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1.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208040

RESUMO

(1) Background: The pro-resolving lipid mediator Resolvin D1 (RvD1) has already shown protective effects in animal models of diabetic retinopathy. This study aimed to investigate the retinal levels of RvD1 in aged (24 months) and younger (3 months) Balb/c mice, along with the activation of macro- and microglia, apoptosis, and neuroinflammation. (2) Methods: Retinas from male and female mice were used for immunohistochemistry, immunofluorescence, transmission electron microscopy, Western blotting, and enzyme-linked immunosorbent assays. (3) Results: Endogenous retinal levels of RvD1 were reduced in aged mice. While RvD1 levels were similar in younger males and females, they were markedly decreased in aged males but less reduced in aged females. Both aged males and females showed a significant increase in retinal microglia activation compared to younger mice, with a more marked reactivity in aged males than in aged females. The same trend was shown by astrocyte activation, neuroinflammation, apoptosis, and nitrosative stress, in line with the microglia and Müller cell hypertrophy evidenced in aged retinas by electron microscopy. (4) Conclusions: Aged mice had sex-related differences in neuroinflammation and apoptosis and low retinal levels of endogenous RvD1.


Assuntos
Envelhecimento/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/patologia , Retina/patologia , Caracteres Sexuais , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Caspase 3/metabolismo , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/metabolismo , Células Ependimogliais/patologia , Células Ependimogliais/ultraestrutura , Feminino , Masculino , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Microglia/ultraestrutura , NF-kappa B/metabolismo , Retina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
2.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062733

RESUMO

Retinopathy of prematurity (ROP) is an ocular vascular disease affecting premature infants, characterized by pathological retinal neovascularization (RNV), dilated and tortuous retinal blood vessels, and retinal or vitreous hemorrhages that may lead to retinal detachment, vision impairment and blindness. Compared with other neovascular diseases, ROP is unique because of ongoing and concurrent physiological and pathological angiogenesis in the developing retina. While the disease is currently treated by laser or cryotherapy, anti-vascular endothelial growth factor (VEGF) agents have been extensively investigated but are not approved in the U.S. because of safety concerns that they negatively interfere with physiological angiogenesis of the developing retina. An ideal therapeutic strategy would selectively inhibit pathological but not physiological angiogenesis. Our group recently described a novel strategy that selectively and safely alleviates pathological RNV in animal models of ROP by targeting secretogranin III (Scg3), a disease-restricted angiogenic factor. The preclinical profile of anti-Scg3 therapy presents a high potential for next-generation disease-targeted anti-angiogenic therapy for the ROP indication. This review focuses on retinal vessel development in neonates, the pathogenesis of ROP and its underlying molecular mechanisms, including different animal models, and provides a summary of current and emerging therapies.


Assuntos
Cromograninas/genética , Neovascularização Patológica/tratamento farmacológico , Oxigênio/uso terapêutico , Retinopatia da Prematuridade/tratamento farmacológico , Animais , Animais Recém-Nascidos , Cromograninas/antagonistas & inibidores , Humanos , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Retina/efeitos dos fármacos , Retina/crescimento & desenvolvimento , Retina/patologia , Retinopatia da Prematuridade/genética , Retinopatia da Prematuridade/patologia , Fator A de Crescimento do Endotélio Vascular/genética
3.
Arq. bras. oftalmol ; 84(3): 225-229, May-June 2021. tab
Artigo em Inglês | LILACS | ID: biblio-1248976

