Molecular Vision[JOURNAL]
Sun
200 papers
Pseudomyopia and cycloplegic changes in young cynomolgus macaques.
Ye G, Zhang Y, Chen K … +12 more , Xie R, Liu W, Wong C, Zhan J, Luo R, Huang S, Zhuo X, Wu J, Leng Y, Zhuo Y, Fu M, Zhu Y
Mol Vis · 2025 · PMID 41867375
PURPOSE: Primate eyes feature a physiologic accommodative system identical to that of humans. Nonetheless, their biometric changes before and after cycloplegia have not been investigated. In this study, we aimed to evalu...
PURPOSE: Primate eyes feature a physiologic accommodative system identical to that of humans. Nonetheless, their biometric changes before and after cycloplegia have not been investigated. In this study, we aimed to evaluate the characteristics of pseudomyopia and explore factors associated with cycloplegic changes in young cynomolgus macaques. METHODS: Refractive and biometric measurements were performed on both eyes before and after cycloplegia in 88 cynomolgus macaques aged 3-6 years without ocular diseases. Pseudomyopia was defined as autorefraction-estimated noncycloplegic spherical equivalent (NSE) < -0.50 D and cycloplegic spherical equivalent (CSE) ≥ -0.50 D. Linear mixed models were established to identify factors associated with cycloplegic differences. RESULTS: After excluding low-quality ophthalmic data, 149 eyes were included in the final analysis. The median NSE was -0.38 (interquartile range: -1.50, 0.25) D and the median CSE was 0.13 (-0.50, 0.90) D, exhibiting a robust Pearson's correlation coefficient of 0.89 (95% confidence interval: 0.78-0.92). Pseudomyopia was observed in 35 of the 149 eyes, with a greater hyperopic shift (median, 1.42 D) compared to that in non-myopic and true-myopic eyes (median, 0.50 D for both, p<0.001). Pseudomyopic eyes demonstrated active accommodation before cycloplegia and exhibited biometric changes after cycloplegia akin to those in true-myopic eyes. Under cycloplegia, non-myopic and pseudomyopic eyes exhibited similar biometric measurements. A greater hyperopic shift correlated with a higher hyperopic NSE and greater reductions in lens thickness. CONCLUSIONS: The use of 1% cyclopentolate yielded discernible alterations in refractive and biometric parameters in 3- to 6-year-old cynomolgus macaques. Notably, compared with non-myopia and true myopia, pseudomyopia exhibited associations and discrepancies in accommodative status. These findings underscore the importance of investigating the role of the lens in animal models employed in myopia research.
Poor glycemic control impairs recovery from central retinal vein occlusion.
Gushansky KY, Karesvuo P, Tuuminen R
Mol Vis · 2025 · PMID 41867374
PURPOSE: To evaluate the association between suboptimal glycemic control and central macular thickness in central retinal vein occlusion patients over a 1-year follow-up period. METHODS: This retrospective cohort study i...
PURPOSE: To evaluate the association between suboptimal glycemic control and central macular thickness in central retinal vein occlusion patients over a 1-year follow-up period. METHODS: This retrospective cohort study included adult patients with central retinal vein occlusion diagnosed at the Helsinki University Hospital, Finland, with HbA1c levels measured within 6 months before or at diagnosis. Patients were divided into two groups: those with good (≤42 mmol/mol) and poor glycemic control (>42 mmol/mol). Central macular thickness and best-corrected visual acuity were assessed at baseline, 3 months, and 1 year. RESULTS: Among 40 patients, 10 had suboptimal glycemic control. At 3 months and 1 year, central macular thickness was significantly higher in the poor glycemic control group compared with the good glycemic control group (367.0 ± 43.3 µm vs. 288.2 ± 36.6 µm, = 0.016 and 380.8 ± 44.8 µm vs. 302.0 ± 71.3 µm, = 0.035, respectively). HbA1c levels correlated with central macular thickness at 3 months ( = 0.514, = 0.045) but did not reach statistical significance at 1 year ( = 0.246, = 0.071). CONCLUSIONS: Poor glycemic control in patients with central retinal vein occlusion is associated with greater central macular thickness at both 3 months and 1 year. These findings emphasize the importance of optimal glycemic control to improve retinal outcomes in central retinal vein occlusion.
Intraocular pressure distribution in old and young cynomolgus monkeys following general anesthesia and mydriasis.
Zhan J, Li Z, Ye G … +7 more , Zhang Y, Chen K, Xie R, Liu W, Wu J, Zhu Y, Zhuo Y
Mol Vis · 2025 · PMID 41867373
PURPOSE: To investigate the intraocular pressure (IOP) distribution of cynomolgus monkeys in different age groups after anesthesia and mydriasis. METHODS: A total of 158 young and 252 old cynomolgus monkeys, aged 3.95 (1...
