Therapeutic Effect of Garcinia cambogia Extract and Hydroxycitric Acid Inhibiting Hypoxia-Inducible Factor in a Murine Model of Age-Related Macular Degeneration

Background: Age-related macular degeneration (AMD) is the leading cause of blindness and can be classified into two types called atrophic AMD (dry AMD) and neovascular AMD (wet AMD). Dry AMD is characterized by cellular degeneration of the retinal pigment epithelium, choriocapillaris, and photoreceptors. Wet AMD is characterized by the invasion of abnormal vessels from the choroid. Although anti-vascular endothelial growth factor (VEGF) therapy has a potent therapeutic effect against the disease, there is a possibility of chorio-retinal atrophy and adverse systemic events due to long-term robust VEGF antagonism. We focused on hypoxia-inducible factor (HIF) regulation of VEGF transcription, and report the suppressive effects of HIF inhibition against ocular phenotypes in animal models. Many of the known HIF inhibitors are categorized as anti-cancer drugs, and their systemic side effects are cause for concern in clinical use. In this study, we explored food ingredients that have HIF inhibitory effects and verified their effects in an animal model of AMD. Methods: Food ingredients were screened using a luciferase assay. C57BL6/J mice were administered the Garcinia cambogia extract (Garcinia extract) and hydroxycitric acid (HCA). Choroidal neovascularization (CNV) was induced by laser irradiation. Results: Garcinia extract and HCA showed inhibitory effects on HIF in the luciferase assay. The laser CNV model mice showed significant reduction of CNV volume by administering Garcinia extract and HCA. Conclusions: Garcinia extract and HCA showed therapeutic effects in a murine AMD model.

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Outer retinal tubulation formation and clinical course of advanced age-related macular degeneration

Scientific Reports ◽

10.1038/s41598-021-94310-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alessandro Arrigo ◽

Emanuela Aragona ◽

Ottavia Battaglia ◽

Andrea Saladino ◽

Alessia Amato ◽

...

Keyword(s):

Macular Degeneration ◽

Müller Cells ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Advanced Age ◽

Age Related ◽

Dry Amd ◽

Foveal Sparing ◽

Wet Amd

AbstractOuter retinal tubulations (ORT) are a relatively new finding characterizing outer retinal atrophy. The main aim of the present study was to describe ORT development in advanced age-related macular degeneration (AMD) and to assess its relationship with disease’s severity. Patients with advanced AMD characterized either by macular neovascularization or geographic atrophy, showing signs of outer retinal disruption or retinal pigment epithelium atrophy on structural optical coherence tomography (OCT) at the inclusion examination were prospectively recruited. All the patients underwent complete ophthalmologic evaluation, structural OCT scans and fundus autofluorescence imaging. The planned follow-up was of 3-years. Main outcome measures were ORT prevalence, mechanism of ORT formation, mean time needed for complete ORT formation, best-corrected visual acuity (BCVA), definitely decreased autofluorescence (DDAF) area, questionably decreased autofluorescence (QDAF) area, retinal layer thickness, foveal sparing, number of intravitreal injections. We also assessed the possible role of external limiting membrane (ELM) and Müller cells in ORT pathogenesis. Seventy eyes (70 patients) were included; 43 showed dry AMD evolving to geographic atrophy, while 27 displayed the features of wet AMD. Baseline BCVA was 0.5 ± 0.5 LogMAR, decreasing to 0.9 ± 0.5 LogMAR at the 3-year follow-up (p < 0.01). We detected completely formed ORT in 26/70 eyes (37%), subdivided as follows: 20 eyes (77%) wet AMD and 6 eyes (23%) dry AMD (p < 0.01). ORT took 18 ± 8 months (range 3–35 months) to develop fully. We described the steps leading to ORT development, characterized by progressive involvement of, and damage to the photoreceptors, the ELM and the RPE. Eyes displaying ORT were associated with a smaller QDAF area, less retinal layers damage and lower rate of foveal sparing than eyes free of ORT (p < 0.01). We also described pigment accumulations simulating ORT, which were detected in 16/70 eyes (23%), associated with a greater loss of foveal sparing, increased DDAF area and smaller QDAF area at the 3-year follow-up (p < 0.01). In conclusion, this study provided a description of the steps leading to ORT development in AMD. ELM and Müller cells showed a role in ORT pathogenesis. Furthermore, we described a subtype of pigment hypertrophy mimicking ORT, evaluating its clinical utility.

