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In recent years, the global prevalence of myopia has reached an unprecedented level, especially‌ in East Asia. Multitude of studies has shown that the etiology of myopia is complex. Some researchers have suggested that oxidative stress (OS) may contribute to myopia, although there are limited reports on the alterations of related signaling pathways. Notably, the Kelch-like ECH-associated protein 1 (KEAP1) -nuclear factor erythroid 2-related factor 2 (NRF2), which plays a significant role in regulating OS and the mechanism, has not been explored in myopia. To investigate the modulation of KEAP1-NRF2 signaling pathway and its downstream superoxide dismutase (SOD) during the development of form-deprivation myopia, three-week-old guinea pigs were randomly assigned to four groups: negative control (NC), self-control (SC), form-deprivation myopia (FDM), and FDM group treated with tert-butylhydroquinone (TBHQ). Spherical equivalent (SE) and axial length (AL) were measured by retinoscopy and A-scan ultrasound, respectively. The results revealed that TBHQ treatment decelerated the progression in SE and AL changes. Immunohistochemistry (IHC) assessed the distribution and expression of KEAP1, NRF2, and SOD. The results shown that they located in the retinal ganglion cells (RGC). Subsequently, retinal mRNA and protein expression levels of KEAP1, NRF2, and SOD were quantified using real-time polymerase chain reaction (RT-PCR) and Western blot (WB) analysis. The RT-PCR and WB results demonstrated that TBHQ could activate NRF2, induce KEAP1 degradation, and enhance the expression of the antioxidant SOD. In summary, the modulation of KEAP1-NRF2 and it downstream SOD expression could alter the retinal antioxidant capacity and influence the development of myopia., Competing Interests: Declarations Ethics approval and consent to participate This research was approved by the Animal Care and Ethics Committee at the North Sichuan Medical College (NSMC2022036), and all methods were carried out in accordance with the Association for Research in Vision and Ophthalmology statement for the use of animals in ophthalmic and vision research. All methods of this study follow ARRIVE guidelines (https://arriveguidelines.org) for reporting animal experiments. Consent for publication Not required. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The incidence of myopia, particularly high myopia, is increasing annually. Myopia has gradually become one of the leading causes of global blindness and is a considerable public-health concern. However, the pathogenesis of myopia remains unclear, and exploring the mechanism underlying myopia has become an urgent scientific priority. Creating animal models of myopia is important for studying the pathogenesis of refractive errors. This approach allows researchers to study and analyze the pathogenesis of myopia from aspects such as changes in refractive development, pathological changes in eye tissue, and molecular pathways related to myopia. This review summarizes the examples of animal models, methods of inducing myopia experimentally, and molecular signaling pathways involved in developing myopia-induced animal models. This review provides solid literature for researchers in the field of myopia prevention and control. It offers guidance in selecting appropriate animal models and research methods to fit their research objectives. By providing new insights and a theoretical basis for studying mechanisms of myopia, we detail how elucidated molecular pathways can be exploited to translate into safe and effective measures for myopia prevention and control., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This study aims to investigate the effect of quercetin (QUE) on scleral remodeling by inhibiting the PERK-EIF2α signaling pathway and to evaluate its potential role in slowing myopia., Methods: Lens-induced myopia (LIM) guinea pigs were obtained and treated with QUE. After 4 and 6 weeks of treatments, ocular biological measurements were conducted. Hematoxylin and eosin (H&E) staining was used to observe the changes in scleral morphology and thickness, and Masson staining was used to examine scleral collagen fiber arrangement. Quantitative PCR (qPCR) and Western bolt were utilized to detect the mRNA and protein expression of PERK, EIF2α, MMP-2, TIMP-2, and collagen I in the scleral tissues. Calcium ion flow in each group was measured using noninvasive micro-test technology, and reactive oxygen species levels were detected by flow cytometry., Results: Compared with the LIM group, the ocular measurements showed that the refractive errors and axial length of the eyes were significantly reduced in the LIM + QUE group (P < 0.01). H&E and Masson staining showed that sclera in the LIM + QUE group was thickened, collagen was dense, and the fiber gap was reduced. In the LIM + QUE group, the expression levels of PERK, EIF2α, and MMP-2 were decreased, whereas the expression levels of TIMP-2 and collagen I were increased. Calcium release and reactive oxygen species (ROS) in the LIM + QUE group were decreased., Conclusions: Quercetin ameliorates scleral remodeling in myopic guinea pigs by inhibiting the PERK-EIF2α signaling pathway, thereby alleviating the progression of myopia. These findings provide new experimental evidence for the potential application of quercetin in myopia prevention and treatment.

