Molecular Vision[JOURNAL]
Sun
200 papers
Mutation of beta-tubulin 4B gene ( causes autosomal dominant retinitis pigmentosa with sensorineural hearing loss in a multigenerational family.
Gregory-Evans CY, Joe AW, Gregory-Evans K
Mol Vis · 2025 · PMID 40606475
PURPOSE: Members of a multigenerational Canadian family presented to an inherited retinal degeneration (IRD) clinic with retinitis pigmentosa (RP) and sensorineural hearing loss, reminiscent of an Usher syndrome phenotyp...
PURPOSE: Members of a multigenerational Canadian family presented to an inherited retinal degeneration (IRD) clinic with retinitis pigmentosa (RP) and sensorineural hearing loss, reminiscent of an Usher syndrome phenotype. Biallelic disease-causing variants in the known Usher syndrome genes were not identified. Therefore, we enrolled further family members in this study and examined whether other IRD gene variants could explain the phenotype in the family. METHODS: Family members underwent a comprehensive ophthalmic examination, including best-corrected visual acuity, direct and indirect ophthalmoscopy, fundus photography, visual field testing, spectral-domain optical coherence tomography, audiological examination, and genetic testing. Some patients also had autofluorescence imaging. Loss-of-function testing was initiated by antisense morpholino knockdown of in zebrafish. RESULTS: Multimodal clinical testing in affected patients revealed an autosomal dominant late-onset presentation of RP associated with progressive, bilateral sensorineural hearing loss that occurred in the second to third decades of life with no vestibular involvement. Panel-based genetic testing revealed a heterozygous c.1168C>T, p.Arg390Trp variant in the beta-tubulin 4B gene () only in affected family members. Based on analysis, segregation analysis through the family, and literature evaluation, this variant is likely to be the disease-causing variant inherited in an autosomal dominant manner. We searched our local database of ~1,000 patients with IRD, and no other variants were identified, confirming this is a rare disease variant. Knockdown of in zebrafish revealed cone and rod photoreceptor abnormalities in the retina and hydrocephalus in the developing brain, resulting in early larval lethality. CONCLUSIONS: For the first time, we describe a multigenerational family with a gene variant p.(Arg390Trp) segregating with deaf-blindness, establishing autosomal dominant inheritance. This further confirms that the Arg390 codon is a mutation hotspot. We also expand the range of phenotypes seen with the p.(Arg390Trp) gene variant to include typical RP as well as a milder, pericentral RP. Furthermore, our studies suggest there is conservation of TUBB4B ciliary function between zebrafish and humans, making zebrafish a better model system for studying vision loss than the mouse model.
Inhibitory effects of ursolic acid on oxygen-induced mouse retinal neovascularization via intravitreal injection.
Yang L, Yang F, Zhang W … +9 more , Wang Y, Chen P, Du S, Liu X, Gao Y, Shi J, Wang P, Li R, Su Q
Mol Vis · 2025 · PMID 40606474
UNLABELLED: Objective: This study aimed to explore the effects and mechanisms of ursolic acid (UA) on oxygen-induced retinal neovascularization (RNV) in mice and its inhibitory effects on human retinal capillary endothel...
UNLABELLED: Objective: This study aimed to explore the effects and mechanisms of ursolic acid (UA) on oxygen-induced retinal neovascularization (RNV) in mice and its inhibitory effects on human retinal capillary endothelial cells (HRCECs) under high-glucose conditions. METHODS: Neonatal mice were divided into five groups: one normal group and four with oxygen-induced retinopathy (OIR), including OIR, phosphate-buffered saline, UA and Lucentis groups. On postnatal day 17 (P17), mice were euthanized and one eye was collected for retinal analysis using fluorescence microscopy. Protein and messenger ribonucleic acid (mRNA) levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, MMP-9 and cyclo-oxygenase-2 (COX-2) were detected. HRCECs cultured under high-glucose conditions were treated with UA to assess its effects on proliferation and molecular expression. RESULTS: UA significantly reduced RNV area in OIR mice and protected astrocytes from hypoxia-induced damage (p<0.01). VEGF, MMP-2, MMP-9 and COX-2 levels were lower in the UA group compared with the OIR and phosphate-buffered saline groups (p<0.05), but slightly higher than in normal controls (p<0.01). Lucentis reduced VEGF levels but did not significantly affect MMP-2, MMP-9 or COX-2. In HRCECs, UA inhibited high-glucose-induced proliferation and reduced VEGF, MMP-2, MMP-9 and COX-2 expression in a time- and dose-dependent manner. CONCLUSIONS: UA inhibits RNV by reducing VEGF, MMP-2, MMP-9 and COX-2 expression, protecting astrocytes and suppressing HRCEC proliferation under high-glucose conditions, highlighting its therapeutic potential for retinal neovascular diseases.
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 40606473
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.
variants in childhood glaucoma: Phenotypic expansion and clinical experience.
Verma A, Khan AO, Pochaboina V … +1 more , Senthil S
Mol Vis · 2025 · PMID 40384769
PURPOSE: This study describes a distinct spectrum of latent transforming growth factor-β-binding protein 2 ()-related ocular phenotypes in pediatric glaucoma with supporting genetic evidence and highlights our clinical e...
