keyword
https://read.qxmd.com/read/32362442/ferrous-but-not-ferric-iron-sulfate-kills-photoreceptors-and-induces-photoreceptor-dependent-rpe-autofluorescence
#21
JOURNAL ARTICLE
Wanting Shu, Bailey H Baumann, Ying Song, Yingrui Liu, Xingwei Wu, Joshua L Dunaief
Iron has been implicated in the pathogenesis of retinal degenerative diseases, including ocular siderosis. However, the mechanisms of iron-induced retinal toxicity are incompletely understood. Previous work shows that intravitreal injection of Fe2+ leads to photoreceptor (PR) oxidative stress, resulting in PR death within 14 days, and cones are more susceptible than rods to iron-induced oxidative damage. In order to further investigate the mechanism of intravitreal iron-induced retinal toxicity and shed light on mechanisms of iron-induced retinopathy in other mouse models, Fe2+ , Fe3+ , or saline were injected into the vitreous of adult wild-type mice...
July 2020: Redox Biology
https://read.qxmd.com/read/32258826/bull-s-eye-maculopathy-associated-with-hereditary-hemochromatosis
#22
Kellyn N Bellsmith, Joshua L Dunaief, Paul Yang, Mark E Pennesi, Ellen Davis, Holly Hofkamp, Brandon J Lujan
PURPOSE: To report a case of bull's eye maculopathy, a novel finding in a patient with iron overload secondary to hereditary hemochromatosis with a homozygous mutation of the HFE gene. OBSERVATIONS: A 39-year-old man with recently diagnosed hereditary hemochromatosis undergoing treatment by serial phlebotomy presented with bilateral progressive blurry vision and recent onset of photopsias and headaches. Fundus examination revealed a symmetric bull's eye maculopathy with photoreceptor loss and retinal pigment epithelium transmission defects in the area of speckled hyper- and hypo-pigmentation by multimodal imaging...
June 2020: American Journal of Ophthalmology Case Reports
https://read.qxmd.com/read/32229292/prolonged-intraocular-residence-and-retinal-tissue-distribution-of-a-fourth-generation-compstatin-based-c3-inhibitor-in-non-human-primates
#23
JOURNAL ARTICLE
Sarah Hughes, Justin Gumas, Rebecca Lee, Merita Rumano, Nadja Berger, Avneesh Kumar Gautam, Georgia Sfyroera, Anna Lorena Chan, Gopalan Gnanaguru, Kip M Connor, Benjamin J Kim, Joshua L Dunaief, Daniel Ricklin, George Hajishengallis, Despina Yancopoulou, Edimara S Reis, Dimitrios C Mastellos, John D Lambris
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the elderly population. Genetic studies in susceptible individuals have linked this ocular disease to deregulated complement activity that culminates in increased C3 turnover, retinal inflammation and photoreceptor loss. Therapeutic targeting of C3 has therefore emerged as a promising strategy for broadly intercepting the detrimental proinflammatory consequences of complement activation in the retinal tissue. In this regard, a PEGylated second-generation derivative of the compstatin family of C3-targeted inhibitors is currently in late-stage clinical development as a treatment option for geographic atrophy, an advanced form of AMD which lacks approved therapy...
May 2020: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://read.qxmd.com/read/32045598/oral-administration-of-the-iron-chelator-deferiprone-protects-against-loss-of-retinal-ganglion-cells-in-a-mouse-model-of-glaucoma
#24
JOURNAL ARTICLE
Qi N Cui, Albert R Bargoud, Ahmara G Ross, Ying Song, Joshua L Dunaief
Glaucoma is a progressive neurodegenerative process affecting the retinal ganglion cells (RGCs) and the optic nerve. Oxidative stress has been implicated in glaucoma pathogenesis, and iron is a potent generator of oxidative stress. The oral iron chelator deferiprone (DFP) is protective against retinal degenerations associated with oxidative stress. To test whether DFP could be protective in glaucoma, we used microbead injections to induce elevated intraocular pressure (IOP) in a cohort of 3-month old C57BL/6J mice...
April 2020: Experimental Eye Research
https://read.qxmd.com/read/31634395/iron-accumulates-in-retinal-vascular-endothelial-cells-but-has-minimal-retinal-penetration-after-ip-iron-dextran-injection-in-mice
#25
JOURNAL ARTICLE
Wanting Shu, Bailey H Baumann, Ying Song, Yingrui Liu, Xingwei Wu, Joshua L Dunaief
Purpose: Iron supplementation therapy is used for iron-deficiency anemia but has been associated with macular degeneration in a 43-year-old patient. Iron entry into the neurosensory retina (NSR) can be toxic. It is important to determine conditions under which serum iron might cross the blood retinal barrier (BRB) into the NSR. Herein, an established mouse model of systemic iron overload using high-dose intraperitoneal iron dextran (IP FeDex) was studied. In addition, because the NSR expresses the iron regulatory hormone hepcidin, which could limit iron influx into the NSR, we gave retina-specific hepcidin knockout (RS-HepcKO) mice IP FeDex to test this possibility...
