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1.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298993

RESUMO

Age-related macular degeneration (AMD) is a complex multifactorial neurodegenerative disease that constitutes the most common cause of irreversible blindness in the elderly in the developed countries. Incomplete knowledge about its pathogenesis prevents the search for effective methods of prevention and treatment of AMD, primarily of its "dry" type which is by far the most common (90% of all AMD cases). In the recent years, AMD has become "younger": late stages of the disease are now detected in relatively young people. It is known that AMD pathogenesis-according to the age-related structural and functional changes in the retina-is linked with inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, and an impairment of neurotrophic support, but the mechanisms that trigger the conversion of normal age-related changes to the pathological process as well as the reason for early AMD development remain unclear. In the adult mammalian retina, de novo neurogenesis is very limited. Therefore, the structural and functional features that arise during its maturation and formation can exert long-term effects on further ontogenesis of this tissue. The aim of this review was to discuss possible contributions of the changes/disturbances in retinal neurogenesis to the early development of AMD.


Assuntos
Envelhecimento/patologia , Degeneração Macular/etiologia , Degeneração Macular/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurogênese , Retina/crescimento & desenvolvimento , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Degeneração Macular/genética , Degeneração Macular/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Retina/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Med Image Anal ; 72: 102130, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34198041

RESUMO

The objective quantification of retinal atrophy associated with age-related macular degeneration (AMD) is required for clinical diagnosis, follow-up, treatment efficacy evaluation, and clinical research. Spectral Domain Optical Coherence Tomography (OCT) has become an essential imaging technology to evaluate the macula. This paper describes a novel automatic method for the identification and quantification of atrophy associated with AMD in OCT scans and its visualization in the corresponding infrared imaging (IR) image. The method is based on the classification of light scattering patterns in vertical pixel-wide columns (A-scans) in OCT slices (B-scans) in which atrophy appears with a custom column-based convolutional neural network (CNN). The network classifies individual columns with 3D column patches formed by adjacent neighboring columns from the volumetric OCT scan. Subsequent atrophy columns form atrophy segments which are then projected onto the IR image and are used to identify and segment atrophy lesions in the IR image and to measure their areas and distances from the fovea. Experimental results on 106 clinical OCT scans (5,207 slices) in which cRORA atrophy (the end point of advanced dry AMD) was identified in 2,952 atrophy segments and 1,046 atrophy lesions yield a mean F1 score of 0.78 (std 0.06) and an AUC of 0.937, both close to the observer variability. Automated computer-based detection and quantification of atrophy associated with AMD using a column-based CNN classification in OCT scans can be performed at expert level and may be a useful clinical decision support and research tool for the diagnosis, follow-up and treatment of retinal degenerations and dystrophies.


Assuntos
Aprendizado Profundo , Macula Lutea , Degeneração Macular , Atrofia/patologia , Humanos , Degeneração Macular/diagnóstico por imagem , Degeneração Macular/patologia , Tomografia de Coerência Óptica
3.
Methods Mol Biol ; 2319: 77-85, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34331245

RESUMO

The laser-induced choroidal neovascularization (CNV) model has been widely used for research on wet age-related macular degeneration (wet-AMD) and other ocular neovascular diseases. In this model, the Bruch membrane is perforated by laser injury, resulting in neovascularization formed from the choroidal capillaries. It has become a standard method to evaluate the effect of different treatments on CNV progression in preclinical studies. This protocol can be used in various species, including rat, mouse, pig, and monkey. The rodent laser-induced CNV model is the most commonly used because of the advantages in both cost- and time-efficiency. It takes only 10-15 min to complete the whole laser procedure after adequate training and practicing the technique. Peak CNV formation occurs at approximately 2 weeks after laser application. The entire protocol may require up to 3 weeks to complete the treatment, fundus image acquisition, and tissue collection for histologic analysis. This chapter describes the detailed procedures, protocols, and useful notes on how to induce CNV by laser.