PURPOSE: This study describes a distinct spectrum of latent transforming growth factor-β-binding protein 2 ()-related ocular phenotypes in pediatric glaucoma with supporting genetic evidence and highlights our clinical experiences in its management. METHODS: A total of 189 children with childhood glaucoma underwent whole-exome sequencing-based genetic testing. Of these, 24 children displayed -related phenotypes, among whom 18 cases who tested positive for variants were included in the study. The identified variants were confirmed through Sanger sequencing whenever possible and analyzed using in silico tools. The clinical presentation, genetic variants, and management of these 18 cases were thoroughly reviewed and presented. RESULTS: All 36 eyes of the 18 children with biallelic variants exhibited megalocornea without Descemet break, iridodonesis, and ectopia lentis. Pupillary changes were noted in all eyes, with persistent pupillary membrane in 78% (28/36) and ectropion uveae in 19% (7/36) eyes. Secondary glaucoma was observed in 72% (26/36) eyes, requiring surgery in 13 of these. Retinal pathology was noted in 47% (17/36) eyes. Lensectomy was performed in 94% (34/36) eyes with a mean age of 4.09 ± 3.5 years. Logistic regression analysis suggested that older age at lensectomy increased the risk of secondary glaucoma (hazard ratio, 1.69; [95% Confidence Interval: 1.00, 2.86], < 0.05). The identified variants included five stop-gain variations, six frameshift variations, and one substitution variation, with five being novel and seven classified as rare variants. CONCLUSIONS: The study expands the classic -related phenotype spectrum in an Indian pediatric glaucoma cohort, highlighting additional features such as persistent pupillary membrane, ectropion uveae, and associated retinal pathology. These ocular manifestations were predominantly linked to nonsense variants. From a management standpoint, early lensectomy can help prevent secondary glaucoma, while timely identification and treatment of peripheral retinal pathology can reduce the risk of sight-threatening complications.
Multikinase inhibition-mediated proliferative vitreoretinopathy therapy by nanoparticles in rabbits.
Arslan E, Ozturk F, Uner B … +3 more , Tureli S, Muftuoglu SF, Tas C
Mol Vis · 2025 · PMID 40384768
PURPOSE: To investigate the efficacy of nanoparticles in treating proliferative vitreoretinopathy (PVR) through clinical observation, histology, and immunohistochemistry, despite unsatisfactory surgical outcomes and fail...
PURPOSE: To investigate the efficacy of nanoparticles in treating proliferative vitreoretinopathy (PVR) through clinical observation, histology, and immunohistochemistry, despite unsatisfactory surgical outcomes and failed therapies for the current PVR treatment. DESIGN: Twelve rabbits were divided into control and nintedanib (NTB) groups. The rabbits underwent weekly ophthalmologic examinations over a period of four weeks. METHODS: At the end of the fourth week, the rabbits' eyes were removed for histological and immunohistochemical evaluation. Three additional rabbits outside the PVR model were administered a 0.5% NTB-loaded liposomal formulation in one eye. The drug concentrations in the vitreous samples were determined using high-pressure liquid chromatography on days 1, 7, 14, and 35. RESULTS: The PVR stages were low in the NTB group, and there was no significant difference between the NTB and control groups (p = 0.108). However, it is worth noting that the group treated with NTB had significantly fewer epiretinal membrane formations during the histological evaluation. In addition, the corrected fluorescence intensity measurement of the subjects for collagen-1 in the NTB group was significantly lower than that in the control group (p = 0.004). Most importantly, no significant adverse effects were observed. CONCLUSIONS: Our study has provided preclinical support for a liposomal formulation containing NTB that, with single-dose administration, has the potential to be effective in vivo in preventing the development of PVR and its correlated pathologies without causing any significant side effects.
DNA methyltransferase 1 regulates epithelial cell functions in corneal and eyelid development.
Christianto A, Mongan M, Xiao B … +4 more , Wang Q, Puga A, Robinson ML, Xia Y
Mol Vis · 2025 · PMID 40384767
PURPOSE: DNA methyltransferase 1 (DNMT1) is a crucial enzyme for the development of the retina and lens in the eye, but its roles in the cornea and eyelids are yet to be investigated. METHODS: Ocular surface epithelium (...
PURPOSE: DNA methyltransferase 1 (DNMT1) is a crucial enzyme for the development of the retina and lens in the eye, but its roles in the cornea and eyelids are yet to be investigated. METHODS: Ocular surface epithelium (OSE)-specific knockout mice, denoted as , were generated. Prenatal eye tissues were characterized by hematoxylin and eosin staining; DNMT1 expression, DNA methylation, epithelial differentiation and cell-cell junctions were determined by immunohistochemistry; proliferation was assessed by 5-ethynyl 2´-deoxyuridin labeling and apoptosis evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Keratinocytes derived from mice were infected with adenoviruses carrying either green fluorescent protein or Cre recombinase to obtain wild-type and deficient cells. In these cells, expression and epithelial terminal differentiation were evaluated by real-time PCR and/or western blotting; adherence junction and apoptosis were assessed by immunohistochemistry; proliferation was determined by 5-ethynyl 2´-deoxyuridin labeling; transcription factor activities were determined by luciferase reporter assays. RESULTS: The abundant DNMT1 expression and cytosine methylation (5meC) detected in the ocular surface epithelia of wild-type embryos were largely diminished in that of embryos. Besides lens degeneration, the fetuses had severe abnormalities of the cornea and eyelids. The surface epithelial cells and stromal keratocytes in the knockout corneas were distorted and the eyelids failed to fuse in the knockout embryos, resulting in an eye-open-at-birth phenotype. At the cellular level, DNMT1-deficient OSE had normal proliferation but increased apoptosis and aberrant cell junctions. In addition, the knockout corneal epithelia failed to express corneal-specific keratin 12, and the knockout eyelid epithelia had increased expression of keratin 10, indicating accelerated terminal differentiation. In vitro studies validated that DNMT1 was required for epithelial cell survival, terminal differentiation and cell junctions, and further identified signaling pathways aberrantly activated by its ablation. CONCLUSION: DNMT1 maintains survival and differentiation of corneal and eyelid epithelium for the development of the eye.