October 1, 2019: Investigative Ophthalmology & Visual Science
https://read.qxmd.com/read/31562844/systemic-knockout-of-tspo-in-mice-does-not-affect-retinal-morphology-function-and-susceptibility-to-degeneration
#26
JOURNAL ARTICLE
Katrin Klee, Federica Storti, Maya Barben, Marijana Samardzija, Thomas Langmann, Joshua Dunaief, Christian Grimm
Translocator protein (18 kDa) (TSPO) is a mitochondrial protein expressed by reactive microglia and astrocytes at the site of neuronal injury. Although TSPO function has not been fully determined, synthetic TSPO ligands have beneficial effects on different pathologies of the central nervous system, including the retina. Here, we studied the pattern of Tspo expression in the aging human retina and in two mouse models of retinal degeneration. Using a newly generated Tspo-KO mouse, we investigated the impact of the lack of TSPO on retinal morphology, function and susceptibility to degeneration...
September 25, 2019: Experimental Eye Research
https://read.qxmd.com/read/31406150/dexras1-deletion-and-iron-chelation-promote-neuroprotection-in-experimental-optic-neuritis
#27
JOURNAL ARTICLE
Reas S Khan, Bailey Baumann, Kimberly Dine, Ying Song, Joshua L Dunaief, Sangwon F Kim, Kenneth S Shindler
Dysregulation of iron metabolism, and resultant cytotoxicity, has been implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative processes. Iron accumulation promotes cytotoxicity through various mechanisms including oxidative stress and glutamate toxicity, and occurs in both MS patients and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Divalent Metal Transporter1, a major iron importer in cells, is stimulated by signaling of Dexras1, a small G protein member of the Ras family...
August 12, 2019: Scientific Reports
https://read.qxmd.com/read/31323276/ferroportin-mediated-iron-export-from-vascular-endothelial-cells-in-retina-and-brain
#28
JOURNAL ARTICLE
Bailey H Baumann, Wanting Shu, Ying Song, Elizabeth M Simpson, Samira Lakhal-Littleton, Joshua L Dunaief
Retinal iron accumulation has been implicated in the pathogenesis of age-related macular degeneration (AMD) and other neurodegenerative diseases. The retina and the brain are protected from the systemic circulation by the blood retinal barrier (BRB) and blood brain barrier (BBB), respectively. Iron levels within the retina and brain need to be tightly regulated to prevent oxidative injury. The method of iron entry through the retina and brain vascular endothelial cells (r&bVECs), an essential component of the BRB and BBB, is not fully understood...
July 16, 2019: Experimental Eye Research
https://read.qxmd.com/read/31287995/liver-specific-but-not-retina-specific-hepcidin-knockout-causes-retinal-iron-accumulation-and-degeneration
#29
JOURNAL ARTICLE
Bailey H Baumann, Wanting Shu, Ying Song, Jacob Sterling, Zbynek Kozmik, Samira Littleton-Lakhal, Joshua L Dunaief
The liver secretes hepcidin (Hepc) into the bloodstream to reduce blood iron levels. Hepc accomplishes this by triggering degradation of the only known cellular iron exporter ferroportin in the gut, macrophages, and the liver. We previously demonstrated that systemic HepcKO mice, which have high serum iron, develop retinal iron overload and degeneration. However, it was unclear whether this is caused by high blood iron levels or alternatively, due to retinal iron influx that would normally be regulated by retina-produced Hepc...
July 6, 2019: American Journal of Pathology
https://read.qxmd.com/read/31263155/multi-copper-ferroxidase-deficiency-leads-to-iron-accumulation-and-oxidative-damage-in-astrocytes-and-oligodendrocytes
#30
JOURNAL ARTICLE
Zheng Chen, Ruiwei Jiang, Mengxia Chen, Jiashuo Zheng, Min Chen, Nady Braidy, Shunli Liu, Guohao Liu, Zaitunamu Maimaitiming, Tianqi Shen, Joshua L Dunaief, Christopher D Vulpe, Gregory J Anderson, Huijun Chen
Accumulation of iron has been associated with the pathobiology of various disorders of the central nervous system. Our previous work has shown that hephaestin (Heph) and ceruloplasmin (Cp) double knockout (KO) mice induced iron accumulation in multiple brain regions and that this was paralleled by increased oxidative damage and deficits in cognition and memory. In this study, we enriched astrocytes and oligodendrocytes from the cerebral cortex of neonatal wild-type (WT), Heph KO and Cp KO mice. We demonstrated that Heph is highly expressed in oligodendrocytes, while Cp is mainly expressed in astrocytes...