Assuntos
Neovascularização de Coroide , Degeneração Macular , Anestesia , Animais , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Lasers , Degeneração Macular/patologia , Ratos
4.
Am J Hum Genet ; 108(8): 1367-1384, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34260947

RESUMO

Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10-6), FHR-2 (p = 1.47 × 10-4), FHR-3 (p = 1.05 × 10-5) and FHR-4A (p = 1.22 × 10-2) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10-17), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10-3 and p = 2.81 × 10-6, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10-16). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.


Assuntos
Proteínas Inativadoras do Complemento C3b/metabolismo , Fator H do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Predisposição Genética para Doença , Haplótipos , Degeneração Macular/patologia , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Proteínas Inativadoras do Complemento C3b/genética , Proteínas do Sistema Complemento/genética , Estudo de Associação Genômica Ampla , Humanos , Degeneração Macular/etiologia , Degeneração Macular/metabolismo
5.
Am J Hum Genet ; 108(8): 1385-1400, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34260948

RESUMO

Age-related macular degeneration (AMD) is a leading cause of vision loss; there is strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor-H-like 1 (FHL-1), and five factor-H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about how AMD-associated variants at this locus might influence FHL-1 and FHR protein concentrations. We have used a bespoke targeted mass-spectrometry assay to measure the circulating concentrations of all seven complement regulators and demonstrated elevated concentrations in 352 advanced AMD-affected individuals for all FHR proteins (FHR-1, p = 2.4 × 10-10; FHR-2, p = 6.0 × 10-10; FHR-3, p = 1.5 × 10-5; FHR-4, p = 1.3 × 10-3; FHR-5, p = 1.9 × 10-4) and FHL-1 (p = 4.9 × 10-4) when these individuals were compared to 252 controls, whereas no difference was seen for FH (p = 0.94). Genome-wide association analyses in controls revealed genome-wide-significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian-randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4, and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how genetically driven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD.


Assuntos
Proteínas Inativadoras do Complemento C3b/metabolismo , Fator H do Complemento/genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Proteínas com Domínio LIM/sangue , Degeneração Macular/sangue , Proteínas Musculares/sangue , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Casos e Controles , Proteínas Inativadoras do Complemento C3b/genética , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Degeneração Macular/genética , Degeneração Macular/patologia , Masculino , Proteínas Musculares/genética , Fatores de Risco
7.
JAMA Ophthalmol ; 139(7): 769-776, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34081099

RESUMO

Importance: Poor adherence or persistence to treatment can be a barrier to optimizing clinical practice (real-world) outcomes to intravitreal injection therapy in patients with neovascular age-related macular degeneration (nAMD). Currently, there is a lack of consensus on the definition and classification of adherence specific to this context. Objective: To describe the development and validation of terminology on patient nonadherence and nonpersistence to anti-vascular endothelial growth factor therapy. Design, Setting, and Participants: Following a systematic review of currently used terminology in the literature, a subcommittee panel of retinal experts developed a set of definitions and classification for validation. Definitions were restricted to use in patients with nAMD requiring intravitreal anti-vascular endothelial growth factor therapy. Validation by the full nAMD Barometer Leadership Coalition was established using a modified Delphi approach, with predetermined mean scores of 7.5 or more signifying consensus. Subsequent endorsement of the definitions was provided from a second set of retinal experts, with more than 50% members agreeing or strongly agreeing with all definitions. Main Outcomes and Measures: Development of consensus definitions for the terms adherence and persistence and a classification system for the factors associated with treatment nonadherence or nonpersistence in patients with nAMD. Results: Nonadherence was defined as missing 2 or more treatment or monitoring visits over a period of 12 months, with a visit considered missed if it exceeded more than 2 weeks from the recommended date. Nonpersistence was defined by nonattendance or an appointment not scheduled within the last 6 months. The additional terms planned discontinuation and transfer of care were also established. Reasons for treatment nonadherence and nonpersistence were classified into 6 dimensions: (1) patient associated, (2) condition associated, (3) therapy associated, (4) health system and health care team associated, (5) social/economic, and (6) other, with subcategories specific to treatment for nAMD. Conclusions and Relevance: This classification system provides a framework for assessing treatment nonadherence and nonpersistence over time and across different health settings in the treatment of nAMD with current intravitreal anti-vascular endothelial growth factor treatments. This may have additional importance, given the potential association of the coronavirus pandemic on adherence to treatment in patients with nAMD.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Degeneração Macular/tratamento farmacológico , Adesão à Medicação , Neovascularização Patológica , Padrões de Prática Médica , Terminologia como Assunto , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/efeitos adversos , Consenso , Técnica Delfos , Humanos , Injeções Intravítreas , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Transdução de Sinais , Fatores Socioeconômicos , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Nat Commun ; 12(1): 3906, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162842