Genetics and phenotypes of mutations in inherited retinal degeneration: A study from a tertiary eye care center in Brazil.
de Freitas Cenachi SP, Frasson M, Mares V … +5 more , Arantes RR, Albuquerque ALB, Marques Nascentes AL, De Marco LAC, Nehemy MB
Mol Vis · 2025 · PMID 40384766
PURPOSE: Biallelic variants in the retinal pigment epithelium-specific 65-kDa protein () gene are linked to several inherited retinal diseases (IRDs), including Leber congenital amaurosis (LCA), early-onset severe retina...
PURPOSE: Biallelic variants in the retinal pigment epithelium-specific 65-kDa protein () gene are linked to several inherited retinal diseases (IRDs), including Leber congenital amaurosis (LCA), early-onset severe retinal dystrophy (EOSRD), and retinitis pigmentosa (RP). This study screened patients from a tertiary center in Brazil with IRDs for variants to characterize the associated phenotypes. METHODS: LCA, EOSRD, and RP diagnoses were based on predefined clinical criteria. Patients underwent comprehensive clinical evaluations and retinal imaging. Genomic DNA was analyzed using a next-generation sequencing panel for IRDs, covering 238 genes. RESULTS: variants were identified in seven of the 68 patients screened. Of these, three were homozygous, and four were compound heterozygous for the identified mutant alleles. A total of six variants were detected, of which one was novel. The p.Leu341Ser (c.1022T>C) mutation was the most prevalent, being found in four of seven patients. Visual loss onset ranged from birth to the third decade of life. A consistent clinical feature observed in all patients was some degree of pigmentary change upon peripheral retinal examination. CONCLUSIONS: variants were found in 10.3% of cases in this series, associated with LCA, EOSRD, and RP. These variants were consistently linked with pigmentary changes in the peripheral retina and exhibited variable manifestations regarding arteriolar attenuation, disc pallor, and macular appearance. In this series, the prevalence of the p.Leu341Ser (c.1022T>C) mutation was 57%.
Serum pro-brain natriuretic peptide correlates with optical coherence tomography indices in diabetic retinopathy.
Chaturvedi S, Saxena S, Kaur A … +4 more , Kumar P, Pandey S, Mahdi AA, Akduman L
Mol Vis · 2025 · PMID 40384765
PURPOSE: Serum pro-brain natriuretic peptide (BNP) is a 108-amino-acid prohormone that inhibits vascular endothelial growth factor (VEGF) secretion, protecting pericytes from cell death and decreasing retinal vasculariza...
PURPOSE: Serum pro-brain natriuretic peptide (BNP) is a 108-amino-acid prohormone that inhibits vascular endothelial growth factor (VEGF) secretion, protecting pericytes from cell death and decreasing retinal vascularization. The purpose of this study was to investigate the correlation of serum pro-BNP with optical coherence tomography (OCT) indices in diabetic retinopathy. METHODS: This cross-sectional study investigated 96 consecutive subjects aged between 40 and 65 years: controls n = 24, no diabetic retinopathy (NoDR) n = 24, non-proliferative diabetic retinopathy (NPDR) n = 24, and proliferative diabetic retinopathy (PDR) n = 24. Same-day analysis of blood samples for serum pro-BNP levels was performed and spectral-domain OCT (SD-OCT) was used to measure the following OCT indices: OCT angiography (OCTA) superficial vessel density (SVD), deep vessel density (DVD), and foveal avascular zone (FAZ); OCT retinal nerve fiber layer (RNFL); and OCT ganglion cell analysis (GCA). RESULTS: The mean serum pro-BNP levels for the control, NoDR, NPDR, and PDR groups were 14.07 ± 11.51, 27.35 ± 11.81, 280.44 ± 106.13, and 122.33 ± 43.66 pg/ml, respectively. The mean values of the various OCT parameters correlated with serum pro-BNP were OCTA SVD (r = 0.360), OCTA DVD (r = 0.408), OCTA FAZ (r = 0.475), OCT RNFL (r = 0.215) and OCT GCA (r = 0.285; p<0.001). CONCLUSIONS: The serum pro-BNP levels were higher in the NPDR group than in the NoDR group and much lower in the PDR group than in the NPDR group, reflecting a lowering of the protective barrier. These results correlated with the changes in various OCT indices.
Subretinal delivery of AAV5-mediated human gene ameliorates the disease phenotype in a rat model of retinitis pigmentosa.
