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1.
Nature ; 581(7806): 83-88, 2020 05.
Article in English | MEDLINE | ID: mdl-32376950

ABSTRACT

Photoreceptor loss is the final common endpoint in most retinopathies that lead to irreversible blindness, and there are no effective treatments to restore vision1,2. Chemical reprogramming of fibroblasts offers an opportunity to reverse vision loss; however, the generation of sensory neuronal subtypes such as photoreceptors remains a challenge. Here we report that the administration of a set of five small molecules can chemically induce the transformation of fibroblasts into rod photoreceptor-like cells. The transplantation of these chemically induced photoreceptor-like cells (CiPCs) into the subretinal space of rod degeneration mice (homozygous for rd1, also known as Pde6b) leads to partial restoration of the pupil reflex and visual function. We show that mitonuclear communication is a key determining factor for the reprogramming of fibroblasts into CiPCs. Specifically, treatment with these five compounds leads to the translocation of AXIN2 to the mitochondria, which results in the production of reactive oxygen species, the activation of NF-κB and the upregulation of Ascl1. We anticipate that CiPCs could have therapeutic potential for restoring vision.


Subject(s)
Cellular Reprogramming/drug effects , Fibroblasts/cytology , Fibroblasts/drug effects , Retinal Degeneration/therapy , Retinal Rod Photoreceptor Cells/cytology , Retinal Rod Photoreceptor Cells/transplantation , Vision, Ocular/drug effects , Animals , Axin Protein/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , Disease Models, Animal , Flow Cytometry , Mice , Mitochondria/drug effects , Mitochondria/metabolism , NF-kappa B/metabolism , Protein Transport/drug effects , Reactive Oxygen Species/metabolism , Retinal Degeneration/pathology , Retinal Rod Photoreceptor Cells/drug effects , Signal Transduction/drug effects , Vision, Ocular/physiology
2.
Am J Pathol ; 188(9): 2087-2096, 2018 09.
Article in English | MEDLINE | ID: mdl-30126549

ABSTRACT

Uveitis is estimated to account for 10% of all cases of blindness in the United States, including 30,000 new cases of legal blindness each year. Intraocular and oral corticosteroids are the effective mainstay treatment, but they carry the risk of serious long-term ocular and systemic morbidity. New noncorticosteroid therapies with a favorable side effect profile are necessary for the treatment of chronic uveitis, given the paucity of existing treatment choices. We have previously demonstrated that Nutlin-3, a small-molecule inhibitor of murine double minute 2 (MDM2) homolog, suppresses pathologic retinal angiogenesis through a p53-dependent mechanism, but the noncanonical p53-independent functions have not been adequately elucidated. Herein, we demonstrate an unanticipated function of MDM2 inhibition, where Nutlin-3 potently abrogates lipopolysaccharide-induced ocular inflammation. Furthermore, we identified a mechanism by which transcription and translation of NF-κB is mediated by MDM2, independent of p53, in ocular inflammation. Small-molecule MDM2 inhibition is a novel noncorticosteroid strategy for inhibiting ocular inflammation, which may potentially benefit patients with chronic uveitis.


Subject(s)
Eye Diseases/prevention & control , Gene Expression Regulation/drug effects , Imidazoles/pharmacology , Inflammation/prevention & control , NF-kappa B/antagonists & inhibitors , Piperazines/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/physiology , Animals , Apoptosis , Cell Proliferation , Cells, Cultured , Eye Diseases/metabolism , Eye Diseases/pathology , Humans , Inflammation/metabolism , Inflammation/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/genetics , NF-kappa B/metabolism , Retinal Pigment Epithelium/drug effects , Retinal Pigment Epithelium/metabolism
3.
Retina ; 36(12): 2304-2310, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27205892

ABSTRACT

PURPOSE: Failure of blood pressure (BP) to dip during sleep (nondipper pattern) is associated with cardiovascular disease and stroke. The prevalence and degree of nondipping and masked hypertension in patients with retinal vein occlusion (RVO), which is associated with stroke, has not been previously examined. METHODS: We measured clinic and 24-hour ambulatory BPs in 22 patients with RVO and 20 control participants without known eye disease matched by age and sex. Mean BP dipping, defined as the ratio of difference in mean awake and sleep systolic BPs to mean awake systolic BP, and masked and nocturnal hypertension were compared between groups. RESULTS: Mean 24-hour ambulatory BP was 144/79 mmHg among those with RVO and 136/77 mmHg among controls. Patients with RVO had an almost 2-fold higher prevalence of nondipping pattern (80.8% [95% confidence interval, 52.8-94.1] vs. 50.4% [95% confidence interval, 26.1-74.5]; P = 0.008). Average sleep systolic BP dip in patients with RVO was 6.1% versus 11.9% in controls (P = 0.004). More patients with RVO had masked hypertension by ambulatory BPs than controls (71% vs. 50%), but this difference was not statistically significant. CONCLUSION: Our data suggest an association between RVO and nondipper BP pattern. Ambulatory BP monitoring may be useful in the evaluation of patients with RVO by identifying those who may benefit from more aggressive BP control.


