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1.
Oxidative stress in retinal pigment epithelium impairs stem cells: a vicious cycle in age-related macular degeneration.
Lazzarini, R, Nicolai, M, Lucarini, G, Pirani, V, Mariotti, C, Bracci, M, Mattioli-Belmonte, M
Molecular and cellular biochemistry. 2022;(1):67-77
Abstract
Aging, chronic oxidative stress, and inflammation are major pathogenic factors in the development and progression of age-related macular degeneration (AMD) with the loss of retinal pigment epithelium (RPE). The human RPE contains a subpopulation of progenitors (i.e., RPE stem cells-RPESCs) whose role in the RPE homeostasis is under investigation. We evaluated the paracrine effects of mature RPE cells exposed to oxidative stress (H2O2) on RPESCs behavior through co-cultural, morphofunctional, and bioinformatic approaches. RPESCs showed a decline in proliferation, an increase of the senescence-associated β-galactosidase activity, the acquisition of a senescent-like secretory phenotype (SASP), and the reduction of their stemness and differentiation competencies. IL-6 and Superoxide Dismutase 2 (SOD2) seem to be key molecules in RPESCs response to oxidative stress. Our results get insight into stress-induced senescent-associated molecular mechanisms implicated in AMD pathogenesis. The presence of chronic oxidative stress in the microenvironment reduces the RPESCs abilities, inducing and/or maintaining a pro-inflammatory retinal milieu that in turn could affect AMD onset and progression.
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2.
Low luminance visual acuity as a clinical measure and clinical trial outcome measure: a scoping review.
Wood, LJ, Jolly, JK, Buckley, TM, Josan, AS, MacLaren, RE
Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists). 2021;(2):213-223
Abstract
PURPOSE The measurement of standard visual acuity (VA) is the most well-known part of any ophthalmic examination to indicate visual function. Despite this, it is insensitive in detecting early disease changes. Therefore, other visual function tests have been developed including low luminance VA (LLVA) and low luminance deficit (LLD). This scoping literature review aims to summarise the current published applications of LLVA and LLD assessments to evaluate their utility as clinical markers and research outcome measures in a variety of ophthalmic conditions. RECENT FINDINGS Sixty-five peer-reviewed publications were included. LLVA was pioneered for use in geographic atrophy, a subtype of age-related macular degeneration, which remains the mainstay of its clinical application. However, other studies have reported additional useful applications in inherited retinal diseases including rare maculopathies and rod-cone dystrophies. Although there are some variations in testing methodology, use of the standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart with a 2.0 log unit neutral density filter is the most popular approach. The optimal testing luminance is still to be defined. SUMMARY Overall, LLVA is an earlier clinical marker of change in central retinal function than standard VA. It has been shown to be a risk factor for disease progression and a better indicator of a patient's level of everyday visual function. It is inexpensive and simple to implement using readily available standard ophthalmic equipment.
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3.
Anti-Inflammatory and Anti-Oxidative Synergistic Effect of Vitamin D and Nutritional Complex on Retinal Pigment Epithelial and Endothelial Cell Lines against Age-Related Macular Degeneration.
Hernandez, M, Recalde, S, González-Zamora, J, Bilbao-Malavé, V, Sáenz de Viteri, M, Bezunartea, J, Moreno-Orduña, M, Belza, I, Barrio-Barrio, J, Fernandez-Robredo, P, et al
Nutrients. 2021;(5)
Abstract
Age-related macular degeneration (AMD) is a multifactorial disease of the retina featured by dysfunction of retinal pigmented epithelial (RPE) and loss of photoreceptor cells under oxidative stress and inflammatory conditions. Vitamin D and antioxidants have beneficial effects against retinal degenerative diseases, such as AMD. We investigated the impact of associating vitamin D (ND) with a nutritional antioxidant complex (Nutrof Total®; N) on oxidative stress and inflammation-like induced conditions by H2O2 and LPS, respectively, in human retinal epithelial (ARPE-19) and human retinal endothelial (HREC) cells. Application of either N or ND treatments to H2O2-induced media in ARPE-19 cells counteracted late apoptosis, attenuated oxidative DNA damage, and increased cell proliferation. Significant reduction in the expression levels of MCP1, IL-8, and IL6 cytokines was observed following application of either N or ND treatments under LPS-induced conditions in ARPE-19 cells and in MCP-1 and IL12p70 cytokine levels in HREC cells. ND and not N revealed significant downregulation of IFNγ in ARPE-19 cells, and of IL-6 and IL-18 in HREC cells. In conclusion, adding vitamin D to Nutrof Total® protects in a synergistic way against oxidative and inflammatory stress-induced conditions in retinal epithelial and endothelial cells.
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4.
Effects of Zinc Acetate Hydrate Treatment on Serum Oxidative Stress Markers in Patients with Macular Drusen.
