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1.
Nat Commun ; 15(1): 4756, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38834544

ABSTRACT

Given the absence of approved treatments for pathogenic variants in Peripherin-2 (PRPH2), it is imperative to identify a universally effective therapeutic target for PRPH2 pathogenic variants. To test the hypothesis that formation of the elongated discs in presence of PRPH2 pathogenic variants is due to the presence of the full complement of rhodopsin in absence of the required amounts of functional PRPH2. Here we demonstrate the therapeutic potential of reducing rhodopsin levels in ameliorating disease phenotype in knockin models for p.Lys154del (c.458-460del) and p.Tyr141Cys (c.422 A > G) in PRPH2. Reducing rhodopsin levels improves physiological function, mitigates the severity of disc abnormalities, and decreases retinal gliosis. Additionally, intravitreal injections of a rhodopsin-specific antisense oligonucleotide successfully enhance the physiological function of photoreceptors and improves the ultrastructure of discs in mutant mice. Presented findings shows that reducing rhodopsin levels is an effective therapeutic strategy for the treatment of inherited retinal degeneration associated with PRPH2 pathogenic variants.


Subject(s)
Peripherins , Rhodopsin , Peripherins/genetics , Peripherins/metabolism , Animals , Rhodopsin/genetics , Rhodopsin/metabolism , Mice , Humans , Disease Models, Animal , Down-Regulation , Retinal Degeneration/genetics , Retinal Degeneration/metabolism , Retinal Degeneration/therapy , Oligonucleotides, Antisense/genetics , Retina/metabolism , Retina/pathology , Retinal Diseases/genetics , Retinal Diseases/metabolism , Retinal Diseases/pathology , Retinal Diseases/therapy , Mice, Inbred C57BL , Mutation , Female , Gene Knock-In Techniques , Male
2.
FASEB J ; 38(10): e23679, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38780117

ABSTRACT

Retinal vascular diseases (RVDs), in particular diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, are leading contributors to blindness. The pathogenesis of RVD involves vessel dilatation, leakage, and occlusion; however, the specific underlying mechanisms remain unclear. Recent findings have indicated that pericytes (PCs), as critical members of the vascular mural cells, significantly contribute to the progression of RVDs, including detachment from microvessels, alteration of contractile and secretory properties, and excessive production of the extracellular matrix. Moreover, PCs are believed to have mesenchymal stem properties and, therefore, might contribute to regenerative therapy. Here, we review novel ideas concerning PC characteristics and functions in RVDs and discuss potential therapeutic strategies based on PCs, including the targeting of pathological signals and cell-based regenerative treatments.


Subject(s)
Pericytes , Pericytes/metabolism , Humans , Animals , Retinal Vessels/metabolism , Retinal Vessels/pathology , Retinal Diseases/therapy , Retinal Diseases/metabolism , Retinal Diseases/pathology , Diabetic Retinopathy/metabolism , Diabetic Retinopathy/therapy , Diabetic Retinopathy/pathology
3.
Cell Commun Signal ; 22(1): 290, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38802833

ABSTRACT

The Crumbs protein (CRB) family plays a crucial role in maintaining the apical-basal polarity and integrity of embryonic epithelia. The family comprises different isoforms in different animals and possesses diverse structural, localization, and functional characteristics. Mutations in the human CRB1 or CRB2 gene may lead to a broad spectrum of retinal dystrophies. Various CRB-associated experimental models have recently provided mechanistic insights into human CRB-associated retinopathies. The knowledge obtained from these models corroborates the importance of CRB in retinal development and maintenance. Therefore, complete elucidation of these models can provide excellent therapeutic prospects for human CRB-associated retinopathies. In this review, we summarize the current animal models and human-derived models of different CRB family members and describe the main characteristics of their retinal phenotypes.


