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1.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445569

RESUMO

Retinol dehydrogenase 12 (RDH12) is expressed in photoreceptor inner segments and catalyses the reduction of all-trans retinal (atRAL) to all-trans retinol (atROL), as part of the visual cycle. Mutations in RDH12 are primarily associated with autosomal recessive Leber congenital amaurosis. To further our understanding of the disease mechanisms, HEK-293 cell lines expressing wildtype (WT) and mutant RDH12 were created. The WT cells afforded protection from atRAL-induced toxicity and oxidative stress. Mutant RDH12 cells displayed reduced protein expression and activity, with an inability to protect cells from atRAL toxicity, inducing oxidative and endoplasmic reticulum (ER) stress, with upregulation of sXBP1, CHOP, and ATF4. Pregabalin, a retinal scavenger, attenuated atRAL-induced ER stress in the mutant RDH12 cell lines. A zebrafish rdh12 mutant model (rdh12u533 c.17_23del; p.(Val6AlafsTer5)) was generated through CRISPR-Cas9 gene editing. Mutant fish showed disrupted phagocytosis through transmission electron microscopy, with increased phagosome size at 12 months post-fertilisation. Rhodopsin mislocalisation and reduced expression of atg12 and sod2 indicated early signs of a rod-predominant degeneration. A lack of functional RDH12 results in ER and oxidative stress representing key pathways to be targeted for potential therapeutics.


Assuntos
Oxirredutases do Álcool/metabolismo , Apoptose , Estresse do Retículo Endoplasmático , Mutação , Estresse Oxidativo , Doenças Retinianas/patologia , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/genética , Animais , Autofagia , Sistemas CRISPR-Cas , Células HEK293 , Humanos , Doenças Retinianas/etiologia , Doenças Retinianas/metabolismo , Peixe-Zebra
2.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201393

RESUMO

Retinal diseases are the leading cause of irreversible blindness. They affect people of all ages, from newborns in retinopathy of prematurity, through age-independent diabetic retinopathy and complications of retinal detachment, to age-related macular degeneration (AMD), which occurs mainly in the elderly. Generally speaking, the causes of all problems are disturbances in blood supply, hypoxia, the formation of abnormal blood vessels, and fibrosis. Although the detailed mechanisms underlying them are varied, the common point is the involvement of Eph receptors and ephrins in their pathogenesis. In our study, we briefly discussed the pathophysiology of the most common retinal diseases (diabetic retinopathy, retinopathy of prematurity, proliferative vitreoretinopathy, and choroidal neovascularization) and collected available research results on the role of Eph and ephrins. We also discussed the safety aspect of the use of drugs acting on Eph and ephrin for ophthalmic indications.


Assuntos
Efrinas/metabolismo , Receptores da Família Eph/metabolismo , Doenças Retinianas/patologia , Neovascularização Retiniana/patologia , Animais , Humanos , Doenças Retinianas/metabolismo , Neovascularização Retiniana/metabolismo
3.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201404

RESUMO

Neurodegenerative-neuroinflammatory disorders of the retina seriously hamper human vision. In searching for key factors that contribute to the development of these pathologies, we considered potential interactions among purinergic neuromodulation, glycinergic neurotransmission, and microglia activity in the retina. Energy deprivation at cellular levels is mainly due to impaired blood circulation leading to increased release of ATP and adenosine as well as glutamate and glycine. Interactions between these modulators and neurotransmitters are manifold. First, P2Y purinoceptor agonists facilitate reuptake of glycine by glycine transporter 1, while its inhibitors reduce reverse-mode operation; these events may lower extracellular glycine levels. The consequential changes in extracellular glycine concentration can lead to parallel changes in the activity of NR1/NR2B type NMDA receptors of which glycine is a mandatory agonist, and thereby may reduce neurodegenerative events in the retina. Second, P2Y purinoceptor agonists and glycine transporter 1 inhibitors may indirectly inhibit microglia activity by decreasing neuronal or glial glycine release in energy-compromised retina. These inhibitions may have a role in microglia activation, which is present during development and progression of neurodegenerative disorders such as glaucomatous and diabetic retinopathies and age-related macular degeneration or loss of retinal neurons caused by thromboembolic events. We have hypothesized that glycine transporter 1 inhibitors and P2Y purinoceptor agonists may have therapeutic importance in neurodegenerative-neuroinflammatory disorders of the retina by decreasing NR1/NR2B NMDA receptor activity and production and release of a series of proinflammatory cytokines from microglial cells.