PURPOSE: To investigate the intraocular pressure (IOP) distribution of cynomolgus monkeys in different age groups after anesthesia and mydriasis. METHODS: A total of 158 young and 252 old cynomolgus monkeys, aged 3.95 (1.61; range, 1.38 to 5.97) and 18.80 (1.67; range, 15.21 to 24.69) years, respectively, were subjected to general anesthesia (intramuscular injection of Zoletil 4 mg/kg mixed with xylazine/ketamine 0.2 mg/kg). IOP was measured using an Icare tonometer at three time points: immediately following the onset of anesthesia, after stabilization but before mydriasis, and after mydriasis (induced by 1% tropicamide eye drops). RESULTS: No significant differences were observed between sexes or between eyes within the colony. After anesthesia stabilization but before mydriasis, the IOP of the old colony was 22.33 mm Hg (4.12; range, 12.33 to 37.33), whereas the IOP of the young colony was 16.67 mm Hg (4.00; range, 10.67 to 25.67). After mydriasis, the IOP of the old colony was 19.33 mm Hg (5.00; range 11.33 to 33.00), while the IOP of the young colony was 15.67 mm Hg (4.50; range, 9.67 to 24.00). All measurements were conducted with the monkeys in a prone position. Notably, both the young and old colonies experienced a significant decrease in IOP after mydriasis ( < 0.001). Moreover, the reduction observed in the young colony was significantly greater than that in the old colony ( < 0.001). CONCLUSIONS: The IOP levels of the old colony were higher than those of the young one, regardless of whether it was after anesthesia, before mydriasis, or after mydriasis. Furthermore, monkeys of different age groups had different reductions in IOP under different interventions (anesthesia, mydriasis). Additionally, within the colony, IOP was equivalent between males and females, as well as between the right and left eyes.
Genetic phenotypic characteristics and inheritance patterns of patients with achromatopsia at a large academic institution and a review of the literature and gene therapies.
Molleti S, Monsalve PF, Sather RN … +3 more , Moon JY, Ihinger J, Montezuma SR
Mol Vis · 2025 · PMID 41867372
PURPOSE: Achromatopsia (ACHM) is a cone dysfunction syndrome associated with low color vision, photophobia, and congenital nystagmus. Pathogenic variants in the and genes are the most common causes of ACHM. Identifying...
PURPOSE: Achromatopsia (ACHM) is a cone dysfunction syndrome associated with low color vision, photophobia, and congenital nystagmus. Pathogenic variants in the and genes are the most common causes of ACHM. Identifying the underlying genetic etiology in patients with clinical findings of ACHM is critical to establishing the diagnosis and selecting targets for gene therapies. This study utilizes the inherited retinal disease (IRD) database at the University of Minnesota (UMN) to understand clinical features of achromatopsia, potential diagnostic methods, and genetic variability at one large academic institution. METHODS: This retrospective cohort study examined patients with a genetically confirmed diagnosis of ACHM evaluated at the UMN/M Health IRD clinic between May 2015 and August 2022. Data were collected through UMN's electronic health record system and included information on demographics, history of ocular illness, visual acuity, and diagnostic exam results, such as electroretinogram, fundus autofluorescence, and optical coherence tomography (OCT) imaging. Genetic testing was performed using next-generation sequencing panels of varying sizes, and variants were interpreted according to American College of Medical Genetics guidelines. RESULTS: A total of 21 patients with a genetically confirmed ACHM were included in the study. Most patients were female (67%) and white (76%). The cohort included one pair of twin siblings and one group of three siblings. The median age of genetic testing conducted was 12 years (interquartile range, 12-20 years). One-third of patients had nyctalopia. All patients experienced difficulties with color vision, 20 of 21 (95.2%) had photosensitivity, and 18 of 21 patients reported congenital nystagmus. Diagnostic imaging showed most patients with a normal scotopic response and absent photopic response on electroretinogram, macular hyperfluorescence on fundus autofluorescence, and normal optical coherence tomography imaging. CONCLUSION: This study contributes to an understanding of the phenotypes and distribution of genetic variants associated with achromatopsia at a single academic institution in the state of Minnesota, particularly those involving the and genes. Future research could explore the prevalence of these variants in larger cohorts to enhance clinical management and treatment strategies for patients with achromatopsia.
Inhibition of sortilin reduces neuronal and vascular damage after ischemia/reperfusion through reduced inflammatory and autophagy actions in retinal Müller cells.
Liu L, Jiang Y, Steinle JJ
Mol Vis · 2025 · PMID 41867371
PURPOSE: Our goal was to explore whether inhibition of sortilin could protect the retina against ischemia/reperfusion (I/R) damage, as well as explore whether this inhibition could reduce inflammatory mediators in retina...
PURPOSE: Our goal was to explore whether inhibition of sortilin could protect the retina against ischemia/reperfusion (I/R) damage, as well as explore whether this inhibition could reduce inflammatory mediators in retinal Müller cells. METHODS: We used both primary human Müller cells and a rat Müller cell line (rMC-1) grown in normal (5 mM) or high (25 mM) glucose. Some cells were treated with AF38469, a small-molecule inhibitor of sortilin. We performed western blotting for the inflammatory mediators, tumor necrosis factor α, and NOD-like receptor protein 3. We also measured protein levels of lysosome-associated membrane glycoprotein 2 (LAMP2), a marker of autophagy, and cleaved caspase 3, a marker of apoptosis, in the cells. We then tested the actions of eye drops containing AF38469 on mice exposed to I/R. We assessed neuronal damage at 2 days post-I/R and vascular damage at 10 days post-I/R. RESULTS: High-glucose culturing conditions significantly increased inflammatory, autophagic, and apoptotic markers in both primary human Müller and rat Müller cells. All markers were reduced by treating the cells with AF38469. AF38469 eye drops also significantly reduced I/R-induced neuronal and vascular damage. CONCLUSION: These studies demonstrate that sortilin regulates the inflammatory, autophagic, and apoptotic pathways in Müller cells grown in high glucose. Inhibition of sortilin using AF38469 eye drops also reduced I/R-induced retinal damage.
