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Yousif Subhi, Marie Krogh Nielsen, Christopher Rue Molbech, Mads Krüger Falk, Amardeep Singh, Thomas Vauvert Faurschou Hviid, Mogens Holst Nissen, Torben Lykke Sørensen
Importance: CD11b+ immune cells have been implicated in the formation of choroidal neovascularization in experimental studies on animals and disease-association studies on humans. However, the clinical importance of such observations remains unknown. Objective: To investigate whether the proportion of CD11b+ circulating monocytes is associated with the number of anti-vascular endothelial growth factor (anti-VEGF) injections in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV)...
March 7, 2019: JAMA Ophthalmology
Anne Louise Askou, Sidsel Alsing, Josephine N E Benckendorff, Andreas Holmgaard, Jacob Giehm Mikkelsen, Lars Aagaard, Toke Bek, Thomas J Corydon
Vascular endothelial growth factor A (VEGFA) is involved in the pathogenesis of vasoproliferative retinal diseases, such as exudative age-related macular degeneration (AMD). The objective of this study was to investigate whether dual-acting therapy based on the simultaneous expression of anti-VEGFA microRNAs (miRNAs) and the secreted, antiangiogenic protein pigment endothelial-derived factor (PEDF) delivered by adeno-associated virus (AAV) vectors provides improved protection against choroidal neovascularization (CNV)...
February 2, 2019: Molecular Therapy. Nucleic Acids
Mihir Shah, Sara Cabrera-Ghayouri, Lori-Ann Christie, Katherine S Held, Veena Viswanath
Preclinical models of human diseases are critical to our understanding of disease etiology, pathology, and progression and enable the development of effective treatments. An ideal model of human disease should capture anatomical features and pathophysiological mechanisms, mimic the progression pattern, and should be amenable to evaluating translational endpoints and treatment approaches. Preclinical animal models have been developed for a variety of human ophthalmological diseases to mirror disease mechanisms, location of the affected region in the eye and severity...
February 25, 2019: Pharmaceutical Research
Thierry Léveillard, Laurence Klipfel
The transplantation of retinal cells has been studied in animals to establish proof of its potential benefit for the treatment of blinding diseases. Photoreceptor precursors have been grafted in animal models of Mendelian-inherited retinal degenerations, and retinal pigmented epithelial cells have been used to restore visual function in animal models of age-related macular degeneration (AMD) and recently in patients. Cell therapy over corrective gene therapy in inherited retinal degeneration can overcome the genetic heterogeneity by providing one treatment for all genetic forms of the diseases...
January 28, 2019: International Journal of Molecular Sciences
Min Zhao, Irmela Mantel, Emmanuelle Gelize, Xinxin Li, Xiaoyue Xie, Alejandro Arboleda, Marie Seminel, Rinath Levy-Boukris, Marilyn Dernigoghossian, Andrea Prunotto, Charlotte Andrieu-Soler, Carlo Rivolta, Jérémie Canonica, Marie-Christine Naud, Sebastian Lechner, Nicolette Farman, Irene Bravo-Osuna, Rocio Herrero-Vanrell, Frederic Jaisser, Francine Behar-Cohen
Choroidal neovascularization (CNV) is a major cause of visual impairment in patients suffering from wet age-related macular degeneration (AMD), particularly when refractory to intraocular anti-VEGF injections. Here we report that treatment with the oral mineralocorticoid receptor (MR) antagonist spironolactone reduces signs of CNV in patients refractory to anti-VEGF treatment. In animal models of wet AMD, pharmacological inhibition of the MR pathway or endothelial-specific deletion of MR inhibits CNV through VEGF-independent mechanisms, in part through upregulation of the extracellular matrix protein decorin...
January 21, 2019: Nature Communications
Ana Artero-Castro, Stepan Popelka, Pavla Jendelova, Jan Motlik, Taras Ardan, Francisco Javier Rodriguez Jimenez, Slaven Erceg
Combinatory strategies using pharmacology and stem cell therapy have emerged due to their potential in the treatment of retinal pigment epithelium (RPE) cell related diseases, and a variety of different stem cell sources have been evaluated both in animal models and in humans. RPE cells derived from human embryonic stem cells (hESCs) and human induced pluripotent cells (hiPSCs) are already in clinical trials, holding great promise for the treatment of age-related macular disease (AMD) and hereditary RPE-related retinal dystrophies...