Subject(s)
Membrane Proteins , Retinal Diseases , Humans , Animals , Membrane Proteins/genetics , Membrane Proteins/metabolism , Retinal Diseases/genetics , Retinal Diseases/pathology , Retinal Diseases/metabolism , Retina/metabolism , Retina/pathology , Eye Proteins/genetics , Eye Proteins/metabolism , Disease Models, Animal , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Mutation
4.
Biomed Pharmacother ; 175: 116703, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38713948

ABSTRACT

The distinctive role of Yes-associated protein (YAP) in the nervous system has attracted widespread attention. This comprehensive review strategically uses the retina as a vantage point, embarking on an extensive exploration of YAP's multifaceted impact from the retina to the brain in development and pathology. Initially, we explore the crucial roles of YAP in embryonic and cerebral development. Our focus then shifts to retinal development, examining in detail YAP's regulatory influence on the development of retinal pigment epithelium (RPE) and retinal progenitor cells (RPCs), and its significant effects on the hierarchical structure and functionality of the retina. We also investigate the essential contributions of YAP in maintaining retinal homeostasis, highlighting its precise regulation of retinal cell proliferation and survival. In terms of retinal-related diseases, we explore the epigenetic connections and pathophysiological regulation of YAP in diabetic retinopathy (DR), glaucoma, and proliferative vitreoretinopathy (PVR). Lastly, we broaden our exploration from the retina to the brain, emphasizing the research paradigm of "retina: a window to the brain." Special focus is given to the emerging studies on YAP in brain disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), underlining its potential therapeutic value in neurodegenerative disorders and neuroinflammation.


Subject(s)
Brain , Retina , YAP-Signaling Proteins , Humans , Animals , Retina/metabolism , Retina/pathology , Brain/metabolism , Brain/pathology , Adaptor Proteins, Signal Transducing/metabolism , Transcription Factors/metabolism , Retinal Diseases/metabolism , Retinal Diseases/pathology , Retinal Diseases/genetics , Epigenesis, Genetic , Retinal Pigment Epithelium/metabolism
5.
Cells ; 13(10)2024 May 18.
Article in English | MEDLINE | ID: mdl-38786093

ABSTRACT

Vision starts in retinal photoreceptors when specialized proteins (opsins) sense photons via their covalently bonded vitamin A derivative 11cis retinaldehyde (11cis-RAL). The reaction of non-enzymatic aldehydes with amino groups lacks specificity, and the reaction products may trigger cell damage. However, the reduced synthesis of 11cis-RAL results in photoreceptor demise and suggests the need for careful control over 11cis-RAL handling by retinal cells. This perspective focuses on retinoid(s) synthesis, their control in the adult retina, and their role during retina development. It also explores the potential importance of 9cis vitamin A derivatives in regulating retinoid synthesis and their impact on photoreceptor development and survival. Additionally, recent advancements suggesting the pivotal nature of retinoid synthesis regulation for cone cell viability are discussed.


Subject(s)
Retinoids , Animals , Humans , Retina/metabolism , Retinal Diseases/metabolism , Retinal Diseases/pathology , Retinaldehyde/metabolism , Retinoids/metabolism , Vitamin A/metabolism
7.
Invest Ophthalmol Vis Sci ; 65(4): 1, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38558095

ABSTRACT

Purpose: The purpose of this study is to report five novel FZD4 mutations identified in familial exudative vitreoretinopathy (FEVR) and to analyze and summarize the pathogenic mechanisms of 34 of 96 reported missense mutations in FZD4. Methods: Five probands diagnosed with FEVR and their family members were enrolled in the study. Ocular examinations and targeted gene panel sequencing were conducted on all participants. Plasmids, each carrying 29 previously reported FZD4 missense mutations and five novel mutations, were constructed based on the selection of mutations from each domain of FZD4. These plasmids were used to investigate the effects of mutations on protein expression levels, Norrin/ß-catenin activation capacity, membrane localization, norrin binding ability, and DVL2 recruitment ability in HEK293T, HEK293STF, and HeLa cells. Results: All five novel mutations (S91F, V103E, C145S, E160K, C377F) responsible for FEVR were found to compromise Norrin/ß-catenin activation of FZD4 protein. After reviewing a total of 34 reported missense mutations, we categorized all mutations based on their functional changes: signal peptide mutations, cysteine mutations affecting disulfide bonds, extracellular domain mutations influencing norrin binding, transmembrane domain (TM) 1 and TM7 mutations impacting membrane localization, and intracellular domain mutations affecting DVL2 recruitment. Conclusions: We expanded the spectrum of FZD4 mutations relevant to FEVR and experimentally demonstrated that missense mutations in FZD4 can be classified into five categories based on different functional changes.


