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1.
Antioxidants (Basel) ; 13(2)2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38397833

ABSTRACT

Retinal detachment (RD) can result in the loss of photoreceptors that cause vision impairment and potential blindness. This study explores the protective effects of the oral administration of green tea extract (GTE) in a rat model of RD. Various doses of GTE or epigallocatechin gallate (EGCG), the most active ingredient in green tea catechins, were administered to Sprague Dawley (SD) rats with experimentally induced retinal detachment. The rats received sub-retinal injections of hyaluronic acid (0.1%) to induce RD and were given different doses of GTE and EGCG twice daily for three days. Notably, a low dose of GTE (142.9 mg/kg) caused significantly higher signal amplitudes in electroretinograms (ERGs) compared to higher GTE doses and any doses of EGCG. After administration of a low dose of GTE, the outer nuclear layer thickness, following normalization, of the detached retina reduced to 82.4 ± 8.2% (Mean ± SEM, p < 0.05) of the thickness by RD treatment. This thickness was similar to non-RD conditions, at 83.5 ± 4.7% (Mean ± SEM) of the thickness following RD treatment. In addition, the number of TUNEL-positive cells decreased from 76.7 ± 7.4 to 4.7 ± 1.02 (Mean ± SEM, p < 0.0001). This reduction was associated with the inhibition of apoptosis through decreased sphingomyelin levels and mitigation of oxidative stress shown by a lowered protein carbonyl level, which may involve suppression of HIF-1α pathways. Furthermore, GTE showed anti-inflammatory effects by reducing inflammatory cytokines and increasing resolving cytokines. In conclusion, low-dose GTE, but not EGCG, significantly alleviated RD-induced apoptosis, oxidative stress, inflammation, and energy insufficiency within a short period and without affecting energy metabolism. These findings suggest the potential of low-dose GTE as a protective agent for the retina in RD.

2.
Ophthalmol Retina ; 2023 Nov 11.
Article in English | MEDLINE | ID: mdl-37956794

ABSTRACT

PURPOSE: To compare the anatomic and functional outcomes of half-dose photodynamic therapy (PDT) and yellow 577-nm subthreshold micropulse laser (SMLT) in treating patients with chronic central serous chorioretinopathy (CSCR). DESIGN: Prospective, double-masked, randomized, controlled clinical trial. PARTICIPANTS: Patients with chronic CSCR confirmed by clinical features and multimodal imaging. METHODS: Eligible patients were randomized (1:1) to receive half-dose PDT or SMLT. The same treatment was repeated if persistent subretinal fluid (SRF) was observed. Treatment responses were evaluated 1 month after treatment and every 3 months until the end point at 12 months. MAIN OUTCOME MEASURES: The primary outcome measure was the complete resolution of SRF on OCT scan at month 12. Secondary outcomes included the changes in best-corrected visual acuity (BCVA), central macular thickness (CMT) as measured by OCT, retinal sensitivity as measured by microperimetry, and vision-related quality of life using the National Eye Institute 25-Item Visual Function Questionnaire. RESULTS: Between April 2017 and October 2020, 68 patients were recruited. At 1 month after treatment, SRF resolved in 8 (24.2%) of 33 patients receiving SMLT and in 20 (58.8%) of 34 patients receiving half-dose PDT. This increased to 23 (82.1%) of 28 patients in the SMLT group and 30 (90.9%) of 33 patients in the half-dose PDT group at 12 months of follow-up. Kaplan-Meier survival curves showed significantly faster resolution of SRF in the half-dose PDT group than the SMLT group (P = 0.016). Both groups showed significant improvement in BCVA (-0.12 ± 0.21, P = 0.005 for SMLT; -0.13 ± 0.12, P < 0.001 for half-dose PDT), CMT (-154.2 ± 105.6, P < 0.001 for SMLT; -140.8 ± 94.0, P < 0.001 for half-dose PDT), and retinal sensitivity (5.70 ± 5.02, P < 0.001 for SMLT; 6.05 ± 3.83, P < 0.001 for half-dose PDT) at 12 months compared with baseline. There was no significant difference between the 2 treatment groups at each time point in all investigations except BCVA at 3 months (P = 0.03). CONCLUSIONS: When comparing half-dose PDT to subthreshold SMLT, this study has shown both treatments to be viable options, with half-dose PDT achieving faster anatomic success and functional improvement. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