RESUMO

ABSTRACT Purpose: This study was conducted to evaluate visual function and changes in the central macular thickness of patients with unresponsive neovascular age-related macular degeneration who were switched from ranibizumab (Lucentis®) to aflibercept (Eylea®) treatment at 30 months. Methods: This retrospective study examined patients with neovascular age-related macular degeneration who were switched to aflibercept after ≥6 previous intravitreal ranibizumab injections at 4- to 8-week intervals. All patients were switched to intravitreal aflibercept (2.0 mg) and analyzed after 3 consecutive injections followed by a prore nata dosing regimen and after 30 months of treatment. Best corrected visual acuity, biomicroscopic examination, intraocular pressure, fundus examination, and central macular thickness were recorded at the start of treatment, before the transition to intravitreal aflibercept treatment, and at 6, 12, 18, 24, and 30 months of intravitreal aflibercept treatment. Results: A total of 33 eyes met the inclusion criteria. The median age of the patients was 73.57 ± 7.98 years, and 21 (61.8%) patients were males and 12 (35.3%) were females. Before the transition, the patients received a mean of 16.8 ± 8.8 ranibizumab injections (range 6-38).After the transition to intravitreal aflibercept treatment, the mean number of aflibercept injections was 9.09 ± 3.94. No significant differences were observed in best corrected visual acuity after the aflibercept switch in any of the months. The central macular thickness was significantly decreased at 6, 12, 18, and 30 months (p=0.01, p=0.03, p=0.05, p=0.05, p<0.001, respectively). Conclusion: Patients with neovascular age-related macular degeneration who were switched to intravitreal aflibercept treatment due to unresponsiveness to intravitreal ranibizumab exhibited a significant anatomic improvement in the retina, and although this state persisted, there was no significant functional gain.(AU)


RESUMO Objetivo: Avaliar, depois de 30 meses, a função visual e as alterações na espessura macular central de pacientes com degeneração macular relacionada à idade sem resposta terapêutica ao ranibizumabe (Lucentis®) que mudaram seu tratamento para o aflibercepte (Eylea®). Métodos: Realizou-se um estudo retrospectivo de pacientes com degeneração macular neovascular relacionada à idade que mudaram o tratamento para o aflibercepte após 6 ou mais injeções intravítreas de ranibizumabe a intervalos de 4-8 semanas. Todos os pacientes mudaram para o aflibercepte intravítreo (2,0 mg) e depois de 3 injeções consecutivas, seguidas de um regime de dosagem pro re nata, foram avaliados após 30 meses de tratamento. A melhor acuidade visual corrigida, o exame biomicroscópico, a pressão intraocular, a fundoscopia e a espessura macular central foram registrados no início do tratamento, antes da transição para o tratamento com aflibercepte intravítreo e aos 6, 12, 18, 24 e 30 meses de tratamento com o aflibercepte intravítreo. Resultados: Satisfizeram aos critérios de inclusão 33 olhos. A mediana da idade dos pacientes foi de 73,57 ± 7,98 anos. Dos pacientes, 21 (61,8%) eram homens e 12 (35,3%) eram mulheres. Antes da transição para o tratamento com o aflibercepte intravítreo, os pacientes receberam em média 16,8 ± 8,8 injeções de ranibizumabe (faixa 6-38).Depois da transição, o número médio de injeções de aflibercepte foi de 9,09 ± 3,94. Não houve diferenças significativas na melhor acuidade visual corrigida depois da mudança para o aflibercepte em qualquer das avaliações. Houve diminuição significativa da espessura macular central aos 6, 12, 18 e 30 meses (respectivamente, p=0,01, p=0,03, p=0,05, p=0,05 e p<0,001). Conclusão: Pacientes com degeneração macular neovascular relacionada à idade que mudaram seu tratamento para o aflibercepte intravítreo devido à falta de resposta ao ranibizumabe intravítreo, tiveram melhora anatômica significativa da retina; mas embora esse estado tenha persistido, não foi observado nenhum ganho funcional significativo.(AU)


Assuntos
Humanos , Retina/patologia , Acuidade Visual , Inibidores da Angiogênese/uso terapêutico , Ranibizumab/uso terapêutico , Degeneração Macular/fisiopatologia , Estudos Retrospectivos
4.
Front Immunol ; 12: 613051, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968016

