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Journal of Neuroinflammation Dec 2021Glaucoma, the leading cause of irreversible blindness, is a retinal neurodegenerative disease, which results from progressive apoptotic death of retinal ganglion cells...
BACKGROUND
Glaucoma, the leading cause of irreversible blindness, is a retinal neurodegenerative disease, which results from progressive apoptotic death of retinal ganglion cells (RGCs). Although the mechanisms underlying RGC apoptosis in glaucoma are extremely complicated, an abnormal cross-talk between retinal glial cells and RGCs is generally thought to be involved. However, how interaction of Müller cells and microglia, two types of glial cells, contributes to RGC injury is largely unknown.
METHODS
A mouse chronic ocular hypertension (COH) experimental glaucoma model was produced. Western blotting, immunofluorescence, quantitative real-time polymerase chain reaction (q-PCR), transwell co-culture of glial cells, flow cytometry assay, ELISA, Ca image, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) techniques were employed to investigate the interaction of Müller cells and microglia, and its underlying mechanisms in COH retina.
RESULTS
We first showed that Müller cell activation in mice with COH induced microglia activation through the ATP/P2X7 receptor pathway. The activation of microglia resulted in a significant increase in mRNA and protein levels of pro-inflammatory factors, such as tumor necrosis factor-α and interleukin-6. These inflammatory factors in turn caused the up-regulation of mRNA expression of pro-inflammatory factors in Müller cells through a positive feedback manner.
CONCLUSIONS
These findings provide robust evidence, for the first time, that retinal inflammatory response may be aggravated by an interplay between activated two types of glial cells. These results also suggest that to reduce the interplay between Müller cells and microglia could be a potential effective strategy for preventing the loss of RGCs in glaucoma.
Topics: Adenosine Triphosphate; Animals; Coculture Techniques; Cytokines; Ependymoglial Cells; Glaucoma; Macrophage Activation; Mice; Mice, Inbred C57BL; Microglia; Ocular Hypertension; Receptors, Purinergic P2X7; Retinal Ganglion Cells; Retinitis; Signal Transduction
PubMed: 34952606
DOI: 10.1186/s12974-021-02366-x -
ELife Aug 2019The devastating effects and incurable nature of hereditary and sporadic retinal diseases such as Stargardt disease, age-related macular degeneration or retinitis...
The devastating effects and incurable nature of hereditary and sporadic retinal diseases such as Stargardt disease, age-related macular degeneration or retinitis pigmentosa urgently require the development of new therapeutic strategies. Additionally, a high prevalence of retinal toxicities is becoming more and more an issue of novel targeted therapeutic agents. Ophthalmologic drug development, to date, largely relies on animal models, which often do not provide results that are translatable to human patients. Hence, the establishment of sophisticated human tissue-based in vitro models is of upmost importance. The discovery of self-forming retinal organoids (ROs) derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) is a promising approach to model the complex stratified retinal tissue. Yet, ROs lack vascularization and cannot recapitulate the important physiological interactions of matured photoreceptors and the retinal pigment epithelium (RPE). In this study, we present the retina-on-a-chip (RoC), a novel microphysiological model of the human retina integrating more than seven different essential retinal cell types derived from hiPSCs. It provides vasculature-like perfusion and enables, for the first time, the recapitulation of the interaction of mature photoreceptor segments with RPE in vitro. We show that this interaction enhances the formation of outer segment-like structures and the establishment of in vivo-like physiological processes such as outer segment phagocytosis and calcium dynamics. In addition, we demonstrate the applicability of the RoC for drug testing, by reproducing the retinopathic side-effects of the anti-malaria drug chloroquine and the antibiotic gentamicin. The developed hiPSC-based RoC has the potential to promote drug development and provide new insights into the underlying pathology of retinal diseases.