3.
Nat Commun ; 14(1): 3298, 2023 06 06.
Article in English | MEDLINE | ID: mdl-37280225

ABSTRACT

Dysregulation of Th17 cell differentiation and pathogenicity contributes to multiple autoimmune and inflammatory diseases. Previously growth hormone releasing hormone receptor (GHRH-R) deficient mice have been reported to be less susceptible to the induction of experimental autoimmune encephalomyelitis. Here, we show GHRH-R is an important regulator of Th17 cell differentiation in Th17 cell-mediated ocular and neural inflammation. We find that GHRH-R is not expressed in naïve CD4+ T cells, while its expression is induced throughout Th17 cell differentiation in vitro. Mechanistically, GHRH-R activates the JAK-STAT3 pathway, increases the phosphorylation of STAT3, enhances both non-pathogenic and pathogenic Th17 cell differentiation and promotes the gene expression signatures of pathogenic Th17 cells. Enhancing this signaling by GHRH agonist promotes, while inhibiting this signaling by GHRH antagonist or GHRH-R deficiency reduces, Th17 cell differentiation in vitro and Th17 cell-mediated ocular and neural inflammation in vivo. Thus, GHRH-R signaling functions as a critical factor that regulates Th17 cell differentiation and Th17 cell-mediated autoimmune ocular and neural inflammation.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Th17 Cells , Mice , Animals , Signal Transduction/physiology , Inflammation/metabolism , Cell Differentiation/genetics , Growth Hormone-Releasing Hormone/genetics , Growth Hormone-Releasing Hormone/metabolism , Mice, Inbred C57BL
4.
Transl Vis Sci Technol ; 11(11): 3, 2022 11 01.
Article in English | MEDLINE | ID: mdl-36331274

ABSTRACT

Purpose: The purpose of the study was to determine if aqueous glucose levels rise in a comparable time frame to interstitial fluid and could therefore be suitable for a continuous glucose monitoring (CGM) site. Methods: An intravenous glucose tolerance test was performed on five New Zealand white rabbits. Aqueous humor from the posterior and anterior chamber of the eye and venous blood were sampled for glucose concentration measurement. Glucose concentrations in the interstitial fluids were monitored using a CGM system. A compartment model was created to map the glucose response curves in each compartment. The delay in rising glucose concentrations between blood and interstitial fluid and aqueous humor in the posterior chamber and anterior chamber of the eye were analyzed. Results: The results showed a statistically similar time lag and rate of change in glucose concentrations between blood and interstitial fluids or aqueous humor in either the posterior or anterior chamber. Conclusions: The results of this study add further support to the aqueous humor being used as an alternative CGM site. Translational Relevance: The study provides the basis for developing an intraocular continuous glucose sensor that can overcome limitations of current CGM systems.


Subject(s)
Blood Glucose Self-Monitoring , Extracellular Fluid , Rabbits , Animals , Blood Glucose Self-Monitoring/methods , Glucose Tolerance Test , Blood Glucose , Glucose
5.
Mol Vis ; 28: 230-244, 2022.
Article in English | MEDLINE | ID: mdl-36284671

ABSTRACT

Background: The mechanism of diabetic macular edema (DME) was explored by comparing the intraocular metabolite profiles of the aqueous humor of patients with DME to those of diabetic patients without DME using untargeted metabolomic analysis. Methods: Aqueous samples from 18 type 2 diabetic patients with DME and 18 type 2 diabetic patients without DME used as controls were analyzed using liquid chromatography-mass spectrometry (LCMS). The two groups of patients were age and gender matched and had no systemic diseases other than diabetes mellitus (DM). The metabolites were analyzed using orthogonal partial least square discriminant analysis. Results: The metabolite profiles in DME patients differed from those in DM controls. This indicates the following metabolic derangements in DME: (a) a higher amount of oxidized fatty acids but a lower amount of endogenous antioxidants (oxidative stress); (b) higher levels of ß-glucose and homocysteine but a lower level of sorbitol (hyperglycemia); (c) a higher amount of prostaglandin metabolites (inflammation); (d) higher amounts of acylcarnitines, odd-numbered fatty acids, and 7,8-diaminononanoate (respiration deterioration); (e) a higher amount of neurotransmitter metabolites and homovanillic acid (neuronal damage); (f) a lower amount of extracellular matrix (ECM) constituents (ECM deterioration); and (g) a higher amount of di-amino peptides (microvascular damage). Conclusions: The change in the metabolic profiles in the aqueous humor of DME patients compared to DM controls without DME indicates that DME patients may have less capability to resist various stresses or damaging pathological conditions, such as oxidative stress, mitochondrial insufficiency, inflammation, and ECM deterioration.


Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Retinopathy , Macular Edema , Humans , Diabetic Retinopathy/metabolism , Aqueous Humor/metabolism , Antioxidants , Homovanillic Acid/metabolism , Diabetes Mellitus, Type 2/complications , Inflammation/metabolism , Homocysteine , Sorbitol/analysis , Sorbitol/metabolism , Prostaglandins/analysis , Prostaglandins/metabolism , Fatty Acids/metabolism , Glucose/metabolism
6.
Front Endocrinol (Lausanne) ; 13: 899271, 2022.
Article in English | MEDLINE | ID: mdl-35909558