RESUMO

Age-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aß, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling-a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to 'nucleotide empty' or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.


Assuntos
Autofagia/genética , Proteínas de Ligação ao Cálcio/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais/genética , Animais , Células COS , Proteínas de Ligação ao Cálcio/deficiência , Células Cultivadas , Chlorocebus aethiops , Modelos Animais de Doenças , Células HEK293 , Humanos , Lisossomos/metabolismo , Degeneração Macular/genética , Degeneração Macular/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout , Retina/metabolismo
9.
Am J Pathol ; 191(8): 1454-1473, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34022179

RESUMO

Age-related macular degeneration (AMD) is a progressive eye disease and the most common cause of blindness among the elderly. AMD is characterized by early atrophy of the choriocapillaris and retinal pigment epithelium (RPE). Although AMD is a multifactorial disease with many environmental and genetic risk factors, a hallmark of the disease is the origination of extracellular deposits, or drusen, between the RPE and Bruch membrane. Human retinal G-protein-coupled receptor (RGR) gene generates an exon-skipping splice variant of RGR-opsin (RGR-d; NP_001012740) that is a persistent component of small and large drusen. Herein, the findings show that abnormal RGR proteins, including RGR-d, are pathogenic in an animal retina with degeneration of the choriocapillaris, RPE, and photoreceptors. A frameshift truncating mutation resulted in severe retinal degeneration with a continuous band of basal deposits along the Bruch membrane. RGR-d produced less severe disease with choriocapillaris and RPE atrophy, including focal accumulation of abnormal RGR-d protein at the basal boundary of the RPE. Degeneration of the choriocapillaris was marked by a decrease in endothelial CD31 protein and choriocapillaris breakdown at the ultrastructural level. Fundus lesions with patchy depigmentation were characteristic of old RGR-d mice. RGR-d was mislocalized in cultured cells and caused a strong cell growth defect. These results uphold the notion of a potential hidden link between AMD and a high-frequency RGR allele.


Assuntos
Modelos Animais de Doenças , Proteínas do Olho/genética , Degeneração Macular/genética , Degeneração Macular/patologia , Receptores Acoplados a Proteínas G/genética , Animais , Atrofia/patologia , Corioide/metabolismo , Corioide/patologia , Proteínas do Olho/metabolismo , Humanos , Camundongos , Receptores Acoplados a Proteínas G/metabolismo , Retina/metabolismo , Retina/patologia
10.
BMJ Health Care Inform ; 28(1)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34035050