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Efficacy of Vitrectomy and Macular Hole Repair in Eyes With Dry Age-Related Macular Degeneration

Journal of VitreoRetinal Diseases ◽

10.1177/2474126418825220 ◽

2019 ◽

Vol 3 (2) ◽

pp. 94-98

Author(s):

Omar M. Ismail ◽

Lauren Mason ◽

John O. Mason

Keyword(s):

Macular Degeneration ◽

Macular Hole ◽

Age Related Macular Degeneration ◽

Complication Rates ◽

Age Related ◽

Macular Holes ◽

Pars Plana ◽

Dry Amd ◽

Wet Amd

Purpose: The purpose of this article is to examine the efficacy of macular hole repair in eyes with coexisting dry age-related macular degeneration (AMD). Methods: A retrospective analysis was performed of charts of 25 patients (27 eyes) diagnosed with mild to moderate dry AMD who underwent macular hole repair via 25-gauge pars plana vitrectomy between 2014 and 2016. Data of interest included anatomic failure rates, complication rates, and best-corrected visual acuity (BCVA) preoperatively, and at 1 month, 3 months, 6 months, and 12 months postoperatively. When available, data at each patient’s most recent visit were also analyzed. Results: Macular hole repair resulted in a statistically significant ( P < .05) visual improvement postoperatively, with BCVA increasing from 20/141 preoperatively to 20/33 1 year postoperatively. Mean BCVA at most recent visit was 20/41. Mean duration of follow-up was 13 months (range, 1-39 months). One of 27 (3.7%) macular holes failed to close after vitrectomy. One of 27 eyes (3.7%) progressed from dry to wet AMD. Four of 27 additional eyes (18.5%) were noted to have worsening of their AMD on exam over the course of follow-up. Conclusions: Macular hole repair in patients with coexisting dry AMD leads to a significant improvement in visual performance and has a low risk of failure or complication.

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THE HOMING TRIAL: A RETROSPECTIVE PILOT STUDY ON THE EFFICACY OF PERSONALIZED BIOIDENTICAL HORMONE, DIETARY SUPPLEMENT AND NUTRITION CARE PLANS FOR AGE-RELATED MACULAR DEGENERATION (AMD)

International Journal of Medical and Biomedical Studies ◽

10.32553/ijmbs.v5i4.1886 ◽

2021 ◽

Vol 5 (4) ◽

Author(s):

George W. Rozakis ◽

Brian A. Bakke

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Visual Acuity ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Control Group ◽

Care Plans ◽

Age Related ◽

Dry Amd ◽

Wet Amd

The objective of the Hormones, Oxidative stress, Methylation, Inflammation and Gene expression (HOMING) trial was to assess the efficacy of personalized bio identical hormone, dietary supplement and nutritional care plans on dry and wet Age-related Macular Degeneration (AMD) outcomes. We evaluated 220 Age-related Macular Degeneration (AMD) patients that followed a personalized clinical care plan for up to 9 months. The care plans consisted of bio identical hormones, dietary supplements and nutrition recommendations with the objective to improve lab and clinical measurements linked to oxidative stress, inflammation and gene expression. Serum concentrations of CRP, HbA1c and homocysteine responded favorably to the HOMING protocol with full program compliance. Sixty percent (42/70) of wet AMD patients reported improvement in visual acuity and/or a reduction in the frequency of anti-VEGF injections during the study period. Forty eight percent (44/92) of dry AMD patients reported improvement in visual acuity during the study period. Nine percent (4/45) patients reported improvement in visual acuity in the dry AMD control group and no (0/13) wet AMD patients in the control group reported improvement. Six percent (4/70) of wet AMD patients reported that their vision declined and/or that their F frequency increased during the study period. Five percent (4/92) of dry AMD patients reported that their vision was worse. Keywords: Bio identical Hormones, Oxidative stress, Methylation, Inflammation, Gene Expression, Nutrition and AMD.