Assuntos
Glicinérgicos/metabolismo , Inflamação/patologia , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Receptores Purinérgicos/metabolismo , Doenças Retinianas/patologia , Animais , Humanos , Inflamação/complicações , Inflamação/metabolismo , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Doenças Retinianas/complicações , Doenças Retinianas/metabolismo
4.
Medicine (Baltimore) ; 100(22): e26094, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087854

RESUMO

RATIONALE: Multisystemic smooth muscle dysfunction syndrome (MSMDS) is a genetic disease that affects multiple organs. The report here concerns a patient with MSMDS, who is known so far as the youngest among all the reported patients. In addition to the typical manifestations, we observed previously unreported ocular abnormalities, including persistent anterior tunica vasculosa lentis (TVL) and early-onset retinal arteriolar tortuosity, by the fluorescein angiography (FA). PATIENT CONCERNS: The patient was admitted to the neonatal intensive care unit immediately after birth for a diagnosis of urinary system dysplasia during fetal life. After a thorough examination, the patient was found with patent ductus arteriosus, pulmonary hypertension, cerebrovascular disease, hypotonic bladder, intestinal malrotation, and congenital mydriasis. The FA of the eyes undertaken in her 6-week demonstrated perfused vasculature in the persistent anterior TVL and prominent retinal arteriolar tortuosity. The whole exome sequencing revealed a de novo heterozygous ACTA2 gene missense mutation p.R179H. DIAGNOSES: The patient was diagnosed with MSMDS. INTERVENTIONS: Follow-up observation. OUTCOMES: At the 3-month follow-up, no change of the ocular disease was observed. LESSONS: The persistent anterior TVL in this case implies that ACTA2 p.R179H mutation affects not only the smooth muscle cells but also the pericytes, and further affects the TVL regression. The prominent retinal arteriolar tortuosity in this 6-week-old infant indicates that the retinal arteriolar tortuosity can present early in MSMDS.


Assuntos
Doenças do Cristalino/complicações , Doenças do Cristalino/patologia , Doenças Musculares/complicações , Doenças Musculares/patologia , Feminino , Humanos , Recém-Nascido , Cristalino/patologia , Músculo Liso/patologia , Doenças Retinianas/complicações , Doenças Retinianas/patologia
5.
Genes (Basel) ; 12(5)2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068831

RESUMO

The rare form of retinal dystrophy, Bietti crystalline dystrophy, is associated with variations in CYP4V2, a member of the cytochrome P450 family. This study reports patients affected by typical and atypical Bietti crystalline dystrophy, expanding the spectrum of this disease. This is an observational case series of patients with a clinical and molecular diagnosis of Bietti crystalline dystrophy that underwent multimodal imaging. Four unrelated patients are described with two known variants, c.802-8_810del17insGC and c.518T > G (p.Leu173Trp), and one novel missense variant, c.1169G > T (p.Arg390Leu). The patient with the novel homozygous variant had the most severe phenotype resulting in macular hole formation and retinal detachment in both eyes. To the best of our knowledge, there is no association of these features with Bietti crystalline dystrophy. Patient 1 was the youngest patient and had the mildest phenotype with crystals in the retina without chorioretinal atrophy and visual complaints. Patients 2 and 3 presented with fewer crystals and chorioretinal atrophy. These three patients presented a classic phenotype. The fourth patient presented with an atypical and severe phenotype. This study reveals a new genotype and new phenotype associated with this disorder.