RESUMO

BACKGROUND/AIMS: To assess the outcomes of home monitoring of distortion caused by macular diseases using a smartphone-based application (app), and to examine them with hospital-based assessments of visual acuity (VA), optical coherence tomography-derived central macular thickness (CMT) and the requirement of intravitreal injection therapy. DESIGN: Observational study with retrospective analysis of data. METHODS: Participants were trained in the correct use of the app (Alleye, Oculocare, Zurich, Switzerland) in person or by using video and telephone consultations. Automated threshold-based alerts were communicated based on a traffic light system. A 'threshold alarm' was defined as three consecutive 'red' scores, and turned into a 'persistent alarm' if present for greater than a 7-day period. Changes of VA and CMT, and the requirement for intravitreal therapy after an alarm were examined. RESULTS: 245 patients performing a total of 11 592 tests (mean 46.9 tests per user) were included and 85 eyes (164 alarms) examined. Mean drop in VA from baseline was -4.23 letters (95% CI: -6.24 to -2.22; p<0.001) and mean increase in CMT was 29.5 µm (95% CI: -0.08 to 59.13; p=0.051). Sixty-six eyes (78.5%) producing alarms either had a drop in VA, increase in CMT or both and 60.0% received an injection. Eyes with persistent alarms had a greater loss of VA, -4.79 letters (95% CI: -6.73 to -2.85; p<0.001) or greater increase in CMT, +87.8 µm (95% CI: 5.2 to 170.4; p=0.038). CONCLUSION: Smartphone-based self-tests for macular disease may serve as reliable indicators for the worsening of pathology and the need for treatment.


Assuntos
Injeções Intravítreas/estatística & dados numéricos , Degeneração Macular , Consulta Remota/estatística & dados numéricos , Smartphone , Acuidade Visual/fisiologia , Idoso , Feminino , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/patologia , Masculino , Aplicativos Móveis , Estudos Retrospectivos , Tomografia de Coerência Óptica
11.
Expert Opin Emerg Drugs ; 26(2): 193-207, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34030572

RESUMO

INTRODUCTION: Age-related macular degeneration (AMD) is the leading cause of blindness in individuals over age 50 in developed countries. Current therapy for nonexudative AMD (neAMD) is aimed at modifying risk factors and vitamin supplementation to slow progression, while intravitreal anti-vascular endothelial factor (VEGF) injections are the mainstay for treatment of choroidal neovascularization in exudative AMD (eAMD). AREAS COVERED: Over the past decade, promising therapies have emerged that aim to improve the current standard of care for both diseases. Clinical trials for neAMD are investigating targets in the complement cascade, vitamin A metabolism, metformin, and tetracycline, whereas clinical trials for eAMD are aiming to decrease treatment burden through novel port delivery systems, increasing drug half-life, and targeting new sites of the VEGF cascade. Stem cell and gene therapy are also being evaluated for treatment of neAMD and eAMD. EXPERT OPINION: With an aging population, the need for effective, long term, low burden treatment options for AMD will be in increasingly high demand. Current investigations aim to address the shortcomings of current treatment options with breakthrough treatment approaches. Therapeutics in the pipeline hold promise for improving the treatment of AMD, and are on track for widespread use within the next decade.


Assuntos
Terapia Biológica/métodos , Neovascularização de Coroide/terapia , Degeneração Macular/terapia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Animais , Neovascularização de Coroide/patologia , Progressão da Doença , Terapia Genética/métodos , Humanos , Injeções Intravítreas , Degeneração Macular/patologia , Pessoa de Meia-Idade , Fatores de Risco , Transplante de Células-Tronco/métodos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
12.
Am J Hum Genet ; 108(5): 903-918, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33909993

RESUMO

Macular degeneration (MD) is characterized by the progressive deterioration of the macula and represents one of the most prevalent causes of blindness worldwide. Abnormal intracellular accumulation of lipid droplets and pericellular deposits of lipid-rich material in the retinal pigment epithelium (RPE) called drusen are clinical hallmarks of different forms of MD including Doyne honeycomb retinal dystrophy (DHRD) and age-related MD (AMD). However, the appropriate molecular therapeutic target underlying these disorder phenotypes remains elusive. Here, we address this knowledge gap by comparing the proteomic profiles of induced pluripotent stem cell (iPSC)-derived RPEs (iRPE) from individuals with DHRD and their isogenic controls. Our analysis and follow-up studies elucidated the mechanism of lipid accumulation in DHRD iRPE cells. Specifically, we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export. CES1 knockdown or overexpression of EFEMP1R345W, a variant of EGF-containing fibulin extracellular matrix protein 1 that is associated with DHRD and attenuated cholesterol efflux and led to lipid droplet accumulation. In iRPE cells, we also found that EFEMP1R345W has a hyper-inhibitory effect on epidermal growth factor receptor (EGFR) signaling when compared to EFEMP1WT and may suppress CES1 expression via the downregulation of transcription factor SP1. Taken together, these results highlight the homeostatic role of cholesterol efflux in iRPE cells and identify CES1 as a mediator of cholesterol efflux in MD.


