scholarly journals UNC569-induced Morphological Changes in Pigment Epithelia and Photoreceptor Cells in the Retina through MerTK Inhibition in Mice

2018 ◽  
Vol 46 (2) ◽  
pp. 193-201 ◽  
Author(s):  
Ayako Sayama ◽  
Keiko Okado ◽  
Koichi Nakamura ◽  
Tatsuya Kawaguchi ◽  
Takuma Iguchi ◽  
...  
Keyword(s):  
Tissue Sample ◽  
Morphological Changes ◽  
Pigment Epithelium ◽  
Outer Nuclear Layer ◽  
Retinal Pigment ◽  
Electron Microscopic Examination ◽  
Photoreceptor Cells ◽  
Electron Microscopic ◽  
Drug Induced ◽  
Photoreceptor Outer Segments

Mer proto-oncogene tyrosine kinase (MerTK), which is expressed in the retinal pigment epithelium (RPE), regulates phagocytosis of shed photoreceptor outer segments (POS). To investigate the effects of drug-induced MerTK inhibition on the retina, UNC569, a specific MerTK inhibitor, was orally administered to male mice at a concentration of 60, 100, or 150 mg/kg for up to 14 days. Furthermore, MerTK inhibition in the retinal tissue sample was examined using a phosphorylation assay following a single dose of UNC569 at 100 mg/kg. In electron microscopic examination, UNC569 at 100 mg/kg or more increased phagosomes and phagolysosomes in the RPE. In addition, UNC569 at 150 mg/kg increased chromatin-condensed nuclei in the outer nuclear layer, indicating the early phase of apoptosis of photoreceptor cells. MiR-183, miR-96, and miR-124, which are enriched in photoreceptor cells, were elevated in the plasma of mice following treatment of 150-mg/kg UNC569, in conjunction with the photoreceptor lesion. Additionally, 100-mg/kg UNC569 inhibited MerTK phosphorylation in the retina. These results suggest that MerTK inhibition impaired phagocytic function of the retina, leading to accumulation of shed POS within the POS layer and increasing phagosomes and phagolysosomes in the RPE to delay POS renewal, resulting in apoptosis of photoreceptor cells.

The effects of intravitreally injected bevacizumab on the retina and retina pigment epithelium: experimental in-vivo electron microscopic study in intact versus vitrectomized eyes

Open Medicine ◽  
2010 ◽  
Vol 5 (6) ◽  
pp. 745-751 ◽  
Author(s):  
Nilufer Kocak ◽  
Candan Ozogul ◽  
Suleyman Kaynak ◽  
Ulker Sonmez ◽  
Mehmet Zengin ◽  
...  
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Intravitreal Bevacizumab ◽  
Electron Microscopic Examination ◽  
Photoreceptor Cells ◽  
Control Group ◽  
Electron Microscopic ◽  
Tissue Samples ◽  
Electron Microscopes

AbstractTo analyze the retinal toxicity of bevacizumab at various doses both in vitrectomized and non-vitrectomized rabbit models. Twenty- eight rabbits were included in the study. Twenty- four rabbits were assigned to six groups, with 4 of the rabbits in the control group. The animals in Groups 1, 2 and 3 received bevacizumab at a dose of 0.3 mg, 0.5 mg and 1.5 mg /eye, respectively. The rabbits in Groups 4, 5 and 6 received intravitreal bevacizumab of 0.3 mg, 0.5 mg and 1.5mg/eye, respectively, after gas compression vitrectomy. Two weeks after the procedure, the rabbits were euthanized. Retina tissue samples were then obtained and examined with both light and electron microscopes. In Groups 1, 2 and 3 after bevacizumab injection, toxic degeneration in the photoreceptor and retinal pigment epithelium cells was observed via electron microscopic examination. The findings in Groups 4 and 5 were normal as compared to the control group. In Group 6, toxicity in the bipolar neurons and photoreceptor cells was noticed. Increased toxicity and retinal penetration were noticed in all administered doses of bevacizumab in the presence of vitreous. In addition, ocular toxicity occurred through the injection of the highest dose of bevacizumab after vitrectomy. It is possible that the bevacizumab dose and the, vitreous are as important as the drug half-life in the vitreous.

scholarly journals The Impact of the Timing of Dosing on the Severity of UNC569-Induced Ultrastructural Changes in the Mouse Retina