Variants in rhodopsin (RHO) have been linked to autosomal dominant congenital stationary night blindness (adCSNB), which affects the ability to see in dim light, and the pathogenetic mechanism is still not well understood. In this study we report two novel RHO variants found in adCSNB families, p.W265R and p.A269V, that map in the sixth transmembrane domain of RHO protein. We applied in silico molecular simulation and in vitro biochemical and molecular studies to characterize the two new variants and compare the molecular determinants to two previously characterized adCSNB variants, p.G90D and p.T94I, that map in the second transmembrane domain of the RHO protein. We demonstrate that W265R and A269V cause constitutive activation of RHO with light-independent G protein coupling and impaired binding to arrestin. Differently, G90D and T94I are characterized by slow kinetics of RHO activation and deactivation. This study provides new evidence on the differential contribution of transmembrane α-helixes two and six to the interaction with intracellular transducers of RHO and mutations in these helixes result in a similar phenotype in patients but with distinct molecular effects., Competing Interests: Declaration of competing interest Authors A.B., S.DA., A.F., C.Z., B.B., F.F., L.C., V.K., I.M. and G.M. declare they have no competing financial interests. Author V.M. is shareholder of the company Mireca Medicines., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The prevalence of myopia is rapidly increasing, significantly impacting the quality of life of affected individuals. Prior research by our group revealed reactive gliosis in Müller cells within myopic retina, prompting further investigation of their role in myopia, which remains unclear. In this study, we analyzed protein expression changes in CD29+ Müller cells isolated from a form deprivation-induced rabbit model of myopia using magnetic activated cell sorting to investigate the role of these cells in myopia. As the principal glial cells in the retina, Müller cells exhibited significant alterations in the components of metabolic pathways, particularly glycolysis and angiogenesis, including the upregulation of glycolytic enzymes, such as lactate dehydrogenase A and pyruvate kinase, implicated in the adaptation to increased metabolic demands under myopic stress. Additionally, a decrease in the expression of proteins associated with oxygen transport suggested enhanced vulnerability to oxidative stress. These findings highlight the proactive role of CD29+ Müller cells in modifying the retinal environment in response to myopic stress and provide valuable insights into mechanisms that could help mitigate myopia progression., (© 2024. The Author(s).)

The retina plays a crucial role in processing and decoding visual information, both in normal development and during myopia progression. Recent advancements have introduced a library-independent approach for data-independent acquisition (DIA) analyses. This study demonstrates deep proteome identification and quantification in individual mice retinas during myopia development, with an average of 6,263 ± 86 unique protein groups. We anticipate that the use of a predicted retinal-specific spectral library combined with the robust quantification achieved within this dataset will contribute to a better understanding of the proteome complexity. Furthermore, a comprehensive mice retinal-specific spectral library was generated, encompassing a total identification of 9,401 protein groups, 70,041 peptides, 95,339 precursors, and 761,868 transitions acquired using SWATH-MS acquisition on a ZenoTOF 7600 mass spectrometer. This dataset surpasses the spectral library generated through high-pH reversed-phase fractionation by data-dependent acquisition (DDA). The data is available via ProteomeXchange with the identifier PXD046983. It will also serve as an indispensable reference for investigations in myopia research and other retinal or neurological diseases., (© 2024. The Author(s).)

The mechanisms underlying myopia pathogenesis are not well understood. Using publicly-available human and animal datasets, we expound on the roles of known, implicated proteins, and new myopia-related signaling pathways were hypothesized. Proteins identified from human serum or ocular fluids, and from ocular tissues in myopic animal models, were uploaded and analyzed with the QIAGEN Ingenuity Pathway Analysis (IPA) software (March 2023). With each IPA database update, more potentially-relevant proteins and signaling pathways previously unavailable during data acquisition are added, allowing extraction of novel conclusions from existing data. Canonical pathway analysis was used to analyze these data and calculate an IPA activation z-score-which indicates not only whether an association is significant, but also whether the pathway is likely activated or inhibited. Cellular immune response and cytokine signaling were frequently found to be affected in both human and animal myopia studies. Analysis of two publicly-available proteomic datasets highlighted a potential role of the innate immune system and inflammation in myopia development, detailing specific signaling pathways involved such as Granzyme A (GzmA) and S100 family signaling in the retina, and activation of myofibroblast trans-differentiation in the sclera. This perspective in myopia research may facilitate development of more effective and targeted therapeutic agents., (© 2024. The Author(s).)

