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Suppression of Light-Induced Oxidative Stress in the Retina by Mitochondria-Targeted Antioxidant
摘要： Light-induced oxidation of lipids and proteins provokes retinal injuries and results in progression of degenerative retinal diseases, such as, for instance, iatrogenic photic maculopathies. Having accumulated over years retinal injuries contribute to development of age-related macular degeneration (AMD). Antioxidant treatment is regarded as a promising approach to protecting the retina from light damage and AMD. Here, we examine oxidative processes induced in rabbit retina by excessive light illumination with or without premedication using mitochondria-targeted antioxidant SkQ1 (10-(6’-plastoquinonyl)decyltriphenyl-phosphonium). The retinal extracts obtained from animals euthanized within 1–7 days post exposure were analyzed for H2O2, malondialdehyde (MDA), total antioxidant activity (AOA), and activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) using colorimetric and luminescence assays. Oxidation of visual arrestin was monitored by immunoblotting. The light exposure induced lipid peroxidation and H2O2 accumulation in the retinal cells. Unexpectedly, it prominently upregulated AOA in retinal extracts although SOD and GPx activities were compromised. These alterations were accompanied by accumulation of disulfide dimers of arrestin revealing oxidative stress in the photoreceptors. Premedication of the eyes with SkQ1 accelerated normalization of H2O2 levels and redox-status of lipids and proteins, contemporarily enhancing AOA and, likely, sustaining normal activity of GPx. Thus, SkQ1 protects the retina from light-induced oxidative stress and could be employed to suppress oxidative damage of proteins and lipids contributing to AMD.
关键词： SkQ1,superoxide dismutase,glutathione peroxidase,disulfide dimerization of proteins,visual arrestin,age-related macular degeneration,mitochondria-targeted antioxidant,antioxidant activity,light-induced retinal damage,oxidative stress
更新于2025-09-23 15:23:52
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RefMoB, a Reflectivity Feature Model-Based Automated Method for Measuring Four Outer Retinal Hyperreflective Bands in Optical Coherence Tomography
摘要： PURPOSE. To validate a model-driven method (RefMoB) of automatically describing the four outer retinal hyperreflective bands revealed by spectral-domain optical coherence tomography (SDOCT), for comparison with histology of normal macula; to report thickness and position of bands, particularly band 2 (ellipsoid zone [EZ], commonly called IS/OS). METHODS. Foveal and superior perifoveal scans of seven SDOCT volumes of five individuals aged 28 to 69 years with healthy maculas were used (seven eyes for validation, five eyes for measurement). RefMoB determines band thickness and position by a multistage procedure that models reflectivities as a summation of Gaussians. Band thickness and positions were compared with those obtained by manual evaluators for the same scans, and compared with an independent published histological dataset. RESULTS. Agreement among manual evaluators was moderate. Relative to manual evaluation, RefMoB reported reduced thickness and vertical shifts in band positions in a band-specific manner for both simulated and empirical data. In foveal and perifoveal scans, band 1 was thick relative to the anatomical external limiting membrane, band 2 aligned with the outer one-third of the anatomical IS ellipsoid, and band 3 (IZ, interdigitation of retinal pigment epithelium and photoreceptors) was cleanly delineated. CONCLUSIONS. RefMoB is suitable for automatic description of the location and thickness of the four outer retinal hyperreflective bands. Initial results suggest that band 2 aligns with the outer ellipsoid, thus supporting its recent designation as EZ. Automated and objective delineation of band 3 will help investigations of structural biomarkers of dark-adaptation changes in aging.
关键词： age-related macular degeneration,retina,ellipsoid,segmentation,optical coherence tomography,photoreceptors,interdigitation,reflectivity,retinal pigment epithelium
更新于2025-09-23 15:23:52
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Isorhamnetin prevents H2O2?induced oxidative stress in human retinal pigment epithelial cells
摘要： Isorhamnetin, a 3-O-methylated metabolite of quercetin, exhibits antioxidant effects. However, to the best of our knowledge, no study to date has focused on the effects of isorhamnetin on retinal pigment epithelium (RPE) cells, and its underlying molecular mechanisms. Therefore, the present study aimed to examine the potential protective effect of isorhamnetin against oxidative stress in human RPE cells. The results demonstrated that pretreatment of RPE cells with isorhamnetin significantly protected cell viability against oxidative stress. In addition, isorhamnetin pretreatment inhibited hydrogen peroxide (H2O2)-induced reactive oxygen species (ROS) production and caspase-3 activation in RPE cells. Furthermore, isorhamnetin pretreatment significantly increased the phosphorylation of phosphoinositide 3-kinase (PI3K) and AKT serine/threonine kinase 1 (Akt) in RPE cells exposed to H2O2, compared with cells treated with H2O2 alone. Taken together, the present results demonstrated that isorhamnetin protected human RPE cells from oxidative stress-induced cell death, and this effect was associated with activation of the PI3K/Akt signaling pathway. Thus, isorhamnetin may be considered as a potential antioxidant useful for the prevention of age-related macular degeneration.