Assuntos
Distrofias Hereditárias da Córnea/genética , Doenças Retinianas/genética , Idoso , Distrofias Hereditárias da Córnea/patologia , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Retina/patologia , Doenças Retinianas/patologia , Adulto Jovem
6.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070382

RESUMO

Caspase-14 is a unique member of the caspase family-a family of molecules participating in apoptosis. However, it does not affect this process but regulates another form of programmed cell death-cornification, which is characteristic of the epidermis. Therefore, it plays a crucial role in the formation of the skin barrier. The cell death cycle has been a subject of interest for researchers for decades, so a lot of research has been done to expand the understanding of caspase-14, its role in cell homeostasis and processes affecting its expression and activation. Conversely, it is also an interesting target for clinical researchers searching for its role in the physiology of healthy individuals and its pathophysiology in particular diseases. A summary was done in 2008 by Denecker et al., concentrating mostly on the biotechnological aspects of the molecule and its physiological role. However, a lot of new data have been reported, and some more practical and clinical research has been conducted since then. The majority of studies tackled the issue of clinical data presenting the role of caspase in the etiopathology of many diseases such as retinal dysfunctions, multiple malignancies, and skin conditions. This review summarizes the available knowledge on the molecular and, more interestingly, the clinical aspects of caspase-14. It also presents how theoretical science may pave the way for medical research. Methods: The authors analyzed publications available on PubMed until 21 March 2021, using the search term "caspase 14".


Assuntos
Caspase 14/metabolismo , Homeostase , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimologia , Doenças Retinianas/enzimologia , Dermatopatias/enzimologia , Animais , Humanos , Neoplasias/patologia , Doenças Retinianas/patologia , Dermatopatias/patologia
7.
Gene ; 790: 145698, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-33964374

RESUMO

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal dystrophy which is caused by the mutations of CYP4V2, usually progressing to legal blindness by the 5th or 6th decade of life. Here we identified CYP4V2 compound heterozygous mutations in two female siblings with BCD without subjective symptoms. After 381 pathogenic genes related to retinal diseases were screened by targeted sequence capture array techniques and confirmed by Sanger sequencing, two compound heterozygous mutations in CYP4V2 were found. One was missense mutation c.1198C>T (p.R400C) and the other was frameshift mutation c.802-8_810delinsGC (p.V268_E329del). Optical coherence tomography (OCT) showed that the ellipsoid zone was absent in the macular regions and electroretinogram (ERG) revealed poor cone and rod responses. Compound heterozygous mutations in CYP4V2 are related to the BCD. Our study expands our knowledge of heterogenic phenotypes and genotypes through genetic diagnosis of the BCD patients.


Assuntos
Distrofias Hereditárias da Córnea/patologia , Família 4 do Citocromo P450/genética , Mutação da Fase de Leitura , Mutação de Sentido Incorreto , Doenças Retinianas/patologia , Adulto , Distrofias Hereditárias da Córnea/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Linhagem , Doenças Retinianas/genética
8.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33836603

RESUMO

Retinal neovascularization is a leading cause of severe visual loss in humans, and molecular mechanisms of microglial activation-driven angiogenesis remain unknown. Using single-cell RNA sequencing, we identified a subpopulation of microglia named sMG2, which highly expressed necroptosis-related genes Rip3 and Mlkl. Genetic and pharmacological loss of function demonstrated that hypoxia-induced microglial activation committed to necroptosis through the RIP1/RIP3-mediated pathway. Specific deletion of Rip3 gene in microglia markedly decreased retinal neovascularization. Furthermore, hypoxia induced explosive release of abundant FGF2 in microglia through RIP3-mediated necroptosis. Importantly, blocking signaling components of the microglia necropotosis-FGF2 axis largely ablated retinal angiogenesis and combination therapy with simultaneously blocking VEGF produced synergistic antiangiogenic effects. Together, our data demonstrate that targeting the microglia necroptosis axis is an antiangiogenesis therapy for retinal neovascular diseases.


Assuntos
Microglia/patologia , Necroptose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Doenças Retinianas/patologia , Animais , Quimioterapia Combinada , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Fator 2 de Crescimento de Fibroblastos/metabolismo , Hipóxia/patologia , Camundongos , Microglia/metabolismo , Necroptose/efeitos dos fármacos , Neovascularização Patológica , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Am J Cardiol ; 149: 1-8, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33892913