Subject(s)
Blood Pressure Monitoring, Ambulatory , Blood Pressure/physiology , Retinal Vein Occlusion/physiopathology , Aged , Case-Control Studies , Circadian Rhythm/physiology , Cross-Sectional Studies , Female , Humans , Hypertension/epidemiology , Hypertension/physiopathology , Male , Middle Aged , Prevalence
4.
Molecules ; 20(11): 19690-8, 2015 Oct 30.
Article in English | MEDLINE | ID: mdl-26528964

ABSTRACT

Tetracycline (TC) is a well-known broad spectrum antibiotic, which is effective against many Gram positive and Gram negative bacteria. Controlled release nanoparticle formulations of TC have been reported, and could be beneficial for application in the treatment of periodontitis and dental bone infections. Furthermore, TC-controlled transcriptional regulation systems (Tet-on and Tet-off) are useful for controlling transgene expression in vitro and in vivo for biomedical research purposes; controlled TC release systems could be useful here, as well. Mesoporous silica nanomaterials (MSNs) are widely studied for drug delivery applications; Mobile crystalline material 41 (MCM-41), a type of MSN, has a mesoporous structure with pores forming channels in a hexagonal fashion. We prepared 41 ± 4 and 406 ± 55 nm MCM-41 mesoporous silica nanoparticles and loaded TC for controlled dug release; TC content in the TC-MCM-41 nanoparticles was 18.7% and 17.7% w/w, respectively. Release of TC from TC-MCM-41 nanoparticles was then measured in phosphate-buffered saline (PBS), pH 7.2, at 37 °C over a period of 5 h. Most antibiotic was released from both over this observation period; however, the majority of TC was released over the first hour. Efficacy of the TC-MCM-41 nanoparticles was then shown to be superior to free TC against Escherichia coli (E. coli) in culture over a 24 h period, while blank nanoparticles had no effect.


Subject(s)
Escherichia coli/drug effects , Nanoparticles , Silicon Dioxide , Tetracycline/administration & dosage , Delayed-Action Preparations , Drug Carriers , Drug Delivery Systems , Microbial Sensitivity Tests , Nanoparticles/chemistry , Nanoparticles/ultrastructure , Silicon Dioxide/chemistry
5.
Cells ; 13(5)2024 Feb 25.
Article in English | MEDLINE | ID: mdl-38474360

ABSTRACT

Embolism, hyperglycemia, high intraocular pressure-induced increased reactive oxygen species (ROS) production, and microglial activation result in endothelial/retinal ganglion cell death. Here, we conducted in vitro and in vivo ischemia/reperfusion (I/R) efficacy studies of a hybrid antioxidant-nitric oxide donor small molecule, SA-10, to assess its therapeutic potential for ocular stroke. METHODS: To induce I/R injury and inflammation, we subjected R28 and primary microglial cells to oxygen glucose deprivation (OGD) for 6 h in vitro or treated these cells with a cocktail of TNF-α, IL-1ß and IFN-γ for 1 h, followed by the addition of SA-10 (10 µM). Inhibition of microglial activation, ROS scavenging, cytoprotective and anti-inflammatory activities were measured. In vivo I/R-injured mouse retinas were treated with either PBS or SA-10 (2%) intravitreally, and pattern electroretinogram (ERG), spectral-domain optical coherence tomography, flash ERG and retinal immunocytochemistry were performed. RESULTS: SA-10 significantly inhibited microglial activation and inflammation in vitro. Compared to the control, the compound SA-10 significantly attenuated cell death in both microglia (43% vs. 13%) and R28 cells (52% vs. 17%), decreased ROS (38% vs. 68%) production in retinal microglia cells, preserved neural retinal function and increased SOD1 in mouse eyes. CONCLUSION: SA-10 is protective to retinal neurons by decreasing oxidative stress and inflammatory cytokines.


Subject(s)
Reperfusion Injury , Retinal Ganglion Cells , Mice , Animals , Reactive Oxygen Species/metabolism , Retinal Ganglion Cells/metabolism , Reperfusion Injury/metabolism , Ischemia/metabolism , Anti-Inflammatory Agents/therapeutic use , Inflammation/metabolism , Reperfusion
6.
Article in English | MEDLINE | ID: mdl-38464735