关键词： age-related macular degeneration,oxidative stress,isorhamnetin,retinal pigment epithelium cells
更新于2025-09-23 15:23:52
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Survival and functionality of xeno-free human embryonic stem cell-derived retinal pigment epithelial cells on polyester substrate after transplantation in rabbits
摘要： Purpose: To study immunogenic properties of human embryonic stem cell–derived retinal pigment epithelium (hESC-RPE) and to evaluate subretinal xenotransplantation of hESC-RPE on porous polyethylene terephthalate (PET) in rabbits. Methods: Human ESC-RPE cells were characterized by morphology, transepithelial electrical resistance (TER), protein expression and photoreceptor outer segment phagocytosis in vitro. Expression of major histocompatibility complex (MHC) proteins was assessed in conventionally or xeno-free produced hESC-RPE with interferon-gamma (IFN-γ) stimulation (n = 1). Xeno-free hESC-RPE on PET with TER < 200 Ω·cm2 or PET alone were transplanted into 18 rabbits with short-term triamcinolone with extended tacrolimus immunosuppression. Rabbits were monitored by spectral domain optical coherence tomography. After 4 weeks, the eyes were processed for histology and transmission electron microscopy. Results: Upon in vitro IFN-γ stimulation, xeno-free hESC-RPE expressed lower level of MHC-II proteins compared to the conventional cells. Outer nuclear layer (ONL) atrophy was observed over the graft in most cases 4 weeks post-transplantation. In 3/4 animals with high TER hESC-RPE, but only in 1/3 animals with low TER hESC-RPE, ONL atrophy was observed already within 1 week. Retinal cell infiltrations were more frequent in animals with high TER hESC-RPE. However, the difference was not statistically significant. In three animals, preservation of ONL was observed. Weekly intravitreal tacrolimus did not affect ONL preservation. In all animals, hESC-RPE cells survived for 4 weeks, but without tacrolimus, enlarged vacuoles accumulated in hESC-RPE (n = 1). Conclusions: Xenografted xeno-free hESC-RPE monolayers can survive and retain some functionality for 4 weeks following short-term immunosuppression. The preliminary findings of this study suggest that further investigations to improve transplantation success of hESC-RPE xenografts in rabbits should be addressed especially toward the roles of hESC-RPE maturation stage and extended intravitreal immunosuppression.
关键词： xeno-free,age-related macular degeneration,cell therapy,RPE transplantation,pluripotent stem cell
更新于2025-09-23 15:23:52
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Fully automated detection of retinal disorders by image-based deep learning
摘要： Purpose With the aging population and the global diabetes epidemic, the prevalence of age-related macular degeneration (AMD) and diabetic macular edema (DME) diseases which are the leading causes of blindness is further increasing. Intravitreal injections with anti-vascular endothelial growth factor (anti-VEGF) medications are the standard of care for their indications. Optical coherence tomography (OCT), as a noninvasive imaging modality, plays a major part in guiding the administration of anti-VEGF therapy by providing detailed cross-sectional scans of the retina pathology. Fully automating OCT image detection can significantly decrease the tedious clinician labor and obtain a faithful pre-diagnosis from the analysis of the structural elements of the retina. Thereby, we explore the use of deep transfer learning method based on the visual geometry group 16 (VGG-16) network for classifying AMD and DME in OCT images accurately and automatically. Method A total of 207,130 retinal OCT images between 2013 and 2017 were selected from retrospective cohorts of 5319 adult patients from the Shiley Eye Institute of the University of California San Diego, the California Retinal Research Foundation, Medical Center Ophthalmology Associates, the Shanghai First People’s Hospital, and the Beijing Tongren Eye Center, with 109,312 images (37,456 with choroidal neovascularization, 11,599 with diabetic macular edema, 8867 with drusen, and 51,390 normal) for the experiment. After images preprocessing, 1000 images (250 images from each category) from 633 patients were selected as validation dataset while the rest images from another 4686 patients were used as training dataset. We used deep transfer learning method to fine-tune the VGG-16 network pre-trained on the ImageNet dataset, and evaluated its performance on the validation dataset. Then, prediction accuracy, sensitivity, specificity, and receiver-operating characteristic (ROC) were calculated. Results Experimental results proved that the proposed approach had manifested superior performance in retinal OCT images detection, which achieved a prediction accuracy of 98.6%, with a sensitivity of 97.8%, a specificity of 99.4%, and introduced an area under the ROC curve of 100%. Conclusion Deep transfer learning method based on the VGG-16 network shows significant effectiveness on classification of retinal OCT images with a relatively small dataset, which can provide assistant support for medical decision-making. Moreover, the performance of the proposed approach is comparable to that of human experts with significant clinical experience. Thereby, it will find promising applications in an automatic diagnosis and classification of common retinal diseases.