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Differential Circulating MicroRNA Expression in Age-Related Macular Degeneration

International Journal of Molecular Sciences ◽

10.3390/ijms222212321 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12321

Author(s):

Hanan ElShelmani ◽

Ian Brennan ◽

David J. Kelly ◽

David Keegan

Keyword(s):

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Published Data ◽

Circulating Microrna ◽

Healthy Controls ◽

Age Related ◽

At Risk Populations ◽

Dry Amd ◽

Polymerase Chain ◽

Wet Amd

This study explored the expression of several miRNAs reported to be deregulated in age-related macular degeneration (AMD). Total RNA was isolated from sera from patients with dry AMD (n = 12), wet AMD (n = 14), and controls (n = 10). Forty-two previously investigated miRNAs were selected based on published data and their role in AMD pathogenesis, such as angiogenic and inflammatory effects, and were co-analysed using a miRCURY LNA miRNA SYBR® Green PCR kit via quantitative real-time polymerase chain reaction (qRT-PCR) to validate their presence. Unsupervised hierarchical clustering indicated that AMD serum specimens have a different miRNA profile to healthy controls. We successfully validated the differentially regulated miRNAs in serum from AMD patients versus controls. Eight miRNAs (hsa-let-7a-5p, hsa-let-7d-5p, hsa-miR-23a-3p, hsa-miR-301a-3p, hsa-miR-361-5p, hsa-miR-27b-3p, hsa-miR-874-3p, hsa-miR-19b-1-5p) showed higher expression in the serum of dry AMD patients than wet AMD patients and compared with healthy controls. Increased quantities of certain miRNAs in the serum of AMD patients indicate that these miRNAs could potentially serve as diagnostic AMD biomarkers and might be used as future AMD treatment targets. The discovery of significant serum miRNA biomarkers in AMD patients would provide an easy screening tool for at-risk populations.

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A Prospective Study on Hereditary Bias of Age-Related Macular Degeneration

Journal of VitreoRetinal Diseases ◽

10.1177/2474126418822890 ◽

2019 ◽

Vol 3 (2) ◽

pp. 90-93

Author(s):

Rami Gabriel ◽

Jaime Toledo-Corral ◽

Maria Cristina Kenney ◽

Mitul Mehta

Keyword(s):

Family History ◽

Macular Degeneration ◽

Transmitted Disease ◽

Disease Process ◽

Age Related Macular Degeneration ◽

Age Related ◽

Increased Risk ◽

History Of ◽

Dry Amd ◽

Wet Amd

Purpose: This study employed a prospective survey to evaluate whether maternal family history or paternal family history is more likely to be found in patients with age-related macular degeneration (AMD). Methods: Family history of AMD was ascertained through a survey questionnaire of 346 patients who were confirmed by an ophthalmologist to have AMD. To compare proportions of maternally and paternally transmitted disease, the data were treated as pair matched and analyzed using the modified chi-squared McNemar test. Probands with either parent deceased before age 60 were excluded. Further analysis was conducted by grouping wet-AMD and dry-AMD patients. Results: Of the 346 surveys conducted, 91 (26.3%) reported at least 1 parent affected with AMD. Probands were 65.9% women and 44.1% men. The mean ± SD age for men was 74.3 ± 6.3 years and for women 72.7 ± 7.7 years. The average age of proband fathers was 75.0 ± 6.9 years and of proband mothers 80.1 ± 6.0 years. Probands with AMD had a higher proportion of affected mothers than fathers with an odds ratio (OR) of 3.00 and a 95% CI of 1.73 to 5.44, P = .0001. For wet AMD, the OR was 4.0 (95% CI 1.46 to 13.6) and for dry AMD, the OR was 2.6 (95% CI 1.35 to 5.4). Conclusions: Our results indicate that individuals with maternal history of AMD may be at a significantly increased risk for developing AMD than if their father had the disease. Owing to limitations in sample size and discrepancies in lifespan between sexes, further studies will be needed to generalize results. The maternal proclivity in our study sample correlates with literature describing a mitochondrial component in the disease process, soliciting further exploration into mitochondrial etiology and larger hereditary studies.

