nrf2-ARE pathway,and the therapeutic effects of drugs associated with this pathway on age-related eye diseases.