Assuntos
Colesterol/metabolismo , Degeneração Macular/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Adolescente , Adulto , Hidrolases de Éster Carboxílico/genética , Diferenciação Celular/genética , Citocinas/metabolismo , Receptores ErbB/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Inflamação/metabolismo , Metabolismo dos Lipídeos , Degeneração Macular/patologia , Pessoa de Meia-Idade , Drusas do Disco Óptico/congênito , Drusas do Disco Óptico/metabolismo , Proteômica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Epitélio Pigmentado da Retina/patologia , Transdução de Sinais , Fator de Transcrição Sp1/metabolismo , Transcrição Genética , Resposta a Proteínas não Dobradas
13.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919990

RESUMO

Age-related macular degeneration (AMD) leads to gradual central vision loss and is the third leading cause of irreversible blindness worldwide. The underlying mechanisms for this progressive neurodegenerative disease remain unclear and there is currently no preventive treatment for dry AMD. Sodium iodate (NaIO3) has been reported to induce AMD-like retinal pathology in mice. We established a mouse model for AMD to evaluate the effects of quercetin on NaIO3-induced retinal apoptosis, and to investigate the pertinent underlying mechanisms. Our in vitro results indicated that quercetin protected human retinal pigment epithelium (ARPE-19) cells from NaIO3-induced apoptosis by inhibiting reactive oxygen species production and loss of mitochondrial membrane potential as detected by Annexin V-FITC/PI flow cytometry. We also evaluated the relative expression of proteins in the apoptosis pathway. Quercetin downregulated the protein expressions of Bax, cleaved caspase-3, and cleaved PARP and upregulated the expression of Bcl-2 through reduced PI3K and pAKT expressions. Furthermore, our in vivo results indicated that quercetin improved retinal deformation and increased the thickness of both the outer nuclear layer and inner nuclear layer, whereas the expression of caspase-3 was inhibited. Taken together, these results demonstrate that quercetin could protect retinal pigment epithelium and the retina from NaIO3-induced cell apoptosis via reactive oxygen species-mediated mitochondrial dysfunction, involving the PI3K/AKT signaling pathway. This suggests that quercetin has the potential to prevent and delay AMD and other retinal diseases involving NaIO3-mediated apoptosis.


Assuntos
Degeneração Macular/tratamento farmacológico , Quercetina/farmacologia , Retina/efeitos dos fármacos , Doenças Retinianas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Apoptose/genética , Caspase 3/genética , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Iodatos/toxicidade , Degeneração Macular/genética , Degeneração Macular/patologia , Mitocôndrias/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/genética , Espécies Reativas de Oxigênio/metabolismo , Retina/patologia , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/genética , Doenças Retinianas/patologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/crescimento & desenvolvimento , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/genética
14.
Nutrients ; 13(5)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922669