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Differential Expression of Kinin Receptors in Human Wet and Dry Age-Related Macular Degeneration Retinae

Pharmaceuticals ◽

10.3390/ph13060130 ◽

2020 ◽

Vol 13 (6) ◽

pp. 130

Author(s):

Rahmeh Othman ◽

Simon Berbari ◽

Elvire Vaucher ◽

Réjean Couture

Keyword(s):

Macular Degeneration ◽

Retinal Disease ◽

Clinical Findings ◽

Age Related Macular Degeneration ◽

Primary Role ◽

Kinin Receptors ◽

Age Related ◽

Mediators Of Inflammation ◽

Dry Amd ◽

Wet Amd

Kinins are vasoactive peptides and mediators of inflammation, which signal through two G protein-coupled receptors, B1 and B2 receptors (B1R, B2R). Recent pre-clinical findings suggest a primary role for B1R in a rat model of wet age-related macular degeneration (AMD). The aim of the present study was to investigate whether kinin receptors are differentially expressed in human wet and dry AMD retinae. The cellular distribution of B1R and B2R was examined by immunofluorescence and in situ hybridization in post-mortem human AMD retinae. The association of B1R with inflammatory proteins (inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor A (VEGFA)), fibrosis markers and glial cells was also studied. While B2R mRNA and protein expression was not affected by AMD, a significant increase of B1R mRNA and immunoreactivity was measured in wet AMD retinae when compared to control and dry AMD retinae. B1R was expressed by Müller cells, astrocytes, microglia and endothelial/vascular smooth muscle cells, and colocalized with iNOS and fibrosis markers, but not with VEGFA. In conclusion, the induction and upregulation of the pro-inflammatory and pro-fibrotic kinin B1R in human wet AMD retinae support previous pre-clinical studies and provide a clinical proof-of-concept that B1R represents an attractive therapeutic target worth exploring in this retinal disease.

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Pharmacological Advances in the Treatment of Age-related Macular Degeneration

Current Medicinal Chemistry ◽

10.2174/0929867326666190726121711 ◽

2020 ◽

Vol 27 (4) ◽

pp. 583-598 ◽

Cited By ~ 4

Author(s):

María Gil-Martínez ◽

Paz Santos-Ramos ◽

Maribel Fernández-Rodríguez ◽

Maximino J. Abraldes ◽

Maria José Rodríguez-Cid ◽

...

Keyword(s):

Clinical Trials ◽

Macular Degeneration ◽

Gold Standard ◽

Standard Treatment ◽

The Other ◽

Age Related Macular Degeneration ◽

Age Related ◽

Safety Studies ◽

Dry Amd ◽

Wet Amd

Age-related macular degeneration is an acquired degenerative disease that is responsible for severe loss of vision in elderly people. There are two types: dry age-related macular degeneration and wet age-related macular degeneration. Its treatment has been improved and tries to be tailored in the future. The aim of this review is to summarize the pharmacological advances in the treatment of age-related macular degeneration. Regarding dry AMD, there is no effective treatment to reduce its progression. However, some molecules such as lampalizumab and eculizumab were under investigation, although they have shown low efficacy. Herein, in an attempt to prevent dry AMD progression, the most important studies suggested increasing the antioxidants intake and quitting the smoke habit. On the other hand, wet AMD has more developed treatment. Nowadays, the gold standard treatment is anti-VEGF injections. However, more effective molecules are currently under investigation. There are different molecules under research for dry AMD and wet AMD. This fact could help us treat our patients with more effective and lasting drugs but more clinical trials and safety studies are required in order to achieve an optimal treatment.

