scholarly journals Autophagy Stimulus Promotes Early HuR Protein Activation and p62/SQSTM1 Protein Synthesis in ARPE-19 Cells by Triggering Erk1/2, p38MAPK, and JNK Kinase Pathways

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Nicoletta Marchesi ◽  
Natthakan Thongon ◽  
Alessia Pascale ◽  
Alessandro Provenzani ◽  
Ali Koskela ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Rna Binding ◽  
De Novo ◽  
Disease Onset ◽  
Age Related Macular Degeneration ◽  
Protein Aggregate ◽  
Altered Expression ◽  
Protein Activation ◽  
Age Related ◽  
Early Effects

RNA-binding protein dysregulation and altered expression of proteins involved in the autophagy/proteasome pathway play a role in many neurodegenerative disease onset/progression, including age-related macular degeneration (AMD). HuR/ELAVL1 is a master regulator of gene expression in human physiopathology. In ARPE-19 cells exposed to the proteasomal inhibitor MG132, HuR positively affects at posttranscriptional level p62 expression, a stress response gene involved in protein aggregate clearance with a role in AMD. Here, we studied the early effects of the proautophagy AICAR + MG132 cotreatment on the HuR-p62 pathway. We treated ARPE-19 cells with Erk1/2, AMPK, p38MAPK, PKC, and JNK kinase inhibitors in the presence of AICAR + MG132 and evaluated HuR localization/phosphorylation and p62 expression. Two-hour AICAR + MG132 induces both HuR cytoplasmic translocation and threonine phosphorylation via the Erk1/2 pathway. In these conditions, p62 mRNA is loaded on polysomes and its translation in de novo protein is favored. Additionally, for the first time, we report that JNK can phosphorylate HuR, however, without modulating its localization. Our study supports HuR’s role as an upstream regulator of p62 expression in ARPE-19 cells, helps to understand better the early events in response to a proautophagy stimulus, and suggests that modulation of the autophagy-regulating kinases as potential therapeutic targets for AMD may be relevant.

scholarly journals Neovascular Macular Degeneration: A Review of Etiology, Risk Factors, and Recent Advances in Research and Therapy

2021 ◽  
Vol 22 (3) ◽  
pp. 1170
Author(s):  
Arunbalaji Pugazhendhi ◽  
Margaret Hubbell ◽  
Pooja Jairam ◽  
Balamurali Ambati
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Kinase Inhibitors ◽  
Rho Kinase ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Gene Therapies ◽  
Rho Kinase Inhibitors ◽  
Age Related ◽  
Endothelial Growth Factor

Neovascular age-related macular degeneration (exudative or wet AMD) is a prevalent, progressive retinal degenerative macular disease that is characterized by neovascularization of the choroid, mainly affecting the elderly population causing gradual vision impairment. Risk factors such as age, race, genetics, iris color, smoking, drinking, BMI, and diet all play a part in nvAMD’s progression, with anti-vascular endothelial growth factor (anti-VEGF) therapy being the mainstay of treatment. Current therapeutic advancements slow the progression of the disease but do not cure or reverse its course. Newer therapies such as gene therapies, Rho-kinase inhibitors, and levodopa offer potential new targets for treatment.

scholarly journals Automated Summarisation of SDOCT Volumes using Deep Learning: Transfer Learning vs de novo Trained Networks

2018 ◽  
Author(s):  
Bhavna J. Antony ◽  
Stefan Maetschke ◽  
Rahil Garnavi
Keyword(s):  
Deep Learning ◽  
Transfer Learning ◽  
De Novo ◽  
Imaging Modality ◽  
Age Related Macular Degeneration ◽  
Learning Approaches ◽  
Non Invasive ◽  
Age Related ◽  
Volumetric Images ◽  
Small Set

AbstractSpectral-domain optical coherence tomography (SDOCT) is a non-invasive imaging modality that generates high-resolution volumetric images. This modality finds widespread usage in ophthalmology for the diagnosis and management of various ocular conditions. The volumes generated can contain 200 or more B-scans. Manual inspection of such large quantity of scans is time consuming and error prone in most clinical settings. Here, we present a method for the generation of visual summaries of SDOCT volumes, wherein a small set of B-scans that highlight the most clinically relevant features in a volume are extracted. The method was trained and evaluated on data acquired from age-related macular degeneration patients, and “relevance” was defined as the presence of visibly discernible structural abnormalities. The summarisation system consists of a detection module, where relevant B-scans are extracted from the volume, and a set of rules that determines which B-scans are included in the visual summary. Two deep learning approaches are presented and compared for the classification of B-scans - transfer learning and de novo learning. Both approaches performed comparably with AUCs of 0.97 and 0.96, respectively, obtained on an independent test set. The de novo network, however, was 98% smaller than the transfer learning approach, and had a run-time that was also significantly shorter.