System biology analysis reveals that Grm6 is associated with glutamate accumulation-induced scotopic vision impairment in diabetic mice.
Lian Y, Zhao Y, Yang X … +8 more , He H, Yang Z, Zhang H, Yan G, Lu L, Mi J, Tian G, Zhu Y
Mol Vis · 2025 · PMID 41867370
PURPOSE: Scotopic vision impairment as an early event is found in diabetic retinopathy. However, the underlying mechanisms behind hyperglycemia-induced scotopic vision impairment remain unclear. This study aims to identi...
PURPOSE: Scotopic vision impairment as an early event is found in diabetic retinopathy. However, the underlying mechanisms behind hyperglycemia-induced scotopic vision impairment remain unclear. This study aims to identify that Grm6 is associated with glutamate accumulation-induced scotopic vision impairment under hyperglycemia. METHODS: In this study, diabetic mice with impaired scotopic vision were induced by streptozotocin, and the retinal electrical activity was evaluated using electroretinography. Label-free quantitative proteomic analysis was used to identify differentially expressed proteins in the retinas of diabetic mice. A retinal transcriptome-wide association analysis and correlation screening were performed in BXD mice strains to explore the potential genes associated with hyperglycemia. Gene function enrichment analysis was used to evaluate gene function and to construct the correlation network. RESULTS: In total, 151 proteins were significantly altered in the retina of diabetic mice. Among these 151 candidates, 22 genes presented a significant correlation with blood glucose level (p<0.05), which were enriched in alanine, aspartate, and glutamate metabolism (p=0.003). Moreover, the glutamate catabolism-related genes Slc1a2, Gad1, and Glud1 were significantly negatively correlated with blood glucose at the transcript and proteome levels, which led to glutamate accumulation under hyperglycemia. Among eight types of metabotropic glutamate receptors, Grm6 had the most significant correlation with blood glucose level (=-0.5291, p=0.0003). Moreover, Grm6 expression was significantly decreased at both the mRNA and protein levels in the diabetic retina. Gene coexpression network analysis further identified that Grm6 was correlated with Rgs9, suggesting that hyperglycemia may impair scotopic vision via the phototransduction pathway. CONCLUSIONS: Our study confirms that Grm6 is associated with scotopic vision impairment induced by glutamate accumulation in diabetic mice and provides an efficient strategy for exploring critical biomarkers and pathways through a combination of proteomics and transcriptome-wide association analysis.
Ferroptosis related genes in retinopathy of prematurity: Screening for potential pharmacological targets.
Liao Q, Liu S, Wei L … +2 more , Cai Y, Li Y
Mol Vis · 2025 · PMID 41867369
PURPOSE: To elucidate the molecular mechanisms of retinopathy of prematurity (ROP) and identify potential drug targets for its treatment based on bioinformatics analysis. METHODS: We obtained gene expression profiles fro...
PURPOSE: To elucidate the molecular mechanisms of retinopathy of prematurity (ROP) and identify potential drug targets for its treatment based on bioinformatics analysis. METHODS: We obtained gene expression profiles from data sets GSE123945 and GSE135844 in the Gene Expression Omnibus database. Differential expression analysis was performed on GSE135844 to identify differentially expressed genes (DEGs). Ferroptosis-related genes were retrieved from FerrDb, and Venn diagrams were used to identify overlapping genes between DEGs and ferroptosis-related genes. Functional enrichment analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis, were conducted to explore the biological roles of these genes. Protein-protein interaction networks were constructed using the STRING database, and hub genes were identified using Cytoscape. Potential drug targets were screened using the Drug-Gene Interaction Database. RESULTS: We identified 23 DEGs associated with ferroptosis in ROP. These genes were significantly enriched in biological processes such as angiogenesis, vasculature development, and wound healing. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the PI3K-Akt signaling pathway plays a central role in ROP pathogenesis. Gene set enrichment analysis identified the defense response as the most significantly enriched gene set. Hub genes, including , and , were identified through protein-protein interaction network analysis. Potential drugs targeting these hub genes, such as stannsoporfin, recombinant neurotrophic factors, zinc chloride, and irisolidone, were identified using the Drug-Gene Interaction Database. CONCLUSIONS: Our study demonstrates the utility of bioinformatics approaches in identifying ferroptosis-related genes and potential drug targets for ROP. The findings provide a foundation for further experimental validation and the development of novel therapeutic strategies for ROP.
Monocyte/macrophage-derived IL-15 activates STAT5 to trigger the EFNA1/NCOA2-positive feedback loop, facilitating retinal angiogenesis in high-glucose environments.