RESUMO

Retinopathy is a microvascular complication of diabetes mellitus (DM); however, it is also increasingly recognized in persons without DM. The microvascular diseases may play a prominent role in coronary heart disease (CHD) development in individuals with DM. We performed the study to evaluate the relation between non-DM retinopathy and CHD and also the association between baseline retinopathy and incidence and progression of CHD in individuals with and without DM. We included 5709 subjects with and without DM from the Multi-Ethnic Study of Atherosclerosis, who had retinal photos and coronary artery calcium score (CACS) available. We studied the association between baseline retinopathy and incidence and progression of coronary artery calcification (CAC) in subjects with and without DM. In DM group, the presence of retinopathy was significantly associated with an increased rate of CAC (RR 1.3 (95% CI [1.02, 1.66]) after adjusting for age, sex, race, follow-up time, and CHD risk factors. In non-DM group, the presence of retinopathy was not significantly associated with increased risk of CAC, however, the interaction between presence of retinopathy and DM status was not statistically significant. Within the DM group with CAC present at baseline, the presence of retinopathy was significantly associated with greater CAC progression (113 Agatson units (AU) greater, (95% CI [51-174]). In the non-DM group with present CAC at baseline; the presence of retinopathy was associated with 24 (95% CI [-0.69, 48.76]) AU higher CAC progression. All findings were adjusted for CHD risk factors. In conclusion, after adjustment for major CHD risk factors, retinopathy was associated with progression of CAC in both DM and non-DM individuals. However, the association was stronger in those with DM.


Assuntos
Doença da Artéria Coronariana/epidemiologia , Retinopatia Diabética/epidemiologia , Doenças Retinianas/epidemiologia , Calcificação Vascular/epidemiologia , Estudos de Casos e Controles , Doença das Coronárias/epidemiologia , Diabetes Mellitus/epidemiologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/patologia , Progressão da Doença , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/patologia , Vasos Retinianos/patologia , Estados Unidos/epidemiologia
10.
Int J Mol Sci ; 22(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922757

RESUMO

Metformin, an anti-hyperglycemic drug of the biguanide class, exerts positive effects in several non-diabetes-related diseases. In this study, we aimed to examine the protective effects of metformin against N-methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal damage in rats and determine the mechanisms of its protective effects. Male Sprague-Dawley rats (7 to 9 weeks old) were used in this study. Following intravitreal injection of NMDA (200 nmol/eye), the number of neuronal cells in the ganglion cell layer and parvalbumin-positive amacrine cells decreased, whereas the number of CD45-positive leukocytes and Iba1-positive microglia increased. Metformin attenuated these NMDA-induced responses. The neuroprotective effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK). The AMPK activator, AICAR, exerted a neuroprotective effect in NMDA-induced retinal injury. The MEK1/2 inhibitor, U0126, reduced the neuroprotective effect of metformin. These results suggest that metformin protects against NMDA-induced retinal neurotoxicity through activation of the AMPK and MEK/extracellular signal-regulated kinase (ERK) signaling pathways. This neuroprotective effect could be partially attributable to the inhibitory effects on inflammatory responses.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Metformina/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , N-Metilaspartato/toxicidade , Fármacos Neuroprotetores/farmacologia , Doenças Retinianas/prevenção & controle , Animais , Agonistas de Aminoácidos Excitatórios/toxicidade , Hipoglicemiantes/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Transdução de Sinais
11.
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
12.
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
13.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922399

RESUMO

Eye drop formulations allowing topical treatment of retinal pathologies have long been sought as alternatives to intravitreal administration. This study aimed to assess whether a novel nanostructured microemulsions system (NaMESys) could be usefully employed to deliver sorafenib to the retina following topical instillation. NaMESys carrying 0.3% sorafenib (NaMESys-SOR) proved to be cytocompatible in vitro on rabbit corneal cells, and well-tolerated following b.i.d. ocular administration to rabbits during a 3-month study. In rats subject to retinal ischemia-reperfusion, NaMESys-SOR significantly inhibited retinal expression of tumor necrosis factor-alpha (TNFα, 20.7%) and inducible nitric oxide synthase (iNos, 87.3%) mRNAs in comparison to controls. Similarly, in streptozotocin-induced diabetic rats, NaMESys-SOR inhibited retinal expression of nuclear factor kappa B (NFκB), TNFα, insulin like growth factor 1 (IGF1), IGF1 receptor (IGF1R), vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2) mRNAs by three-fold on average compared to controls. Furthermore, a reduction in TNFα, VEGFR1 and VEGFR2 protein expression was observed by western blot. Moreover, in mice subject to laser-induced choroidal neovascularization, NaMESys-SOR significantly inhibited neovascular lesions by 54%. In conclusion, NaMESys-SOR was shown to be a well-tolerated ophthalmic formulation able to deliver effective amounts of sorafenib to the retina, reducing proinflammatory and pro-angiogenic mediators in reliable models of proliferative retinopathies. These findings warrant further investigations on the full therapeutic potential of NaMESys-SOR eye drops, aiming to address unmet needs in the pharmacotherapy of retinal neovascular diseases.