January 8, 2019: Expert Opinion on Drug Discovery
Ying Cheng, Tongjie Cheng, Yi Qu
PURPOSE: To investigate the role of tissue inhibitor of metalloproteinases-3 (TIMP-3) as a key moderator of macrophage polarization in choroidal neovascularization (CNV) lesions of model mice and in bone marrow-derived macrophage (BMDM). METHOD: We used siR-TIMP-3 to transfect BMDM and gave an intravitreal injection of siR-TIMP-3 to laser-induced CNV mice model, real time-PCR and western blot were applied for detecting the expressions of TIMP-3 and macrophages' biomarker...
December 27, 2018: Molecular Immunology
Viktoriia E Baksheeva, Veronika V Tiulina, Natalia K Tikhomirova, Olga S Gancharova, Sergey V Komarov, Pavel P Philippov, Andrey A Zamyatnin, Ivan I Senin, Evgeni Yu Zernii
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)...
December 21, 2018: Antioxidants (Basel, Switzerland)
Xincheng Yao, Taeyoon Son, Tae-Hoon Kim, Yiming Lu
Retinal photoreceptors are the primary target of age-related macular degeneration (AMD) which is the leading cause of severe vision loss and legal blindness. An objective method for functional assessment of photoreceptor physiology can benefit early detection and better treatment evaluation of AMD and other eye diseases that are known to cause photoreceptor dysfunctions. This article summarizes in vitro study of IOS mechanisms and in vivo demonstration of IOS imaging of intact animals. Further development of the functional IOS imaging may provide a revolutionary solution to achieve objective assessment of human photoreceptors...
November 27, 2018: Experimental Biology and Medicine
Karis Little, Jacey H Ma, Nan Yang, Mei Chen, Heping Xu
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in developed countries. Neovascular AMD (nAMD) accounts for 90% of AMD-related vision loss. Although intravitreal injection of VEGF inhibitors can improve vision in nAMD, approximately 1/3 of patients do not benefit from the therapy due to macular fibrosis. The molecular mechanism underlying the transition of the neovascular lesion to a fibrovascular phenotype remains unknown. Here we discussed the clinical features and risk factors of macular fibrosis secondary to nAMD...
November 22, 2018: EBioMedicine
Sylvia J Gasparini, Sílvia Llonch, Oliver Borsch, Marius Ader
The mammalian retina displays no intrinsic regenerative capacities, therefore retinal degenerative diseases such as age-related macular degeneration (AMD) or retinitis pigmentosa (RP) result in a permanent loss of the light-sensing photoreceptor cells. The degeneration of photoreceptors leads to vision impairment and, in later stages, complete blindness. Several therapeutic strategies have been developed to slow down or prevent further retinal degeneration, however a definitive cure i.e. replacement of the lost photoreceptors, has not yet been established...
November 13, 2018: Progress in Retinal and Eye Research
Zi-Bing Jin, Mei-Ling Gao, Wen-Li Deng, Kun-Chao Wu, Sunao Sugita, Michiko Mandai, Masayo Takahashi
Cell replacement therapy is a promising treatment for irreversible retinal cell death in diverse diseases, such as age-related macular degeneration (AMD), Stargardt's disease, retinitis pigmentosa (RP) and glaucoma. These diseases are all characterized by the degeneration of one or two retinal cell types that cannot regenerate spontaneously in humans. Aberrant retinal pigment epithelial (RPE) cells can be observed through optical coherence tomography (OCT) in AMD patients. In RP patients, the morphological and functional abnormalities of RPE and photoreceptor layers are caused by a genetic abnormality...
November 9, 2018: Progress in Retinal and Eye Research
Christine A Curcio
AMD is a major cause of legal blindness in older adults approachable through multidisciplinary research involving human tissues and patients. AMD is a vascular-metabolic-inflammatory disease, in which two sets of extracellular deposits, soft drusen/basal linear deposit (BLinD) and subretinal drusenoid deposit (SDD), confer risk for end-stages of atrophy and neovascularization. Understanding how deposits form can lead to insights for new preventions and therapy. The topographic correspondence of BLinD and SDD with cones and rods, respectively, suggest newly realized exchange pathways among outer retinal cells and across Bruch's membrane and the subretinal space, in service of highly evolved, eye-specific physiology...
March 20, 2018: Investigative Ophthalmology & Visual Science
Zeljka Smit-McBride, Johnny Nguyen, Garrett W Elliott, Zhe Wang, Ryan A McBride, Anthony T Nguyen, Sharon L Oltjen, Glenn Yiu, Sara M Thomasy, Kent E Pinkerton, Eugene S Lee, David Cunefare, Sina Farsiu, Lawrence S Morse
Purpose: To identify changes induced by environmental tobacco smoke (ETS) in circulatory microRNA (miRNA) in plasma and ocular fluids of the Rhesus macaque and compare these changes to normal age-related changes. Tobacco smoke has been identified as the leading environmental risk factor for age-related macular degeneration (AMD). Methods: All Rhesus macaques were housed at the California National Primate Research Center (CNPRC), University of California, Davis. Four groups of animals were used: Group 1 (1-3 years old), Group 2 (19-28 years old), Group 3 (10-16 years old), and Group 4 (middle aged, 9-14 years old)...