Subject(s)
Retinal Diseases , beta Catenin , Humans , Familial Exudative Vitreoretinopathies , beta Catenin/metabolism , Retinal Diseases/pathology , HEK293 Cells , HeLa Cells , Frizzled Receptors/genetics , Mutation , Pedigree , DNA Mutational Analysis , Tetraspanins/genetics
8.
Proc Natl Acad Sci U S A ; 121(18): e2311028121, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38657052

ABSTRACT

Increased cellular senescence burden contributes in part to age-related organ dysfunction and pathologies. In our study, using mouse models of natural aging, we observed structural and functional decline in the aged retina, which was accompanied by the accumulation of senescent cells and senescence-associated secretory phenotype factors. We further validated the senolytic and senomorphic properties of procyanidin C1 (PCC1) both in vitro and in vivo, the long-term treatment of which ameliorated age-related retinal impairment. Through high-throughput single-cell RNA sequencing (scRNA-seq), we comprehensively characterized the retinal landscape after PCC1 administration and deciphered the molecular basis underlying the senescence burden increment and elimination. By exploring the scRNA-seq database of age-related retinal disorders, we revealed the role of cellular senescence and the therapeutic potential of PCC1 in these pathologies. Overall, these results indicate the therapeutic effects of PCC1 on the aged retina and its potential use for treating age-related retinal disorders.


Subject(s)
Aging , Catechin , Cellular Senescence , Proanthocyanidins , Retina , Animals , Retina/metabolism , Retina/drug effects , Mice , Proanthocyanidins/pharmacology , Proanthocyanidins/metabolism , Aging/drug effects , Aging/metabolism , Cellular Senescence/drug effects , Catechin/pharmacology , Catechin/metabolism , Catechin/chemistry , Biflavonoids/pharmacology , Senotherapeutics/pharmacology , Mice, Inbred C57BL , Humans , Retinal Diseases/drug therapy , Retinal Diseases/metabolism , Retinal Diseases/pathology
9.
Mol Genet Genomics ; 299(1): 32, 2024 Mar 13.
Article in English | MEDLINE | ID: mdl-38472449

ABSTRACT

Familial exudative vitreoretinopathy (FEVR) is a severe inherited disease characterized by defective retinal vascular development. With genetic and clinical heterogeneity, FEVR can be inherited in different patterns and characterized by phenotypes ranging from moderate visual defects to complete vision loss. This study was conducted to unravel the genetic and functional etiology of a 4-month-old female FEVR patient. Targeted gene panel and Sanger sequencing were utilized for genetic evaluation. Luciferase assays, western blot, quantitive real-time PCR, and immunocytochemistry were performed to verify the functional defects in the identified candidate variant. Here, we report a 4-month-old girl with bilateral retinal folds and peripheral avascularization, and identified a novel frameshift heterozygous variant c.37dup (p.Leu13ProfsTer13) in NDP. In vitro experiments revealed that the Leu13ProfsTer13 variant led to a prominent decrease in protein levels instead of mRNA levels, resulting in compromised Norrin/ß-catenin signaling activity. Human androgen receptor assay further revealed that a slight skewing of X chromosome inactivation could partially cause FEVR. Thus, the pathogenic mechanism by which heterozygous frameshift or nonsense variants in female carriers cause FEVR might largely result from a loss-of-function variant in one X chromosome allele and a slightly skewed X-inactivation. Further recruitment of more FEVR-affected females carrying NDP variants and genotype-phenotype correlation analysis can ultimately offer valuable information for the prognosis prediction of FEVR.


Subject(s)
Retinal Diseases , Female , Humans , Infant , DNA Mutational Analysis , Eye Proteins/genetics , Familial Exudative Vitreoretinopathies/genetics , Heterozygote , Mutation , Nerve Tissue Proteins/genetics , Pedigree , Phenotype , Retina/metabolism , Retinal Diseases/genetics , Retinal Diseases/metabolism , Retinal Diseases/pathology
10.
J Neuroinflammation ; 21(1): 65, 2024 Mar 07.
Article in English | MEDLINE | ID: mdl-38454477

ABSTRACT

Myeloid cells including microglia and macrophages play crucial roles in retinal homeostasis by clearing cellular debris and regulating inflammation. These cells are activated in several blinding ischemic retinal diseases including diabetic retinopathy, where they may exert both beneficial and detrimental effects on neurovascular function and angiogenesis. Myeloid cells impact the progression of retinal pathologies and recent studies suggest that targeting myeloid cells is a promising therapeutic strategy to mitigate diabetic retinopathy and other ischemic retinal diseases. This review summarizes the recent advances in our understanding of the role of microglia and macrophages in retinal diseases and focuses on the effects of myeloid cells on neurovascular injury and angiogenesis in ischemic retinopathies. We highlight gaps in knowledge and advocate for a more detailed understanding of the role of myeloid cells in retinal ischemic injury to fully unlock the potential of targeting myeloid cells as a therapeutic strategy for retinal ischemia.