ABSTRACT

Introduction: Green tea extract (GTE) alleviated ocular inflammations in endotoxin-induced uveitis (EIU) rat model induced by lipopolysaccharide (LPS) but the underlying mechanism is unclear. Objectives: To investigate the systematic and local mechanisms of the alleviation by untargeted metabolomics using liquid chromatography-tandem mass spectrometry. Methods: Sprague-Dawley rats were divided into control group, LPS treatment group, and LPS treatment group treated with GTE two hours after LPS injection. The eyes were monitored by slip lamp and electroretinography examination after 24 hours. The plasma and retina were collected for metabolomics analysis. Results: In LPS treated rats, the iris showed hyperemia. Plasma prostaglandins, arachidonic acids, corticosteroid metabolites, and bile acid metabolites increased. In the retina, histamine antagonists, corticosteroids, membrane phospholipids, free antioxidants, and sugars also increased but fatty acid metabolites, N-acetylglucosamine-6-sulphate, pyrocatechol, and adipic acid decreased. After GTE treatment, the a- and b- waves of electroretinography increased by 13%. Plasma phosphorylcholine lipids increased but plasma prostaglandin E1, cholanic metabolites, and glutarylglycine decreased. In the retina, tetranor-PGAM, pantothenic derivatives, 2-ethylacylcarinitine, and kynuramine levels decreased but anti-oxidative seleno-peptide level increased. Only phospholipids, fatty acids, and arachidonic acid metabolites in plasma and in the retina had significant correlation (p < 0.05, r > 0.4 or r < -0.4). Conclusions: The results showed GTE indirectly induced systemic phosphorylcholine lipids to suppress inflammatory responses, hepatic damage, and respiratory mitochondrial stress in EIU rats induced by LPS. Phospholipids may be a therapeutic target of GTE for anterior chamber inflammation.


Subject(s)
Lipopolysaccharides , Uveitis , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/metabolism , Endotoxins , Inflammation/metabolism , Lipopolysaccharides/toxicity , Phosphorylcholine/adverse effects , Phosphorylcholine/metabolism , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Rats , Rats, Sprague-Dawley , Retina/metabolism , Tea/adverse effects , Tea/chemistry , Tea/metabolism , Uveitis/chemically induced , Uveitis/drug therapy , Uveitis/metabolism
7.
Microorganisms ; 9(7)2021 Jul 11.
Article in English | MEDLINE | ID: mdl-34361917

ABSTRACT

Uveitis is characterized by inflammatory lesions of intraocular structures. It is one of the important manifestations in patients with Reiter's syndrome, an inflammatory arthritis, which is caused by enteric infection with bacteria, including Salmonella typhimurium. Corticosteroids remain the most frequently used therapies against uveitis associating with inflammatory arthritis. However, the long-term administration of steroids results in many side effects, and some uveitis patients do not respond to steroid treatment. Non-steroidal treatments are needed for uveitis patients. Our previous study found that Janus kinase (JAK) 1/2 inhibitor, ruxolitinib could suppress the expression of proinflammatory mediators in the ciliary body and iris. However, the impacts of ruxolitinib on ophthalmic features in uveitic eyes are still unknown. In this study, Salmonella typhimurium endotoxin-induced uveitis (EIU) was induced in Sprague Dawley rats by the injection of lipopolysaccharide (LPS). Compared with LPS-induced rats treated with water, ruxolitinib significantly attenuated the clinical manifestations, infiltrating cells and protein exudation in the aqueous humor, and retina-choroid thickening. Amplitudes of b-wave in both scotopic and photopic electroretinogram (ERG), and the amplitude of a-wave in scotopic ERG in EIU animals were alleviated by ruxolitinib. Collectively, we propose ruxolitinib could attenuate endotoxin-induced uveitis and rescue visual functions in rats by inhibiting the JAK2-STAT3 pathway.

8.
Br J Ophthalmol ; 105(4): 555-560, 2021 04.
Article in English | MEDLINE | ID: mdl-32532761

ABSTRACT

PURPOSE: The purpose of this study was to investigate the signal changes in choriocapillaris flow deficits and choroidal thickness changes using swept-source optical coherence tomography angiography (OCTA) following different treatments. DESIGN: A double-blind, randomised controlled trial. METHODS: Patients with unilateral chronic central serous chorioretinopathy (CSC) were randomised to receive subthreshold micropulse laser therapy (MLT) or half-dose photodynamic therapy (PDT). Choroidal thickness and choriocapillaris flow deficit signals were investigated. RESULTS: Eighteen patients were randomised into the MLT group and 15 patients into the PDT group. Areas with flow deficit signals were identified in all baseline OCTA images of the choriocapillaris, with mean areas of 0.420 and 0.465 mm2 in the MLT and PDT groups, respectively. These flow deficit signal areas were significantly reduced at 6 months (p=0.011) in the MLT group and at 3 months (p=0.008) in the PDT group. Patients from the PDT group were shown to have smaller flow deficit areas than patients from the MLT group at all time points after treatment (p=0.001, analyses of variance). The mean choroidal volume of the fovea showed a significant reduction at 1 month (p=0.003), 3 months (p=0.199) and 6 months (p=0.006) in the PDT group. CONCLUSION: The flow deficit areas identified in the choriocapillaris layer may suggest possible relative choroidal ischaemia. With measurement of choroidal volume reduction and faster rates of flow deficit area change, PDT has a stronger effect than MLT in promoting choriocapillaris recovery.