Zhang L, Guo Y
Mol Vis · 2025 · PMID 41867368
PURPOSE: Diabetic retinopathy (DR) is of the most prevalent complications among diabetic patients. The potential role of interleukin 15 (IL-15) in modulating immune cell function and angiogenesis has drawn considerable a...
PURPOSE: Diabetic retinopathy (DR) is of the most prevalent complications among diabetic patients. The potential role of interleukin 15 (IL-15) in modulating immune cell function and angiogenesis has drawn considerable attention. Nevertheless, the precise mechanism through which IL-15 operates in DR remains elusive. METHODS: The GSE185011 and GSE221521 data sets were harnessed to screen for upregulated genes in the blood and peripheral blood mononuclear cells (PBMCs) of patients with DR. The GSE236333 and GSE179568 data sets were used to identify upregulated genes in retinal tissues. In the clinical investigation, IL-15 was detected in T and B lymphocytes, as well as in monocytes/macrophages within the PBMCs of patients. Human retinal microvascular endothelial cells and human umbilical vein endothelial cells were either cocultured with the monocyte/macrophage cell line THP-1 under high-glucose (HG) conditions or treated with IL-15. RESULTS: Among the three cell types in PBMCs, monocytes/macrophages exhibited the most substantial upregulation of IL-15 under HG conditions. In vitro, IL-15 secreted by THP-1 cells augmented the STAT5 in human retinal microvascular endothelial cells and human umbilical vein endothelial cells, thereby enhancing their angiogenic potential. Inhibition of STAT5 expression counteracted the proangiogenic effect of IL-15 on endothelial cells and diminished the expression of epithelial cell adhesion molecule 1 (EFNA1). After the knockdown of nuclear receptor coactivator 2 (NCOA2), the binding affinity of STAT5 to the EFNA1 gene promoter was significantly attenuated, and the influence of IL-15 on EFNA1 expression and angiogenesis was markedly reduced. Intriguingly, knockdown of either EFNA1 or NCOA2 led to a concurrent decrease in the expression of both genes in endothelial cells, suggesting a positive feedback regulatory loop between them. CONCLUSIONS: IL-15 secreted by monocytes/macrophages activates STAT5, which in turn induces a positive feedback regulation of the EFNA1/NCOA2 axis, ultimately promoting retinal angiogenesis under HG conditions.
Nitazoxanide reduced inflammatory markers and mitochondrial changes in human retinal endothelial cells grown in high glucose.
Jiang Y, Purandare N, Liu L … +3 more , Al-Shabrawey M, Grossman LI, Steinle JJ
Mol Vis · 2025 · PMID 41867367
PURPOSE: To determine whether nitazoxanide (NZT) can increase mitochondrial nuclear retrograde regulator 1 (MNRR1) in retinal endothelial cells (RECs) grown in normal or high glucose and thereby reduce inflammation. METH...
PURPOSE: To determine whether nitazoxanide (NZT) can increase mitochondrial nuclear retrograde regulator 1 (MNRR1) in retinal endothelial cells (RECs) grown in normal or high glucose and thereby reduce inflammation. METHODS: We used control and diabetic human retinal protein samples, control and diabetic mouse retinal samples, and RECs grown in normal (5 mM) and high (25 mM) glucose protein samples to explore levels of MNRR1, high mobility group box 1, interleukin 1β, tumor necrosis factor α, and Tom20 by western blotting. We used immunostaining to localize MNRR1 in the retina. We also used a Seahorse XF24 Bioanalyzer to measure the oxygen consumption rate in RECs under different conditions. Some cells were treated with NZT to increase MNRR1 levels. RESULTS: MNRR1 protein levels were reduced in the diabetic retina of both humans and mice. MNRR1 was localized to RECs. RECs grown in normal or high glucose and treated with NZT had significantly higher MNRR1 levels. NZT reduced inflammatory markers in RECs grown in high glucose. NZT increased the oxygen consumption rate in RECs grown in high glucose, which was associated with an increase in Tom20. CONCLUSIONS: MNRR1 is reduced in the diabetic retina. NZT increased MNRR1 levels in RECs. NZT protected RECs grown in high glucose by reducing inflammatory mediators and mitochondrial dysfunction and increasing mitochondrial mass. NZT may offer a new therapeutic option for diabetic retinopathy.
Deciphering the genetic basis of inherited retinal dystrophies via whole-exome sequencing in a Turkish cohort.
Keles Z, Fatihoglu OU, Ayhan Z … +3 more , Saatci AO, Caglayan AO, Ulgenalp A
Mol Vis · 2025 · PMID 41867366
PURPOSE: Inherited retinal dystrophies (IRDs) encompass a genetically and clinically heterogeneous group of disorders, with over 300 genes currently implicated. Early and precise genetic diagnosis is critical for advanci...