Subject(s)
Diabetic Retinopathy , Retinal Diseases , Humans , Retinal Diseases/pathology , Retina/pathology , Macrophages/pathology , Ischemia/pathology
11.
JAMA Ophthalmol ; 142(4): 310-319, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38451488

ABSTRACT

Importance: The relevance of visualizing scleral fiber orientation may offer insights into the pathogenesis of pathologic myopia, including dome-shaped maculopathy (DSM). Objective: To investigate the orientation and density of scleral collagen fibers in highly myopic eyes with and without DSM by polarization-sensitive optical coherence tomography (PS-OCT). Design, Setting, and Participants: This case series included patients with highly myopic eyes (defined as a refractive error ≥6 diopters or an axial length ≥26.5 mm) with and without a DSM examined at a single site in May and June 2019. Analysis was performed from September 2019 to October 2023. Exposures: The PS-OCT was used to study the birefringence and optic axis of the scleral collagen fibers. Main Outcomes and Measures: The orientation and optic axis of scleral fibers in inner and outer layers of highly myopic eyes were assessed, and the results were compared between eyes with and without a DSM. Results: A total of 72 patients (51 [70.8%] female; mean [SD] age, 61.5 [12.8] years) were included, and 89 highly myopic eyes were examined (mean [SD] axial length, 30.4 [1.7] mm); 52 (58.4%) did not have a DSM and 37 (41.6%) had a DSM (10 bidirectional [27.0%] and 27 horizontal [73.0%]). Among the 52 eyes without DSM, the 13 eyes with simple high myopia had primarily inner sclera visible, displaying radially oriented fibers in optic axis images. In contrast, the entire thickness of the sclera was visible in 39 eyes with pathologic myopia. In these eyes, the optic axis images showed vertically oriented fibers within the outer sclera. Eyes presenting with both horizontal and bidirectional DSMs had clusters of fibers with low birefringence at the site of the DSM. In the optic axis images, horizontally or obliquely oriented scleral fibers were aggregated in the inner layer at the DSM. The vertical fibers located posterior to the inner fiber aggregation were not thickened and appeared thin compared with the surrounding areas. Conclusions and Relevance: This study using PS-OCT revealed inner scleral fiber aggregation without outer scleral thickening at the site of the DSM in highly myopic eyes. Given the common occurrence of scleral pathologies, such as DSM, and staphylomas in eyes with pathologic myopia, recognizing these fiber patterns could be important. These insights may be relevant to developing targeted therapies to address scleral abnormalities early and, thus, mitigate potential damage to the overlying neural tissue.


Subject(s)
Macular Degeneration , Myopia, Degenerative , Retinal Diseases , Humans , Female , Middle Aged , Male , Sclera/pathology , Tomography, Optical Coherence/methods , Visual Acuity , Retinal Diseases/pathology , Macular Degeneration/pathology , Collagen
12.
Sci Rep ; 14(1): 6936, 2024 03 23.
Article in English | MEDLINE | ID: mdl-38521801

ABSTRACT

This study aimed to evaluate the clinical benefits of incorporating a widefield lens (WFL) in optical coherence tomography angiography (OCT-A) in patients with retinal vascular diseases in comparison to standard single-shot OCT-A scans. Sixty patients with retinal vascular diseases including diabetic retinopathy (DR) and retinal vein occlusion (RVO) were recruited. OCT-A imaging (PlexElite 9000) with and without WFL was performed in randomized order. The assessment included patient comfort, time, field of view (FoV), image quality and pathology detection. Statistical analysis included paired t-tests, Mann-Whitney U-tests and Bonferroni correction for multiple tests, with inter-grader agreement using the kappa coefficient. Using a WFL did not lead to statistically significant differences in DR and RVO group test times. Patient comfort remained high, with similar responses for WFL and non-WFL measurements. The WFL notably expanded the scan field (1.6× FoV increase), enhancing peripheral retinal visibility. However, image quality varied due to pathology and eye dominance, affecting the detection of peripheral issues in RVO and DR cases. The use of a WFL widens the scan field, aiding vascular retinal disease imaging with minor effects on comfort, time, and image quality. Further enhancements are needed for broader view angles, enabling improved quantification of non-perfused areas and more reliable peripheral proliferation detection.