Assuntos
Neovascularização de Coroide/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/tratamento farmacológico , Nanoestruturas/administração & dosagem , Doenças Retinianas/tratamento farmacológico , Neovascularização Retiniana/tratamento farmacológico , Sorafenibe/farmacologia , Administração Oftálmica , Animais , Retinopatia Diabética/etiologia , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Emulsões , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanoestruturas/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Coelhos , Ratos , Ratos Sprague-Dawley , Doenças Retinianas/patologia , Sorafenibe/administração & dosagem
14.
Int J Mol Sci ; 22(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33806238

RESUMO

In an intraocular inflammatory state, microglia residing in the retina become active and migrate inside the retina. In this study, we investigated whether cyclooxygenase-1 (COX-1) expressed by retinal microglia/macrophage can be a biomarker for the diagnosis of retinal diseases. COX-1 was immunopositive in microglia/macrophage and neutrophils, while COX-2 was immunopositive in astrocytes and neurons in the inner layer of normal retina. The number of COX-1 positive cells per section of the retinal tissue was 14 ± 2.8 (mean ± standard deviation) in normal mice, which showed significant increase in the lipopolysaccharide (LPS)-administrated model (62 ± 5.0, p = 8.7 × 10-9). In addition to microglia, we found neutrophils that were positive for COX-1. In the early stage of inflammation in the experimental autoimmune uveoretinitis (EAU), COX-1 positive cells, infiltrating from the ciliary body into the retinal outer nuclear layer, were observed. The number of infiltrating COX-1 positive cells correlated with the severity of EAU. Taken together, the increased number of COX-1 positive microglia/macrophage with morphological changes were observed in the retinas of retinal inflammatory disease models. This suggests that COX-1 can be a marker of disease-related activities of microglia/macrophage, which should be useful for the diagnosis of retinal diseases.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Macrófagos/patologia , Proteínas de Membrana/metabolismo , Microglia/patologia , Doenças Retinianas/patologia , Animais , Astrócitos/metabolismo , Biomarcadores , Feminino , Inflamação , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Neurônios/metabolismo , Neutrófilos/metabolismo , Tomografia de Coerência Óptica
15.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673358

RESUMO

Alternative splicing of mRNA is an essential mechanism to regulate and increase the diversity of the transcriptome and proteome. Alternative splicing frequently occurs in a tissue- or time-specific manner, contributing to differential gene expression between cell types during development. Neural tissues present extremely complex splicing programs and display the highest number of alternative splicing events. As an extension of the central nervous system, the retina constitutes an excellent system to illustrate the high diversity of neural transcripts. The retina expresses retinal specific splicing factors and produces a large number of alternative transcripts, including exclusive tissue-specific exons, which require an exquisite regulation. In fact, a current challenge in the genetic diagnosis of inherited retinal diseases stems from the lack of information regarding alternative splicing of retinal genes, as a considerable percentage of mutations alter splicing or the relative production of alternative transcripts. Modulation of alternative splicing in the retina is also instrumental in the design of novel therapeutic approaches for retinal dystrophies, since it enables precision medicine for specific mutations.


Assuntos
Processamento Alternativo , Doenças Genéticas Inatas , Retina/metabolismo , Doenças Retinianas , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Humanos , Retina/patologia , Doenças Retinianas/genética , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia
16.
Nutrients ; 13(3)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673449

RESUMO

Retinal diseases can be induced by a variety of factors, including gene mutations, environmental stresses and dysmetabolic processes. The result is a progressive deterioration of visual function, which sometimes leads to blindness. Many treatments are under investigation, though results are still mostly unsatisfactory and restricted to specific pathologies, particularly in the case of gene therapy. The majority of treatments have been tested in animal models, but very few have progressed to human clinical trials. A relevant approach is to study the relation between the type of treatments and the degenerative characteristics of the animal model to better understand the effectiveness of each therapy. Here we compare the results obtained from different animal models treated with natural compounds (saffron and naringenin) to anticipate the potentiality of a single treatment in different pathologies.