Topics: Humans; Induced Pluripotent Stem Cells; Lab-On-A-Chip Devices; Organoids; Retina
PubMed: 31451149
DOI: 10.7554/eLife.46188 -
Acta Ophthalmologica Nov 2019The relationship between ocular haemodynamics and retinitis pigmentosa (RP) has not been fully understood. Reductions in blood flow have been established in RP patients... (Review)
Review
The relationship between ocular haemodynamics and retinitis pigmentosa (RP) has not been fully understood. Reductions in blood flow have been established in RP patients by a variety of studies; however, questions have yet to be answered regarding the role of vascular dysfunction in photoreceptors (PR) degeneration, the causes of vascular dysfunction in RP, as well as the diagnostic, prognostic and perhaps therapeutic potential of measuring ocular haemodynamics in RP patients. While significant evidence supports the theory that vascular dysfunction is associated with but not the cause of PR death in retinitis pigmentosa, evidence suggests that vascular abnormalities in the foveal and parafoveal regions may exacerbate cone cell loss. Additional evidence demonstrates that vascular dysfunction likely results from changes in metabolic demand due to death of PR cells in the retina. Detection and monitoring of ocular blood flow, retinal oxygen saturation, endothelin-1 levels and vascular structural abnormalities could provide diagnostic, prognostic and therapeutic potential for patients with RP.
Topics: Humans; Prognosis; Retina; Retinal Vessels; Retinitis Pigmentosa; Tomography, Optical Coherence
PubMed: 31099494
DOI: 10.1111/aos.14138 -
Indian Journal of Ophthalmology Jul 2023To study the clinical presentation and treatment outcome of epidemic retinitis (ER) during pregnancy. (Observational Study)
Observational Study
PURPOSE
To study the clinical presentation and treatment outcome of epidemic retinitis (ER) during pregnancy.
METHODS
This is a retrospective, observational chart review of pregnant patients diagnosed with ER from January 2014 to February 2023. Demographic details, month of pregnancy at the onset of ocular symptoms, history of present illness, clinical manifestations, and treatment outcomes were studied.
RESULTS
In 9 years, ER was seen in 86 females, of whom 12 (13.9%) were pregnant. Twenty-one eyes of those 12 patients were studied. Most of the patients presented in the sixth month of pregnancy (range: 5-9 months, mean: 6.3 months). Physicians diagnosed viral exanthematous fever in six, typhoid in three, and suspected rickettsia in one patient. Medical termination of pregnancy (MTP) was performed in two patients before presentation. Weil-Felix test was positive in five, Brucella in one, WIDAL in three, and coronavirus disease 2019 (COVID-19) IgG and dengue IgG in one patient each. Oral antibiotics were given in five patients (two post-medical termination of pregnancy [MTP]) for the retinitis. All except four received oral steroids. Mean presenting corrected distant visual acuity (n = 21) was 20/125 (range: 20/20-20/20,000), which improved to (n = 18) 20/30 (range: 20/20-20/240). Macular edema (n = 11) resolved in 33.18 days (range: 20-50 days), and retinitis (n = 13) resolved in 58 days (range: 30-110 days). Ocular and systemic examination of newborn was possible in two and the babies were normal.
CONCLUSION
ER is seen commonly at the beginning of the third trimester. Lack of antibiotics may delay the resolution of retinitis. Ocular health needs to be assessed in larger series to conclude absence of retinal involvement in newborns.
Topics: Infant, Newborn; Female; Humans; Pregnancy; COVID-19; Retinitis; Retina; Anti-Bacterial Agents; Immunoglobulin G; Retrospective Studies
PubMed: 37417121
DOI: 10.4103/IJO.IJO_3169_22 -
Drug Discovery Today Jan 2021Ocular disorders, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), and glaucoma, can cause irreversible visual loss,... (Review)
Review
Ocular disorders, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), and glaucoma, can cause irreversible visual loss, and affect the quality of life of millions of patients. However, only very few 3D systems can mimic human ocular pathophysiology, especially the retinal degenerative diseases, which involve the loss of retinal ganglion cells (RGCs), photoreceptors, or retinal pigment epithelial cells (RPEs). In this review, we discuss current progress in the 3D modeling of ocular tissues, and review the use of the aforementioned technologies for optic neuropathy treatment according to the categories of associated disease models and their applications in drug screening, mechanism studies, and cell and gene therapies.