Subject(s)
Diabetic Retinopathy , Retinal Diseases , Retinal Vein Occlusion , Humans , Diabetic Retinopathy/diagnostic imaging , Diabetic Retinopathy/pathology , Fluorescein Angiography/methods , Retina/diagnostic imaging , Retinal Diseases/diagnostic imaging , Retinal Diseases/pathology , Retinal Vein Occlusion/pathology , Retinal Vessels/pathology , Tomography, Optical Coherence/methods
13.
J Fr Ophtalmol ; 47(6): 104097, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38518704

ABSTRACT

PURPOSE: To report the ocular manifestations, multimodal imaging characteristics and genetic testing results of six patients with autosomal recessive bestrophinopathy (ARB). METHODS: This was an observational case series including 12 eyes of 6 patients who were diagnosed with ARB. All patients underwent a complete ophthalmic examination including refraction, slit-lamp biomicroscopy, dilated fundus examination, fundus autofluorescence, optical coherence tomography and electrooculography. BEST1 gene sequencing was also performed for all patients. RESULTS: The mean age was 22.8years and the male-female ratio was 0.50. All ARB patients had a hyperopic refractive error. A spectrum of fundus abnormalities, including multifocal yellowish subretinal deposits in the posterior pole, subfoveal accumulation of vitelliform material and cystoid macular edema, was observed. Fundus autofluorescence imaging demonstrated marked hyperautofluorescence corresponding to the yellowish subretinal deposits. Optical coherence tomography revealed serous retinal detachment, intraretinal cysts, brush border appearance caused by elongation of the outer segments of photoreceptors, and hyperreflective dome-shaped deposits at the level of the retinal pigment epithelium. Fundus fluorescein angiography showed hyperfluorescence with staining of the yellowish subretinal deposits. Electrooculography showed reduced Arden ratio in all patients. In addition, biallelic pathogenic variants in the BEST1 gene were detected in all patients. CONCLUSION: ARB is a rare autosomal recessive inherited retinal disorder with biallelic pathogenic variants in the BEST1 gene and may present with a wide range of ocular abnormalities that may not be easily diagnosed. Multimodal retinal imaging in conjunction with EOG is helpful to establish the correct diagnosis.


Subject(s)
Bestrophins , Eye Diseases, Hereditary , Multimodal Imaging , Retinal Diseases , Tomography, Optical Coherence , Humans , Female , Male , Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/diagnosis , Adult , Young Adult , Retinal Diseases/genetics , Retinal Diseases/diagnosis , Retinal Diseases/pathology , Bestrophins/genetics , Adolescent , Fluorescein Angiography , Electrooculography , Genes, Recessive , Child
14.
Prog Retin Eye Res ; 100: 101248, 2024 May.
Article in English | MEDLINE | ID: mdl-38369182

ABSTRACT

Blindness poses a growing global challenge, with approximately 26% of cases attributed to degenerative retinal diseases. While gene therapy, optogenetic tools, photosensitive switches, and retinal prostheses offer hope for vision restoration, these high-cost therapies will benefit few patients. Understanding retinal diseases is therefore key to advance effective treatments, requiring in vitro models replicating pathology and allowing quantitative assessments for drug discovery. Pluripotent stem cells (PSCs) provide a unique solution given their limitless supply and ability to differentiate into light-responsive retinal tissues encompassing all cell types. This review focuses on the history and current state of photoreceptor and retinal pigment epithelium (RPE) cell generation from PSCs. We explore the applications of this technology in disease modelling, experimental therapy testing, biomarker identification, and toxicity studies. We consider challenges in scalability, standardisation, and reproducibility, and stress the importance of incorporating vasculature and immune cells into retinal organoids. We advocate for high-throughput automation in data acquisition and analyses and underscore the value of advanced micro-physiological systems that fully capture the interactions between the neural retina, RPE, and choriocapillaris.