RESUMO

Optical coherence tomography (OCT) allows us to identify, into retinal layers, new morphological entities, which can be considered clinical biomarkers of retinal diseases. According to the literature, solitary, small (<30 µm), medium level hyperreflective (similar to retinal fiber layer) retinal foci (HRF) may represent aggregates of activated microglial cells and an in vivo biomarker of retinal inflammation. The identification and quantification of this imaging biomarker allows for estimating the level and possibly the amount of intraretinal inflammation in major degenerative retinal disorders, whose inflammatory component has already been demonstrated (diabetic retinopathy, age-related macular degeneration, radiation retinopathy). Currently, diabetic retinopathy (DR) probably represents the best clinical model to apply this analysis in the definition of this clinical biomarker. However, the main limitation to the clinical use of HRF is related to the technical difficulty of counting them: a time-consuming methodology, which also needs trained examiners. To contribute to solve this limitation, we developed and validated a new method for the semi-automatic detection of HRF in OCT scans. OCT scans of patients affected by DR, were analyzed. HRF were manually counted in High Resolution spectral domain OCT images. Then, the same OCT scans underwent semi-automatic HRF counting, using an ImageJ software with four different settings profiles. Statistical analysis showed an excellent intraclass correlation coefficient (ICC) between the manual count and each of the four semi-automated methods. The use of the second setting profile allows to obtain at the Bland-Altman graph a bias of -0.2 foci and a limit of agreement of ±16.3 foci. This validation approach opens the way not only to the reliable and daily clinical applicable quantification of HRF, but also to a better knowledge of the inflammatory component-including its progression and regression changes-of diabetic retinopathy.


Assuntos
Retinopatia Diabética/diagnóstico por imagem , Retinopatia Diabética/patologia , Retina/diagnóstico por imagem , Retina/patologia , Tomografia de Coerência Óptica , Idoso , Automação , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos
5.
PLoS One ; 16(5): e0251682, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1226904

RESUMO

BACKGROUND/OBJECTIVES: The systemic organ involvement of SARS-CoV-2 needs to be thoroughly investigated including the possibility of an ocular reservoir in humans. To examine retinal tissues and vitreous for histopathology and SARS-CoV-2 presence with regard to possible effects on the human retina and/ or vitreous. We performed histopathological analyses and quantitative (q)RT-PCR-testing for SARS-CoV-2 RNA on retinal tissues and vitreous of COVID-19 postmortem donors. SUBJECTS/METHODS: Included in this study were 10 eyes of 5 deceased COVID-19 patients. The diagnosis of SARS-CoV-2 infection was confirmed via pharyngeal swabs and broncho-alveolar fluids. The highest level of personal protective equipment (PPE) and measures was employed during fluid-tissue procurement and preparation. Histopathological examinations and qRT-PCR-testing were carried out for all retinal tissues and vitreous fluids. RESULTS: The histopathological examinations revealed no signs of morphologically identifiable retinal inflammation or vessel occlusions based on hematoxylin and eosin stains. By qRT-PCRs, we detected no significant level of viral RNA in human retina and vitreous. CONCLUSIONS: In this study, no significant level of SARS-CoV-2-RNA was detected in the human retinal and vitreous fluid samples of deceased COVID-19 patients. Histopathological examinations confirmed no morphological sign of damage to retinal vasculature or tissues. Further studies are needed to confirm or refute the results.


Assuntos
COVID-19/diagnóstico , Retina/virologia , SARS-CoV-2/isolamento & purificação , Autopsia , COVID-19/patologia , Teste de Ácido Nucleico para COVID-19 , Humanos , RNA Viral/análise , Retina/patologia , Corpo Vítreo/patologia , Corpo Vítreo/virologia
6.
FASEB J ; 35(6): e21579, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33960001

RESUMO

Endoplasmic reticulum (ER) Ca2+ homeostasis relies on an appropriate balance between efflux- and influx-channel activity responding to dynamic changes of intracellular Ca2+ levels. Dysregulation of this complex signaling network has been shown to contribute to neuronal and photoreceptor death in neuro- and retinal degenerative diseases, respectively. In mice with cone cyclic nucleotide-gated (CNG) channel deficiency, a model of achromatopsia/cone dystrophy, cones display early-onset ER stress-associated apoptosis and protein mislocalization. Cones in these mice also show reduced cytosolic Ca2+ level and subsequent elevation in the ER Ca2+ -efflux-channel activity, specifically the inositol-1,4,5-trisphosphate receptor type 1 (IP3 R1), and deletion of IP3 R1 results in preservation of cones. This work investigated how preservation of ER Ca2+ stores leads to cone protection. We examined the effects of cone specific deletion of IP3 R1 on ER stress responses/cone death, protein localization, and ER proteostasis/ER-associated degradation. We demonstrated that deletion of IP3 R1 improves trafficking of cone-specific proteins M-/S-opsin and phosphodiesterase 6C to cone outer segments and reduces localization to cone inner segments. Consistent with the improved protein localization, deletion of IP3 R1 results in increased ER retrotranslocation protein expression, reduced proteasome subunit expression, reduced ER stress/cone death, and reduced retinal remodeling. We also observed the enhanced ER retrotranslocation in mice that have been treated with a chemical chaperone, supporting the connection between improved ER retrotranslocation/proteostasis and alleviation of ER stress. Findings from this work demonstrate the importance of ER Ca2+ stores in ER proteostasis and protein trafficking/localization in photoreceptors, strengthen the link between dysregulation of ER Ca2+ homeostasis and ER stress/cone degeneration, and support an involvement of improved ER proteostasis in ER Ca2+ preservation-induced cone protection; thereby identifying IP3 R1 as a critical mediator of ER stress and protein mislocalization and as a potential target to preserve cones in CNG channel deficiency.