Subject(s)
Blood Flow Velocity/physiology , Central Serous Chorioretinopathy/therapy , Choroid/pathology , Laser Therapy/methods , Photochemotherapy/methods , Photosensitizing Agents/therapeutic use , Retinal Vessels/physiopathology , Central Serous Chorioretinopathy/diagnosis , Central Serous Chorioretinopathy/physiopathology , Double-Blind Method , Female , Fluorescein Angiography/methods , Follow-Up Studies , Fundus Oculi , Humans , Male , Middle Aged , Retrospective Studies , Tomography, Optical Coherence/methods , Visual Acuity
9.
Transl Vis Sci Technol ; 9(7): 45, 2020 06.
Article in English | MEDLINE | ID: mdl-32832250

ABSTRACT

Purpose: The aim of this study was to evaluate and compare the electrical performance and properties of commercially available electroretinography (ERG) electrodes. Methods: A passive ionic model was used to measure impedance, noise, and potential drift in 10 types of ocular surface and skin ERG electrodes. Results: The impedance for silver-based ocular electrodes are generally lower (range, 65.35-343.3 Ω) with smaller phase angles (range, -6.41° to -33.91°) than gold-based electrodes (impedance ranged from 285.95 Ω to 2.913 kΩ, and phase angle ranged from -59.65° to -70.01°). Silver-based ocular electrodes have less noise (median line noise of 6.48 x 104nV2/Hz) than gold-based electrodes (median line noise of 2.26 x 105nV2/Hz). Although silver-based electrodes usually achieve a drift rate less than 5 µV/s within 15 minutes, gold-base ocular electrode cannot achieve a stable potential. The exception is the RETeval strip type of silver electrode, which had an unusual drift at 20 minutes. The noise spectral density showed no change over time indicating that noise was not dependent on the stabilization of the electrode. Conclusions: From the range of electrodes tested, lower impedance, lower capacitance, and lower noise was observed in silver-based electrodes. Stabilization of an electrode is effective against drift of the electrode potential difference but not the noise. Translational Relevance: Application of electrodes with optimized materials improve the quality of clinical electrophysiology signals and efficiency of the recording.


Subject(s)
Electricity , Electroretinography , Electric Impedance , Electrodes , Silver
10.
Acta Biomater ; 94: 219-231, 2019 08.
Article in English | MEDLINE | ID: mdl-31176841

ABSTRACT

Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides chronic, mild to moderate elevation of intraocular pressure (IOP) with preservation of optical media clarity for long term, in vivo interrogation of the structural and functional integrity of the retinal ganglion cells (RGCs). Here, we designed and formulated an injectable hydrogel based on in situ cross-linking of hyaluronic acid functionalized with vinyl sulfone (HA-VS) and thiol groups (HA-SH). Intracameral injection of HA-VS and HA-SH in C57BL/6J mice exhibited mild to moderate elevation of IOP with daily mean IOP ranged between 14 ±â€¯3 and 24 ±â€¯3 mmHg, which led to progressive, regional loss of RGCs evaluated with in vivo, time-lapse confocal scanning laser ophthalmoscopy; a reduction in fractional anisotropy in the optic nerve and the optic tract projected from the eye with increased IOP in diffusion tensor magnetic resonance imaging; a decrease in positive scotopic threshold response in electroretinography; and a decline in visual acuity measured with an optokinetic virtual reality system. The proportion of RGC loss was positively associated with the age of the animals, and the levels and the duration of IOP elevation. The new glaucoma model recapitulates key characteristics of human glaucoma which is pertinent to the development and pre-clinical testing of neuroprotective and neuroregenerative therapies. STATEMENT OF SIGNIFICANCE: A new model to study chronic neurodegeneration in glaucoma has been developed via intracameral injection of a specifically designed hyaluronic acid functionalized with vinyl sulfone and thiol groups for cross-linking. Intracameral injection of the chemically cross-linked hydrogel generates mild to moderate IOP elevation, resulting in progressive degeneration of the retinal ganglion cells, optic nerve, and optic tract, and a decline in visual function. The model recapitulates the key features of neurodegeneration in human glaucoma, which will facilitate and expedite the development of neuroprotective and neuroregenerative therapies.