scholarly journals Bmp6 Regulates Retinal Iron Homeostasis and Has Altered Expression in Age-Related Macular Degeneration

2011 ◽  
Vol 179 (1) ◽  
pp. 335-348 ◽  
Author(s):  
Majda Hadziahmetovic ◽  
Ying Song ◽  
Natalie Wolkow ◽  
Jared Iacovelli ◽  
Leon Kautz ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Iron Homeostasis ◽  
Age Related Macular Degeneration ◽  
Altered Expression ◽  
Age Related

scholarly journals Oxidative and Nitrosative Stress in Age-Related Macular Degeneration: A Review of Their Role in Different Stages of Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 653
Author(s):  
Caterina Toma ◽  
Stefano De Cillà ◽  
Aurelio Palumbo ◽  
Divya Praveen Garhwal ◽  
Elena Grossini
Keyword(s):  
Macular Degeneration ◽  
Nitrosative Stress ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Choroidal Blood Flow ◽  
Oxidative And Nitrosative Stress ◽  
In Vivo Models ◽  
Altered Expression ◽  
Age Related

Although the exact pathogenetic mechanisms leading to age-related macular degeneration (AMD) have not been clearly identified, oxidative damage in the retina and choroid due to an imbalance between local oxidants/anti-oxidant systems leading to chronic inflammation could represent the trigger event. Different in vitro and in vivo models have demonstrated the involvement of reactive oxygen species generated in a highly oxidative environment in the development of drusen and retinal pigment epithelium (RPE) changes in the initial pathologic processes of AMD; moreover, recent evidence has highlighted the possible association of oxidative stress and neovascular AMD. Nitric oxide (NO), which is known to play a key role in retinal physiological processes and in the regulation of choroidal blood flow, under pathologic conditions could lead to RPE/photoreceptor degeneration due to the generation of peroxynitrite, a potentially cytotoxic tyrosine-nitrating molecule. Furthermore, the altered expression of the different isoforms of NO synthases could be involved in choroidal microvascular changes leading to neovascularization. The purpose of this review was to investigate the different pathways activated by oxidative/nitrosative stress in the pathogenesis of AMD, focusing on the mechanisms leading to neovascularization and on the possible protective role of anti-vascular endothelial growth factor agents in this context.

scholarly journals Transplantation of retinal pigment epithelium and photoreceptors generated concomitantly via small molecule-mediated differentiation rescues visual function in rodent models of retinal degeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Harshini Surendran ◽  
Swapna Nandakumar ◽  
Vijay Bhaskar Reddy K ◽  
Jonathan Stoddard ◽  
Varsha Mohan K ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Visual Function ◽  
De Novo ◽  
Pigment Epithelium ◽  
Outer Nuclear Layer ◽  
Retinal Pigment ◽  
Safety Data ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Promising Therapeutic Approach

Abstract Background Age-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors. A promising therapeutic approach for both is the replacement of lost/damaged cells with human induced pluripotent stem cell (hiPSC)-derived retinal cells. Methods The aim of this study was to investigate the in vivo functionality of RPE and photoreceptor progenitor (PRP) cells derived from a clinical-grade hiPSC line through a unified protocol. De novo-generated RPE and PRP were characterized extensively to validate their identity, purity, and potency. Results RPE expressed tight junction proteins, showed pigmentation and ciliation, and secreted polarization-related factors vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). PRP expressed neural retina proteins and cone and rod markers, and responded to KCl-induced polarization. Transcriptomic analysis demonstrated an increase in the expression of mature retinal tissue-specific genes coupled with concomitant downregulation of genes from undesired lineages. RPE transplantation rescued visual function in RCS rats shown via optokinetic tracking and photoreceptor rescue. PRP transplantation improved light perception in NOD.SCID-rd1 mice, and positive electroretinography signals indicated functional photoreceptor activity in the host’s outer nuclear layer. Graft survival and integration were confirmed using immunohistochemistry, and no animals showed teratoma formation or any kind of ectopic growth in the eye. Conclusions To our knowledge, this is the first demonstration of a unified, scalable, and GMP-adaptable protocol indicating strong animal efficacy and safety data with hiPSC-derived RPE and PRP cells. These findings provide robust proof-of-principle results for IND-enabling studies to test these potential regenerative cell therapies in patients.

scholarly journals Sleeping pattern and activities of daily living modulate protein expression in AMD

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0248523
Author(s):  
Kaushal Sharma ◽  
Ramandeep Singh ◽  
Suresh Kumar Sharma ◽  
Akshay Anand
Keyword(s):  
Regression Analysis ◽  
Environmental Factors ◽  
Activities Of Daily Living ◽  
Daily Living ◽  
Age Related Macular Degeneration ◽  
Multinomial Regression ◽  
Altered Expression ◽  
Age Related ◽  
Multinomial Regression Analysis