Assuntos
Cálcio/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/deficiência , Retículo Endoplasmático/patologia , Receptores de Inositol 1,4,5-Trifosfato/fisiologia , Proteostase , Retina/patologia , Animais , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transporte Proteico , Retina/metabolismo , Transdução de Sinais
7.
Life Sci ; 277: 119567, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965378

RESUMO

AIM: This study aimed to evaluate the effects of Asiatic acid (AA), a naturally occurring compound of pentacyclic triterpenoid, on the pathological processes of diabetic retinopathy (DR). METHODS: SD rats were induced to develop early DR by intraperitoneal injection of STZ (60 mg/kg). Four weeks after injection, the diabetic rats were orally administrated with 37.5 mg/kg or 75 mg/kg AA every day for four weeks. The integrity of blood-retinal barrier (BRB) was measured by Evans blue staining. The polarization of microglia was determined by real-time PCR, western blot, and ELISA assays. The inner BRB (iBRB) or outer BRB (oBRB) breakdown was induced in human retinal endothelial cells or APRE19 cells through co-culture with high glucose and LPS-stimulated microglia BV2 cells. The damage to the iBRB and oBRB was measured using transendothelial/transepithelial electrical resistance (TEER/TER) and FITC-conjugated dextran cell permeability assays. KEY FINDINGS: Results demonstrated that AA alleviated BRB breakdown, as evidenced by decreased protein expression of occludin, claudin-5, and ZO-1. Furthermore, AA treatment suppressed inflammation and M1 polarization, while it increased M2 polarization in the retina of DR rats. In vitro, the iBRB or oBRB breakdown was alleviated by AA. LPS-induced M1-polarization of BV2 cells under high glucose condition was also repressed through AA administration. Finally, we demonstrated that AA weakened the TLR4/MyD88/NF-κB p65 signaling pathway both in vivo and in vitro. SIGNIFICANCE: AA ameliorated early DR by regulating microglia polarization via the TLR4/MyD88/NF-κB p65 pathway. These data indicate that AA is a potential candidate for DR treatment.


Assuntos
Retinopatia Diabética/metabolismo , Triterpenos Pentacíclicos/farmacologia , Animais , Barreira Hematorretiniana/efeitos dos fármacos , Polaridade Celular/fisiologia , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/tratamento farmacológico , Inflamação/patologia , Masculino , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Triterpenos Pentacíclicos/metabolismo , Ratos , Ratos Sprague-Dawley , Retina/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo
8.
PLoS One ; 16(5): e0251682, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33984050

RESUMO

BACKGROUND/OBJECTIVES: The systemic organ involvement of SARS-CoV-2 needs to be thoroughly investigated including the possibility of an ocular reservoir in humans. To examine retinal tissues and vitreous for histopathology and SARS-CoV-2 presence with regard to possible effects on the human retina and/ or vitreous. We performed histopathological analyses and quantitative (q)RT-PCR-testing for SARS-CoV-2 RNA on retinal tissues and vitreous of COVID-19 postmortem donors. SUBJECTS/METHODS: Included in this study were 10 eyes of 5 deceased COVID-19 patients. The diagnosis of SARS-CoV-2 infection was confirmed via pharyngeal swabs and broncho-alveolar fluids. The highest level of personal protective equipment (PPE) and measures was employed during fluid-tissue procurement and preparation. Histopathological examinations and qRT-PCR-testing were carried out for all retinal tissues and vitreous fluids. RESULTS: The histopathological examinations revealed no signs of morphologically identifiable retinal inflammation or vessel occlusions based on hematoxylin and eosin stains. By qRT-PCRs, we detected no significant level of viral RNA in human retina and vitreous. CONCLUSIONS: In this study, no significant level of SARS-CoV-2-RNA was detected in the human retinal and vitreous fluid samples of deceased COVID-19 patients. Histopathological examinations confirmed no morphological sign of damage to retinal vasculature or tissues. Further studies are needed to confirm or refute the results.