Subject(s)
Cross-Linking Reagents/chemistry , Glaucoma/metabolism , Hyaluronic Acid/chemistry , Hydrogels/chemistry , Neurodegenerative Diseases/metabolism , Age Factors , Animals , Disease Models, Animal , Elasticity , Electroretinography , Hydrogels/administration & dosage , Hydrogels/metabolism , Injections , Injections, Intraocular , Intraocular Pressure/drug effects , Kinetics , Magnetic Resonance Imaging , Mice, Inbred C57BL , Neurodegenerative Diseases/complications , Optic Nerve/drug effects , Retinal Ganglion Cells/drug effects , Sulfhydryl Compounds/chemistry , Sulfones/chemistry , Viscosity
11.
Exp Eye Res ; 185: 107687, 2019 08.
Article in English | MEDLINE | ID: mdl-31173765

ABSTRACT

Sclerocornea is a cornea opacification disorder. Disorganized corneal stroma fibrils are observed in patients' cornea. Previously we identified a RAD21C1348T variant that is associated with a peripheral sclerocornea pedigree. To explore whether this RAD21 variant can induce sclerocornea-related phenotype, and to investigate the possible mechanisms of such phenotype, the orthologous rad21 wild-type and variant mRNAs were injected into Xenopus laevis embryos and the developed eyes were subjected for histological examination. Transmission electron microscopy was applied for corneal stroma organization check. rad21 is highly expressed in the eye region during X. laevis development. Disrupted eye development was observed in the rad21 variant injected embryos. Disorganized corneal stroma and decreased diameters of collagen fibrils were observed in the rad21 variant injected X. laevis eyes. These eye defects can be rescued by overexpression of the wild-type rad21. Histological examination found stroma attracting center, a key structure in X. laevis corneal development, was impaired in rad21 variant injected embryos. Our results suggest a key role of RAD21 during corneal development. Our data indicates the RAD21R450C variant contributes to peripheral sclerocornea by disturbing collagen fibril organization in the corneal stroma.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Cell Cycle Proteins/genetics , Cornea/abnormalities , Corneal Diseases/embryology , Corneal Stroma/pathology , Gene Expression Regulation, Developmental/physiology , Xenopus Proteins/genetics , Xenopus laevis/embryology , Animals , Collagen/metabolism , Cornea/embryology , Cornea/ultrastructure , Corneal Diseases/genetics , Corneal Stroma/ultrastructure , Genetic Variation , In Situ Hybridization , Microscopy, Electron, Transmission , Mutagenesis, Site-Directed , Plasmids , RNA, Messenger/genetics
12.
Sci Rep ; 9(1): 2301, 2019 02 19.
Article in English | MEDLINE | ID: mdl-30783194

ABSTRACT

Autoimmune uveitis is a sight-threatening disease mainly caused by dysregulation of immunity. We investigated the therapeutic effects of green tea extract (GTE) and its major component, epigallocatechin-3-gallate (EGCG), on a murine model of experimental autoimmune uveoretinitis (EAU). Oral administration of GTE, EGCG, dexamethasone, or water, which started 5 days before the induction, was fed every two days to each group. On day 21 post induction, the eyes were examined by confocal scanning laser ophthalmoscopy, optical coherence tomography (OCT), fundus fluorescein angiography (FFA) and electroretinography (ERG) prior to sacrificing the animals for histological assessments and gene expression studies. Retinal-choroidal thicknesses (RCT) and major retinal vessel diameter were measured on OCT sections and FFA images, respectively. Comparing to water-treated EAU animals, GTE attenuated uveitis clinical manifestations, RCT increase (1.100 ± 0.013 times vs 1.005 ± 0.012 times, P < 0.001), retinal vessel dilation (308.9 ± 6.189 units vs 240.8 units, P < 0.001), ERG amplitudes attenuation, histopathological ocular damages, and splenomegaly in EAU mice. The therapeutic effects of GTE were dose dependent and were comparable to dexamethasone. EGCG, a major active constituent of GTE, partially alleviated uveitic phenotypes including recovering visual function. Th-17 associated pro-inflammatory gene [interleukin 1 beta (IL-1ß), IL-6, IL-17A, and tumor necrosis factor alpha (TNF-α)] expressions were down regulated by GTE and EGCG treatments, which showed no detectable morphological defects in liver and kidney in non-induced and EAU mice. Our findings suggest that GTE consumption can serve as a potent therapeutic agent as well as a food supplement for developing alternative treatments against autoimmune uveitis.


Subject(s)
Catechin/therapeutic use , Inflammation/drug therapy , Tea/chemistry , Uveitis/drug therapy , Animals , Catechin/analogs & derivatives , Disease Models, Animal , Electroretinography , Interleukin-17/metabolism , Interleukin-6/metabolism , Mice , Microscopy, Confocal , Papilledema/drug therapy , Papilledema/metabolism , Th17 Cells/drug effects , Th17 Cells/metabolism , Tomography, Optical Coherence , Tumor Necrosis Factor-alpha/metabolism , Uveitis/metabolism , Vision Disorders/drug therapy
13.
Cornea ; 37 Suppl 1: S55-S57, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30216333

ABSTRACT

Pterygium is a fibrovascular subepithelial growth of degenerative tissue over the limbus. It is a common condition worldwide that is especially prevalent in tropical countries within the "pterygium belt." Its exact etiology remains to be elucidated; however, it is strongly associated with exposure to ultraviolet light. The high expression levels of tumor protein p53 (TP53) observed in laboratory studies of pterygium seem to contradict the fast-growing nature of its clinical behavior, and TP53 mutations have been suggested. We demonstrated that mouse double minute 2 (MDM2), a TP53-binding protein, contributes to the inhibition of TP53 activity in human pterygium. Thus, disruption of the MDM2-TP53 interaction should attenuate human pterygium cell growth. For primary pterygium, treatment is relatively straightforward and involves surgical excision. To minimize the risk of recurrence, many adjunctive therapies are adopted, including antimetabolites, such as mitomycin C and 5-fluorouracil, amniotic membrane, different variations on conjunctival and/or limbal conjunctival grafts, and other medications such as anti-vascular endothelial growth factor. In the future, MDM2 antagonists may help further lower the recurrence rates after the treatment of pterygium.