The vitreous humor (VH) is a transparent gelatin-like substance that occupies two-thirds of the eyeball and undergoes the most significant changes during eye elongation. Quantitative proteomics on the normal growth period in the VH could provide new insights into understanding its progression mechanism in the early stages of myopia. In this study, a data-independent acquisition (SWATH-MS) was combined with targeted LC-ESI-MS/MS to identify and quantify the relative protein changes in the vitreous during the normal growth period (4, 7, 14, 21 and 28 days old) in the chick model. Chicks were raised under normal growing conditions (12/12 h Dark/light cycle) for 28 days, where ocular measurements, including refractive and biometric measurements, were performed on days 4 (baseline), 7, 14, 21 and 28 ( n = 6 chicks at each time point). Extracted vitreous proteins from individual animals were digested and pooled into a left eye pool and a right pool at each time point for protein analysis. The vitreous proteome for chicks was generated using an information-dependent acquisition (IDA) method by combining injections from individual time points. Using individual pool samples, SWATH-MS was employed to quantify proteins between each time point. DEPs were subsequently confirmed in separate batches of animals individually on random eyes ( n = 4) using MRMHR between day 7 and day 14. Refraction and vitreous chamber depth (VCD) were found to be significantly changed ( p < 0.05, n = 6 at each time point) during the period. A comprehensive vitreous protein ion library was built with 1576 non-redundant proteins (22987 distinct peptides) identified at a 1% false discovery rate (FDR). A total of 12 up-regulated and 26 down-regulated proteins were found across all time points compared to day 7 using SWATH-MS. Several DEPs, such as alpha-fetoprotein, the cadherin family group, neurocan, and reelin, involved in structural and growth-related pathways, were validated for the first time using MRMHR under this experimental condition. This study provided the first comprehensive spectral library of the vitreous for chicks during normal growth as well as a list of potential growth-related protein biomarker candidates using SWATH-MS and MRMHR during the emmetropization period.

Myopia is a global public health concern, with a higher prevalence in women than that in male. As the relationship between sex hormone and myopia remains unclear, we aimed to reveal the relationship between sex hormone and myopia by removing the ovaries of mice and measuring changes in ocular parameters related to myopia. Lens-induced myopia (LIM) surgeries were performed on 3-week-old male mice and age-matched female mice to evaluate the effects of sex on myopia development, which indicated a high degree of myopia and rapid progression of axial elongation in male mice. Bilateral ovariectomy (OVX) performed on 4-week-old female mice induced myopic refraction status in ovariectomized mice. Although axial length elongation was larger in ovariectomized mice than that in sham control mice, the result was insignificant. To further reveal the relationship between female sex hormones and myopia, LIM combined with OVX was performed, which revealed a magnified myopic refraction status in ovariectomized mice. Nevertheless, elongation of the anterior chamber depth in the - 30 D lens-treated eyes significantly increased in LIM + OVX mice compared with the frame-treated eyes in LIM + OVX mice and - 30 D lens-treated eyes in LIM + Sham surgery mice. Sex hormones play a role in regulating myopia development in female mice., (© 2024. The Author(s).)