Assuntos
COVID-19/diagnóstico , Retina/virologia , SARS-CoV-2/isolamento & purificação , Autopsia , COVID-19/patologia , Teste de Ácido Nucleico para COVID-19 , Humanos , RNA Viral/análise , Retina/patologia , Corpo Vítreo/patologia , Corpo Vítreo/virologia
9.
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
10.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810434

RESUMO

Diabetic macular edema (DME) is a critical complication of diabetic retinopathy, a condition that arises from the breakdown of the blood-retinal barrier and the consequent increase in vascular permeability. Over the years, attempts have been made to treat DME by various approaches, including laser photocoagulation, steroid triamcinolone acetonide, and vitrectomy. However, treatment was unsatisfactory until research identified vascular endothelial growth factor (VEGF) as a factor in the pathogenesis of DME. Intraocular anti-VEGF agents show good efficacy in DME. Nevertheless, in some patients the condition recurs or becomes resistant to treatment, suggesting that other factors may be involved. Because inflammation and retinal hypoxia are seen in DME, research has examined the potential role of cytokines and other inflammatory mediators. In this review, we provide an overview of this research and describe feedback mechanisms that may represent a target for novel treatments.


Assuntos
Citocinas/metabolismo , Complicações do Diabetes/metabolismo , Retinopatia Diabética/metabolismo , Edema Macular/metabolismo , Animais , Velocidade do Fluxo Sanguíneo , Barreira Hematorretiniana , Permeabilidade Capilar , Humanos , Hipóxia/metabolismo , Inflamação , Injeções Intravítreas , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Retina/patologia , Triancinolona Acetonida/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Acta Neurol Scand ; 144(2): 149-154, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33881171

RESUMO

OBJECTIVES: Wilson disease (WD) is an autosomal recessive disorder that leads to copper accumulation and deposition in different organs, frequently affecting visual pathways. Recent studies have detected morphological changes of the retina in patients with WD using optical coherence tomography (OCT). Measuring the thickness of the retinal nerve fibre layer (RNFL) with OCT provides an objective assessment of integrity and morphological abnormalities of the retina. The aim of this study was to evaluate the relationship between OCT parameters and form of the disease, therapy and symptoms duration, as well as severity of neurological impairment. METHODS: The study comprised of 52 patients with WD and 52 healthy controls (HC). All the patients were on a regular and stable chelation therapy and/or zinc salts. Patients were divided into two groups, with neurological (NWD) or hepatic form of the disease (HWD). OCT was performed to assess the RNFL thickness. RESULTS: The WD patients had significantly lower intraocular pressure in both eyes and lower RNFL thickness than the HC. There were no differences between NWD and HWD in any of the ophthalmologically tested parameters. No significant correlations were found between clinical features and retinal thickness parameters. Stratification of the cohort according to the disease duration showed that disease duration did not influence the RNFL thickness. CONCLUSION: We found that involvement of the retina represented a subclinical finding in neurologically intact patients in the HWD group. Nevertheless, the value of OCT as a biomarker for the assessment of the clinical course and progression of WD still remains uncertain.


Assuntos
Degeneração Hepatolenticular/complicações , Retina/diagnóstico por imagem , Retina/patologia , Doenças Retinianas/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/etiologia , Adulto Jovem
12.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925119

RESUMO

Glaucoma is a multifactorial disease that is conventionally managed with treatments to lower intraocular pressure (IOP). Despite these efforts, many patients continue to lose their vision. The degeneration of retinal ganglion cells (RGCs) and their axons in the optic tract that characterizes glaucoma is similar to neurodegeneration in other age-related disorders of the central nervous system (CNS). Identifying the different molecular signaling pathways that contribute to early neuronal dysfunction can be utilized for neuroprotective strategies that prevent degeneration. The discovery of insulin and its receptor in the CNS and retina led to exploration of the role of insulin signaling in the CNS. Historically, insulin was considered a peripherally secreted hormone that regulated glucose homeostasis, with no obvious roles in the CNS. However, a growing number of pre-clinical and clinical studies have demonstrated the potential of modulating insulin signaling in the treatment of neurodegenerative diseases. This review will highlight the role that insulin signaling plays in RGC neurodegeneration. We will focus on how this pathway can be therapeutically targeted to promote RGC axon survival and preserve vision.