PURPOSE: Inherited retinal dystrophies (IRDs) encompass a genetically and clinically heterogeneous group of disorders, with over 300 genes currently implicated. Early and precise genetic diagnosis is critical for advancing targeted gene therapies and personalized treatment strategies. This study aims to investigate genetic findings in IRDs using whole-exome sequencing (WES) in a cohort of affected individuals. METHODS: WES was performed on 34 unrelated probands diagnosed with diverse IRD subtypes. Variant analysis focused on identifying clinically relevant variants consistent with the patients' phenotypes and inheritance patterns, emphasizing novel and rare variants. RESULTS: Clinically relevant variants consistent with the patients' phenotypes and inheritance patterns were identified in 24 cases. Among these, four variants were novel: c.181_182del, c.377T>G, c.1414G>A, and c.267C>G. Additionally, we identified a patient with isolated IRD carrying a homozygous c.1969C>T (p.Gln657Ter) variant, a gene typically associated with syndromic phenotypes. Furthermore, we reported a relatively rare presentation of ARSG-related Usher syndrome in a patient harboring a homozygous c.263G>T (p.Arg88Leu) alteration. CONCLUSIONS: This study underscores the diagnostic power of WES in IRDs, revealing novel variants and supporting its integration into clinical practice to enhance early diagnosis and enable precision medicine.
Molecular insights into foveal hypoplasia: development, genetics, mechanisms, and models.
Gregory-Evans K, Gregory-Evans CY
Mol Vis · 2025 · PMID 41867365
The fovea is an anatomic specialization of the human retina critical for high visual acuity, color vision, and contrast sensitivity. The molecular and cellular pathways directing this focal topography are still to be det...
The fovea is an anatomic specialization of the human retina critical for high visual acuity, color vision, and contrast sensitivity. The molecular and cellular pathways directing this focal topography are still to be determined. Abnormalities of the fovea (e.g., foveal hypoplasia in children) are considered a significant contributor to reduced quality of life. In addition, the fovea is often damaged in common retinal diseases, such as age-related macular degeneration and diabetic retinopathy, with a global economic burden of $500 billion USD. Currently, there are no treatments for foveal defects. Most genes contributing to foveal abnormalities have been identified but are yet to be characterized and studied. This is because common laboratory animals do not have a fovea, and only rare human tissue samples are available during the major phase of foveal maturation, from birth to the end of the fourth year of life. We discuss validation of the anole lizard, which has a foveal structure, for research studies into foveal development. Since foveal development continues after birth, it may be possible to stimulate new foveal maturation where there is developmental damage. From this review, we propose an evidence-based cellular mechanism that offers new possibilities for testing future therapies for foveal defects.
Analysis of cytogenetic germline changes in Polish patients with retinoblastoma.
Wicher D, Sielska-Rotblum D, Zawadzka-Wiech U … +5 more , Kowalczyk-Rusak M, Rutynowska-Pronicka O, Gietka A, Kulicka E, Mlynek M
Mol Vis · 2025 · PMID 41867364
PURPOSE: Retinoblastoma, the most common eye tumor in children, can occur in hereditary or nonhereditary forms. In the hereditary form, various germline alterations, single nucleotide (SNVs) or copy number variations (CN...
PURPOSE: Retinoblastoma, the most common eye tumor in children, can occur in hereditary or nonhereditary forms. In the hereditary form, various germline alterations, single nucleotide (SNVs) or copy number variations (CNVs) in the gene can be detected in patients. The aim of this study was to analyze cytogenetic germline changes in Polish patients with retinoblastoma and to assess whether cytogenetic techniques still have their application in diagnostics for retinoblastoma patients in the era of next-generation sequencing (NGS). METHODS: The results of genetic testing for germline mutations in patients with retinoblastoma performed between 2013 and 2023 were analyzed. In patients with cytogenetic alterations (CNV group, n = 19), the form of disease, age of onset, the first symptom, family history, and the type and extent of cytogenetic changes were verified. Comparative analyses were conducted between the CNV and SNV (n = 83) groups as well as the group of patients with normal genetic test results (n = 126). RESULTS: Cytogenetic changes were detected in 19 probands. These included: 16 deletions (10 partial and 6 whole gene deletions), 2 duplications, and 1 balanced translocation. Partial gene deletions included from 1 to 16 exons. In the CNV group, bilateral involvement predominated, with strabismus being the most common initial symptom. The mean age of onset was 16.9 months (median = 11 months; IQR, 8-22 months) and was lower in patients with bilateral involvement and partial gene deletions. Statistically significant differences compared to patients with normal genetic test results were observed in terms of laterality, the age of onset, initial symptom, and the family history of retinoblastoma. No such differences were found between the CNV and SNV groups. CONCLUSIONS: Cytogenetic changes constitute a significant part of germline alterations in patients with retinoblastoma. Cytogenetic techniques should still be considered in diagnostic protocols, especially in patients with bilateral involvement and/or positive family history, as well as in parents of patients with CNV.
Hyperosmolar stress induces monocyte chemoattractant protein 1 expression in retinal pigmented epithelial arising retinal pigmented epithelial 19 cells.
Hamou MO, Masset M, Weber C … +11 more , Scifo L, Libert S, Bryla A, Gregoire F, Delforge V, Bolaky N, Datlibagi A, Springael JY, Perret J, Willermain F, Delporte C
Mol Vis · 2025 · PMID 41867363
PURPOSE: Diabetes is a chronic inflammatory disease that may damage the blood-retinal barrier, leading to diabetic retinopathy (DR). Blood-retinal barrier rupture may subject the retinal pigmented epithelial cells to a h...