Congenital microcoria (MCOR) is a rare hereditary developmental defect of the iris dilator muscle frequently associated with high axial myopia and high intraocular pressure (IOP) glaucoma. The condition is caused by submicroscopic rearrangements of chromosome 13q32.1. However, the mechanisms underlying the failure of iris development and the origin of associated features remain elusive. Here, we present a 3D architecture model of the 13q32.1 region, demonstrating that MCOR-related deletions consistently disrupt the boundary between two topologically associating domains (TADs). Deleting the critical MCOR-causing region in mice reveals ectopic Sox21 expression precisely aligning with Dct, each located in one of the two neighbor TADs. This observation is consistent with the TADs' boundary alteration and adoption of Dct regulatory elements by the Sox21 promoter. Additionally, we identify Tgfb2 as a target gene of SOX21 and show TGFΒ2 accumulation in the aqueous humor of an MCOR-affected subject. Accumulation of TGFB2 is recognized for its role in glaucoma and potential impact on axial myopia. Our results highlight the importance of SOX21-TGFB2 signaling in iris development and control of eye growth and IOP. Insights from MCOR studies may provide therapeutic avenues for this condition but also for glaucoma and high myopia conditions, affecting millions of people., Competing Interests: Declaration of interests The SOX21-TGFB2 pathway in iris development, axial myopia, and GLC has been officially patented under the title “Methods and pharmaceutical compositions for treating ocular diseases” (WO/2021/245224). The inventors of this patent are J.-M.R., L.F.T., B.N., C.A., and J.K., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate changes of hydroxyproline concentration and its influencing factors of small incision lenticule extraction (SMILE)-derived corneal stromal lenticules with different preservation methods., Methods: A total of 390 corneal stromal lenticules of 195 patients were derived from SMILE surgeries. Thirty of the lenticules were classified as the fresh (control) group, and the rest were randomly and evenly divided and stored in anhydrous glycerol, silicone oil, Optisol, and cryopreservation for 1 day, 1 week, or 1 month. A hydroxyproline assay kit (ab222941, Abcam) was used to measure the hydroxyproline concentration in each preservation method. Concentrations of MMP-2, TIMP-2, TNFα, TGFβ2, and reactive oxygen species were also evaluated., Results: In the anhydrous glycerol group, the concentration of hydroxyproline decreased within 1 week (fresh: 1 dΔ = 0.229, P < 0.001*; 1 d - 1 wΔ = 0.055, P < 0.001*) while that in the silicone oil group remained stable in 1 week (1 d - 1 wΔ = -0.005, P = 0.929) and decreased significantly in 1 m (1 m - 1 wΔ = -0.041, P = 0.003*). The sequence of hydroxyproline concentration in the Optisol group was 1 m > 1 day > 1 week. Hydroxyproline concentration in the cryopreservation group decreased within 1 m. Hydroxyproline concentration was highest in the Optisol group and lowest in the anhydrous glycerol group under the same preservation time. Hydroxyproline concentration was negatively correlated with MMP-2 (r = -0.16, P = 0.421) and TIMP-2 (r = -0.56, P = 0.002*) while MMP-2 and TNFα (r = 0.17, P = 0.242), TIMP-2 and TGFβ2 (r = 0.21, P = 0.207), and TNFα and reactive oxygen species (r = 0.52, P = 0.007*) were positively correlated., Conclusions: More collagen was retained in SMILE lenticules preserved in Optisol under the same preservation time. The mechanism of the changes of collagen in preserved SMILE-derived lenticules and oxidative stress requires additional investigation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We examined the lipid profiles in the aqueous humor (AH) of myopic patients to identify differences and investigate the relationships among dissertating lipids. Additionally, we assessed spherical equivalents and axial lengths to explore the pathogenesis of myopia. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was employed to qualitatively and quantitatively analyze the lipid composition of samples from myopic patients with axial lengths <26 mm (Group A) and >28 mm (Group B). Differences in lipid profiles between the two groups were determined using univariate and multivariate analyses. Receiver operator characteristic (ROC) curves were used to identify discriminating lipids. Spearman correlation analysis explored the associations between lipid concentrations and biometric parameters. Three hundred and nine lipids across 21 lipid classes have been identified in this study. Five lipids showed significant differences between Group B and Group A (VIP >1, P < 0.05): BMP (20:3/22:3), PG (22:1/24:0), PS (14:1/22:4), TG (44:2)&#95;FA18:2, and TG (55:3)&#95;FA18:1. The area under the curve (AUC) for these lipids was >0.75. Notably, the concentrations of BMP (20:3/22:3), PS (14:1/22:4), and TG (55:3)&#95;FA18:1 were correlated with spherical equivalents, while BMP (20:3/22:3) and PS (14:1/22:4) correlated with axial lengths. Our study identified five differential lipids in myopic patients, with three showing significant correlations