2020 ◽  
Vol 48 (5) ◽  
pp. 669-676
Author(s):  
Ayako Sayama ◽  
Keiko Okado ◽  
Mayu Yamaguchi ◽  
Naozumi Samata ◽  
Masako Imaoka ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Electron Microscopic Examination ◽  
Photoreceptor Cells ◽  
Ultrastructural Changes ◽  
Mouse Retina ◽  
Visual Cycle ◽  
Electron Microscopic ◽  
The Impact

Mer proto-oncogene tyrosine kinase (MerTK), expressed in the retinal pigment epithelium (RPE), regulates the phagocytosis of shed photoreceptor outer segments. To investigate the influence of dosing time on MerTK inhibitor UNC569-induced retinal toxicity, UNC569 at 100 mg/kg was orally administered to male mice at 2 different Zeitgeber times (ZT5.5 or ZT22) for 28 days. Electron microscopy was conducted at ZT2 after the final dosing. Additionally, the visual cycle components (11-cis-retinal, all-trans-retinal, all-trans-retinol, and 11-cis-retinol), which play an important role in maintaining retinal homeostasis, were quantified by liquid chromatography/mass spectrometry/mass spectrometry. Under electron microscopic examination, the number of phagosomes and phagolysosomes in the RPE increased in both the ZT5.5 and ZT22 administered groups, while endoplasmic reticulum dilatation in the RPE and chromatin aggregation of photoreceptor nuclei were observed only in the ZT22 administered group. No change was observed in any of the visual cycle components. These results suggest that the timing of the dosing in relation to the physiological MerTK phosphorylation affected the severity of changes in the RPE, leading to the apoptosis of the photoreceptor cells.

scholarly journals Analysis of retinal sublayer thicknesses and rates of change in ABCA4-associated Stargardt disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
S. Scott Whitmore ◽  
Christopher R. Fortenbach ◽  
Justine L. Cheng ◽  
Adam P. DeLuca ◽  
D. Brice Critser ◽  
...  
Keyword(s):  
Vision Loss ◽  
Pigment Epithelium ◽  
Outer Nuclear Layer ◽  
Retinal Pigment ◽  
Macular Dystrophy ◽  
Stargardt Disease ◽  
Fiber Layer ◽  
Thickness Change ◽  
Photoreceptor Outer Segments ◽  
Sublayer Thickness

Abstract Stargardt disease, the most common inherited macular dystrophy, is characterized by vision loss due to central retinal atrophy. Although clinical trials for Stargardt are currently underway, the disease is typically slowly progressive, and objective, imaging-based biomarkers are critically needed. In this retrospective, observational study, we characterize the thicknesses of individual retinal sublayers by macular optical coherence tomography (OCT) in a large cohort of patients with molecularly-confirmed, ABCA4-associated Stargardt disease (STGD1) relative to normal controls. Automated segmentation of retinal sublayers was performed with manual correction as needed, and thicknesses in various macular regions were compared using mixed effects models. Relative to controls (42 eyes, 40 patients), STGD1 patients (107 eyes, 63 patients) had slight thickening of the nerve fiber layer and retinal pigment epithelium-Bruch’s membrane, with thinning in other sublayers, especially the outer nuclear layer (ONL) (p < 0.0015). When comparing the rate of retinal sublayer thickness change over time (mean follow-up 3.9 years for STGD1, 2.5 years for controls), STGD1 retinas thinned faster than controls in the outer retina (ONL to photoreceptor outer segments). OCT-based retinal sublayer thickness measurements are feasible in STGD1 patients and may provide objective measures of disease progression or treatment response.

scholarly journals Effect of methanol on the ultrastructure of chorioretinal complex of rats’ eyes in the early stages of the experiment

2014 ◽  
Vol 18 (1 (69)) ◽  
Author(s):  
N. І. Molchanyuk
Keyword(s):  
Smooth Endoplasmic Reticulum ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Photoreceptor Cells ◽  
Electron Microscopic ◽  
White Rats ◽  
Intraperitoneal Dose ◽  
A Cell ◽  
Number Of Cells ◽  
Observation Period