Assuntos
Glaucoma/metabolismo , Insulina/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Modelos Animais de Doenças , Glaucoma/patologia , Glaucoma/terapia , Humanos , Terapia de Alvo Molecular , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia , Neuroproteção , Retina/metabolismo , Retina/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Transdução de Sinais
13.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33921065

RESUMO

Peroxisomes are multifunctional organelles, well known for their role in cellular lipid homeostasis. Their importance is highlighted by the life-threatening diseases caused by peroxisomal dysfunction. Importantly, most patients suffering from peroxisomal biogenesis disorders, even those with a milder disease course, present with a number of ocular symptoms, including retinopathy. Patients with a selective defect in either peroxisomal α- or ß-oxidation or ether lipid synthesis also suffer from vision problems. In this review, we thoroughly discuss the ophthalmological pathology in peroxisomal disorder patients and, where possible, the corresponding animal models, with a special emphasis on the retina. In addition, we attempt to link the observed retinal phenotype to the underlying biochemical alterations. It appears that the retinal pathology is highly variable and the lack of histopathological descriptions in patients hampers the translation of the findings in the mouse models. Furthermore, it becomes clear that there are still large gaps in the current knowledge on the contribution of the different metabolic disturbances to the retinopathy, but branched chain fatty acid accumulation and impaired retinal PUFA homeostasis are likely important factors.


Assuntos
Peroxissomos/metabolismo , Retina/patologia , Animais , Modelos Animais de Doenças , Metaboloma , Fosfolipídeos/deficiência , Retina/metabolismo , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia
14.
Int J Mol Sci ; 22(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922602

RESUMO

Mutations in GPR179 lead to autosomal recessive complete congenital stationary night blindness (cCSNB). This condition represents a signal transmission defect from the photoreceptors to the ON-bipolar cells. To confirm the phenotype, better understand the pathogenic mechanism in vivo, and provide a model for therapeutic approaches, a Gpr179 knock-out mouse model was genetically and functionally characterized. We confirmed that the insertion of a neo/lac Z cassette in intron 1 of Gpr179 disrupts the same gene. Spectral domain optical coherence tomography reveals no obvious retinal structure abnormalities. Gpr179 knock-out mice exhibit a so-called no-b-wave (nob) phenotype with severely reduced b-wave amplitudes in the electroretinogram. Optomotor tests reveal decreased optomotor responses under scotopic conditions. Consistent with the genetic disruption of Gpr179, GPR179 is absent at the dendritic tips of ON-bipolar cells. While proteins of the same signal transmission cascade (GRM6, LRIT3, and TRPM1) are correctly localized, other proteins (RGS7, RGS11, and GNB5) known to regulate GRM6 are absent at the dendritic tips of ON-bipolar cells. These results add a new model of cCSNB, which is important to better understand the role of GPR179, its implication in patients with cCSNB, and its use for the development of therapies.


Assuntos
Modelos Animais de Doenças , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/patologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Miopia/genética , Miopia/patologia , Cegueira Noturna/genética , Cegueira Noturna/patologia , Receptores Acoplados a Proteínas G/fisiologia , Retina/patologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fenótipo , Retina/metabolismo , Transdução de Sinais
15.
Int J Mol Sci ; 22(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33923095

RESUMO

Diabetic retinopathy is characterized by dysfunction of the retinal vascular network, combined with a persistent low-grade inflammation that leads to vision-threatening complications. Netrin-4 (NTN4) is a laminin-related secreted protein and guidance cue molecule present in the vascular basal membrane and highly expressed in the retina. A number of studies inferred that the angiogenic abilities of NTN4 could contribute to stabilize vascular networks and modulate inflammation. Analyzing human specimens, we show that NTN4 and netrin receptors are upregulated in the diabetic retina. We further evaluated a knock-out model for NTN4 undergoing experimental diabetes induced by streptozotocin. We investigated retina function and immune cells in vivo and demonstrated that NTN4 provides a protective milieu against inflammation in the diabetic retina and prevents cytokine production.