ABSTRACT

Glaucoma is a chronic and progressive eye disease, commonly associated with elevated intraocular pressure (IOP) and characterized by optic nerve degeneration, cupping of the optic disc, and loss of retinal ganglion cells (RGCs). The pathological changes in glaucoma are triggered by multiple mechanisms and both mechanical effects and vascular factors are thought to contribute to the etiology of glaucoma. Various studies have shown that endothelin-1 (ET-1), a vasoactive peptide, acting through its G protein coupled receptors, ETA and ETB, plays a pathophysiologic role in glaucoma. However, the mechanisms by which ET-1 contribute to neurodegeneration remain to be completely understood. Our laboratory and others demonstrated that macitentan (MAC), a pan endothelin receptor antagonist, has neuroprotective effects in rodent models of IOP elevation. The current study aimed to determine if oral administration of a dual endothelin antagonist, macitentan, could promote neuroprotection in an acute model of intravitreal administration of ET-1. We demonstrate that vasoconstriction following the intravitreal administration of ET-1 was attenuated by dietary administration of the ETA/ETB dual receptor antagonist, macitentan (5 mg/kg body weight) in retired breeder Brown Norway rats. ET-1 intravitreal injection produced a 40% loss of RGCs, which was significantly lower in macitentan-treated rats. We also evaluated the expression levels of glial fibrillary acidic protein (GFAP) at 24 h and 7 days post intravitreal administration of ET-1 in Brown Norway rats as well as following ET-1 treatment in cultured human optic nerve head astrocytes. We observed that at the 24 h time point the expression levels of GFAP was upregulated (indicative of glial activation) following intravitreal ET-1 administration in both retina and optic nerve head regions. However, following macitentan administration for 7 days after intravitreal ET-1 administration, we observed an upregulation of GFAP expression, compared to untreated rats injected intravitreally with ET-1 alone. Macitentan treatment in ET-1 administered rats showed protection of RGC somas but was not able to preserve axonal integrity and functionality. The endothelin receptor antagonist, macitentan, has neuroprotective effects in the retinas of Brown Norway rats acting through different mechanisms, including enhancement of RGC survival and reduction of ET-1 mediated vasoconstriction.

11.
Ophthalmology ; 116(12): 2448-56, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19766317

ABSTRACT

PURPOSE: To elucidate the subclinical anatomy of retinopathy of prematurity (ROP) using spectral domain optical coherence tomography (SD OCT). DESIGN: Prospective, observational case series. PARTICIPANTS: Three low-birth-weight, severely premature infants. METHODS: Clinical examination was performed using a portable slit lamp and indirect ophthalmoscope. Imaging was performed by using a handheld SD OCT device and Retcam (Clarity Medical Systems, Pleasanton, CA) or video-indirect recording. Spectral domain optical coherence tomography imaging was conducted without sedation at the bedside in the neonatal intensive care unit on 1 patient. The other 2 patients had an examination under anesthesia with SD OCT imaging in the operating room. MAIN OUTCOME MEASURES: In vivo determination of vitreoretinal morphology, anatomy, and pathology by clinical examination, imaging, and SD OCT. RESULTS: Linear and volumetric imaging was achieved with the handheld system in infant eyes despite tunica vasculosa lentis and vitreous bands. Imaging was not possible in eyes with notable vitreous hemorrhage. Analysis of SD OCT images revealed preretinal structures (ranging from 409 to 2700 microm in width and 212 to 440 microm in height), retinoschisis, and retinal detachment in the posterior pole of patients with advanced ROP. Both the retinoschisis and the preretinal structures were not identified on conventional examination or imaging by expert pediatric ophthalmologists. The preretinal structures varied in location and size, and may represent preretinal fibrovascular proliferation. Some were found in close proximity to blood vessels, whereas others were near the optic nerve. CONCLUSIONS: Handheld SD OCT imaging can be performed on the sedated or nonsedated neonate and provides valuable subclinical anatomic information. This novel imaging modality can reveal the location and extent of posterior ROP pathology not evident on standard examination. This could affect future clinical decision-making if studies validate a management strategy based on findings from this imaging technique.


Subject(s)
Retina/pathology , Retinopathy of Prematurity/diagnosis , Tomography, Optical Coherence , Gestational Age , Humans , Imaging, Three-Dimensional , Infant, Extremely Low Birth Weight , Infant, Newborn , Infant, Premature , Male , Prospective Studies , Retinal Detachment/diagnosis , Retinopathy of Prematurity/classification , Retinoschisis/diagnosis , Video Recording
12.
Invest Ophthalmol Vis Sci ; 60(8): 3064-3073, 2019 07 01.
Article in English | MEDLINE | ID: mdl-31348824