Electron-microscopic structure of the chorioretinal complex were investigated (СRC), [choriocapillaries (HC) – retinal pigment epithelium (RPE) – photoreceptor cells (FC)], of white rats in a period of 40 min. to 3 days after a single intraperitoneal dose of methanol 0.75 g/kg body weight. It has been established that RPE cells are the most responsiveto the dose of the methanol used. In the dynamics (from 40 min. up to 3 days), they grew destructive changes of mitochondria and elements of smooth endoplasmic reticulum, the smoothness of the basal folds and patchy destruction of the apical microvilli. The changes in CC and FC were similar. By the end of the observation period, these phenomena in the CRC structure spread to a larger number of cells. At the same time, during the whole period of the study, and, in particular, after a day, some signs of recovery of compensatory nature were obvious. Attention is drawn to pronounced reaction of mitochondria, which are energy forming structures of a cell.

scholarly journals Vertebrate features revealed in the rudimentary eye of the Pacific hagfish ( Eptatretus stoutii )

2021 ◽  
Vol 288 (1942) ◽  
pp. 20202187
Author(s):  
Emily M. Dong ◽  
W. Ted Allison
Keyword(s):  
Ganglion Cells ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Photoreceptor Cells ◽  
Photoreceptor Outer Segments ◽  
The Pacific ◽  
Cell Layers ◽  
Eptatretus Stoutii ◽  
Animal Vision ◽  
Ciliary Marginal Zone

Hagfish eyes are markedly basic compared to the eyes of other vertebrates, lacking a pigmented epithelium, a lens and a retinal architecture built of three cell layers: the photoreceptors, interneurons and ganglion cells. Concomitant with hagfish belonging to the earliest-branching vertebrate group (the jawless Agnathans), this lack of derived characters has prompted competing interpretations that hagfish eyes represent either a transitional form in the early evolution of vertebrate vision, or a regression from a previously elaborate organ. Here, we show the hagfish retina is not extensively degenerating during its ontogeny, but instead grows throughout life via a recognizable PAX6 + ciliary marginal zone. The retina has a distinct layer of photoreceptor cells that appear to homogeneously express a single opsin of the RH1 rod opsin class. The epithelium that encompasses these photoreceptors is striking because it lacks the melanin pigment that is universally associated with animal vision; notwithstanding, we suggest this epithelium is a homologue of gnathosome retinal pigment epithelium (RPE) based on its robust expression of RPE65 and its engulfment of photoreceptor outer segments. We infer that the hagfish retina is not entirely rudimentary in its wiring, despite lacking a morphologically distinct layer of interneurons: multiple populations of cells exist in the hagfish inner retina and subsets of these express markers of vertebrate retinal interneurons. Overall, these data clarify Agnathan retinal homologies, reveal characters that now appear to be ubiquitous across the eyes of vertebrates, and refine interpretations of early vertebrate visual system evolution.

A Bibliometric Analysis of the Top 100 Cited Papers in Retinal Detachment

2021 ◽  
pp. 247412642110073
Author(s):  
Masumi George Asahi ◽  
Haig Pakhchanian ◽  
Christine Doepker ◽  
Rahul Raiker ◽  
Ron P. Gallemore
Keyword(s):  
Retinal Detachment ◽  
Bibliometric Analysis ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Microscopic Analysis ◽  
The United States ◽  
Electron Microscopic ◽  
Research Areas ◽  
Science Index ◽  
Funding Agencies

Purpose: This work aimed to identify and analyze the most frequently cited articles in retinal detachment (RD). Methods: Institute for Scientific Information’s Web of Science index (Thomas Scientific) was used to identify the top 100 most cited articles on RD between 1900 and 2019. Data from the top 100 most cited articles that met inclusion criteria were analyzed based on title, citation frequency, authorship, institution, journal, year of publication, and country of origin. Results: The top 100 articles in RD were cited 88 to 480 times. Steven K. Fisher was the most cited individual, with the University of California system being the most cited organization. Sixty-four percent of the top 100 articles originated from the United States and were published in the American Journal of Ophthalmology, Ophthalmology, and Archives of Ophthalmology at frequencies of 36%, 24%, and 11%, respectively. The top funding agencies included the US Department of Health and Human Services, the National Institutes of Health, and the National Eye Institute at 29%, 28%, and 27%, respectively. The top-cited article, which assessed the role of the retinal pigment epithelium by histologic and electron microscopic analysis of RDs in eyes of owl monkeys, was by Machemer and Laqua in the American Journal of Ophthalmology. Conclusions: This bibliometric analysis provides researchers and clinicians with a detailed overview of the most cited manuscripts in RD. Such analyses may guide researchers and funding agencies on important research areas in the field.