with the degree of myopia. These findings enhance our understanding of myopia pathogenesis through lipidomic alterations, emphasizing changes in cell membrane composition and function, energy metabolism and storage, and pathways involving inflammation, peroxisome proliferator-activated receptors (PPAR), and metabolic processes related to phosphatidylserine, phosphatidylglycerol, triglycerides, polyunsaturated fatty acids, and cholesterol., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The purpose of the experimental interventional study was to examine the influence of intraocularly applied amphiregulin, a member of the epidermal growth factor (EGF) family, on axial length in young non-human primates. It included three non-human primates (Macaca mulatta), aged 4-6 years. The left eyes received three intravitreal injections of amphiregulin (400ng/50 μl) in intervals of 4 weeks, while the right eyes received three intravitreal injections of phosphate buffered solution (50 μl) at the same time points. Ocular biometry was performed in weekly intervals. At baseline, the left eyes (study eyes) were shorter than the right (control) eyes (20.69 ± 0.21 mm versus 20.79 ± 0.24 mm; P < 0.001), with an inter-eye axial length (AL) difference (left minus right eye) of -0.10 ± 0.23 mm. Inter-eye AL difference increased (P < 0.001) to 0.15 ± 0.18 mm at study end, at 12 weeks after baseline. Axial elongation during the study was higher (P < 0.001) in the left eyes (20.69 ± 0.21 mm to 21.05 ± 0.29 mm or 0.36 ± 0.30 mm) than in the right eyes (20.79 ± 0.24 mm to 20.90 ± 0.31 mm or 0.11 ± 0.17 mm). In a parallel manner, inter-eye difference in vitreous cavity depth combined with lens thickness (left eye minus right eye) increased from -0.04 ± 0.17 mm at baseline to -0.02 ± 0.21 mm (P = 0.02), 0.04 ± 0.10 mm (P = 0.002), and to 0.42 ± 0.67 mm (P < 0.001) at 5, 6, and 12 weeks after baseline, respectively. The results suggest that intravitreally applied amphiregulin as EGF family member led to an increase in axial length in adolescent non-human primates. It supports the hypothesis of amphiregulin as EGF family member being involved in the process of axial elongation., Competing Interests: Declaration of competing interest J.B. Jonas, S. Panda-Jonas: European patent EP 3 271 392, JP 2021–119 187, and US 11 008 385: "Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Patent application: European patent application: WO 2021/198 369 A1; PCT/EP2021/058 500: Agents for use in the therapeutic or prophylactic treatment of retinal pigment epithelium-associated diseases. All other authors explicitly state that they have no conflicts of interest in connection with this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Scleral hypoxia is considered a trigger in scleral remodeling-induced myopia. Identifying differentially expressed molecules within the sclera is essential for understanding the mechanism of myopia. We developed a scleral fibroblast hypoxia model and conducted RNA sequencing and bioinformatic analysis. RNA interference technology was then applied to knock down targeted genes with upregulated expression, followed by an analysis of COLLAGEN I protein level. Microarray data analysis showed that the expression of Adamts1 and Adamts5 were upregulated in fibroblasts under hypoxia (t-test, p < 0.05). Western blot analysis confirmed increased protein levels of ADAMTS1 and ADAMTS5, and a concurrent decrease in COLLAGEN I in hypoxic fibroblasts. The knockdown of either Adamts1 or Adamts5 in scleral fibroblasts under hypoxia resulted in an upregulation of COLLAGEN I. Moreover, a form-deprivation myopia (FDM) mouse model was established for validation. The sclera tissue from FDM mice exhibited increased levels of ADAMTS1 and ADAMTS5 protein and a decrease in COLLAGEN I, compared to controls. The study suggests that Adamts1 and Adamts5 may be involved in scleral remodeling induced by hypoxia and the development of myopia., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Myopia is the most common eye disease in the world which is caused by a mismatch between the optical power of the eye and its excessive axial length. Scleral remodeling, oxidative stress, inflammation, pathological states of angiogenesis and fibrosis and metabolism are closely associated with the onset and progression of myopia and the pathological changes that may ultimately result. Intraocular fluid is a collective term for the fluid within the eye, and changes in its composition can reflect the physiological and pathological status within the eye, with aqueous humor and vitreous being the commonly tested specimens. Recent studies have revealed potential changes in a variety of molecules in intraocular fluid during myopia progression. Abnormal expression of these molecules may reflect different stages of myopia and provide new perspectives for disease monitoring and treatment. Therefore, in this review, we systematically review the molecular changes in intraocular fluid associated with myopia, as well as the possible mechanisms, with a view to informing basic myopia research and clinical work., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