Subject(s)
Proto-Oncogene Proteins c-mdm2/physiology , Pterygium , Tumor Suppressor p53-Binding Protein 1/physiology , Amnion/transplantation , Combined Modality Therapy , Conjunctiva/transplantation , Humans , Mitomycin/therapeutic use , Pterygium/drug therapy , Pterygium/etiology , Pterygium/metabolism , Pterygium/surgery
14.
Exp Eye Res ; 175: 142-147, 2018 10.
Article in English | MEDLINE | ID: mdl-29932882

ABSTRACT

AIMS: To confirm that mouse double minute 2 (MDM2) could inhibit p53 activity in human pterygium. And to show the disruption of MDM2-p53 interaction could reactive the functions of p53 in pterygium. METHOD: Pterygium and corresponding conjunctiva tissues were collected for establishment of primary cell lines. Expression patterns of MDM2 and p53 were detected by immunofluorescence. Protein localization of p53 and MDM2, and transcriptional activity of p53 in both untreated and MDM2 antagonist (Nutlin) treated pterygium cells were quantified. RESULTS: In pterygium, p53 was highly expressed in cytoplasm and slightly expressed in the nuclei. MDM2 was localized in the nuclei. A p53 transcriptional regulated target gene, p21, was not expressed in pterygium tissues, suggesting the p53 transcriptional activity was not active in pterygium. After treatment with Nutlin, increased nuclear localization of p53 (4.05%-80.56%) was observed in pterygium cells along with increasing Nutlin dosages (from 0 to 50 µM, p < 0.001). The expression of p21 was increased after Nutlin treatments in pterygium cells (2.49 folds in 20 µM Nutlin treated cells compared to control treated cells, p = 0.012). CONCLUSION: We discovered a novel mechanism in pterygium whereby MDM2 suppresses p53 transcriptional activity despite abundant p53 in pterygium. Disruption of MDM2-p53 interaction by Nutlin could be a potential treatment for pterygium.


Subject(s)
Proto-Oncogene Proteins c-mdm2/physiology , Pterygium/metabolism , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/metabolism , Adult , Aged , Aged, 80 and over , Cell Line , Conjunctiva/metabolism , Female , Fluorescent Antibody Technique, Indirect , Humans , Imidazoles/pharmacology , Immunoblotting , Male , Middle Aged , Piperazines/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors
15.
Exp Eye Res ; 176: 46-52, 2018 11.
Article in English | MEDLINE | ID: mdl-29908144

ABSTRACT

The aim of this study was to compare the quality of electroretinogram (ERG) recordings using a custom built active electrode with attached amplifier versus a standard (passive) ERG electrode. Scotopic and photopic ERG responses were recorded from five adult albino rabbits using a custom built active electrode on one eye and a passive electrode on the other. For the active electrode, the ERG-jet electrode (Universo S.A., La Chaux-De-Fonds, Switzerland) was used as the transducer with the cable cut short and soldered directly to the input of a customized amplifier. The passive electrode was a standard ERG jet electrode. The signal to noise ratio and reproducibility of ERGs were compared. The noise was significantly lower in the active electrode compared to the passive electrode (p = 0.009) resulting in signals being recorded at lower stimulation strengths with the active electrode. The scotopic a-wave was significantly larger in the active electrode at all supra-threshold stimulation intensities (p < 0.05) and the scotopic b-wave amplitudes were also higher in the active electrode at all supra-threshold stimulation intensities but was only statistically significant between -3.25 and -1 log cd.s.m-2 (p < 0.05). The photopic a- and b-wave amplitudes were also higher in the active electrode and statistically significant between -0.75 and 0.48 log cd.s.m-2 for the a-wave and -1.25 to -1 log cd.s.m-2 for the b-wave (p < 0.05). The intra-observer repeatability, inter-sessions reproducibility and reliability of the signals were better in the active electrode as evidenced by lower coefficient of variation (CV) and coefficient of repeatability (CR) with high intra-class correlation coefficient (ICC) of the a- and b-wave parameters of the active electrode. These findings suggest that the custom built active ERG electrode produces less noise than the passive electrode, allowing responses to be recorded at lower stimulation strengths. It produces greater signal amplitudes and improved reproducibility and is therefore a better device for investigating retinal function.