Mano, F, Sakata, S, Chang, KC, Mano, T
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics. 2021;(9):518-524
Abstract
Purpose: To measure the serum levels of the oxidative stress markers superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GPx) and compare them before and after zinc supplementation in patients with early age-related macular degeneration (AMD). Methods: We measured serum zinc levels in 65 patients with early AMD. Of these, 29 patients with macular drusen and a serum zinc level <80 μg/dL received oral zinc acetate dihydrate (50 mg/day). Serum trace metal levels (zinc and copper) and oxidative stress marker levels (SOD, MDA, and GPx) were measured at baseline and 12 weeks after the treatment. The macular drusen areas and best-corrected visual acuity were evaluated in 24 participants who attended the 3-month follow-up. Results: MDA level was significantly decreased from baseline to 12 weeks after zinc administration (170.5 ± 100.9 vs. 148.3 ± 57.9 pmol/mL, P = 0.03), while SOD was significantly increased from baseline to 12 weeks after zinc intake (4.2 ± 0.9 vs. 4.6 ± 0.9 U/mL, P = 0.03). The serum zinc level was significantly correlated with the MDA level (P = 0.03, ρ = -0.26). The area of soft drusen was significantly decreased after zinc treatment (1,936,654.9 ± 1,348,267.6 vs. 966,883.9 ± 719,938.1 μmm2, P = 0.04). Conclusions: The levels of oxidative stress markers MDA and SOD decreased and increased, respectively, after oral zinc administration to 24 patients with AMD. The therapeutic effect of zinc treatment on drusen area might differ depending on the drusen phenotype in early AMD.
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5.
Impact of the Natural Compound Urolithin A on Health, Disease, and Aging.
D'Amico, D, Andreux, PA, Valdés, P, Singh, A, Rinsch, C, Auwerx, J
Trends in molecular medicine. 2021;(7):687-699
Abstract
Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranate, berries, and nuts. UA was discovered 40 years ago, but only recently has its impact on aging and disease been explored. UA enhances cellular health by increasing mitophagy and mitochondrial function and reducing detrimental inflammation. Several preclinical studies show how UA protects against aging and age-related conditions affecting muscle, brain, joints, and other organs. In humans, benefits of UA supplementation in the muscle are supported by recent clinical trials in elderly people. Here, we review the state of the art of UA's biology and its translational potential as a nutritional intervention in humans.
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6.
Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.
Yeong, JL, Loveman, E, Colquitt, JL, Royle, P, Waugh, N, Lois, N
The Cochrane database of systematic reviews. 2020;(12):CD013154
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Abstract
BACKGROUND Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein. OBJECTIVES To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy). DATA COLLECTION AND ANALYSIS Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach. MAIN RESULTS We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm2/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. AUTHORS' CONCLUSIONS There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.
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Diagnostic Accuracy of Technology-based Eye Care Services: The Technology-based Eye Care Services Compare Trial Part I.
Maa, AY, Medert, CM, Lu, X, Janjua, R, Howell, AV, Hunt, KJ, McCord, S, Giangiacomo, A, Lynch, MG
Ophthalmology. 2020;(1):38-44
Abstract
PURPOSE Ophthalmologic telemedicine has the ability to provide eye care for patients remotely, and many countries have used screening tele-ophthalmology programs for several years. One such initiative at the Veterans Affairs (VA) Healthcare System is Technology-based Eye Care Services (TECS). The TECS services are located in primary care clinics and provide basic screening eye care, including vision, refraction, and retinal photography. Eye care providers ("readers") review the clinical data and recommend appropriate follow-up. One of the most common referrals from TECS has been for glaucoma, and this study was powered for glaucoma/glaucoma suspect detection. The current study was undertaken to identify aspects of the protocol that could be refined to enhance accuracy. DESIGN Prospective comparison between the standard TECS protocol versus a face-to-face (FTF) examination on 256 patients, all of whom had no known history of significant ocular disease. PARTICIPANTS Patients with no known ocular disease who were scheduled for an in-person eye appointment at the Atlanta VA. Patients underwent screening through the TECS protocol and received an FTF examination on the same day (gold standard). The TECS readers were masked to the results of the FTF examination. MAIN OUTCOME MEASURES Percent agreement, kappa, sensitivity, and specificity were calculated for the TECS readers' interpretations versus the FTF examination. RESULTS The TECS readers showed substantial agreement for cataract (κ ≥ 0.71) and diabetic retinopathy (κ ≥ 0.61) and moderate to substantial agreement for glaucoma/glaucoma suspect (κ ≥ 0.52) compared with an FTF examination. Age-related macular degeneration (AMD) showed moderate agreement (κ ≥ 0.34). Percent agreement with the TECS protocol was high (84.3%-98.4%) for each of the disease categories. Overall sensitivity and specificity were ≥75% and ≥55%, respectively, for any diagnosis resulting in referral. Inter-reader and intra-reader agreement was substantial for most diagnoses (κ > 0.61) with percent agreements ranging from 66% to 99%. CONCLUSIONS Our results indicate that the standard TECS protocol is accurate when compared with an FTF examination for the detection of common eye diseases. The inclusion of additional testing such as OCT could further enhance diagnostic capability.