GPR179, an orphan class C GPCR, is expressed at the dendritic tips of ON-bipolar cells in the retina. It plays a pivotal role in the initial synaptic transmission of visual signals from photoreceptors, and its deficiency is known to be the cause of complete congenital stationary night blindness. Here, we present the cryo-electron microscopy structure of human GPR179. Notably, the transmembrane domain (TMD) of GPR179 forms a homodimer through the TM1/7 interface with a single inter-protomer disulfide bond, adopting a noncanonical dimerization mode. Furthermore, the TMD dimer exhibits architecture well-suited for the highly curved membrane of the dendritic tip and distinct from the flat membrane arrangement observed in other class C GPCR dimers. Our structure reveals unique structural features of GPR179 TMD, setting it apart from other class C GPCRs. These findings provide a foundation for understanding signal transduction through GPR179 in visual processing and offers insights into the underlying causes of ocular diseases., (© 2024. The Author(s).)

The study assessed selected parameters of redox status in the plasma of patients suffering from high myopia (HM). Thirty-five children with mean age 13.7 ± 2.7 years with HM and 40 healthy children were included. Plasma redox status parameters were determined using colorimetric kits. The levels of retinol, α-tocopherol and coenzyme Q10 were determined with a high-performance liquid chromatograph. Negative correlations were observed between the concentrations of retinol and the axial length of the eye (r = - 0.514 p < 0.001). Increased myeloperoxidase (MPO) activity (p < 0.018), and decreased concentrations of retinol (p < 0.001) and α-tocopherol (p < 0.023) in patients with HM and the axial length of the eye > 26 mm compared to controls were established. Significantly lower retinol and α-tocopherol concentrations were found in patients with the axial length of the eye > 26 mm compared to those with the axial length of the eye ≤ 26 mm (p < 0.001, p < 0.021, respectively). Increased MPO activity in advanced stages of HM may confirm an inflammatory process in HM patients. Reduced retinol and α-tocopherol concentrations and their link to disease progression indicate a need for monitoring their levels and supplementation in children with HM., (© 2024. The Author(s).)

Purpose: To determine whether the Lrit3-/- mouse model of complete congenital stationary night blindness with an ON-pathway defect harbors myopic features and whether the genetic defect influences the recovery from lens-induced myopia., Methods: Retinal levels of dopamine (DA) and 3,4 dihydroxyphenylacetic acid (DOPAC) from adult isolated Lrit3-/- retinas were quantified using ultra performance liquid chromatography after light adaptation. Natural refractive development of Lrit3-/- mice was measured from three weeks to nine weeks of age using an infrared photorefractometer. Susceptibility to myopia induction was assessed using a lens-induced myopia protocol with -25 D lenses placed in front of the right eye of the animals for three weeks; the mean interocular shift was measured with an infrared photorefractometer after two and three weeks of goggling and after one and two weeks after removal of goggles., Results: Compared to wild-type littermates (Lrit3+/+), both DA and DOPAC were drastically reduced in Lrit3-/- retinas. Natural refractive development was normal but Lrit3-/- mice showed a higher myopic shift and a lower ability to recover from induced myopia., Conclusions: Our data consolidate the link between ON pathway defect altered dopaminergic signaling and myopia. We document for the first time the role of ON pathway on the recovery from myopia induction.

Purpose: This study investigates alterations in intrinsically photosensitive retinal ganglion cells (ipRGCs) and dopaminergic amacrine cells (DACs) in lid suture myopia (LSM) rats., Methods: LSM was induced in rats by suturing the right eyes for 4 weeks. Double immunofluorescence staining of ipRGCs and DACs in whole-mount retinas was performed to analyze changes in the density and morphology of control, LSM, and fellow eyes. Real-time quantitative PCR and Western blotting were used to detect related genes and protein expression levels., Results: Significant myopia was induced in the lid-sutured eye, but the fellow eye was not different to control. Decreased ipRGC density with paradoxically increased overall melanopsin expression and enlarged dendritic beads was observed in both the LSM and fellow eyes of the LSM rat retinas. In contrast, DAC changes occurred only in the LSM eyes, with reduced DAC density and tyrosine hydroxylase (TH) expression, sparser dendritic processes, and fewer varicosities. Interestingly, contacts between ipRGCs and DACs in the inner plexiform layer (IPL) and the expression of pituitary adenylate cyclase-activating polypeptide (PACAP) and vesicular monoamine transporter protein 2 (VMAT2) mRNA were decreased in the LSM eyes., Conclusions: The ipRGCs and DACs in LSM rat retinas undergo multiple alterations in density, morphology, and related molecule expressions. However, the ipRGC changes alone appear not to be required for the development of myopia, given that myopia is only induced in the lid-sutured eye, and they are unlikely alone to drive the DAC changes. Reduced contacts between ipRGCs and DACs in the LSM eyes may be the structural foundation for the impaired signaling between them. PACAP and VMAT2, strongly associated with ipRGCs and DACs, may play important roles in LSM through complex mechanisms.