Assuntos
Crocus , Flavanonas/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Doenças Retinianas/tratamento farmacológico , Neurônios Retinianos/patologia , Envelhecimento , Animais , Suplementos Nutricionais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Ratos , Ratos Endogâmicos F344 , Doenças Retinianas/patologia , Neurônios Retinianos/efeitos dos fármacos
17.
Commun Biol ; 4(1): 245, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627778

RESUMO

Acquired and inherited retinal disorders are responsible for vision loss in an increasing proportion of individuals worldwide. Photoreceptor (PR) death is central to the vision loss individuals experience in these various retinal diseases. Unfortunately, there is a lack of treatment options to prevent PR loss, so an urgent unmet need exists for therapies that improve PR survival and ultimately, vision. The retina is one of the most energy demanding tissues in the body, and this is driven in large part by the metabolic needs of PRs. Recent studies suggest that disruption of nutrient availability and regulation of cell metabolism may be a unifying mechanism in PR death. Understanding retinal cell metabolism and how it is altered in disease has been identified as a priority area of research. The focus of this review is on the recent advances in the understanding of PR metabolism and how it is critical to reduction-oxidation (redox) balance, the outer retinal metabolic ecosystem, and retinal disease. The importance of these metabolic processes is just beginning to be realized and unraveling the metabolic and redox pathways integral to PR health may identify novel targets for neuroprotective strategies that prevent blindness in the heterogenous group of retinal disorders.


Assuntos
Reprogramação Celular , Metabolismo Energético , Células Fotorreceptoras/metabolismo , Doenças Retinianas/metabolismo , Transtornos da Visão/metabolismo , Visão Ocular , Animais , Morte Celular , Humanos , Metaboloma , Metabolômica , Células Fotorreceptoras/patologia , Doenças Retinianas/patologia , Doenças Retinianas/fisiopatologia , Doenças Retinianas/terapia , Transtornos da Visão/patologia , Transtornos da Visão/fisiopatologia , Transtornos da Visão/terapia
18.
Int J Mol Sci ; 22(4)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33572210

RESUMO

Dissociated optic nerve fiber layer (DONFL) appearance is characterized by dimpling of the fundus when observed after vitrectomy with the internal limiting membrane (ILM) peeling in macular diseases. However, the cause of DONFL remains largely unknown. Optical coherence tomography (OCT) findings have indicated that the nerve fiber layer (NFL) and ganglion cells are likely to have been damaged in patients with DONFL appearance. Since DONFL appearance occurs at a certain postoperative period, it is unlikely to be retinal damage directly caused by ILM peeling because apoptosis occurs at a certain period after tissue damage and/or injury. However, it may be due to ILM peeling-induced apoptosis in the retinal tissue. Anoikis is a type of apoptosis that occurs in anchorage-dependent cells upon detachment of those cells from the surrounding extracellular matrix (i.e., the loss of cell anchorage). The anoikis-related proteins ßA3/A1 crystallin and E-cadherin are reportedly expressed in retinal ganglion cells. Thus, we theorize that one possible cause of DONFL appearance is ILM peeling-induced anoikis in retinal ganglion cells.


Assuntos
Anoikis , Nervo Óptico/patologia , Doenças Retinianas/cirurgia , Células Ganglionares da Retina/patologia , Vitrectomia/efeitos adversos , Membrana Basal/diagnóstico por imagem , Membrana Basal/cirurgia , Fundo de Olho , Humanos , Macula Lutea/citologia , Macula Lutea/patologia , Macula Lutea/cirurgia , Fibras Nervosas/patologia , Nervo Óptico/citologia , Nervo Óptico/diagnóstico por imagem , Período Pós-Operatório , Doenças Retinianas/patologia , Tomografia de Coerência Óptica , Vitrectomia/métodos
19.
J Clin Invest ; 131(4)2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586674