PURPOSE: Diabetes is a chronic inflammatory disease that may damage the blood-retinal barrier, leading to diabetic retinopathy (DR). Blood-retinal barrier rupture may subject the retinal pigmented epithelial cells to a hyperosmolar stress (HOS), activating the transcription factor nuclear factor of activated T cells 5 (NFAT5). In addition, inflammatory cytokines, such as monocyte chemoattractant protein 1 (MCP-1/CCL2), play a crucial role in DR. The aims of our study were to determine whether HOS induces MCP-1 levels in arising retinal pigmented epithelial 19 (ARPE-19) cells and to decipher the responsible intracellular cascade involved in such stimulation. METHODS: ARPE-19 cells or ARPE-19 cells transfected with dominant negative NFAT5 plasmid or NFAT5 short hairpin RNA plasmids were preincubated or not for 1 h in the absence or presence of a protein kinase or transcription factor inhibitor and then incubated for 8 h with iso-osmolar or hyperosmolar medium in the absence or presence of inhibitor. NFAT5 reporter gene activity was quantified by luminescence. MCP-1 messenger RNA (mRNA) and protein levels were determined by quantitative real-time PCR and enzyme-linked immunosorbent assay, respectively. Biologically active MCP-1 was assessed by a calcium mobilization assay performed using Chinese hamster ovary cells expressing or not the MCP-1 receptor and apoaequorin. RESULTS: In response to HOS, ARPE-19 cells showed a significant increase in MCP-1 mRNA levels independent of NFAT5 activation. Moreover, the MCP-1 protein secreted by ARPE-19 in response to HOS is biologically active. The use of various inhibitors of protein kinase and transcription factors suggest that the HOS-induced increase in MCP-1 mRNA levels is dependent on a protein kinase C (PKC) and/or a MEK1/2-p38 pathway activating p53, as well as a PKC-p38-PI3K-PDK1-AKT activating hypoxia-inducible factor 1 alpha (HIF1α). CONCLUSION: HOS increases the expression of MCP-1 mRNA and protein levels in ARPE-19 cells, and the secreted MCP-1 is biologically active. The HOS-induced increase of MCP-1 mRNA appears to be independent of NFAT5 activation. Despite the activation of NFAT5 upon HOS and the presence of NFAT5 binding sites in the MCP-1 gene promoter, activated NFAT5 may not be sufficient to induce MCP-1 gene transactivation in response to HOS in ARPE-19 cells. The intracellular cascade involved in the HOS-induced increase of MCP-1 mRNA in ARPE-19 cells may consist of a PKC-p38-PI3K-PDK1-AKT-HIF1α axis and/or a MEK1/2-p38-p53 axis.
Reticular fiber distribution in sclera: Key to understanding pathologic myopia and posterior staphylomas.
Kakizaki H, Ahn H, Abumanhal M … +4 more , Lian D, Ishijima K, Mito H, Morishige N
Mol Vis · 2025 · PMID 41867362
PURPOSE: To characterize the distribution of reticular fibers in the human sclera and explore their potential role in the pathogenesis of pathologic myopia and posterior staphyloma. METHODS: Central sagittal sections of...
PURPOSE: To characterize the distribution of reticular fibers in the human sclera and explore their potential role in the pathogenesis of pathologic myopia and posterior staphyloma. METHODS: Central sagittal sections of 13 globes (6 right eyes and 7 left eyes) were obtained from 12 East Asian cadavers aged 38-94 years (mean age: 74.9 years). Three scleral regions were examined: the pars plana, 3:00-3:30 clock-hour position, and 5:00-5:30 clock-hour position. Specimens were fixed in 10% formalin and stained with silver nitrate. ImageJ software was used for image processing and quantification of fiber density. RESULTS: Reticular fiber density exhibited considerable inter- and intraindividual variability. The average densities at the pars plana, 3:00-3:30, and 5:00-5:30 were 31.07%, 26.10%, and 22.70%, respectively. Density ranges were 23.46%-58.51% (pars plana), 19.18%-43.07% (3:00-3:30), and 13.48%-50.95% (5:00-5:30). In 10 eyes, the pars plana showed the highest density, followed by 3:00-3:30 and then 5:00-5:30. Two eyes had the lowest density at 3:00-3:30, while one eye exhibited the highest density in this region. CONCLUSIONS: Reticular fiber density in the sclera exhibits considerable interindividual variability. Our findings suggest that regions of structural vulnerability within the sclera may extend beyond the posterior pole, potentially offering new insights into the pathogenesis of posterior staphyloma. A reduction in reticular fiber density may be implicated in the progression of pathologic myopia and the development of posterior staphylomas, although further investigation is warranted to substantiate this association.
Bietti crystalline corneoretinal dystrophy: Advances in understanding and gene therapeutic approaches.
Zhao G, Ding D
Mol Vis · 2025 · PMID 41306488
Bietti crystalline dystrophy (BCD), an autosomal recessive inherited retinal disorder caused by mutations in the gene, has long remained therapeutically challenging. Recent advances in adeno-associated virus-based gene...