2018: Molecular Vision
Nataliya G Kolosova, Oyuna S Kozhevnikova, Darya V Telegina, Anzhela Zh Fursova, Natalia A Stefanova, Natalia A Muraleva, Franco Venanzi, Michael Y Sherman, Sergey I Kolesnikov, Albert A Sufianov, Vladimir L Gabai, Alexander M Shneider
P62/SQSTM1, a multi-domain protein that regulates inflammation, apoptosis, and autophagy, has been linked to age-related pathologies. For example, previously we demonstrated that administration of p62/SQSTM1-encoding plasmid reduced chronic inflammation and alleviated osteoporosis and metabolic syndrome in animal models. Herein, we built upon these findings to investigate effect of the p62-encoding plasmid on an age-related macular degeneration (AMD), a progressive neurodegenerative ocular disease, using spontaneous retinopathy in senescence-accelerated OXYS rats as a model...
August 28, 2018: Aging
Rehan M Hussain, Thomas A Ciulla, Audina M Berrocal, Ninel Z Gregori, Harry W Flynn, Byron L Lam
Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that lacks effective treatment options. Gene therapy, stem cell therapy, and pharmacotherapy with visual cycle modulators (VCMs) and complement inhibitors are discussed as potential treatments. Areas covered: Investigational therapies for STGD1 aim to reduce toxic bisretinoids and lipofuscin in the retina and retinal pigment epithelium (RPE). These agents include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Avacincaptad pegol is a C5 complement inhibitor that may reduce inflammation-related RPE damage...
October 2018: Expert Opinion on Biological Therapy
Akane Kashimura, Kouji Tanaka, Hiroko Sato, Hidefumi Kaji, Masaharu Tanaka
To evaluate the usefulness of imaging mass spectrometry (IMS) technology for assessing drug toxicity, we analyzed animal tissues in an amiodarone (AMD)-induced phospholipidosis model by IMS and confirmed the relationship between the distribution of AMD, its metabolites, and representative phospholipids (phosphatidylcholine, PC) and histological changes. AMD was administered to rats for 7 days at 150 mg/kg/day. The lung, spleen, and mesenteric lymph node were histologically examined and analyzed using IMS. The detection intensities of AMD, its metabolites, and typical PCs were higher in regions infiltrated by foamy macrophages compared with normal areas...
July 2018: Journal of Toxicologic Pathology
Yizhe Cui, Qiuju Wang, Rui Sun, Li Guo, Mengzhu Wang, Junfeng Jia, Chuang Xu, Rui Wu
BACKGROUND: Astragalus membranaceus (Fisch.) Bunge is one of the most widely used traditional Chinese herbal medicines. It is used as immune stimulant, tonic, antioxidant, hepatoprotectant, diuretic, antidiabetic, anticancer, and expectorant. The purpose of the study was to investigate the curative effects of the decoction obtained from Astragalus membranaceus root in intestinal mucosal injury induced by LPS in mice. An LPS-induced intestinal mucosal injury mice model was applied in the study...
August 3, 2018: BMC Complementary and Alternative Medicine
David A Copland, Sofia Theodoropoulou, Jian Liu, Andrew D Dick
Despite strong genetic associations, compelling human histological data and numerous hypotheses generated with supportive animal data, the mechanisms of inflammation or inflammatory control of cell health during progression of age-related macular degeneration arguably remain elusive. This perspective delivers a view that maintaining tissue health requires active immune cellular and tissue pathways, but when responses are perturbed or exaggerated, chronic inflammation is destructive. There are potential pathways and processes to enable understanding and determine how potential causative factors including altered cellular metabolism, senescence, oxidative stress disrupt tissue homeostasis are engaged...
March 20, 2018: Investigative Ophthalmology & Visual Science
Naoko A Chapman, Robert J Jacobs, Andrea J Braakhuis
A systematic literature review was conducted to evaluate the role of diet and food intake in age-related macular degeneration (AMD). Eighteen high-quality studies were identified. Adherence to a Mediterranean diet had decreased risk of AMD progression. An Oriental diet pattern had decreased association with AMD prevalence, whereas a Western diet pattern had increased association with AMD prevalence. High consumption of vegetables rich in carotenoids and fatty fish containing omega-3 fatty acids was beneficial for those at risk of AMD...
June 21, 2018: Clinical & Experimental Ophthalmology
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