RESUMO

Age-related macular degeneration (AMD) is a multifactorial disease of the retina featured by dysfunction of retinal pigmented epithelial (RPE) and loss of photoreceptor cells under oxidative stress and inflammatory conditions. Vitamin D and antioxidants have beneficial effects against retinal degenerative diseases, such as AMD. We investigated the impact of associating vitamin D (ND) with a nutritional antioxidant complex (Nutrof Total®; N) on oxidative stress and inflammation-like induced conditions by H2O2 and LPS, respectively, in human retinal epithelial (ARPE-19) and human retinal endothelial (HREC) cells. Application of either N or ND treatments to H2O2-induced media in ARPE-19 cells counteracted late apoptosis, attenuated oxidative DNA damage, and increased cell proliferation. Significant reduction in the expression levels of MCP1, IL-8, and IL6 cytokines was observed following application of either N or ND treatments under LPS-induced conditions in ARPE-19 cells and in MCP-1 and IL12p70 cytokine levels in HREC cells. ND and not N revealed significant downregulation of IFNγ in ARPE-19 cells, and of IL-6 and IL-18 in HREC cells. In conclusion, adding vitamin D to Nutrof Total® protects in a synergistic way against oxidative and inflammatory stress-induced conditions in retinal epithelial and endothelial cells.


Assuntos
Anti-Inflamatórios/farmacologia , Células Endoteliais/patologia , Degeneração Macular/patologia , Epitélio Pigmentado da Retina/patologia , Vitamina D/farmacologia , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Humanos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos
15.
Exp Eye Res ; 207: 108576, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33895162

RESUMO

We have reported previously that retinal pigment epithelium (RPE) differentiated from induced pluripotent stem cells (iPSC) generated from fibroblasts of patients with age-related macular degeneration (AMD) exhibit a retinal degenerative disease phenotype and a distinct transcriptome compared to age-matched controls. Since the genetic composition of the iPSC and RPE are inherited from fibroblasts, we investigated whether differential behavior was present in the parental fibroblasts and iPSC prior to differentiation of the cell lines into RPE. Principal component analyses revealed significant overlap (essentially no differences) in the transcriptome of fibroblasts between AMD and controls. After reprogramming, there was no significant difference in the transcriptome of iPSC generated from AMD versus normal donors. In contrast, the transcriptome of RPE derived from iPSC segregated into two distinct clusters of AMD-derived cells versus controls. Interestingly, mitochondrial dysfunction in AMD-derived RPE was evident after approximately two months in culture. Moreover, these differences in mitochondrial dysfunction were not evident in the parental fibroblasts and iPSC. This study demonstrates an altered transcriptome and impaired mitochondrial function in RPE derived from AMD patients versus controls, and demonstrates these differences are not present in the original fibroblasts or iPSC. These results suggest that pathology in AMD is triggered upon differentiation of parent cells into RPE. More study of this phenomenon could advance the current understandings of the etiology of AMD and the development of novel therapeutic targets.


Assuntos
Diferenciação Celular/fisiologia , Fibroblastos/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Degeneração Macular/patologia , Transcriptoma/fisiologia , Linhagem Celular , Separação Celular , Expressão Gênica , Humanos , Degeneração Macular/genética , Fenótipo , Epitélio Pigmentado da Retina , Análise Serial de Tecidos
16.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920794

RESUMO

Few studies report drusenoid pigment epithelial detachment (DPED) in Asians. In this multicenter study, we report the clinical and genetic characteristics of 76 patients with DPED, and, for comparison, 861 patients with exudative age-related macular degeneration (AMD) were included. On the initial presentation, the mean best-corrected visual acuity was 0.087 ± 0.17 (logMAR unit), and mean DPED height and width were 210 ± 132 and 1633 ± 1114 µm, respectively. Fifty-one (67%) patients showed macular neovascularization in the contralateral eye. The risk allele frequency of both ARMS2 A69S and CFH I62V was significantly higher in DPED than in typical AMD and polypoidal choroidal vasculopathy (PCV) (ARMS2 A69S risk allele frequency: DPED 77% vs. typical AMD 66% vs. PCV 57%, CFH I62V risk allele frequency: DPED 87% vs. typical AMD 73% vs. PCV 73%), although the risk allele frequency of both genes was similar between the DPED group and retinal angiomatous proliferation (RAP) group (ARMS2 A69S: p = 0.32, CFH I62V, p = 0.11). The prevalence of reticular pseudodrusen (RPD) was highest in RAP (60%), followed by DPED (22%), typical AMD (20%), and PCV (2%). Although the prevalence of RPD differs between DPED and RAP, these entities share a similar genetic background in terms of ARMS2 and CFH genes.