Bietti crystalline dystrophy (BCD), an autosomal recessive inherited retinal disorder caused by mutations in the gene, has long remained therapeutically challenging. Recent advances in adeno-associated virus-based gene therapy have emerged as promising therapeutic strategies for patients with BCD. This review synthesizes current knowledge regarding the molecular genetic mechanisms underlying BCD pathogenesis and examines recent developments in diagnostic approaches and gene therapeutic interventions. We specifically analyze the clinical outcomes of three investigational gene therapy products-ZVS101e, NGGT001, and VGR-R01-focusing on their preliminary efficacy, safety profiles, and tolerability. Key parameters evaluated include dosing strategies, routes of administration, adverse event profiles, and improvements in best-corrected visual acuity. The collective evidence suggests these therapeutic candidates show potential for decelerating disease progression and enhancing visual function. Future optimization of these approaches should carefully consider administration sites and modalities, injection volumes, and disease severity at intervention. With gene replacement therapy for BCD advancing through late-stage clinical development, regulatory approval and clinical implementation may be anticipated in the near future.
Unravelling γD-crystallin aggregation pathway to understand cataract formation using fluorescence correlation spectroscopy.
Bawankar M, Sengupta B, Malik S … +2 more , Sen P, Thakur AK
Mol Vis · 2025 · PMID 41306487
PURPOSE: To characterize the aggregation behavior of the γD-crystallin protein in an acidic environment with a focus on the formation of intermediate species. The research employs fluorescence correlation spectroscopy to...
PURPOSE: To characterize the aggregation behavior of the γD-crystallin protein in an acidic environment with a focus on the formation of intermediate species. The research employs fluorescence correlation spectroscopy to unravel the intricate molecular events leading to aggregation, contributing to a comprehensive understanding of cataract formation. METHODS: The kinetics of γD-crystallin protein aggregation were studied with a reversed-phase high-performance liquid chromatography sedimentation assay, a ThT binding assay, and light scattering. We used fluorescence correlation spectroscopy (FCS) to recognize intermediate aggregate species and characterized them with Fourier transform infrared spectroscopy (FTIR). Further, the morphologic characterization of aggregates was done by transmission electron microscopy (TEM), and their hydrophobic characteristics were analyzed using the 8-anilino-1-naphthalenesulfonic acid binding assay. RESULTS: A negligible lag phase was observed in the aggregation kinetic experiments of the γD-crystallin protein. Pentamer, 25-mer, and higher oligomer intermediates were formed on the aggregation pathway. Conformation studies by FCS and FTIR have shown that oligomers are rich in cross-β sheet and random coil structure; however, they constitute more α-helix and less cross-β sheet structure than fibrils. TEM analysis revealed the approximate size of oligomers (diameter ~10 nm), protofibrils (~15 nm), and fibrils (~15 to ~35 nm). CONCLUSIONS: In this study, we reported the presence of various intermediate aggregate species formed on the aggregation pathway of γD-crystallin protein at low pH. This will open new areas of research in understanding the detailed aggregation mechanism and aggregation hotspot within unfolded γD-crystallin monomers. The insights gained will also pave the way for future research in the realm of amyloid formation in cataract.
Mutations in retinal cyclic nucleotide-gated channels identified in familial cases of inherited retinal dystrophies from Pakistan.
Akhtar Z, Afshan K, Li Y … +7 more , Altaf S, Asghar A, Sughra U, Khan WA, Kaul H, Chen R, Firasat S
Mol Vis · 2025 · PMID 41306486
PURPOSE: Cyclic nucleotide-gated (CNG) channels are ligand-gated ion channels that transduce light signals into electrical signals in the retinal photoreceptors. Pathogenic variants in CNG channel genes are reported to c...
PURPOSE: Cyclic nucleotide-gated (CNG) channels are ligand-gated ion channels that transduce light signals into electrical signals in the retinal photoreceptors. Pathogenic variants in CNG channel genes are reported to cause inherited retinal dystrophies (IRDs). The current study used targeted panel sequencing to describe the mutational spectrum of CNG channel genes in familial cases of IRDs from eight consanguineous Pakistani families. METHODS: The current study included consanguineous Pakistani families with at least two affected members. DNA was extracted from whole blood samples by the phenol-chloroform method. Two affected members from each family were initially analyzed using targeted panel sequencing of 344 known IRD genes. The pathogenicity of candidate variants was assessed using the American College of Medical Genetics and Genomics guidelines. Segregation testing was performed by Sanger sequencing. RESULTS: Results of eight IRD families revealed a total of four reported variants in (c.827A>G, c.955T>C, c.1641C>A, c.1810C>T) and three novel variants, including c.1633A>T, c.800G>T, and c.1153T>C in , , and genes, respectively, segregating in each respective family. Among disease-causing variants identified in our study cohort, 87.5% were missense. Furthermore, one of the reported missense variants (i.e., c.1641C>A in ) was segregating in two unrelated families. All identified variants were homozygous and segregated in an autosomal recessive form. CONCLUSIONS: was the most frequently mutated gene in our study cohort. Only the c.1641C>A variant of was repeated in two families, showing genetic diversity. The identification of three novel pathogenic variants in CNG channel genes in the present study reaffirms the allelic and genetic heterogeneity of IRDs in the Pakistani population.