Subject(s)
Electrodes , Electroretinography/standards , Retina/physiology , Animals , Color Vision/physiology , Electroretinography/methods , Night Vision/physiology , Rabbits , Reproducibility of Results , Signal-To-Noise Ratio
16.
Cornea ; 37(6): 760-766, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29595761

ABSTRACT

PURPOSE: Nutlin is a drug that has been reported to activate p53 in various cell lines. We aim to study the effects of Nutlin in pterygium and compare the effects of Nutlin and mitomycin C (MMC) in pterygium cell lines. METHODS: Pterygium samples (n = 3) were collected during surgical excision. Normal conjunctival tissues (n = 3) were collected from another quadrant of the same eye. Cell lines were established, and cells from passages 2 to 5 were used. Pterygium and conjunctival cells were treated with different doses of Nutlin and MMC. Cell proliferation and cell migration were measured. RESULTS: Cell proliferation was reduced by 39-fold after treatment with 50 µM Nutlin. Cell migration was inhibited with increasing dosages of Nutlin (95% and 28% after treating with 2 and 50 µM Nutlin, respectively). Compared with MMC, Nutlin induced more pterygium cell death and less conjunctival cell death at low doses. At 50% lethal dose for pterygium cells, 95% of conjunctival cells survived after Nutlin treatment, whereas only 63% of conjunctival cells survived after MMC treatment. p21 expression was not detectable in MMC-treated pterygium cells but was detectable after Nutlin treatment. CONCLUSIONS: In our study, MMC induced cell death in pterygium and conjunctival cell lines, whereas Nutlin had a targeted impact on pterygium cells. Our results implied that MMC inhibited both pterygium cell proliferation and migration through an apoptosis-independent pathway.


Subject(s)
Cell Movement/drug effects , Cell Proliferation/drug effects , Imidazoles/pharmacology , Mitomycin/pharmacology , Piperazines/pharmacology , Pterygium , Analysis of Variance , Apoptosis/drug effects , Cell Line , Conjunctiva/cytology , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Humans , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors
17.
Invest Ophthalmol Vis Sci ; 58(10): 4193-4200, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28837731

ABSTRACT

Purpose: To accurately evaluate the autoimmune inflammation, we aim to develop three quantitative measurements to monitor the inflammatory changes in the retina: retinal-choroidal thickness, major retinal vessel diameter, and electroretinography amplitudes. Methods: During a 21-day experimental period, eyes were examined by confocal scanning laser ophthalmoscopy, optical coherence tomography, fundus fluorescein angiography, and electroretinography in living mice, which were then subsequently killed for histologic assessments. Results: On day 21 postimmunization, inflammation was observed both in vivo and in vitro. Fold change of retinal-choroidal thickness and major retinal vessel diameter in experimental autoimmune uveoretinitis mice were significantly greater than controls (P < 0.001). Both scotopic and photopic electroretinography amplitudes were significantly attenuated when compared with control mice (P < 0.01). Our results showed that these three quantifiable indicators provided an objective and accurate evaluation of autoimmune inflammation, which are in good correlations with the reported clinical and histopathologic scoring systems (P < 0.05). Conclusions: These three indicators will be useful to detect the small but significant differences in the severity of experimental autoimmune uveoretinitis for future longitudinally therapeutic studies.


Subject(s)
Autoimmune Diseases/diagnosis , Disease Models, Animal , Retina/physiopathology , Retinal Vessels/pathology , Retinitis/diagnosis , Uveitis/diagnosis , Animals , Autoantigens , Autoimmune Diseases/immunology , Autoimmune Diseases/physiopathology , Capillary Permeability , Dilatation, Pathologic , Electroretinography , Eye Proteins , Female , Fluorescein Angiography , Mice , Mice, Inbred C57BL , Oligopeptides , Ophthalmoscopy , Retinitis/immunology , Retinitis/physiopathology , Retinol-Binding Proteins , Uveitis/immunology , Uveitis/physiopathology
18.
Sci Rep ; 7: 45081, 2017 03 27.
Article in English | MEDLINE | ID: mdl-28345626

ABSTRACT

Angiopoietin 2 (ANG2) is a proangiogenic cytokine which may have an implication in neovascular age related macular degeneration (nAMD). In 24 eyes of 24 subjects presenting with treatment naïve nAMD and 26 eyes of 26 control patients, aqueous humor samples were collected at the time of intervention (intravitreal injection of anti-vascular endothelial growth factor or cataract extraction). Best corrected visual acuity (BCVA) with and central macular thickness (CMT) using optical coherence tomography (OCT) were measured before each injection in the nAMD group. Aqueous cytokine levels were determined by immunoassay using a multiplex array (Quansys Biosciences, Logan, UT). Levels of ANG2 in the aqueous were significantly higher in nAMD patients than those of the control group (p < 0.0001), so were hepatocyte growth factor (HGF), interleukin-8 (IL-8) and tissue inhibitor of metalloproteinase 1 (TIMP 1), all with p < 0.001. ANG2 correlated with worse BCVA (r = 0.44, p-value = 0.027) and greater CMT (r = 0.66, p-value < 0.0001) on optical coherence tomography (OCT). ANG2 is upregulated in patients with nAMD and correlates with severity of disease at presentation.