Assuntos
Descolamento Retiniano/genética , Descolamento Retiniano/patologia , Drusas Retinianas/genética , Drusas Retinianas/patologia , Epitélio Pigmentado da Retina/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Degeneração Macular/genética , Degeneração Macular/patologia , Masculino
17.
Genes (Basel) ; 12(2)2021 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672973

RESUMO

(1) Background: The aim of our study was to investigate the relationship between retinal metabolic alterations (retinal vessel oximetry, RO) and structural findings (retinal vessel diameter, central retinal thickness and retinal nerve fiber layer thickness, RNFL) in patients with inherited retinal diseases (IRDs). (2) Methods: A total of 181 eyes of 92 subjects were examined: 121 eyes of 62 patients with IRDs were compared to 60 eyes of 30 healthy age-matched controls. The retinal vessel oximetry was performed with the oxygen saturation measurement tool of the Retinal Vessel Analyser (RVA; IMEDOS Systems UG, Jena, Germany). The oxygen saturation in all four major peripapillary retinal arterioles (A-SO2; %) and venules (V-SO2; %) were measured and their difference (A-V SO2; %) was calculated. Additionally, retinal vessel diameters of the corresponding arterioles (D-A; µm) and venules (D-V; µm) were determined. The peripapillary central retinal thickness and the RNFL thickness were measured using spectral domain optical coherence tomography (SD-OCT) (Carl Zeiss Meditec, Dublin, CA, USA). Moreover, we calculated the mean central retinal oxygen exposure (cO2-E; %/µm) and the mean peripapillary oxygen exposure (pO2-E; %/µm) per micron of central retinal thickness and nerve fiber layer thickness by dividing the mean central retinal thickness (CRT) and the RNFL thickness with the mean A-V SO2. (3) Results: Rod-cone dystrophy patients had the highest V-SO2 and A-SO2, the lowest A-V SO2, the narrowest D-A and D-V and the thickest RNFL, when compared not only to controls (p ≤ 0.040), but also to patients with other IRDs. Furthermore, in rod-cone dystrophies the cO2-E and the pO2-E were higher in comparison to controls and to patients with other IRDs (p ≤ 0.005). Cone-rod dystrophy patients had the lowest cO2-E compared to controls and patients with other IRDs (p ≤ 0.035). Evaluated in central zones, the cO2-E was significantly different when comparing cone-rod dystrophy (CRD) against rod-cone dystrophy (RCD) patients in all zones (p < 0.001), whereas compared with controls and patients with inherited macular dystrophy this was observed only in zones 1 and 2 (p ≤ 0.018). The oxygen exposure was also the highest in the RCD group for both the nasal and the temporal peripapillary area, among all the evaluated groups (p ≤ 0.025). (4) Conclusions: The presented metabolic-structural approach enhances our understanding of inherited photoreceptor degenerations. Clearly demonstrated through the O2-E comparisons, the central and the peripapillary retina in rod-cone dystrophy eyes consume less oxygen than the control-eyes and eyes with other IRDs. Rod-cone dystrophy eyes seem to be proportionally more exposed to oxygen, the later presumably leading to more pronounced oxidative damage-related remodeling.


Assuntos
Degeneração Macular/metabolismo , Retina/metabolismo , Retinite Pigmentosa/genética , Adulto , Feminino , Alemanha , Humanos , Degeneração Macular/diagnóstico por imagem , Degeneração Macular/genética , Degeneração Macular/patologia , Masculino , Pessoa de Meia-Idade , Oximetria , Oxigênio/metabolismo , Consumo de Oxigênio/genética , Retina/diagnóstico por imagem , Retina/patologia , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Retinite Pigmentosa/diagnóstico por imagem , Retinite Pigmentosa/patologia
18.
Cell Mol Life Sci ; 78(10): 4487-4505, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33751148

RESUMO

Age-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress.