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Recent advances in the management and understanding of macular degeneration

F1000Research ◽

10.12688/f1000research.10998.1 ◽

2017 ◽

Vol 6 ◽

pp. 519 ◽

Cited By ~ 5

Author(s):

Sepehr Bahadorani ◽

Michael Singer

Keyword(s):

Vascular Endothelial Growth Factor ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Vascular Endothelial ◽

Current Management ◽

Vegf Inhibitors ◽

Age Related ◽

Dry Amd ◽

Endothelial Growth Factor ◽

Wet Amd

Current management of age-related macular degeneration (AMD) is directed at intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors for the treatment of wet AMD and supplementation with oral antioxidants for the treatment of dry AMD. In this article, we will review recent clinical trials for the treatment of dry and wet AMD.

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Bioprinted 3D Outer Retina Barrier Uncovers RPE-dependent Choroidal Phenotype in Advanced Macular Degeneration

10.21203/rs.3.rs-135775/v1 ◽

2021 ◽

Author(s):

Kapil Bharti ◽

Min Jae Song ◽

Russell Quinn ◽

Eric Nguyen ◽

Tea Soon Park ◽

...

Keyword(s):

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Specific Gene ◽

Tissue Integration ◽

Age Related ◽

Dry Amd ◽

Barrier Resistance ◽

Wet Amd

Abstract Age-related macular degeneration (AMD), a leading cause of blindness, initiates in the outer-blood-retina-barrier (oBRB) formed by Retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris. The mechanism of AMD initiation and progression remain poorly understood due to the lack of physiologically relevant oBRB models. We engineered a native-like 3D-oBRB tissue by bioprinting endothelial cells, pericytes, and fibroblasts on the basal side of a biodegradable scaffold and establishing an RPE monolayer on top. In this 3D-oBRB, a fully-polarized RPE monolayer with apical processes and basal infoldings provides barrier resistance, induces fenestration and choroid-specific gene expression in the choriocapillaris, and supports the formation of a Bruch’s-like membrane that allows tissue integration in rat eyes. Complement activation in the 3D-oBRB triggers dry-AMD phenotypes (including subRPE drusen and choriocapillaris degeneration), and hypoxia activated HIF-α induces wet-AMD phenotypes (choriocapillaris neovascularization). Anti-VEGF drug treatment suppresses neovascularization - validating this model for clinical translation and drug discovery.

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PPAR-αLigands as Potential Therapeutic Agents for Wet Age-Related Macular Degeneration

PPAR Research ◽

10.1155/2008/821592 ◽

2008 ◽

Vol 2008 ◽

pp. 1-5 ◽

Cited By ~ 6

Author(s):

Marisol del V Cano ◽

Peter L. Gehlbach

Keyword(s):

Macular Degeneration ◽

Immune Modulation ◽

Age Related Macular Degeneration ◽

Peroxisome Proliferator ◽

Vascular Endothelial ◽

Age Related ◽

Dry Amd ◽

Peroxisome Proliferator Activated Receptors ◽

Endothelial Growth Factor ◽

Wet Amd

The peroxisome proliferator-activated receptors (PPAR's) are members of the steroid/thyroid nuclear receptor, superfamily of transcription factors. There are currently three known PPAR subtypes,α,β, andγ. The PPARs are now recognized participants in a number of biological pathways some of which are implicated in the pathogenesis of age-related macular degeneration (AMD). These include immune modulation, lipid regulation, and oxidant/antioxidant pathways important to the onset and progression of “dry” AMD, and vascular endothelial growth factor (VEGF) mediated pathways that stimulate choroidal neovascularization (CNV), characteristic of “wet” AMD. PPAR-αis found in retina and also on vascular cells important to formation of CNV. At this time, however, relatively little is known about potential contributions of PPAR-αto the pathogenesis of dry and wet AMD. This review examines current literature for potential roles of PPAR-αin the pathogenesis and potential treatment of AMD with emphasis on prevention and treatment of wet AMD.

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