Subject(s)
Pluripotent Stem Cells , Retinal Diseases , Animals , Humans , Cell Differentiation/physiology , Retinal Diseases/drug therapy , Retinal Diseases/pathology , Retinal Pigment Epithelium/pathology
15.
Clin Genet ; 105(6): 661-665, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38361102

ABSTRACT

Familial exudative vitreoretinopathy (FEVR) is linked to disruption of the Norrin/Frizzled-4 signaling pathway, which plays an important role in retinal angiogenesis. Severe or complete knock-down of proteins in the pathway also causes syndromic forms of the condition. Both heterozygous and biallelic pathogenic variants in the FZD4 gene, encoding the pathway's key protein frizzled-4, are known to cause FEVR. However, it is not clear what effect different FZD4 variants have, and whether extraocular features should be expected in those with biallelic pathogenic FZD4 variants. Biallelic FZD4 variants were found in a young boy with isolated, severe FEVR. His parents were heterozygous for one variant each and reported normal vision. In-vitro studies of the two variants, demonstrated that it was the combination of the two which led to severe inhibition of the Norrin/Frizzled-4 pathway. Our observations demonstrate that biallelic FZD4-variants are associated with a severe form of FEVR, which does not necessarily include extraocular features. In addition, variants causing severe FEVR in combination, may have no or minimal effect in heterozygous parents as non-penetrance is also a major feature in dominant FZD4-FEVR disease. This underscores the importance of genetic testing of individuals and families with FEVR.


Subject(s)
Alleles , Familial Exudative Vitreoretinopathies , Frizzled Receptors , Humans , Male , Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/pathology , Familial Exudative Vitreoretinopathies/genetics , Frizzled Receptors/genetics , Genetic Predisposition to Disease , Heterozygote , Mutation/genetics , Pedigree , Phenotype , Retinal Diseases/genetics , Retinal Diseases/pathology , Infant , Child, Preschool
16.
Front Immunol ; 15: 1340224, 2024.
Article in English | MEDLINE | ID: mdl-38348025

ABSTRACT

Purpose: To assess the retinal vasculature changes quantitatively using wide-field optical coherence tomography angiography (OCTA) in systemic lupus erythematosus (SLE), and explore its correlation with systemic clinical features. Design: Prospective, cross-sectional, observational study. Participants and controls: Patients with SLE who presented to the Ophthalmology Department of Peking Union Medical College Hospital from November 2022 to April 2023 were collected. The subjects were divided into retinopathy and without retinopathy groups. Age and gender-matched healthy subjects were selected as controls. Methods: Patients with SLE and control subjects were imaged with 24×20 mm OCTA scans centered on the fovea and 6×6 mm OCTA scans centered on the optic disc. The sub-layers of OCTA images were stratified by the built-in software of the device and then the retinal thickness and vessel density were measured automatically. The characteristics of retinal OCTA parameters of SLE and its correlation with systemic clinical indicators of patients without retinopathy were analyzed. Main outcome measures: OCTA parameters, visual acuity, intraocular pressure, and systemic clinical indicators of patients such as disease activity index, autoimmune antibodies, and inflammatory marker levels were collected. Results: A total of 102 SLE patients were included, 24 of which had retinopathy, and 78 had unaffected retina. Wide-field OCTA could effectively detect retinal vascular obstruction, non-perfusion area, and morphological abnormalities in patients with lupus retinopathy. SLE patients without retinopathy had significantly higher retinal superficial vessel density (SVD) in foveal (P=0.02), para-foveal temporal (P=0.01), nasal (P=0.01), peripheral foveal temporal (P=0.02), and inferior areas (P=0.02), as well as subregion temporal (P=0.01) and inferior areas (P=0.03) when compared with healthy controls (n=65 eyes from 65 participants). The area under curve (AUC) value of subregion inferior SVD combined parafoveal temporal SVD was up to 0.70. There was a significantly positive correlation between SVD and disease activity in SLE without retinopathy group. Patients with severe activity had the most significant increase in SVD. Conclusion: Wide-field OCTA can provide a relatively comprehensive assessment of the retinal vasculature in SLE. In the absence of pathological changes of the retina, the SVD was significantly increased and was positively correlated with the disease activity of SLE.