July 1, 2019: Scientific Reports
https://read.qxmd.com/read/30864945/impaired-abca1-abcg1-mediated-lipid-efflux-in-the-mouse-retinal-pigment-epithelium-rpe-leads-to-retinal-degeneration
#31
JOURNAL ARTICLE
Federica Storti, Katrin Klee, Vyara Todorova, Regula Steiner, Alaa Othman, Saskia van der Velde-Visser, Marijana Samardzija, Isabelle Meneau, Maya Barben, Duygu Karademir, Valda Pauzuolyte, Sanford L Boye, Frank Blaser, Christoph Ullmer, Joshua L Dunaief, Thorsten Hornemann, Lucia Rohrer, Anneke I den Hollander, Arnold von Eckardstein, Jürgen Fingerle, Cyrille Maugeais, Christian Grimm
Age-related macular degeneration (AMD) is a progressive disease of the retinal pigment epithelium (RPE) and the retina leading to loss of central vision. Polymorphisms in genes involved in lipid metabolism, including the ATP-binding cassette transporter A1 ( ABCA1 ), have been associated with AMD risk. However, the significance of retinal lipid handling for AMD pathogenesis remains elusive. Here, we study the contribution of lipid efflux in the RPE by generating a mouse model lacking ABCA1 and its partner ABCG1 specifically in this layer...
March 13, 2019: ELife
https://read.qxmd.com/read/30711487/complement-factor-h-mutation-w1206r-causes-retinal-thrombosis-and-ischemic-retinopathy-in-mice
#32
JOURNAL ARTICLE
Delu Song, Yoshiyasu Ueda, Rupak Bhuyan, Imran Mohammed, Takashi Miwa, Damodar Gullipali, Hangsoo Kim, Lin Zhou, Ying Song, Hannah Schultz, Albert Bargoud, Joshua L Dunaief, Wen-Chao Song
Single-nucleotide polymorphisms and rare mutations in factor H (FH; official name, CFH) are associated with age-related macular degeneration and atypical hemolytic uremic syndrome, a form of thrombotic microangiopathy. Mice with the FH W1206R mutation (FHR/R ) share features with human atypical hemolytic uremic syndrome. Herein, we report that FHR/R mice exhibited retinal vascular occlusion and ischemia. Retinal fluorescein angiography demonstrated delayed perfusion and vascular leakage in FHR/R mice. Optical coherence tomography imaging of FHR/R mice showed retinal degeneration, edema, and detachment...
February 1, 2019: American Journal of Pathology
https://read.qxmd.com/read/30665232/selective-ablation-of-megalin-in-the-retinal-pigment-epithelium-results-in-megaophthalmos-macromelanosome-formation-and-severe-retina-degeneration
#33
JOURNAL ARTICLE
Tina Storm, Thomas Burgoyne, Joshua L Dunaief, Erik I Christensen, Clare Futter, Rikke Nielsen
Purpose: Mutations in the megalin-encoding gene, LRP2, cause high myopia as seen in patients suffering from Donnai-Barrow/facio-oculo-acoustico-renal syndrome. Megalin is present in both the nonpigmented epithelium of the ciliary body and in the RPE. In this study, we set out to establish an animal model to study the mechanisms underlying the ocular phenotype and to establish if high myopia/megaophthalmos is induced by postnatal megalin-deficiency in the RPE. Methods: Postnatal RPE-specific deletion of megalin was generated by crossing mice bearing a homozygous loxP-flanked Lrp2 allele with transgenic mice expressing the Cre recombinase driven by the BEST1 promotor...
January 2, 2019: Investigative Ophthalmology & Visual Science
https://read.qxmd.com/read/30653965/comparative-localization-of-cystathionine-beta-synthases-and-cystathionine-gamma-lyase-in-canine-non-human-primate-and-human-retina
#34
JOURNAL ARTICLE
Alireza Badiei, Raghavi Sudharsan, Evelyn Santana, Joshua L Dunaief, Gustavo D Aguirre
Chronic exposure of the retina to light and high concentrations of polyunsaturated fatty acid in photoreceptor cells make this tissue susceptible to oxidative damage. As retinal degenerative diseases are associated with photoreceptor degeneration, the antioxidant activity of both hydrogen sulfide (H2 S) and glutathione (GSH) may play an important role in ameliorating disease progression. H2 S production is driven by cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), the key enzymes that also drive transsulfuration pathway (TSP) necessary for GSH production...