Assuntos
Envelhecimento , Ativação do Complemento , Proteínas do Sistema Complemento/metabolismo , Inflamação/fisiopatologia , Degeneração Macular/patologia , Estresse Oxidativo , Animais , Predisposição Genética para Doença , Humanos , Degeneração Macular/imunologia , Degeneração Macular/metabolismo , Fatores de Risco
19.
Biochem Biophys Res Commun ; 551: 148-154, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33740621

RESUMO

Waste product deposition and light stress in the retinal pigment epithelium (RPE) are crucial factors in the pathogenesis of various retinal degenerative diseases, including age-related macular degeneration (AMD), a leading cause of vision loss in elderly individuals worldwide. Given that autophagy in the RPE suppresses waste accumulation, determining the molecular mechanism by which autophagy is compromised in degeneration is necessary. Using polarized human RPE sheets, we found that bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), a major toxic fluorophore of lipofuscin, causes significant impairment of autophagy and the simultaneous upregulation of Rubicon, a negative regulator of autophagy. Importantly, this impairment was reversed in Rubicon-specific siRNA-treated RPE sheets. In a retinal functional analysis using electroretinograms (ERGs), mice with the RPE-specific deletion of Rubicon showed no significant differences from control cre-expressing mice but presented partially but significantly enhanced amplitudes compared with Atg7 knockout mice. We also found that an inflammatory reaction in the retina in response to chronic blue light irradiation was alleviated in mice with the RPE-specific deletion of Rubicon. In summary, we propose that upregulating basal autophagy by targeting Rubicon is beneficial for protecting the RPE from functional damage with ageing and the inflammatory reaction caused by light-induced cellular stress.


Assuntos
Autofagia/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/patologia , Envelhecimento/metabolismo , Animais , Proteína 7 Relacionada à Autofagia/metabolismo , Eletrorretinografia , Feminino , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipofuscina/metabolismo , Degeneração Macular/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose , Epitélio Pigmentado da Retina/metabolismo , Estresse Fisiológico/efeitos da radiação
20.
Mar Drugs ; 19(2)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670685

RESUMO

Oxidative stress is identified as a major inducer of retinal pigment epithelium (RPE) cell dysregulation and is associated with age-related macular degeneration (AMD). The protection of RPE disorders plays an essential role in the pathological progress of retinal degeneration diseases. The pharmacological functions of fucoxanthin, a characteristic carotenoid, including anti-inflammatory and antioxidant properties, may ameliorate an outstanding bioactivity against premature senescence and cellular dysfunction. This study demonstrates that fucoxanthin protects RPE cells from oxidative stress-induced premature senescence and decreased photoreceptor cell loss in a sodium iodate-induced AMD animal model. Similarly, oxidative stress induced by hydrogen peroxide, nuclear phosphorylated histone (γH2AX) deposition and premature senescence-associated ß-galactosidase staining were inhibited by fucoxanthin pretreatment in a human RPE cell line, ARPE-19 cells. Results reveal that fucoxanthin treatment significantly inhibited reactive oxygen species (ROS) generation, reduced malondialdehyde (MDA) concentrations and increased the mitochondrial metabolic rate in oxidative stress-induced RPE cell damage. Moreover, atrophy of apical microvilli was inhibited in cells treated with fucoxanthin after oxidative stress. During aging, the RPE undergoes well-characterized pathological changes, including amyloid beta (Aß) deposition, beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) expression and tight junction disruption, which were also reduced in fucoxanthin-treated groups by immunofluorescence. Altogether, pretreatment with fucoxanthin may protect against premature senescence and cellular dysfunction in retinal cells by oxidative stress in experimental AMD animal and human RPE cell models.


Assuntos
Degeneração Macular/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Xantofilas/farmacologia , Animais , Antioxidantes/farmacologia , Linhagem Celular , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Degeneração Macular/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/citologia
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