关键词： Diabetic macular edema,Visual geometry group 16 network,Age-related macular degeneration,Optical coherence tomography,Deep transfer learning
更新于2025-09-23 15:22:29
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Is Spectral-Domain Optical Coherence Tomography Always Able to Detect the Anti-Vascular Endothelial Growth Factor Action on Neovascular Membrane
摘要： Purpose: To show the presence of an active neovascular membrane in age-related macular degeneration even if optical coherence tomography (OCT) does not detect intra- or sub-retinal edema. Methods: This is a retrospective case report. During the follow-up after the intravitreal injection, 3 patients showed no intraretinal or subretinal edema by OCT; however, there was a progressive reduction in their visual acuity; thus, a fluorangiography (FA) examination was performed. Results: In these 3 cases, FA showed an active neovascular network. Conclusion: OCT could show a real reduction in the edema, but it is not always able to detect neovessel presence. Intravitreal injection could improve the vessel permeability without care and delete the neovascular network.
关键词： Intravitreal injection,Spectral-domain optical coherence tomography,Age-related macular degeneration
更新于2025-09-23 15:22:29
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Characterization of Rod Function Phenotypes Across a Range of Age-Related Macular Degeneration Severities and Subretinal Drusenoid Deposits
摘要： PURPOSE. To examine spatial changes in rod-mediated function in relationship to local structural changes across the central retina in eyes with a spectrum of age-related macular degeneration (AMD) disease severity. METHODS. Participants were categorized into five AMD severity groups based on fundus features. Scotopic thresholds were measured at 14 loci spanning 6° to 18° along the vertical meridian from one eye of each of 42 participants (mean = 71.7 ± 9.9 years). Following a 30% bleach, dark adaptation was measured at eight loci (4° to 12°). Rod intercept time (RIT) was defined from the time to detect a ?3.1 log cd/m2 stimulus. RITslope was defined from the linear fit of RIT with decreasing retinal eccentricity. The presence of subretinal drusenoid deposits (SDD), ellipsoid (EZ) band disruption, and drusen at the test loci was evaluated using optical coherence tomography. RESULTS. Scotopic thresholds indicated greater rod function loss in the macula, which correlated with increasing AMD group severity. RITslope, which captures the spatial change in the rate of dark adaptation, increased with AMD severity (P < 0.0001). Three rod function phenotypes emerged: RF1, normal rod function; RF2, normal scotopic thresholds but slowed dark adaptation; and RF3, elevated scotopic thresholds with slowed dark adaptation. Dark adaptation was slowed at all loci with SDD or EZ band disruption, and at 32% of loci with no local structural changes. CONCLUSIONS. Three rod function phenotypes were defined from combined measurement of scotopic threshold and dark adaptation. Spatial changes in dark adaptation across the macula were captured with RITslope, which may be a useful outcome measure for functional studies of AMD.
关键词： age-related macular degeneration,RIT,SDD,scotopic thresholds,dark adaptation,rod intercept time,subretinal drusenoid deposits,AMD
更新于2025-09-23 15:22:29
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Determining Optimal Test Parameters for Assessing Dark Adaptation in People With Intermediate Age-Related Macular Degeneration
摘要： PURPOSE. The primary aim was to determine optimal test conditions for evaluating dark adaptation in intermediate age-related macular degeneration (iAMD) in order to minimize test time while maintaining diagnostic sensitivity. METHODS. People with AMD and age-similar controls were recruited (aged >55 years). Rod intercept time (RIT) was assessed after a 76%, 70%, and 65% rhodopsin bleach at 5° eccentricity and 76% and 70% bleach at 12°. Test order was randomized and a 30-minute washout period added between tests. Results were compared between control and iAMD groups and receiver operating characteristics (ROC) curves were constructed. RESULTS. A total of 26 participants with variable grades of macular health attended for two visits. There was a statistically significant difference in average RIT between the control and iAMD groups at 5° (median, IQR controls = 5.8 minutes, 3.8–7.5; iAMD = 20.6 minutes, 11.1–30.0; Mann-Whitney, P = 0.01) and at 12° (mean, controls: 4.54 minutes ± 2.12 SD, iAMD = 7.72 minutes ± 3.37 SD; independent samples t-test, P = 0.03) following a 76% bleach. Area under the ROC curves was 0.83 (confidence interval [CI]: 0.64–1.0) and 0.79 (CI: 0.59–0.99) for these two test conditions, respectively. Five participants (45%) in the iAMD group had RITs >20 minutes for 76% bleach at 5°, but none for any other test condition. CONCLUSIONS. Nearly half of the participants with iAMD produced unacceptably long recovery times (>20 minutes) using a 76% bleach at 5° eccentricity. The 76% bleach at 12° provided almost equivalent separation between AMD and controls but recovery was achieved within 20 minutes.