Kim HJ, Kwak JH, Choi JS … +7 more , Kim J, Moon SY, Lee SHS, Lee H, Park K, Lee JY, Won SY
Mol Vis · 2025 · PMID 40384764
PURPOSE: A genetic disorder that affects the beta subunit of cyclic guanosine monophosphate-phosphodiesterase type 6 (PDE6B) in humans leads to autosomal recessive retinitis pigmentosa (RP). This condition causes severe...
PURPOSE: A genetic disorder that affects the beta subunit of cyclic guanosine monophosphate-phosphodiesterase type 6 (PDE6B) in humans leads to autosomal recessive retinitis pigmentosa (RP). This condition causes severe vision loss in early life due to fast deterioration of photoreceptors. This study evaluated the therapeutic potential of subretinal delivery of the adeno-associated virus (AAV)5-mediated human gene in an RP rat model caused by gene knockout (KO). METHODS: We compared the transduction efficiency and tropism of different AAV serotypes (2, 5 and 8) in KO rats and found that AAV5 had the highest and most specific expression in photoreceptors. We injected AAV5- into the subretinal space of KO rats on postnatal day 21. We assessed the protective effects six weeks postinjection by measuring PDE6B protein expression, photoreceptor structure, retinal morphology and thickness, retinal pigment epithelium integrity and visual function. RESULTS: AAV5- treatment ameliorated the disease phenotype in KO rats by restoring PDE6B protein expression, preserving photoreceptor structure, improving retinal morphology and thickness, and maintaining retinal pigment epithelium integrity. Functional analysis of vision by scotopic electroretinogram (ERG) and optokinetic nystagmus revealed that AAV5- treatment significantly improved the visual function of gene KO rats compared with AAV5--injected KO rats. CONCLUSIONS: Our results demonstrate that AAV5- may be a potential therapeutic gene candidate for RP caused by mutations.
Astragaloside IV improves the survival rates of retinal ganglion cells in traumatic optic neuropathy by regulating autophagy mediated by the AMPK-MTOR-ULK signaling pathway.
Sun W, Chao G, Wu Q … +5 more , Xia Y, Shang M, Wei Q, Zhou J, Liao L
Mol Vis · 2025 · PMID 40384763
PURPOSE: Autophagy is involved in the pathological changes of traumatic optic neuropathy (TON), and the regulation of autophagy mediated by the AMPK-mTOR-ULK pathway is a potential therapeutic approach. Astragaloside IV...
PURPOSE: Autophagy is involved in the pathological changes of traumatic optic neuropathy (TON), and the regulation of autophagy mediated by the AMPK-mTOR-ULK pathway is a potential therapeutic approach. Astragaloside IV (AS-IV) can regulate autophagy and play a therapeutic role in various diseases. This study aimed to observe the therapeutic effect of astragaloside on TON and the role of AMPK-MTOR-ULK pathway-mediated autophagy in this process. METHODS: After the TON model was established, varying doses of AS-IV were administered as an intervention. Additionally, compound C (an AMPK inhibitor) or 3-methyladenine (an autophagy inhibitor) was administered intraperitoneally in conjunction with AS-IV. Samples were collected following a 7-day intervention period. Western blot analysis was conducted to measure the protein and phosphorylation levels of AMPK, mTOR, and ULK proteins. Moreover, western blot and quantitative reverse transcription PCR assays were used to quantify LC3 levels in retinal tissue. LC3 immunofluorescence was performed to examine autophagy levels in the ganglion cell layer (GCL), while transmission electron microscopy was employed to observe autophagosomes. Additionally, BRN3A immunofluorescence was used to label retinal ganglion cells (RGCs) in the GCL, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was used to assess apoptosis within the GCL. Finally, optic nerve conduction function was evaluated using flash visual evoked potentials. RESULTS: After 7 days, the phosphorylation levels of AMPK, mTOR, and ULK proteins in retinal tissue exhibited significant changes following TON. AS-IV treatment enhanced LC3 messenger RNA and protein levels in TON model rats, and the autophagy-promoting effect of AS-IV was reversed by 3-methyladenine. Moreover, AS-IV elevated P-AMPK and P-ULK levels while decreasing P-mTOR levels. AS-IV also improved the survival rate of RGCs and reduced the P2 peak latency of flash visual evoked potentials. These effects were attenuated by the AMPK inhibitor compound C. Additionally, AS-IV increased the levels of AKT1 and P-AKT1 while decreasing P-S6RP levels in the retinal tissue of TON model rats. CONCLUSIONS: AS-IV can increase the survival rate of RGCs and improve visual function after TON, which may be related to the improvement of autophagy by regulating the AMPK-MTORC1-ULK pathway.
Syndromic forms of inherited retinal dystrophies: a comprehensive molecular diagnosis of consanguineous Pakistani families using capture panel sequencing.
Asghar A, Wazir S, Fatima S … +8 more , Bilal H, Shoaib M, Rehman SU, Altaf S, Li Y, Afshan K, Chen R, Firasat S
Mol Vis · 2025 · PMID 40384762
BACKGROUND: Inherited retinal dystrophies (IRDs) represent a clinically and genetically heterogeneous group of genetic disorders that involve photoreceptors and/or retinal pigment epithelium degeneration. IRDs may occur...