Assuntos
Retinopatia Diabética/genética , Netrinas/genética , Retinite/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Eletrorretinografia , Regulação da Expressão Gênica , Humanos , Camundongos Transgênicos , Netrinas/metabolismo , Retina/patologia , Retina/fisiologia , Retinite/etiologia
16.
Int J Mol Sci ; 22(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918777

RESUMO

It has been shown previously that a novel tetrapeptide, Arg-Leu-Tyr-Glu (RLYE), derived from human plasminogen inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis, suppresses choroidal neovascularization in mice by an inhibition of VEGF receptor-2 (VEGFR-2) specific signaling pathway. In this study, we report that a modified tetrapeptide (Ac-RLYE) showed improved anti-choroidal neovascularization (CNV) efficacy in a number of animal models of neovascular age-related macular degeneration (AMD) which include rat, rabbit, and minipig. The preventive and therapeutic in vivo efficacy of Ac-RLYE via following intravitreal administration was determined to be either similar or superior to that of ranibizumab and aflibercept. Assessment of the intraocular pharmacokinetic and toxicokinetic properties of Ac-RLYE in rabbits demonstrated that it rapidly reached the retina with minimal systemic exposure after a single intravitreal dose, and it did not accumulate in plasma during repetitive dosing (bi-weekly for 14 weeks). Our results suggested that Ac-RLYE has a great potential for an alternative therapeutics for neovascular (wet) AMD. Since the amino acids in human VEGFR-2 targeted by Ac-RLYE are conserved among the animals employed in this study, the therapeutic efficacies of Ac-RLYE evaluated in those animals are predicted to be observed in human patients suffering from retinal degenerative diseases.


Assuntos
Degeneração Macular/etiologia , Degeneração Macular/metabolismo , Oligopeptídeos/farmacologia , Acetilação , Animais , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Angiofluoresceinografia , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/tratamento farmacológico , Masculino , Camundongos , Oligopeptídeos/química , Regiões Promotoras Genéticas , Coelhos , Ranibizumab/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão/farmacologia , Retina/metabolismo , Retina/patologia , Neovascularização Retiniana/tratamento farmacológico , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Suínos , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806565

RESUMO

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.


Assuntos
Fibrose/patologia , Músculos Oculomotores/patologia , Oftalmoplegia/patologia , Nervo Óptico/patologia , Retina/patologia , Adulto , Nervos Cranianos/patologia , Feminino , Fibrose/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Oftalmoplegia/genética , Disco Óptico/patologia , Fenótipo , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos , Adulto Jovem
18.
Int J Mol Sci ; 22(6)2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33801118

RESUMO

Diabetic retinopathy (DR) is one of the main causes of vision loss in the working age population. It is characterized by a progressive deterioration of the retinal microvasculature, caused by long-term metabolic alterations inherent to diabetes, leading to a progressive loss of retinal integrity and function. The mammalian retina presents an orderly layered structure that executes initial but complex visual processing and analysis. Gap junction channels (GJC) forming electrical synapses are present in each retinal layer and contribute to the communication between different cell types. In addition, connexin hemichannels (HCs) have emerged as relevant players that influence diverse physiological and pathological processes in the retina. This article highlights the impact of diabetic conditions on GJC and HCs physiology and their involvement in DR pathogenesis. Microvascular damage and concomitant loss of endothelial cells and pericytes are related to alterations in gap junction intercellular communication (GJIC) and decreased connexin 43 (Cx43) expression. On the other hand, it has been shown that the expression and activity of HCs are upregulated in DR, becoming a key element in the establishment of proinflammatory conditions that emerge during hyperglycemia. Hence, novel connexin HCs blockers or drugs to enhance GJIC are promising tools for the development of pharmacological interventions for diabetic retinopathy, and initial in vitro and in vivo studies have shown favorable results in this regard.