Subject(s)
Angiopoietin-2/metabolism , Aqueous Humor/metabolism , Macular Degeneration/metabolism , Aged , Aged, 80 and over , Biomarkers/metabolism , Case-Control Studies , Female , Hepatocyte Growth Factor/metabolism , Humans , Interleukin-8/metabolism , Macular Degeneration/pathology , Male , Middle Aged , Tissue Inhibitor of Metalloproteinase-1/metabolism , Visual Acuity
19.
J Refract Surg ; 33(2): 96-103, 2017 Feb 01.
Article in English | MEDLINE | ID: mdl-28192588

ABSTRACT

PURPOSE: To study the differences in early corneal cellular events and biomechanical properties after femtosecond laser-assisted LASIK performed using conventional or inverted side-cut angles. METHODS: In the laboratory study, left eyes of 24 rabbits underwent LASIK flap creation with a 70° or 115° side-cut. The contralateral eyes served as controls. The corneas were harvested 24 hours postoperatively. In the clinical study, 2 eyes of each patient (n = 29) were randomized to corneal flap creation with 70° or 115° side-cut angles during LASIK. The Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Depew, NY) was used to assess biomechanical properties of the cornea. RESULTS: In rabbit eyes, epithelial ingrowth was observed more frequently in flaps with 70° side cuts compared to flaps with 115° side-cuts. Corneas with 70° side-cuts showed significantly increased apoptotic cells compared to 115° side-cuts in the central (P = .001) and peripheral (P = .004) regions. Fifty-eight eyes of 29 patients were included in the clinical study. An overall reduction in Goldmann-correlated intraocular pressure, corneal-compensated intraocular pressure, corneal resistance factor, corneal hysteresis measurements, p1 area, p2 area, and p1 area 1 and p2 area 1 was noted 37 ± 2 months after surgery (P < .001). No significant difference was observed in the change of any of these parameters between both groups (P ≥ .146). CONCLUSIONS: Significant differences in wound healing were observed in rabbit corneas that underwent LASIK with conventional or inverted side-cuts. Variation in flap side-cut angles did not alter the long-term biomechanical properties measured with the ORA in patients after LASIK. [J Refract Surg. 2017;33(2):96-103.].


Subject(s)
Corneal Stroma/surgery , Keratomileusis, Laser In Situ/methods , Lasers, Excimer/therapeutic use , Myopia/surgery , Surgical Flaps , Wound Healing/physiology , Adult , Animals , Apoptosis , Biomechanical Phenomena , CD11b Antigen/metabolism , Corneal Keratocytes/pathology , Female , Fluorescent Antibody Technique, Indirect , Humans , In Situ Nick-End Labeling , Intraocular Pressure/physiology , Ki-67 Antigen/metabolism , Male , Middle Aged , Myopia/metabolism , Myopia/physiopathology , Rabbits , Visual Acuity/physiology , Young Adult
20.
Sci Rep ; 6: 29546, 2016 07 07.
Article in English | MEDLINE | ID: mdl-27383468

ABSTRACT

Green tea extracts exhibit anti-oxidative and anti-inflammatory actions in different disease conditions. We hypothesized that green tea extract and its catechin constituents ameliorate sodium iodate-induced retinal degeneration in rats by counteracting oxidative stress. In this study, adult Sprague-Dawley rats were intravenously injected with a single dose of sodium iodate. Green tea extract (GTE; Theaphenon-E) or combinations of its catechin constituents, including (-)-epigallocatechin gallate (EGCG), were administered intra-gastrically before injection. Live imaging analysis using confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography showed a progressive increase of degenerating profile across the retinal surface and decrease in thickness of outer nuclear layer (ONL) at Day-14 of post-injection. These lesions were significantly ameliorated by Theaphenon-E and catechin combinations with EGCG. Catechins with exclusion of EGCG did not show obvious protective effect. Histological analyses confirmed that Theaphenon-E and catechins containing EGCG protect the retina by reducing ONL disruption. Retinal protective effects were associated with reduced expression of superoxide dismutase, glutathione peroxidase and caspase-3, and suppression of 8-iso-Prostaglandin F2α generation in the retina. In summary, GTE and its catechin constituents are potent anti-oxidants that offer neuroprotection to the outer retinal degeneration after sodium iodate insult, among which EGCG is the most active constituent.


Subject(s)
Catechin/pharmacology , Retinal Degeneration/drug therapy , Tea/chemistry , Administration, Oral , Animals , Antioxidants/pharmacology , Catechin/administration & dosage , Catechin/analogs & derivatives , Dinoprost/analogs & derivatives , Dinoprost/metabolism , Gene Expression Regulation/drug effects , Iodates/toxicity , Ophthalmoscopy/methods , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Retinal Degeneration/chemically induced , Retinal Degeneration/pathology , Retinal Pigment Epithelium/drug effects , Retinal Pigment Epithelium/pathology
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