BACKGROUND: Inherited retinal dystrophies (IRDs) represent a clinically and genetically heterogeneous group of genetic disorders that involve photoreceptors and/or retinal pigment epithelium degeneration. IRDs may occur as an isolated condition or may represent an ocular manifestation of a multisystemic disorder referred as syndromic IRD. To increase the understanding of the molecular determinants of syndromic IRD-related genes in the Pakistani population, we revealed the genetic profile of 13 consanguineous Pakistani families using capture panel sequencing. METHODS: We performed comprehensive molecular testing on 72 IRD segregating Pakistani families using targeted capture panel sequencing of 344 known genes. The pathogenicity of candidate variants was assessed using American College of Medical Genetics and Genomics guidelines, followed by Sanger sequencing for segregation analysis. RESULTS: Causative variants in previously reported syndromic IRDs genes were detected in 13/72 (18%) IRD families, including 5/72 (6.94%), 4/72 (5.55%), 2/72 (2.8%), 1/72(1.38%) and 1/72 (1.38%) in Usher syndrome, Bardet-Biedl syndrome, Batten disease, retinitis pigmentosa with situs inversus and Stickler syndrome segregated families, respectively. Disease-causing variants included nine previously reported and six novel homozygous variants, i.e., c.1143G>C in , c.470G>A in , c.877-2A>G in , c.347C>T in , c.581C>T in and c.100+1G>T in gene segregation with disease phenotype in eight families. Two heterozygous variants of the gene, i.e., c.12093C>A and c.9815C>T, were segregated in a compound heterozygous form in family RP243. Furthermore, RP151 showed segregation of a heterozygous variant c.247G>A in a Stickler syndrome gene, i.e., , in an autosomal dominant manner. CONCLUSIONS: This study reaffirms the clinical and genetic heterogeneity of syndromic IRD-associated genes and confirms the usefulness of molecular methods in advancing our understanding of these conditions in consanguineous populations. The most commonly mutated Bardet-Biedl syndrome gene was (75%) and the most commonly mutated Usher syndrome genes were (40%) and (40%). Our data could serve as a reference for future studies and the development of treatment modalities for affected families of Pakistani origin.
WTAP-mediated N6-methyladenosine mRNA methylation regulates laser-induced macular neovascularization.
Gong Q, Hu L, Liu G … +8 more , Yin X, Zhao X, Li Q, Li Y, Sun Y, Zhou Y, Guo C, Du Z
Mol Vis · 2024 · PMID 40330498
PURPOSE: Neovascular age-related macular degeneration (nAMD) is now a major cause of central vision loss in older adults worldwide. The primary characteristic of nAMD is the formation of macular neovascularization (MNV),...
PURPOSE: Neovascular age-related macular degeneration (nAMD) is now a major cause of central vision loss in older adults worldwide. The primary characteristic of nAMD is the formation of macular neovascularization (MNV), which is a pathologic form of angiogenesis. Epigenetics plays a role in multiple pathological physiologic processes. N6-methyladenosine (m6A) modification is the most common, abundant, and reversible modification in eukaryotic mRNAs, and it plays a role in various pathological angiogenesis processes. This study intends to reveal the expression and functions of m6A during the macular neovascularization (MNV) process. METHODS: A laser-induced MNV mouse model was used in this study. m6A quantitative analysis was performed to detect the expression of m6A. Subsequently, the expression of various m6A writers and erasers was detected using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Immunohistochemistry was used to detect Wilms' tumor 1-associating protein (WTAP) expression in the MNV lesions. Intravitreal injection of WTAP siRNA in MNV mice to silence the WTAP gene. Hematoxylin and eosin (H&E) were used to determine the thickness and length of the MNV. Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were examined to measure the leakage area of the MNV. Proliferating cell nuclear antigen (PCNA) expression was detected with a western blot. The mRNA and protein levels of β-catenin were tested with qRT-PCR and western blot. RESULTS: We found increased m6A modification levels after laser induction compared with the normal control group. Subsequently, the expression of various m6A writers and erasers was detected. The results showed that WTAP increased in the MNV model in mice. After the injection of WTAP siRNA into the vitreous body, the expression of WTAP significantly decreased, subsequently decreasing the m6A modification levels. The width, breadth, and leakage area of MNV damage markedly decreased, and endothelial cell proliferation was inhibited. After laser-induced MNV, the expression of β-catenin increased, and that of β-catenin significantly decreased after WTAP knockout. CONCLUSIONS: In conclusion, this study suggests that WTAP-mediated m6A methylation can regulate pathological angiogenesis during MNV and that WTAP may participate in the formation of MNV through the wingless-related integration site (Wnt) pathway. WTAP may be a potential target for MNV treatment.
Subclinical parents assist in the detection of genetic variants in keratoconus by trio-based whole-exome sequencing.
Li X, Yao Y, Xing S … +4 more , Ma S, Pang S, Zhou Y, Chen S
Mol Vis · 2025 · PMID 40098727
PURPOSE: To explore the genetic variants of 14 keratoconus trios containing subclinical parents. METHODS: Trio-based whole-exome sequencing was performed in 14 keratoconus trios containing subclinical parents. The varian...