Subject(s)
Diabetic Retinopathy , Lupus Erythematosus, Systemic , Retinal Diseases , Humans , Tomography, Optical Coherence/methods , Fluorescein Angiography/methods , Cross-Sectional Studies , Prospective Studies , Diabetic Retinopathy/pathology , Retinal Vessels/diagnostic imaging , Retinal Vessels/pathology , Retina/diagnostic imaging , Retinal Diseases/etiology , Retinal Diseases/pathology , Lupus Erythematosus, Systemic/pathology
17.
Biomed Pharmacother ; 173: 116318, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38401522

ABSTRACT

Retinal ischemia is a significant factor in various vision-threatening diseases, but effective treatments are currently lacking. This study explores the potential of stem cell factor (SCF) in regulating the neurovascular unit as a therapeutic intervention for retinal ischemic diseases. A chronic retinal ischemia model was established in Brown Norway rats using bilateral common carotid artery occlusion (BCCAO). Subsequent SCF treatment resulted in a remarkable recovery of retinal function, as indicated by electroretinogram, light/dark transition test, and optokinetic head tracking test results. Histological examination demonstrated a significant increase in the number of retinal neurons and an overall thickening of the retina. Immunofluorescence confirmed these findings and further demonstrated that SCF treatment regulated retinal remodeling. Notably, SCF treatment ameliorated the disrupted expression of synaptic markers in the control group's BCCAO rats and suppressed the activation of Müller cells and microglia. Retinal whole-mount analysis revealed a significant improvement in the abnormalities in retinal vasculature following SCF treatment. Transcriptome sequencing analysis revealed that SCF-induced transcriptome changes were closely linked to the Wnt7 pathway. Key members of the Wnt7 pathway, exhibited significant upregulation following SCF treatment. These results underscore the protective role of SCF in the neurovascular unit of retinal ischemia rats by modulating the Wnt7 pathway. SCF administration emerges as a promising therapeutic strategy for retinal ischemia-related diseases, offering potential avenues for future clinical interventions.


Subject(s)
Arterial Occlusive Diseases , Carotid Artery Diseases , Retinal Diseases , Rats , Animals , Stem Cell Factor , Ischemia/metabolism , Retinal Diseases/prevention & control , Retinal Diseases/pathology , Retina , Retinal Vessels/metabolism , Arterial Occlusive Diseases/pathology
18.
Int Immunopharmacol ; 128: 111480, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38194747

ABSTRACT

BACKGROUND: Retinal ischemia-reperfusion (I/R) serves as a significant contributor to ocular diseases, triggering a cascade of pathological processes. The interplay between neuroinflammation and the apoptosis of retinal ganglion cell (RGC) is a well-explored aspect of retinal I/R-induced tissue damage. Within this intricate landscape, the inflammatory cytokine Interleukin-21 (IL21) emerges as a potent mediator of neuroinflammation with known detrimental effects on neuronal integrity. However, its specific impact on RGC apoptosis in the context of retinal I/R has remains to be uncovered. This study aims to unravel the potential anti-apoptotic effects of IL21 siRNA on RGC, shedding light on the neuroprotection of retinal I/R. METHODS: Sprague-Dawley (SD) rats underwent a controlled elevation of intraocular pressure (IOP) to 110 mmHg for 60 min to simulate retinal I/R conditions. To explore the influence of IL21 on RGC apoptosis and its underlying molecular mechanisms, a comprehensive array of techniques such immunohistochemistry, immunofluorescence, TUNEL, Hematoxylin-eosin (H&E), immunoblotting, and qRT-PCR were carried out. RESULTS: The landscape of retinal I/R injury revealed an increase in the expression of IL21, reaching its peak at 72 h. Notably, IL21 markedly induced RGC apoptosis within the retinal I/R milieu. The introduction of IL21 siRNA showed promising outcomes, manifesting as an amelioration of neurological function deficits, a reduction in RGC loss, and an increase in the thickness of the inner retinal layer at the 72-hour reperfusion. Additionally, IL21 siRNA demonstrated its ability to hinder the release of proteins associated with apoptosis via the JAK/STAT signaling pathway. In the in vitro setting, IL21 siRNA efficiently reduced R28 cell apoptosis by suppressing the production of proteins associated with apoptosis by regulating the JAK/STAT signaling pathway. CONCLUSIONS: This study provides evidence for the pathogenic role of IL21 in retinal I/R. The findings underscore IL21 siRNA as a promising therapeutic target for ischemic retinal injury. Its efficacy lies in its ability to mitigate RGC apoptosis by suppressing the JAK/STAT signaling pathway. These findings not only enhance our comprehension of retinal I/R pathology but also suggests IL21 siRNA as a potential transformative factor in the development of targeted therapies for ischemic retinal injuries.