January 14, 2019: Experimental Eye Research
https://read.qxmd.com/read/30476517/five-year-follow-up-of-nonfibrotic-scars-in-the-comparison-of-age-related-macular-degeneration-treatments-trials
#35
RANDOMIZED CONTROLLED TRIAL
Ebenezer Daniel, Gui-Shuang Ying, Benjamin J Kim, Cynthia A Toth, Frederick Ferris, Daniel F Martin, Juan E Grunwald, Glenn J Jaffe, Joshua L Dunaief, Wei Pan, Maureen G Maguire
PURPOSE: To describe changes in visual acuity (VA) and macular morphologic features at 5 years in eyes with nonfibrotic scar (NFS) identified at 1 year in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). DESIGN: Prospective cohort study within a randomized clinical trial. PARTICIPANTS: Participants in CATT. METHODS: Participants assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens were released from the clinical trial protocol after 2 years and recalled at 5 years...
May 2019: Ophthalmology
https://read.qxmd.com/read/30360383/potential-treatment-of-retinal-diseases-with-iron-chelators
#36
REVIEW
Wanting Shu, Joshua L Dunaief
Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich's ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation...
October 22, 2018: Pharmaceuticals
https://read.qxmd.com/read/30355956/speckled-hypoautofluorescence-as-a-sign-of-resolved-subretinal-hemorrhage-in-neovascular-age-related-macular-degeneration
#37
JOURNAL ARTICLE
S Amal Hussnain, Rosa Dolz-Marco, Joshua L Dunaief, Christine A Curcio, K Bailey Freund
PURPOSE: To describe patterns of hypoautofluorescence in eyes with neovascular age-related macular degeneration occurring after subretinal hemorrhage. METHODS: This was a retrospective descriptive analysis of neovascular age-related macular degeneration eyes presenting with subretinal hemorrhage over the last 5 years that underwent serial multimodal imaging. A review of color fundus photographs, fundus autofluorescence, near-infrared reflectance, and optical coherence tomography was performed at baseline and all available follow-up visits to document the course and evolution of subretinal hemorrhage in these eyes...
October 2019: Retina
https://read.qxmd.com/read/30333155/mechanisms-that-minimize-retinal-impact-of-apolipoprotein-e-absence
#38
JOURNAL ARTICLE
Aicha Saadane, Alexey Petrov, Natalia Mast, Nicole El-Darzi, Tung Dao, Ahab Alnemri, Ying Song, Joshua L Dunaief, Irina A Pikuleva
Apolipoprotein E (APOE) is a component of lipid-transporting particles and a recognition ligand for receptors, which bind these particles. The APOE isoform 2 is a risk factor for age-related macular degeneration; nevertheless APOE absence in humans and mice does not significantly affect the retina. We found that retinal cholesterol biosynthesis and the levels of retinal cholesterol were increased in Apoe-/- mice, whereas cholesterol elimination by metabolism was decreased. No focal cholesterol deposits were observed in the Apoe-/- retina...
October 17, 2018: Journal of Lipid Research
https://read.qxmd.com/read/30182051/severe-iron-metabolism-defects-in-mice-with-double-knockout-of-the-multicopper-ferroxidases-hephaestin-and-ceruloplasmin
#39
JOURNAL ARTICLE
Brie K Fuqua, Yan Lu, David M Frazer, Deepak Darshan, Sarah J Wilkins, Linda Dunn, Alex V Loguinov, Scott C Kogan, Pavle Matak, Huijun Chen, Joshua L Dunaief, Chris D Vulpe, Gregory J Anderson
Background & Aims: Multicopper ferroxidases (MCFs) facilitate intestinal iron absorption and systemic iron recycling, likely by a mechanism involving the oxidization of Fe2+ from the iron exporter ferroportin 1 for delivery to the circulating Fe3+ carrier transferrin. Hephaestin (HEPH), the only MCF known to be expressed in enterocytes, aids in the basolateral transfer of dietary iron to the blood. Mice lacking HEPH in the whole body ( Heph -/- ) or intestine alone ( Heph int/int ) exhibit defects in dietary iron absorption but still survive and grow...
2018: Cellular and Molecular Gastroenterology and Hepatology
https://read.qxmd.com/read/30025090/retinal-basal-laminar-deposits-in-complement-fh-fp-mouse-model-of-dense-deposit-disease
#40
JOURNAL ARTICLE
Delu Song, Imran Mohammed, Rupak Bhuyan, Takashi Miwa, Allison Lesher Williams, Damodar Gullipalli, Sayaka Sato, Ying Song, Joshua L Dunaief, Wen-Chao Song
Purpose: Dense deposit disease (DDD) is caused by dysregulation of the alternative pathway of the complement cascade and characterized by electron-dense deposits in the kidney glomerular basement membrane (GBM) and drusen in Bruch's membrane (BrM). Complement factor H (fH) and factor properdin (fP) regulate complement activation; fH inhibits alternative pathway (AP) activation, whereas fP promotes it. We report pathologic changes in eyes of an fH and fP double-mutant mouse, which we previously showed have dense deposits in the GBM and early mortality from nephropathy...
July 2, 2018: Investigative Ophthalmology & Visual Science
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