PURPOSE: To explore the genetic variants of 14 keratoconus trios containing subclinical parents. METHODS: Trio-based whole-exome sequencing was performed in 14 keratoconus trios containing subclinical parents. The variants identified in candidate genes of keratoconus were analyzed by multiple bioinformatics tools. RESULTS: We identified 12 variants in 10 candidate genes of keratoconus (, , , , , , , , , and ). All variants were novel, not previously reported, and defined as uncertain significance according to the American College of Medical Genetics and Genomics guidelines. All variants were heterozygous and autosomal dominant cosegregated in keratoconus families. CONCLUSIONS: We found that the candidate variants identified in clinically diagnosed patients and their subclinical parents may cause keratoconus through an autosomal dominant inheritance pattern, with different variable expressivity. This study indicates that genetic testing may play an important role in identifying patients with latent keratoconus and high-risk individuals for corneal ectasia after refractive surgery.
An improved method of transducing retinal ganglion cells using AAV via transpupillary injection in adult mouse eyes.
Lin F, Lin ST, Wang J … +5 more , Sellers JT, Chrenek MA, Nickerson JM, Boatright JH, Geisert EE
Mol Vis · 2025 · PMID 40084287
PURPOSE: Intravitreal injection of adeno-associated virus (AAV) vectors is a good approach for transducing retinal ganglion cells (RGCs) in mice. It allows for high transduction efficiency and is relatively specific to R...
PURPOSE: Intravitreal injection of adeno-associated virus (AAV) vectors is a good approach for transducing retinal ganglion cells (RGCs) in mice. It allows for high transduction efficiency and is relatively specific to RGCs. To deliver vectors, most studies use a transscleral approach that can have potentially negative effects, causing damage to the lens or retina. We optimized the intravitreal injection method using a transpupillary approach to minimize ocular damage and efficiently transfect RGCs. METHODS: C57BL/6J mice were anesthetized, and their irises were dilated. The eyeball was held with forceps while a small, full-thickness incision was made halfway between the center and periphery of the cornea. Using a bent 35-gauge blunt needle, the tip was navigated through the incision across the anterior chamber to reach the distal aspect of the pupil. The needle was inserted through the pupil, swept around the lens, and entered the vitreous, delivering expression vectors containing cytomegalovirus (CMV) promoter-driving green fluorescent protein (AAV-CMV-GFP) into the vitreous chamber. Fourteen days after injection, live fluorescent fundus images were taken, followed by immunostaining for GFP. RESULTS: With the improved injection technique, the lens remained clear and undamaged. Fundus imaging and GFP staining showed that over 90% of the mouse retinas sustained no visible damage. Retinas injected via the transpupillary approach also exhibited GFP transduction throughout the ganglion cell layer. CONCLUSIONS: Transpupillary intravitreal injection reduces the potential risk compared to the transscleral approach, offering a promising and efficient method for delivering reporter genes to RGCs and ensuring high levels of gene expression without damage to the lens or retina.
Identification of genetic factors underlying severe retinopathy of prematurity in preterm infants.
Sun H, Xia Z, Li M … +6 more , Yu Z, Wang Z, Xing S, Cheng P, Zhang H, Li L
Mol Vis · 2025 · PMID 40084286
OBJECTIVE: Retinopathy of prematurity (ROP) is a pathological condition characterized by abnormal proliferation of retinal vessels and it represents the primary cause of visual impairment in preterm infants. There is inc...
OBJECTIVE: Retinopathy of prematurity (ROP) is a pathological condition characterized by abnormal proliferation of retinal vessels and it represents the primary cause of visual impairment in preterm infants. There is increasing backing for the involvement of genetic factors in the onset of ROP. METHODS: A prospective cohort study assessed the allele frequency and genotype distribution of gene polymorphisms in angiogenesis, inflammation and oxygen-sensing pathways in preterm infants with severe ROP. The role of genetic polymorphism in ROP development was investigated using next-generation sequencing (NGS) combined with candidate genes and data mining methods. RESULTS: A total of 47 confirmed severe ROP cases and gestational age, birthweight and days of oxygen therapy plus 35 similar control infants were enrolled in this study. In the initial hypothesis-generating survey, we selected a p value of 0.01 to minimize false positives while retaining true positives. Using this criterion, we identified 19 single-nucleotide polymorphisms across 11 genes that were associated with the occurrence of ROP (, , , , , , , , , and ; all p<0.001). Compared with the control group, 62 single-nucleotide polymorphisms in 19 candidate genes (, , , , , , , , , , , , , , , , , ) representing angiogenic, inflammation, oxygen-sensing pathways and proliferative retinopathic diseases were found to be associated with the development of severe ROP (all p<0.01). CONCLUSIONS: Using NGS gene analysis suggests that genetic risk factors may play an important role in susceptibility to the development of ROP.
Serum pro-brain natriuretic peptide correlates with optical coherence tomography indices in diabetic retinopathy.
Chaturvedi S, Saxena S, Kaur A … +4 more , Kumar P, Pandey S, Mahdi AA, Akduman L
Mol Vis · 2025 · PMID 40084285
PURPOSE: Serum pro-brain natriuretic peptide (BNP) is a 108-amino-acid prohormone that inhibits vascular endothelial growth factor (VEGF) secretion, protecting pericytes from cell death and decreasing retinal vasculariza...