关键词： rod intercept time,age-related macular degeneration,dark adaptation
更新于2025-09-23 15:22:29
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Critical evaluation of the off-label indication and of the risks associated to the use of multi-dose vials on the treatment of age-related macular degeneration
摘要： Age-related macular degeneration (AMD) is an ocular inflammatory diseases treated mainly by means of a bevacizumab (Avastin?) or ranibizumab (Lucentis?) intravitreal injection. Among these drugs, only ranibizumab has a specific therapeutic indication for AMD. Considering that, the off-label use on ophthalmic therapy seems to become a rule when it should be an exception. Furthermore, bevacizumab presentation consists of multi-dose vials although it does not contain preservatives in its formula. The current literature review aimed at assessing the risks for the patient related to the use of off-label indication and multi-dose vials on AMD treatment. Considering this, the proposal related to the Brazilian Public Consultation no.10, dated September 12, 2012, which proposes the Clinical Protocol and Therapeutic Guidelines for AMD treatment, was evaluated. This systematic review allowed to conclude that the bevacizumab off-label indication results in increased risks for the patient when compared to the product with specific therapeutic indication for AMD treatment (ranibizumab), especially referring to the significant raise in the adverse events. The risks for the patient related to the multi-dose vial use, referring to the microbiological stability and dose precision, were also made clear.
关键词： Multi-dose vials/patients risks,Ranibizumab/intravitreal injection,Age-related macular degeneration/treatment,Off-label indication/patients risks,Ophthalmic therapy/off-label use,Bevacizumab/intravitreal injection
更新于2025-09-23 15:22:29
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DeepSeeNet: A Deep Learning Model for Automated Classification of Patient-based Age-related Macular Degeneration Severity from Color Fundus Photographs
摘要： In assessing the severity of age-related macular degeneration (AMD), the Age-Related Eye Disease Study (AREDS) Simplified Severity Scale predicts the risk of progression to late AMD. However, its manual use requires the time-consuming participation of expert practitioners. Although several automated deep learning systems have been developed for classifying color fundus photographs (CFP) of individual eyes by AREDS severity score, none to date has used a patient-based scoring system that uses images from both eyes to assign a severity score. Design: DeepSeeNet, a deep learning model, was developed to classify patients automatically by the AREDS Simplified Severity Scale (score 0e5) using bilateral CFP. Participants: DeepSeeNet was trained on 58 402 and tested on 900 images from the longitudinal follow-up of 4549 participants from AREDS. Gold standard labels were obtained using reading center grades. Methods: DeepSeeNet simulates the human grading process by first detecting individual AMD risk factors (drusen size, pigmentary abnormalities) for each eye and then calculating a patient-based AMD severity score using the AREDS Simplified Severity Scale. Main Outcome Measures: Overall accuracy, specificity, sensitivity, Cohen’s kappa, and area under the curve (AUC). The performance of DeepSeeNet was compared with that of retinal specialists. Results: DeepSeeNet performed better on patient-based classification (accuracy ? 0.671; kappa ? 0.558) than retinal specialists (accuracy ? 0.599; kappa ? 0.467) with high AUC in the detection of large drusen (0.94), pigmentary abnormalities (0.93), and late AMD (0.97). DeepSeeNet also outperformed retinal specialists in the detection of large drusen (accuracy 0.742 vs. 0.696; kappa 0.601 vs. 0.517) and pigmentary abnormalities (accuracy 0.890 vs. 0.813; kappa 0.723 vs. 0.535) but showed lower performance in the detection of late AMD (accuracy 0.967 vs. 0.973; kappa 0.663 vs. 0.754). Conclusions: By simulating the human grading process, DeepSeeNet demonstrated high accuracy with increased transparency in the automated assignment of individual patients to AMD risk categories based on the AREDS Simplified Severity Scale. These results highlight the potential of deep learning to assist and enhance clinical decision-making in patients with AMD, such as early AMD detection and risk prediction for developing late AMD. DeepSeeNet is publicly available on https://github.com/ncbi-nlp/DeepSeeNet.
关键词： deep learning,age-related macular degeneration,automated classification,AREDS Simplified Severity Scale,color fundus photographs
更新于2025-09-23 15:22:29