To evaluate the changes of choroidal thickness (CT) and blood flow related to myopia, and its effects of vascular endothelial growth factor (VEGFA) on choroidal vessels in myopia. Subjects were included and divided into emmetropia (EM), non-high myopia (Non-HM) and high myopia (HM) groups. we measured choroidal thickness (CT), choriocapillaris vessel density (VD), and VEGFA content in tears in humans (137 subjects for CT, VD and 84 for tear) and detected the role of VEGFA in the choroid in form-deprivation myopia (FDM) in guinea pigs. Twenty-four guinea pigs were divided into control and FDM groups, and the expression changes of choroidal vessels and VEGFA were observed and compared using immunohistochemistry and Western blotting. Twenty-one guinea pigs were divided into control, FDM + Vehicle and FDM + Conbercept groups. The changes of diopter, axis length and choroidal vessels after intravitreal injection of Conbercept were observed. There were significant differences in CT and VD among the three groups (p < 0.05). VEGFA levels in tears were significantly lower in the myopic groups, with a decreasing trend from EM to Non-HM to HM. The choroidal vascular area fraction of FDM decreased compared to the control group. FDM guinea pigs exhibited reduced choroidal vasculature and significant downregulation of VEGFA expression. Following intravitreal injection of conbercept, the FDM + Conbercept group showed greater myopia, longer axial length, and lower choroidal vascular area fraction compared to the control group. VEGFA may participate in the regulation of choroidal blood vessels and blood flow in the progression of myopia. The reduction in VEGFA may accelerates the progression of myopia., (© 2024. The Author(s).)

Background: This study aimed to investigate cell degeneration, apoptosis, and ultrastructural differences in refractive lenticules (RL) obtained using small incision lenticule extraction (SMILE) compared with spherical equivalence (SE) refraction values., Methods: This study included 84 eyes from 42 patients. Patients were divided into two groups according to the SE values: those with values below 4 diopters (D) (Group 1) and above 4 diopters (D) (Group 2). Patients who did not belong to the same SE group were excluded from the study. One RL obtained from each patient was separated for light microscopy and immunohistochemical examinations, and another for transmission electron microscopy (TEM) examinations. Caspase-3 for apoptosis and alpha-smooth muscle actin (α-SMA) for cell degeneration were evaluated using immunohistochemical examinations., Results: Histological analyses showed that the density of collagen fibres was greater in Group 1 than in Group 2. Glycoaminoglycan and glycoprotein staining intensities were also higher in Group 1. TEM observations showed that Group 1 had intact cell and nuclear membranes, peripheral heterochromatin, and large nuclei, while Group 2 showed heterochromatin condensation and fragmentation, increased intracellular vacuoles, and loss of cytoplasm. Immunohistochemical analyses revealed that α-SMA and caspase-3 were significantly higher in Group 2 than in Group 1 (p < 0.001 and p < 0.001, respectively)., Conclusions: Cell degeneration and apoptosis were significantly more common in the RLs with high SE values after SMILE surgery. The tissue response induced by surgery was more severe in the RLs with high SE values. This should be considered when reusing RLs., (© 2024 The Author(s). Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

Different types of refractive surgeries often exhibit differences in wound healing responses. The current study investigated post-operative tear protein profiles in subjects who underwent LASIK and SMILE to elucidate global changes to the proteomic profile during the period the patient cornea undergoes healing. In this study, 10 patients underwent LASIK and SMILE surgery with a contralateral paired eye design. Tear samples were collected using Schirmer's strips preoperatively, at 1 month, 3 months and 6 months postoperatively. Quantitative ITRAQ labeled proteomics was performed and the tear protein ratios were normalized to pre-operative protein levels for each subject. Whole proteomics identified 1345 proteins in tears from LASIK and 1584 proteins in SMILE across time points. About 67 proteins were common in LASIK and SMILE tears across all the time points. Wound healing responses were differentially regulated between two refractive surgeries (SMILE and LASIK). The proteins Ceruloplasmin, Clusterin, Serotransferrin were upregulated at 1 month and 3 months and downregulated at 6 months post operatively in LASIK surgery where as in SMILE these were downregulated. Galectin 3 binding protein showed upregulation at 1 month and the levels decreased at 3 months and 6 months postop in LASIK tears whereas the levels increased at 3 months and 6 months post-op in SMILE tears. The levels of proteins that protect from oxidative stress were higher in SMILE as compared to LASIK postoperatively. The extracellular matrix proteins showed an increase in expression at 6 months in SMILE tears and was stabilized at 6 months in LASIK tears post operatively. Different refractive surgeries induce distinct wound healing responses as identified in tears. This study has implications in targeting key proteins for improving the clinical outcome postrefractive surgery., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