PURPOSE: Serum pro-brain natriuretic peptide (BNP) is a 108-amino-acid prohormone that inhibits vascular endothelial growth factor (VEGF) secretion, protecting pericytes from cell death and decreasing retinal vascularization. The purpose of this study was to investigate the correlation of serum pro-BNP with optical coherence tomography (OCT) indices in diabetic retinopathy. METHODS: This cross-sectional study investigated 96 consecutive subjects aged between 40 and 65 years: controls n = 24, no diabetic retinopathy (NoDR) n = 24, non-proliferative diabetic retinopathy (NPDR) n = 24, and proliferative diabetic retinopathy (PDR) n = 24. Same-day analysis of blood samples for serum pro-BNP levels was performed and spectral-domain OCT (SD-OCT) was used to measure the following OCT indices: OCT angiography (OCTA) superficial vessel density (SVD), deep vessel density (DVD), and foveal avascular zone (FAZ); OCT retinal nerve fiber layer (RNFL); and OCT ganglion cell analysis (GCA). RESULTS: The mean serum pro-BNP levels for the control, NoDR, NPDR, and PDR groups were 14.07 ± 11.51, 27.35 ± 11.81, 280.44 ± 106.13, and 122.33 ± 43.66 pg/ml, respectively. The mean values of the various OCT parameters correlated with serum pro-BNP were OCTA SVD (r = 0.360), OCTA DVD (r = 0.408), OCTA FAZ (r = 0.475), OCT RNFL (r = 0.215) and OCT GCA (r = 0.285; p<0.001). CONCLUSIONS: The serum pro-BNP levels were higher in the NPDR group than in the NoDR group and much lower in the PDR group than in the NPDR group, reflecting a lowering of the protective barrier. These results correlated with the changes in various OCT indices.
Retinal and metabolic changes in a high-fat diet (HFD)+STZ model of Type II diabetes.
Phillips S, Feola A, Solomon J … +11 more , Cardelle L, Douglass A, Bales KL, Coulter M, Hutson L, Khayat CT, Grubman A, Worthy C, Boatright JH, Pardue MT, Allen RS
Mol Vis · 2024 · PMID 39959182
While the high-dose streptozotocin (STZ; 100 mg/kg) rodent model is the gold standard in modeling Type I diabetes, models for Type II diabetes are needed for this more common form of diabetes. We investigated the retinal...
While the high-dose streptozotocin (STZ; 100 mg/kg) rodent model is the gold standard in modeling Type I diabetes, models for Type II diabetes are needed for this more common form of diabetes. We investigated the retinal, cognitive, and metabolic alterations in a Type II diabetic model induced by high-fat diet (HFD) and low-dose STZ (30 mg/kg). Long Evans rats were assigned to naïve control, HFD, or HFD+STZ groups. Diabetic rats were further stratified into Type I and Type II based on metabolic assessments. Optomotor response (OMR, visual function), electroretinograms (retinal function), and Y-maze (cognitive function) were tested. Serum was analyzed for 12 metabolic markers using a multiplex panel. Type I rats showed severe increases in blood glucose accompanied by impairments in insulin and glucose tolerance, reduced bodyweight, and low insulin levels. In contrast, Type II rats showed moderate changes in blood glucose and insulin and glucose tolerance with weights and insulin levels similar to naïve controls. Type I and II rats showed OMR deficits (p<0.05) and electroretinogram changes (p<0.05). No cognitive deficits were observed. Type I rats displayed reduced serum levels of brain-derived neurotrophic factor (BDNF), C-Peptide, and leptin (p<0.05), and alterations in C-Peptide, PYY, and glucagon levels correlated with retinal function changes (p<0.05). Type II rats exhibited a moderate diabetic state while still developing retinal and visual deficits, which recapitulates phenotypes reported in patients.
Expression of cytokines in the aqueous humor of cataract patients with pathologic myopia and simple high myopia.
Han X, Hu Y, Chen Y … +7 more , Cai J, Chen Y, Li N, Xu C, Zhou Q, Wang F, Wang J
Mol Vis · 2024 · PMID 39959181
PURPOSE: To explore the role of cytokines during the progression process of cataract patients with pathologic myopia (PMC) and simple high myopia (SHMC). METHODS: A total of 63 cataract patients who underwent cataract su...
PURPOSE: To explore the role of cytokines during the progression process of cataract patients with pathologic myopia (PMC) and simple high myopia (SHMC). METHODS: A total of 63 cataract patients who underwent cataract surgery were classified into a PMC group (22 eyes), an SHMC group (21 eyes), and an age-related cataract (ARC) group (20 eyes), based on axial length (AL) and International Myopia Institute (IMI)'s classification. Aqueous humor samples were extracted before surgery. Cytometric bead array (CBA) was employed to measure the level of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), transforming growth factor-β1 (TGF-β1), basic fibroblast growth factor (bFGF), interleukin-10 (IL-10), interleukin-17a (IL-17a), interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor -α (TNF-α), intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM). Additionally, the correlations between cytokines and the AL or myopic maculopathy categories were examined. RESULTS: VEGF, IL-6, MCP-1, ICAM, and VCAM (all p<0.001), TGF-β1 (p=0.018), and IL-8 (p=0.008) were statistically different among the three groups. In parallel, the levels of VCAM (=0.718), MCP-1 (=0.591), ICAM (=0.584), IL-8 (=0.435), IL-6 (=0.396), and TNF-α (=0.280) were positively associated with myopic maculopathy, while VEGF (=-0.542), TGF-β1 (=-0.381), and IL-17a (=-0.284) were correlated inversely with myopic maculopathy (all p<0.05). Furthermore, a significant positive correlation was observed between AL and levels of VCAM (=0.726), MCP-1 (=0.644), ICAM (=0.573), IL-6 (=0.386), and IL-8(=0.376). VEGF (=-0.610), TGF-β1 (=-0.361), and IL-17a (=-0.319) were inversely associated with AL (all p<0.05). Further analysis using multiple regression indicated that, after adjusting for confounding factors, lower VEGF and higher VCAM were significantly associated with AL. However, the limitations of this study were reflected in the inability to determine whether the changes in cytokines were the consequences or causes of the formation of high myopia. CONCLUSIONS: The pathogeneses of PMC and SHMC may differ, and there are significant changes associated with inflammation and the immune response in eyes with PMC.