Assuntos
Conexinas/metabolismo , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Suscetibilidade a Doenças , Junções Comunicantes/metabolismo , Animais , Conexinas/genética , Retinopatia Diabética/patologia , Junções Comunicantes/genética , Expressão Gênica , Humanos , Neuroglia/metabolismo , Retina/metabolismo , Retina/patologia
19.
Eur J Pharmacol ; 900: 174035, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33727052

RESUMO

Vascular endothelial growth factor (VEGF) is the principal growth factor responsible for the retinal neovascularization in the pathogenesis of retinopathy of prematurity (ROP). Current therapies for ROP include laser ablation and intravitreal anti-VEGF injection. However, these treatments either destroy the peripheral retina or associate with problems of persistent peripheral avascular retina or later recurrence of ROP. In the present study we investigated a new therapeutic approach by exploring the potential role of a specific microRNA, miR-126, in regulating VEGFA expression and retinal neovascularization in a rat oxygen-induced retinopathy (OIR) model. We demonstrated that miR-126 mimic and plasmid effectively suppresses VEGFA mRNA expression in both human and rat retinal pigment epithelium cell lines, quantified with qRT-PCR. Animal experiments on rat OIR model revealed that intravitreal injection of miR-126 plasmid efficiently downregulated VEGFA expression in the intraocular fluid and retinal tissues measured by ELISA, and significantly suppressed retinal neovascularization, which was confirmed by calculating sizes of neovascularization areas on fluorescence microscopic images of flat mounted retina stained with Alexa Fluor 594-conjugated isolectin B4 to visualize blood vessels. Together, these results showed that intravitreal injection of miR-126 plasmid could inhibit retinal neovascularization by down-regulating VEGFA expression, suggesting a potential therapeutic effect for ROP.


Assuntos
MicroRNAs/uso terapêutico , Neovascularização Retiniana/prevenção & controle , Retinopatia da Prematuridade/prevenção & controle , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Humanos , Oxigênio , Plasmídeos , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Retina/patologia , Vasos Retinianos/patologia , Retinopatia da Prematuridade/induzido quimicamente , Retinopatia da Prematuridade/metabolismo
20.
PLoS One ; 16(3): e0246681, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1117478

RESUMO

Central nervous system and visual dysfunction is an unfortunate consequence of systemic hypoxia in the setting of cardiopulmonary disease, including infection with SARS-CoV-2, high-altitude cerebral edema and retinopathy and other conditions. Hypoxia-induced inflammatory signaling may lead to retinal inflammation, gliosis and visual disturbances. We investigated the consequences of systemic hypoxia using serial retinal optical coherence tomography and by assessing the earliest changes within 24h after hypoxia by measuring a proteomics panel of 39 cytokines, chemokines and growth factors in the plasma and retina, as well as using retinal histology. We induced severe systemic hypoxia in adult C57BL/6 mice using a hypoxia chamber (10% O2) for 1 week and rapidly assessed measurements within 1h compared with 18h after hypoxia. Optical coherence tomography revealed retinal tissue edema at 18h after hypoxia. Hierarchical clustering of plasma and retinal immune molecules revealed obvious segregation of the 1h posthypoxia group away from that of controls. One hour after hypoxia, there were 10 significantly increased molecules in plasma and 4 in retina. Interleukin-1ß and vascular endothelial growth factor were increased in both tissues. Concomitantly, there was significantly increased aquaporin-4, decreased Kir4.1, and increased gliosis in retinal histology. In summary, the immediate posthypoxic period is characterized by molecular changes consistent with systemic and retinal inflammation and retinal glial changes important in water transport, leading to tissue edema. This posthypoxic inflammation rapidly improves within 24h, consistent with the typically mild and transient visual disturbance in hypoxia, such as in high-altitude retinopathy. Given hypoxia increases risk of vision loss, more studies in at-risk patients, such as plasma immune profiling and in vivo retinal imaging, are needed in order to identify novel diagnostic or prognostic biomarkers of visual impairment in systemic hypoxia.


Assuntos
Hipóxia/complicações , Inflamação/etiologia , Retina/patologia , Animais , Sistema Nervoso Central/patologia , Citocinas/análise , Citocinas/sangue , Feminino , Hipóxia/sangue , Hipóxia/patologia , Inflamação/sangue , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular/análise , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Camundongos Endogâmicos C57BL
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