RESUMO

Abnormal angiogenesis and regression of the diseased retinal vasculature are key processes associated with ischemic retinopathies, but the underlying mechanisms that regulate vascular remodeling remain poorly understood. Here, we confirmed the specific expression of semaphorin 3G (Sema3G) in retinal endothelial cells (ECs), which was required for vascular remodeling and the amelioration of ischemic retinopathy. We found that Sema3G was elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and in the neovascularization regression phase of oxygen-induced retinopathy (OIR). Endothelial-specific Sema3G knockout mice exhibited decreased vessel density and excessive matrix deposition in the retinal vasculature. Moreover, loss of Sema3G aggravated pathological angiogenesis in mice with OIR. Mechanistically, we demonstrated that HIF-2α directly regulated Sema3G transcription in ECs under hypoxia. Sema3G coordinated the functional interaction between ß-catenin and VE-cadherin by increasing ß-catenin stability in the endothelium through the neuropilin-2 (Nrp2)/PlexinD1 receptor. Furthermore, Sema3G supplementation enhanced healthy vascular network formation and promoted diseased vasculature regression during blood vessel remodeling. Overall, we deciphered the endothelium-derived Sema3G-dependent events involved in modulating physiological vascular remodeling and regression of pathological blood vessels for reparative vascular regeneration. Our findings shed light on the protective effect of Sema3G in ischemic retinopathies.


Assuntos
Endotélio Vascular/metabolismo , Isquemia/metabolismo , Doenças Retinianas/metabolismo , Vasos Retinianos/metabolismo , Semaforinas/metabolismo , Remodelação Vascular , beta Catenina/metabolismo , Animais , Endotélio Vascular/patologia , Feminino , Humanos , Isquemia/genética , Isquemia/patologia , Masculino , Camundongos , Camundongos Transgênicos , Doenças Retinianas/genética , Doenças Retinianas/patologia , Vasos Retinianos/patologia , Semaforinas/genética , beta Catenina/genética
20.
Invest Ophthalmol Vis Sci ; 62(2): 14, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33591357

RESUMO

Purpose: Besides regulating paracellular diffusion, claudin-19 modulates the expression of proteins essential for the retinal pigment epithelium (RPE). This study asks how RPE responds when the expression of claudin-19 is reduced. Methods: In stem cell-derived RPE, claudin-19 and sequestosome-1/p62 (SQSTM1) were knocked down with siRNAs. Expression was monitored by quantitative RT-PCR and western blotting. Morphology and function were monitored by immunocytochemistry and transepithelial electrical resistance (TER). Phagocytosis of photoreceptor outer segments (POSs) was followed by fluorescence-activated cell sorting and western blotting. Pharmacology was used to assess the effects of AMP-activated protein kinase (AMPK) and SQSTM1 on phagocytosis. Enzymatic activity was measured using commercial assay kits. Results: Knockdown of claudin-19 reduced the TER without affecting the integrity of the apical junctional complex, as assessed by the distribution of zonula occludens-1 and filamentous actin. AMPK was activated without apparent effect on autophagy. Activation of AMPK alone had little effect on phagocytosis. Without affecting ingestion, knockdown reduced the rate of POS degradation and increased the steady-state levels of LC3B and SQSTM1. Proteasome inhibitors also retarded degradation, as did knockdown of SQSTM1. The expression of metallothioneins and the activity of superoxide dismutase increased. Conclusions: Knockdown of claudin-19 slowed the degradation of internalized POSs. The study questions the role of activated AMPK in phagocytosis and suggests a role for SQSTM1. Further, knockdown was associated with a partial oxidative stress response. The study opens new avenues of experimentation to explore these essential RPE functions.


Assuntos
Claudinas/genética , Regulação da Expressão Gênica , RNA/genética , Doenças Retinianas/genética , Epitélio Pigmentado da Retina/metabolismo , Proteína Sequestossoma-1/genética , Western Blotting , Linhagem Celular , Claudinas/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Proteínas Imediatamente Precoces , Imuno-Histoquímica , Microscopia Confocal , Fagocitose , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Epitélio Pigmentado da Retina/patologia , Proteína Sequestossoma-1/biossíntese
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