Cysteinyl leukotriene receptor 1 regulates cellular glucose levels in human retinal cells.
Koller A, Brunner SM, Preishuber-Pflügl J … +4 more , Mayr D, Runge C, Reitsamer HA, Trost A
Mol Vis · 2025 · PMID 41306485
PURPOSE: Cysteinyl leukotriene receptor 1 (CysLTR1), originally described as a proinflammatory G protein-coupled receptor, has been shown to possess diverse nonimmunological properties. One of these functions is to modul...
PURPOSE: Cysteinyl leukotriene receptor 1 (CysLTR1), originally described as a proinflammatory G protein-coupled receptor, has been shown to possess diverse nonimmunological properties. One of these functions is to modulate glucose-stimulated insulin secretion in β cells. Furthermore, the inhibition of CysLTR1 increases retinal cell survival in early diabetic retinopathy. Nevertheless, the potential of CysLTR1 to modulate glucose levels in retinal vascular cells, such as endothelial cells (ECs) and pericytes (PCs), is unknown. Therefore, we determined the intracellular glucose levels in retinal cells in vitro after the inhibition of CysLTR1 under standard and high-glucose culture conditions. METHODS: Primary human ECs, PCs, and the ARPE-19 cell line were cultured under standard (5.5 mmol/l glucose + 27.5 mmol/l mannitol) and high-glucose (33.0 mmol/l) conditions in the absence and presence of the specific CysLTR1 antagonists montelukast and zafirlukast for 1, 3, and 7 days. CysLTR1 expression was determined by immunofluorescence microscopy. CysLT secretion was measured by enzyme-linked immunosorbent assay. The effects of high glucose and CysLTR1 inhibition on cell viability and intracellular glucose levels were analyzed by luminescence-based assays. Furthermore, the transendothelial and transepithelial electrical resistance of the ECs and ARPE-19 monolayers was measured. RESULTS: CysLTR1 inhibition under standard glucose culture conditions increased the cellular glucose levels in retinal ECs, PCs, and ARPE-19 cells after 1 and 3 days of treatment. Under high-glucose culture conditions, CysLTR1 inhibition for 1 day reduced the intracellular glucose level in ARPE-19 cells. However, CysLTR1 inhibition for 3 days increased the level of intracellular glucose in ARPE-19 cells under high-glucose culture conditions. Furthermore, CysLTR1 inhibition reduced the tightness of the EC and ARPE-19 monolayers under standard culture conditions but increased the tightness of the ARPE-19 monolayers under high-glucose conditions. CONCLUSIONS: CysLTR1 is considered a potential target for the treatment of type 2 diabetes and early diabetic retinopathy. Our data revealed that CysLTR1 activity directly regulates cellular glucose levels in retinal cells, supporting these hypotheses. Interestingly, the effect of CysLTR1 activity on glucose levels was reversed under acute metabolic stress. Thus, the activity of CysLTR1 appears to be more complex in terms of glucose metabolism and needs to be studied in more detail.
Phenotype-genotype correlation of patients with congenital cataracts and hair anomalies.
Wang Q, Lin X, Wang D … +10 more , Qin T, Chen W, Chen J, Zhang X, Lin Y, Lin Z, Li J, Li X, Hejtmancik JF, Chen W
Mol Vis · 2025 · PMID 41306484
PURPOSE: Hair anomalies represent a common associated symptom of congenital cataracts. Early diagnosis is crucial for treatment and predicting prognosis. However, the insidious and nonspecific nature of the symptoms in y...
PURPOSE: Hair anomalies represent a common associated symptom of congenital cataracts. Early diagnosis is crucial for treatment and predicting prognosis. However, the insidious and nonspecific nature of the symptoms in young children makes diagnosis challenging, often necessitating tools such as whole-exome sequencing (WES) for accurate assessment. This study aims to propose a simple and expedient approach to guide clinical management by analyzing phenotype-genotype correlations. METHODS: A prospective cohort study was conducted among participants who underwent clinical examinations and WES between 2021 and 2023. Bioinformatic analysis was performed. In total, 170 unrelated congenital cataract probands were tested. The suspected pathogenic variants were validated through Sanger sequencing in both the probands and available family members. Correlation analyses were then performed, integrating clinical characteristics, cataract phenotype, and genotype data. RESULTS: Nine probands presented with both cataracts and hair anomalies. Potential pathogenic variants were detected in all patients with hair anomalies, including a novel variant in . Phenotype-genotype analysis supports the classification of patients into two groups: hypotrichosis 14 and ichthyosis follicularis with atrichia and photophobia syndrome 2, based on the cataract phenotype, severity of the hair anomalies, and the presence of corneal pannus. These patients should be monitored closely for the development and progression of glaucoma and corneal lesions. CONCLUSIONS: We identified nine probands with hair anomalies in our large cohort of congenital cataract probands. Using WES and comprehensive clinical examinations, we established definitive diagnoses, broadened the phenotype and genotype, and proposed phenotype-genotype correlations.
Erratum: Ablation of C3 modulates macrophage reactivity in the outer retina during photo-oxidative damage.
Mol Vis · 2025 · PMID 40661870
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