Exploring the protective effects of vasoactive intestinal peptides on dry eye disease in SARS-CoV-2 survivors.
Gushansky KY, Tuuminen R
Mol Vis · 2024 · PMID 39959180
PURPOSE: This study aimed to investigate the association between proton pump inhibitors and dry eye disease (DED) among hospitalized SARS-CoV-2 patients. METHODS: We conducted a retrospective cohort study using electroni...
PURPOSE: This study aimed to investigate the association between proton pump inhibitors and dry eye disease (DED) among hospitalized SARS-CoV-2 patients. METHODS: We conducted a retrospective cohort study using electronic medical records from patients hospitalized for SARS-CoV-2 between April 2020 and December 2023. Eligible participants were aged over 18 years and hospitalized for SARS-CoV-2 without preexisting DED. Exclusions included ICU admissions, malignancies, recent ocular interventions, or chronic medications known to induce dry eye disease. Logistic regression adjusted for age, gender, and vaccination status evaluated associations between gastrointestinal (GI) medications and the subsequent development of dry eye disease within 6 months following hospital discharge. RESULTS: The age and gender distributions within the cohort were representative of the general SARS-CoV-2 infected population. Among 1165 patients, 167 (14.3%) developed dry eye disease post-hospitalization. Laxative use (lactulose and polyethylene glycol) correlated positively with dry eye disease (OR 1.939, p = 0.016; OR 2.094, p = 0.015, respectively). Metoclopramide treatment showed the strongest association (OR 13.413, p < 0.001), with over 50% incidence in affected patients. Conversely, omeprazole showed an inverse correlation with dry eye disease (OR 0.332, p < 0.001). Polypharmacy increased the odds of DED (odds ration [OR] 1.629, p = 0.015), while age, gender, and vaccination status did not significantly influence the outcomes. CONCLUSIONS: Our findings emphasize significant correlations between GI medications and dry eye disease in SARS-CoV-2 survivors. Proton pump inhibitors may mitigate the risk of dry eye disease, contrasting with adverse effects linked to laxatives and metoclopramide. Vasoactive intestinal peptide (VIP), which links gut and lacrimal gland functions, is a strong candidate for the basis of the underlying pathophysiological mechanisms.
The association of endothelial nitric oxide synthase () gene polymorphisms and diabetic retinopathy among patients with type 2 diabetes: A case-control study.
Abu-Hassan DW, Al-Bdour MD, Aolymat I … +1 more , El-Khateeb M
Mol Vis · 2024 · PMID 39959179
PURPOSE: Diabetic patients experience chronic hyperglycemia that increases oxidative stress by enhancing free radical formation and nitric oxide (NO) production. Genetic mutations in the endothelial nitric oxide synthase...
PURPOSE: Diabetic patients experience chronic hyperglycemia that increases oxidative stress by enhancing free radical formation and nitric oxide (NO) production. Genetic mutations in the endothelial nitric oxide synthase () enzyme gene affect the levels of NO formation. These mutations, together with chronic hyperglycemia, may increase the risk of diabetic retinopathy (DR) development and/or DR progression as a complication of diabetes. This study aimed to determine whether the polymorphisms intron 4ab, exon 7 Glu298Asp variant (G894T), and T-786C are associated with DR severity. METHODS: This case-control study involved 250 subjects (172 with type 2 diabetes mellitus (DM) with or without DR and 78 healthy controls). DR was detected by slit lamp biomicroscopy and its severity was determined with the evidence-based International Clinical Diabetic Retinopathy Disease Severity Scale. The genotyping of eNOS polymorphisms was analyzed by polymerase chain reaction (PCR) only or with restriction fragment length polymorphism. The haplotype analysis was performed using the SNPStats tool. RESULTS: The genotype distribution for the three polymorphisms was significantly different in patients with diabetes compared to controls (intron 4 ab: a/a, 1.7%; a/b, 20.4%; b/b, 77.9%. G894T: GG, 56.4%; GT, 34.3%; TT, 9.3%. T-786C: TT, 58.2%; TC, 33.5%; CC, 8.3%). Differences in genotype or allele frequency was non-significant between subjects with diabetes and DR compared to those without DR, except the C allele of the T-786C polymorphism was significantly less common in DR patients. DR severity was not affected by any polymorphisms. Haplotypes bTC and aTT were significantly less common or more prevalent in DR than DM patients, respectively. CONCLUSIONS: We demonstrated that type 2 DM patients exhibited a higher prevalence of the three polymorphisms when compared to the control group. The C allele of T-786C polymorphism may have a protective effect against DR. Also, none of the mutations was correlated with a higher DR risk nor with the severity of DR. Haplotype aTT increased the risk for DR, while the bTC haplotype reduced it.
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