Degeneration of macular photoreceptors is a prominent characteristic of age-related macular degeneration (AMD) which leads to devastating and irreversible vision loss in the elderly population. In this exploratory study, the contribution of environmental factors on the progression of AMD pathology by probing the expression of candidate proteins was analyzed. Four hundred and sixty four participants were recruited in the study comprising of AMD (n = 277) and controls (n = 187). Genetics related data was analyzed to demonstrate the activities of daily living (ADL) by using regression analysis and statistical modeling, including contrast estimate, multinomial regression analysis in AMD progression. Regression analysis revealed contribution of smoking, alcohol, and sleeping hours on AMD by altered expression of IER-3, HTRA1, B3GALTL, LIPC and TIMP3 as compared to normal levels. Contrast estimate supports the gender polarization phenomenon in AMD by significant decreased expression of SLC16A8 and LIPC in control population which was found to be unaltered in AMD patients. The smoking, food habits and duration of night sleeping hours also contributed in AMD progression as evident from multinomial regression analysis. Predicted model (prediction estimate = 86.7%) also indicated the crucial role of night sleeping hours along with the decreased expression of TIMP-3, IER3 and SLC16A8. Results revealed an unambiguous role of environmental factors in AMD progression mediated by various regulatory proteins which might result in intermittent AMD phenotypes and possibly influence the outcome of anti-VEGF treatment.

scholarly journals Retinal pathology is associated with increased blood–retina barrier permeability in a diabetic and hypercholesterolaemic pig model: Beneficial effects of the LpPLA2 inhibitor Darapladib

2017 ◽  
Vol 14 (3) ◽  
pp. 200-213 ◽  
Author(s):  
Nimish K Acharya ◽  
Xin Qi ◽  
Eric L Goldwaser ◽  
George A Godsey ◽  
Hao Wu ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Retinopathy ◽  
Structural Changes ◽  
Pyramidal Neurons ◽  
Cell Loss ◽  
Age Related Macular Degeneration ◽  
Altered Expression ◽  
Barrier Permeability ◽  
Beneficial Effects ◽  
Age Related

Using a porcine model of diabetes mellitus and hypercholesterolaemia, we previously showed that diabetes mellitus and hypercholesterolaemia is associated with a chronic increase in blood–brain barrier permeability in the cerebral cortex, leading to selective binding of immunoglobulin G and deposition of amyloid-beta1-42 peptide in pyramidal neurons. Treatment with Darapladib (GlaxoSmithKline, SB480848), an inhibitor of lipoprotein-associated phospholipase-A2, alleviated these effects. Here, investigation of the effects of chronic diabetes mellitus and hypercholesterolaemia on the pig retina revealed a corresponding increased permeability of the blood–retina barrier coupled with a leak of plasma components into the retina, alterations in retinal architecture, selective IgG binding to neurons in the ganglion cell layer, thinning of retinal layers due to cell loss and increased glial fibrillary acidic protein expression in Müller cells, all of which were curtailed by treatment with Darapladib. These findings suggest that chronic diabetes mellitus and hypercholesterolaemia induces increased blood–retina barrier permeability that may be linked to altered expression of blood–retina barrier–associated tight junction proteins, claudin and occludin, leading to structural changes in the retina consistent with diabetic retinopathy. Additionally, results suggest that drugs with vascular anti-inflammatory properties, such as Darapladib, may have beneficial effects on eye diseases strongly linked to vascular abnormalities such as diabetic retinopathy and age-related macular degeneration.

scholarly journals Lutein Supplementation for Eye Diseases

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1721 ◽  
Author(s):  
Long Hin Li ◽  
Jetty Chung-Yung Lee ◽  
Ho Hang Leung ◽  
Wai Ching Lam ◽  
Zhongjie Fu ◽  
...  
Keyword(s):  
De Novo ◽  
Egg Yolk ◽  
Nutritional Supplement ◽  
Eye Diseases ◽  
Age Related Macular Degeneration ◽  
Leafy Vegetables ◽  
High Concentration ◽  
Green Leafy Vegetables ◽  
Beneficial Effects ◽  
Age Related

Lutein is one of the few xanthophyll carotenoids that is found in high concentration in the macula of human retina. As de novo synthesis of lutein within the human body is impossible, lutein can only be obtained from diet. It is a natural substance abundant in egg yolk and dark green leafy vegetables. Many basic and clinical studies have reported lutein’s anti-oxidative and anti-inflammatory properties in the eye, suggesting its beneficial effects on protection and alleviation of ocular diseases such as age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, myopia, and cataract. Most importantly, lutein is categorized as Generally Regarded as Safe (GRAS), posing minimal side-effects upon long term consumption. In this review, we will discuss the chemical structure and properties of lutein as well as its application and safety as a nutritional supplement. Finally, the effects of lutein consumption on the aforementioned eye diseases will be reviewed.

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