Topics: Cell- and Tissue-Based Therapy; Computer Simulation; Drug Design; Engineering; Humans; Models, Biological; Optic Nerve Diseases; Printing, Three-Dimensional; Retina
PubMed: 33038525
DOI: 10.1016/j.drudis.2020.09.034 -
Biomedicine & Pharmacotherapy =... Aug 2023Vitamin A (retinol) is a lipid-soluble vitamin that acts as a precursor for several bioactive compounds, such as retinaldehyde (retinal) and isomers of retinoic acid....
Vitamin A (retinol) is a lipid-soluble vitamin that acts as a precursor for several bioactive compounds, such as retinaldehyde (retinal) and isomers of retinoic acid. Retinol and all-trans-retinoic acid (atRA) penetrate the blood-brain barrier and are reported to be neuroprotective in several animal models. We characterised the impact of retinol and its metabolites, all-trans-retinal (atRAL) and atRA, on ferroptosis-a programmed cell death caused by iron-dependent phospholipid peroxidation. Ferroptosis was induced by erastin, buthionine sulfoximine or RSL3 in neuronal and non-neuronal cell lines. We found that retinol, atRAL and atRA inhibited ferroptosis with a potency superior to α-tocopherol, the canonical anti-ferroptotic vitamin. In contrast, we found that antagonism of endogenous retinol with anhydroretinol sensitises ferroptosis induced in neuronal and non-neuronal cell lines. Retinol and its metabolites atRAL and atRA directly interdict lipid radicals in ferroptosis since these compounds displayed radical trapping properties in a cell-free assay. Vitamin A, therefore, complements other anti-ferroptotic vitamins, E and K; metabolites of vitamin A, or agents that alter their levels, may be potential therapeutics for diseases where ferroptosis is implicated.
Topics: Animals; Vitamin A; Ferroptosis; Lipid Peroxidation; Tretinoin; Vitamins; Retinaldehyde; Lipids
PubMed: 37236031
DOI: 10.1016/j.biopha.2023.114930 -
Biomedicine & Pharmacotherapy =... Nov 2021The sphingolipids ceramide (Cer), ceramide-1-phosphate (C1P), sphingosine (Sph), and sphingosine-1-phosphate (S1P)) are key signaling molecules that regulate many... (Review)
Review
The sphingolipids ceramide (Cer), ceramide-1-phosphate (C1P), sphingosine (Sph), and sphingosine-1-phosphate (S1P)) are key signaling molecules that regulate many patho-biological processes. During the last decade, they have gained increasing attention since they may participate in important and numerous retinal processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Cer for instance has emerged as a key mediator of inflammation and death of neuronal and retinal pigment epithelium cells in experimental models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. S1P may have opposite biological actions, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide 1- phosphate may also contribute to uveitis. Furthermore, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), have been shown to preserve neuronal viability and retinal function. Collectively, the expanding role for these sphingolipids in the modulation of vital processes in retina cell types and in their dysregulation in retinal degenerations makes them attractive therapeutic targets.
Topics: Animals; Ceramides; Fingolimod Hydrochloride; Humans; Lysophospholipids; Molecular Targeted Therapy; Photoreceptor Cells, Vertebrate; Retina; Retinal Diseases; Retinal Ganglion Cells; Retinal Pigment Epithelium; Signal Transduction; Sphingolipids; Sphingosine; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors
PubMed: 34560541
DOI: 10.1016/j.biopha.2021.112197 -
American Journal of Ophthalmology Aug 2021To determine classification criteria for toxoplasmic retinitis.
PURPOSE
To determine classification criteria for toxoplasmic retinitis.
DESIGN
Machine learning of cases with toxoplasmic retinitis and 4 other infectious posterior uveitides / panuveitides.