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Potential Therapeutic Benefit of NAD+ Supplementation for Glaucoma and Age-Related Macular Degeneration.
Cimaglia, G, Votruba, M, Morgan, JE, André, H, Williams, PA
Nutrients. 2020;(9)
Abstract
Glaucoma and age-related macular degeneration are leading causes of irreversible blindness worldwide with significant health and societal burdens. To date, no clinical cures are available and treatments target only the manageable symptoms and risk factors (but do not remediate the underlying pathology of the disease). Both diseases are neurodegenerative in their pathology of the retina and as such many of the events that trigger cell dysfunction, degeneration, and eventual loss are due to mitochondrial dysfunction, inflammation, and oxidative stress. Here, we critically review how a decreased bioavailability of nicotinamide adenine dinucleotide (NAD; a crucial metabolite in healthy and disease states) may underpin many of these aberrant mechanisms. We propose how exogenous sources of NAD may become a therapeutic standard for the treatment of these conditions.
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9.
Beyond AREDS Formulations, What Is Next for Intermediate Age-Related Macular Degeneration (iAMD) Treatment? Potential Benefits of Antioxidant and Anti-inflammatory Apocarotenoids as Neuroprotectors.
Camelo, S, Latil, M, Veillet, S, Dilda, PJ, Lafont, R
Oxidative medicine and cellular longevity. 2020;:4984927
Abstract
Age-related macular degeneration (AMD) is the commonest cause of severe visual loss and blindness in developed countries among individuals aged 60 and older. AMD slowly progresses from early AMD to intermediate AMD (iAMD) and ultimately late-stage AMD. Late AMD encompasses either neovascular AMD (nAMD) or geographic atrophy (GA). nAMD is defined by choroidal neovascularization (CNV) and hemorrhage in the subretinal space at the level of the macula. This induces a rapid visual impairment caused by the death of photoreceptor cells. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) antibodies is the standard treatment of nAMD but adds to the burden of patient care. GA is characterized by slowly expanding photoreceptor, and retinal pigment epithelium (RPE) degeneration patches progressively leading to blindness. There is currently no therapy to cure GA. Late AMD continues to be an unmet medical need representing a major health problem with millions of patients worldwide. Oxidative stress and inflammation are recognized as some of the main risk factors to developing late AMD. The antioxidant formulation AREDS (Age-Related Eye Disease Studies), contains β-carotene, which has been replaced by lutein and zeaxanthin in AREDS2, are given to patients with iAMD but have a limited effect on the incidence of nAMD and GA. Thus, to avoid or slowdown the development of late stages of AMD (nAMD or GA), new therapies targeting iAMD are needed such as crocetin obtained through hydrolysis of crocin, an important component of saffron (Crocus sativus L.), and norbixin derived from bixin extracted from Bixa orellana seeds. We have shown that these apocarotenoids preserved more effectively RPE cells against apoptosis following blue light exposure in the presence of A2E than lutein and zeaxanthin. In this review, we will discuss the potential use of apocarotenoids to slowdown the progression of iAMD, to reduce the incidence of both forms of late AMD.
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10.
Dietary Patterns, Carbohydrates, and Age-Related Eye Diseases.
Francisco, SG, Smith, KM, Aragonès, G, Whitcomb, EA, Weinberg, J, Wang, X, Bejarano, E, Taylor, A, Rowan, S
Nutrients. 2020;(9)
Abstract
Over a third of older adults in the U.S. experience significant vision loss, which decreases independence and is a biomarker of decreased health span. As the global aging population is expanding, it is imperative to uncover strategies to increase health span and reduce the economic burden of this age-related disease. While there are some treatments available for age-related vision loss, such as surgical removal of cataracts, many causes of vision loss, such as dry age-related macular degeneration (AMD), remain poorly understood and no treatments are currently available. Therefore, it is necessary to better understand the factors that contribute to disease progression for age-related vision loss and to uncover methods for disease prevention. One such factor is the effect of diet on ocular diseases. There are many reviews regarding micronutrients and their effect on eye health. Here, we discuss the impact of dietary patterns on the incidence and progression of age-related eye diseases, namely AMD, cataracts, diabetic retinopathy, and glaucoma. Then, we focus on the specific role of dietary carbohydrates, first by outlining the physiological effects of carbohydrates on the body and then how these changes translate into eye and age-related ocular diseases. Finally, we discuss future directions of nutrition research as it relates to aging and vision loss, with a discussion of caloric restriction, intermittent fasting, drug interventions, and emerging randomized clinical trials. This is a rich field with the capacity to improve life quality for millions of people so they may live with clear vision for longer and avoid the high cost of vision-saving surgeries.