scholarly journals Loss of melanoregulin (MREG) enhances cathepsin-D secretion by the retinal pigment epithelium

2013 ◽  
Vol 30 (3) ◽  
pp. 55-64 ◽  
Author(s):  
LAURA S. FROST ◽  
VANDA S. LOPES ◽  
FRANK P. STEFANO ◽  
ALVINA BRAGIN ◽  
DAVID S. WILLIAMS ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Cathepsin D ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Disease ◽  
Protective Role ◽  
Phagocytic Cells ◽  
Phagocytic Capacity ◽  
Photoreceptor Outer Segments ◽  
Age Dependent

AbstractCathepsin-D (Cat-D) is a major proteolytic enzyme in phagocytic cells. In the retinal pigment epithelium (RPE), it is responsible for the daily degradation of photoreceptor outer segments (POSs) to maintain retinal homeostasis. Melanoregulin (MREG)-mediated loss of phagocytic capacity has been linked to diminished intracellular Cat-D activity. Here, we demonstrate that loss of MREG enhances the secretion of intermediate Cat-D (48 kDa), resulting in a net enhancement of extracellular Cat-D activity. These results suggest that MREG is required to maintain Cat-D homeostasis in the RPE and likely plays a protective role in retinal health. In this regard, in the Mregdsu/dsu mouse, we observe increased basal laminin. Loss of the Mregdsu allele is not lethal and therefore leads to slow age-dependent changes in the RPE. Thus, we propose that this model will allow us to study potential dysregulatory functions of Cat-D in retinal disease.

scholarly journals Spectral OCT-Angiography in En Face Mode for Detection of Morphological Changes in the Retinal Pigment Epithelium before and after Selective Micro-Pulse Laser Exposure in Patients with Central Serous Chorioretinopathy

2019 ◽  
Vol 16 (2) ◽  
pp. 192-201
Author(s):  
P. L. Volodin ◽  
E. V. Ivanova ◽  
E. Iu. Polyakova ◽  
A. V. Fomin
Keyword(s):  
Retinal Pigment Epithelium ◽  
Central Serous Chorioretinopathy ◽  
Morphological Changes ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Laser System ◽  
Subretinal Fluid ◽  
Micropulse Laser ◽  
En Face ◽  
Before And After

Purpose — to study the morphological changes of the retinal pigment epithelium (RPE) by optical coherence tomography-angiography (OCT-A) in En Face mode before and after selective micropulse laser irradiation in patients with central serous chorioretinopathy (CSC), determine the correspondence between the topographic location of RPE defects and detachment on the OCT-angiogram in En Face mode and points of leakage on the FAG.Patients and methods. There were 20 patients (21 eyes) with CSC before and after laser treatment under the observation. All patients underwent high-resolution FAG and OCT-A using Angio Retina 2×2 or 3×3 mm protocol and Angio Retina HD 6×6 mm. The treatment was carried out in a selective micropulse mode with individual selection of parameters using the Navilas 577s navigation laser system (OD-OS, Germany) or the IQ 577 laser system (IRIDEX, USA).Results were evaluated at 2 weeks and 1 month after treatment. Results. In all cases, the leaking points of the subretinal fluid on FAG corresponded to the topographic location of defects and detachments of RPE detachment on OKT-A En Face. According to OCT-A En Face, the following morphological changes were revealed: in 5 cases — single defects of RPE, in 7 cases — multiple defects of RPE, in 9 cases of slit-like detachment of RPE, in 3 patients a combination of slit-like detachment and defect RPE. The sizes of RPE defects varied in the range from 21 to 159 microns, while their rounded shape prevailed. 1 month after the selective micropulse laser effect on OCT-A in the En Face mode, the defects were closed and the RPE detachments fit in all patients, which resulted in resorption of the subretinal fluid and the neurosensory retina attachment.Findings. OCT-A in En Face mode is a highly informative diagnostic method that allows noninvasive detection of morphological changes in RPE with a clear topographic localization relative to the retinal vascular network, as well as evaluating the effectiveness of selective micropulse laser treatment in patients with CSC. 

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