METHODS
Cases of infectious posterior uveitides / panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior uveitides / panuveitides. The resulting criteria were evaluated on the validation set.
RESULTS
Eight hundred three cases of infectious posterior uveitides / panuveitides, including 174 cases of toxoplasmic retinitis, were evaluated by machine learning. Key criteria for toxoplasmic retinitis included focal or paucifocal necrotizing retinitis and either positive polymerase chain reaction assay for Toxoplasma gondii from an intraocular specimen or the characteristic clinical picture of a round or oval retinitis lesion proximal to a hyperpigmented and/or atrophic chorioretinal scar. Overall accuracy for infectious posterior uveitides / panuveitides was 92.1% in the training set and 93.3% (95% confidence interval 88.2, 96.3) in the validation set. The misclassification rates for toxoplasmic retinitis were 8.2% in the training set and 10% in the validation set.
CONCLUSIONS
The criteria for toxoplasmic retinitis had a low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.
Topics: Adult; Animals; Antibodies, Protozoan; Aqueous Humor; DNA, Protozoan; Eye Infections, Parasitic; Female; Humans; Machine Learning; Male; Retinitis; Toxoplasma; Toxoplasmosis, Ocular; Young Adult
PubMed: 33845002
DOI: 10.1016/j.ajo.2021.03.042 -
JCI Insight Nov 2023Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4...
Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4 patients presenting with RP from 3 unrelated families with variants in TBC1D32, which to date has never been associated with an IRD. To validate TBC1D32 as a putative RP causative gene, we combined Xenopus in vivo approaches and human induced pluripotent stem cell-derived (iPSC-derived) retinal models. Our data showed that TBC1D32 was expressed during retinal development and that it played an important role in retinal pigment epithelium (RPE) differentiation. Furthermore, we identified a role for TBC1D32 in ciliogenesis of the RPE. We demonstrated elongated ciliary defects that resulted in disrupted apical tight junctions, loss of functionality (delayed retinoid cycling and altered secretion balance), and the onset of an epithelial-mesenchymal transition-like phenotype. Last, our results suggested photoreceptor differentiation defects, including connecting cilium anomalies, that resulted in impaired trafficking to the outer segment in cones and rods in TBC1D32 iPSC-derived retinal organoids. Overall, our data highlight a critical role for TBC1D32 in the retina and demonstrate that TBC1D32 mutations lead to RP. We thus identify TBC1D32 as an IRD-causative gene.
Topics: Humans; Induced Pluripotent Stem Cells; Retina; Retinitis Pigmentosa; Retinal Degeneration; Retinal Pigment Epithelium; Adaptor Proteins, Signal Transducing
PubMed: 37768732
DOI: 10.1172/jci.insight.169426 -
Indian Journal of Ophthalmology Sep 2020Post-fever retinitis (PFR) is an infectious or para-infectious uveitic entity caused by bacterial or viral agents and seen mainly in tropical countries. Systemic... (Review)
Review
Post-fever retinitis (PFR) is an infectious or para-infectious uveitic entity caused by bacterial or viral agents and seen mainly in tropical countries. Systemic symptoms such as joint pain, skin rash are common during the febrile stage. On the basis of only clinical presentation, it is difficult to pin-point the exact etiology for PFR. Serological investigations, polymerase chain reaction, and knowledge of concurrent epidemics in the community may help to identify the etiological organism. Bacterial causes of PFR such as rickettsia and typhoid are treated with systemic antibiotics, with or without systemic steroid therapy, whereas PFR of viral causes such as chikungunya, dengue, West Nile virus, and Zika virus have no specific treatment and are managed with steroids. Nevertheless, many authors have advocated mere observation and the uveitis resolved with its natural course of the disease. In this article, we have discussed the clinical features, pathogenesis, investigations, and management of PFR.
Topics: Chikungunya Fever; Dengue; Humans; Retinitis; Zika Virus; Zika Virus Infection
PubMed: 32823394
DOI: 10.4103/ijo.IJO_1352_20