ABSTRACT

Purpose: Determine the toxicity, bioavailability in the retina, and neuroprotective effects of a hybrid antioxidant-nitric oxide donor compound SA-2 against oxidative stress-induced retinal ganglion cell (RGC) death in neurodegenerative animal models. Methods: Optic nerve crush (ONC) and ischemia reperfusion (I/R) injury models were used in 12-week-old C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mice were treated intravitreally with either vehicle or SA-2. Retinal thickness was measured by spectral-domain optical coherence tomography (SD-OCT). The electroretinogram and pattern ERG (PERG) were used to assess retinal function. RGC survival was determined by counting RBPMS-positive RGCs and immunohistochemical analysis of superoxide dismutase 1 (SOD1) levels was carried out in the retina sections. Concentrations of SA-2 in the retina and choroid were determined using HPLC and MS. In addition, the direct effect of SA-2 treatment on RGC survival was assessed in ex vivo rat retinal explants under hypoxic (0.5% O2) conditions. Results: Compound SA-2 did not induce any appreciable change in retinal thickness, or in a- or b-wave amplitude in naive animals. SA-2 was found to be bioavailable in both the retina and choroid after a single intravitreal injection (2% wt/vol). An increase in SOD1 levels in the retina of mice subjected to ONC and SA-2 treatment, suggests an enhancement in antioxidant activity. SA-2 provided significant (P < 0.05) RGC protection in all three of the tested RGC injury models in rodents. PERG amplitudes were significantly higher in both I/R and ONC mouse eyes following SA-2 treatment (P ≤ 0.001) in comparison with the vehicle and control groups. Conclusions: Compound SA-2 was effective in preventing RGC death and loss of function in three different rodent models of acute RGC injury: ONC, I/R, and hypoxia.


Subject(s)
Neuroprotection/drug effects , Nitric Oxide Donors/pharmacokinetics , Oxidative Stress , Retinal Degeneration/drug therapy , Retinal Ganglion Cells/pathology , Animals , Cell Survival/drug effects , Disease Models, Animal , Electroretinography , Female , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley , Retinal Degeneration/metabolism , Retinal Degeneration/pathology , Retinal Ganglion Cells/metabolism , Tomography, Optical Coherence
15.
Methods Mol Biol ; 1357: 395-401, 2016.
Article in English | MEDLINE | ID: mdl-25403469

ABSTRACT

Reprogramming fibroblasts into induced pluripotent stem cells (iPSC) remains a promising technique for cell replacement therapy. Diverse populations of somatic cells have been examined for their reprogramming potential. Recently, ocular ciliary body epithelial cells (CECs) have been reprogrammed with high reprogramming efficiency and single transcription factor reprogramming, making them an exciting candidate for cellular reprogramming strategies.


Subject(s)
Cell Culture Techniques/methods , Cellular Reprogramming Techniques/methods , Cellular Reprogramming , Ciliary Body/cytology , Induced Pluripotent Stem Cells/cytology , Animals , Cell Differentiation , Cells, Cultured , Cellular Reprogramming/drug effects , Culture Media/pharmacology , Epithelial Cells/cytology , Genetic Vectors/genetics , Induced Pluripotent Stem Cells/drug effects , Lentivirus/genetics , Mice , Recombinant Fusion Proteins/genetics , Spheroids, Cellular , Transcription Factors/genetics , Transcription Factors/physiology
16.
Eur J Intern Med ; 16(6): 447-8, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16198909

ABSTRACT

There are many neurological manifestations of vitamin B(12) deficiency. Optic neuropathy is a rare, but important, manifestation of vitamin B(12) deficiency that should be suspected in patients with risk factors for malnutrition. We present a case of a 68-year-old male who presented with bilateral decreased central vision for months and was found to have a low vitamin B(12) level. After a few months, his vision improved with parenteral vitamin B(12) supplementation. Vitamin B(12) optic neuropathy is a reversible, treatable cause of vision loss and may be a harbinger for other manifestations of the disease.

18.
Am J Ophthalmol Case Rep ; 18: 100677, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32322747
19.
JAAD Case Rep ; 6(9): 868-870, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32875037
20.
Surv Ophthalmol ; 49(4): 399-418, 2004.
Article in English | MEDLINE | ID: mdl-15231396

ABSTRACT

Vasculitic disorders are relatively rare. Their etiology and pathophysiology remain enigmatic, leading to confusing nomenclature and multiple classification schemes. Untreated vasculitis can be fatal. Early diagnosis is the key to successful treatment and better prognosis. However, early diagnosis can be difficult; vasculitic conditions usually present with non-specific symptoms for a long period before clinically overt manifestations occur. Ophthalmologists should be familiar with the ocular manifestations of the vasculitic disorders because they may not only be sight-threatening, but more importantly could be the presenting manifestations of active, potentially lethal systemic disease. This review summarizes clinical and ocular manifestations of systemic vasculitic disorders. Furthermore, it discusses general concepts in diagnosis and treatment of these diseases in an effort to provide a practical framework for the ophthalmologist evaluating patients with vasculitis.


Subject(s)
Eye Diseases/etiology , Vasculitis/complications , Eye Diseases/diagnosis , Eye Diseases/therapy , Humans , Vasculitis/diagnosis , Vasculitis/therapy
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