Subject(s)
Interleukins , Reperfusion Injury , Retinal Diseases , Rats , Animals , Retinal Ganglion Cells , Neuroinflammatory Diseases , Rats, Sprague-Dawley , Apoptosis , Retinal Diseases/pathology , Reperfusion Injury/drug therapy , Ischemia/metabolism , RNA, Small Interfering/metabolism
19.
BMC Ophthalmol ; 24(1): 5, 2024 Jan 03.
Article in English | MEDLINE | ID: mdl-38172762

ABSTRACT

BACKGROUND: Torpedo maculopathy (TM) is a rare, congenital condition characterized by an oval-shaped, chorioretinal lesion in the temporal macula of unknown etiology. To our knowledge, the longest reported follow-up of TM is 5 years. Herein we report 10 years of follow-up on two patients with TM to further characterize the long-term natural history of the condition. CASE REPORTS: Two patients with torpedo maculopathy were examined at baseline and then again at 5 years and 10 years from baseline. Eyes were evaluated using color fundus photography, automated perimetry, fundus autofluorescence and spectral domain optical coherence tomography. Visual function of both patients remained stable throughout the observation period. In case 1, there was no evidence of change in lesion morphology over the 10 year observation period. Case 2 showed progression of cystic degeneration of the neurosensory retina within the torpedo lesion. Case 1 reported a history of supernumerary teeth and underwent gene sequence with deletion/duplication analyses of the APC gene but no clinically significant variants were detected. CONCLUSIONS: Our findings support the position that TM is a nonprogressive condition with long-term stability of visual function. Genetic analysis of case 1 failed to detect any association with Gardner syndrome.


Subject(s)
Macular Degeneration , Retinal Diseases , Humans , Follow-Up Studies , Retinal Pigment Epithelium/pathology , Fluorescein Angiography/methods , Visual Acuity , Retinal Diseases/diagnosis , Retinal Diseases/genetics , Retinal Diseases/pathology , Macular Degeneration/pathology , Tomography, Optical Coherence/methods , Rare Diseases/pathology
20.
Invest Ophthalmol Vis Sci ; 65(1): 27, 2024 Jan 02.
Article in English | MEDLINE | ID: mdl-38214685

ABSTRACT

Purpose: Acute retinal arterial ischemia diseases (ARAIDs) are ocular emergencies that require immediate intervention within a restricted therapeutic window to prevent blindness. However, the underlying molecular mechanisms contributing to the pathogenesis of ARAIDs remain enigmatic. Herein, we present the single-cell RNA sequencing (scRNA-seq) alterations during ischemia in the primate retina as a preliminary endeavor in understanding the molecular complexities of ARAIDs. Methods: An ophthalmic artery occlusion model was established through ophthalmic artery ligation in two Macaca fascicularis. scRNA-seq and bioinformatics analyses were used to detect retinal changes during ischemia, which are further validated by immunofluorescence analysis. Western blot and flow cytometry assays were performed to measure the microglia polarization status. Results: The findings of this study reveal notable changes in the retina under acute ischemic conditions. Particularly, retinal ischemia compromised mitochondrial functions of rod photoreceptors, partly leading to the rapid loss of healthy rods. Furthermore, we observed a noteworthy transcriptional alteration in the activation of microglia induced by ischemia. The targeted correction of the proinflammatory cytokine CXCL8 effectively suppresses microglia M1 polarization in retinal ischemia, ultimately reducing the proinflammatory transformation in vitro. In addition, retina ischemia induced the apoptotic inclination of endothelial cells and the heightened interaction with microglia, which signifies the influence of microglia in disrupting the retinal-blood barrier. Conclusions: Our research has successfully identified and described the pathologic alterations occurring in several cell types during a short period of ischemia. These observations provide valuable insights for ameliorating retinal damage and promoting the restoration of vision.


Subject(s)
Endothelial Cells , Retinal Diseases , Animals , Macaca fascicularis , Endothelial Cells/metabolism , Retina/metabolism , Retinal Diseases/pathology , Microglia/metabolism , Ischemia/metabolism , Gene Expression Profiling
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