High myopia (HM) is the primary cause of blindness, with the microstructural organization and composition of collagenous fibers in the cornea and sclera playing a crucial role in the biomechanical behavior of these tissues. In a previously reported myopic linkage region, MYP5 (17q21-22), a potential candidate gene, LRRC46 (c.C235T, p.Q79X), was identified in a large Han Chinese pedigree. LRRC46 is expressed in various eye tissues in humans and mice, including the retina, cornea, and sclera. In subsequent cell experiments, the mutation (c.C235T) decreased the expression of LRRC46 protein in human corneal epithelial cells (HCE-T). Further investigation revealed that Lrrc46 -/- mice (KO) exhibited a classical myopia phenotype. The thickness of the cornea and sclera in KO mice became thinner and more pronounced with age, the activity of limbal stem cells decreased, and microstructural changes were observed in the fibroblasts of the sclera and cornea. We performed RNA-seq on scleral and corneal tissues of KO and normal control wild-type (WT) mice, which indicated a significant downregulation of the collagen synthesis-related pathway (extracellular matrix, ECM) in KO mice. Subsequent in vitro studies further indicated that LRRC46, a member of the important LRR protein family, primarily affected the formation of collagens. This study suggested that LRRC46 is a novel candidate gene for HM, influencing collagen protein VIII (Col8a1) formation in the eye and gradually altering the biomechanical structure of the cornea and sclera, thereby promoting the occurrence and development of HM., (© 2024. Science China Press.)

Myopia is predicted to impact approximately 5 billion people by 2050, necessitating mechanistic understanding of its development. Myopia results from dysregulated genetic mechanisms of emmetropization, caused by over-exposure to aberrant visual environments; however, these genetic mechanisms remain unclear. Recent human genome-wide association studies have identified a range of novel myopia-risk genes. To facilitate large-scale in vivo mechanistic examination of gene-environment interactions, this study aims to establish a myopia model platform that allows efficient environmental and genetic manipulations. We established an environmental zebrafish myopia model by dark-rearing. Ocular biometrics including relative ocular refraction were quantified using optical coherence tomography images. Spatial vision was assessed using optomotor response (OMR). Retinal function was analyzed via electroretinography (ERG). Myopia-associated molecular contents or distributions were examined using RT-qPCR or immunohistochemistry. Our model produces robust phenotypic changes, showing myopia after 2 weeks of dark-rearing, which were recoverable within 2 weeks after returning animals to normal lighting. 2-week dark-reared zebrafish have reduced spatial-frequency tuning function. ERG showed reduced photoreceptor and bipolar cell function (a- and b-waves) after only 2 days of dark-rearing, which worsened after 2 weeks of dark-rearing. We also found dark-rearing-induced changes to expression of myopia-risk genes, including egr1, vegfaa, vegfab, rbp3, gjd2a and gjd2b, inner retinal distribution of EFEMP1, TIMP2 and MMP2, as well as transiently reduced PSD95 density in the inner plexiform layer. Coupled with the gene editing tools available for zebrafish, our environmental myopia model provides an excellent platform for large-scale investigation of gene-environment interactions in myopia development., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Myopia represents a widespread global public health concern influenced by a combination of environmental and genetic factors. The prevailing theory explaining myopia development revolves around scleral extracellular matrix (ECM) remodeling, characterized by diminished Type I collagen (Col-1) synthesis and increased degradation, resulting in scleral thinning and eye axis elongation. Existing studies underscore the pivotal role of scleral hypoxia in myopic scleral remodeling. This study investigates the peroxidase-like activity and catalytic performance of octahedral Palladium (Pd) nanocrystals, recognized as nanozymes with antioxidative properties. We explore their potential in reducing oxidative stress and alleviating hypoxia in human scleral fibroblasts (HSF) and examine the associated molecular mechanisms. Our results demonstrate the significant peroxidase-like activity of Pd nanocrystals. Furthermore, we observe a substantial reduction in oxidative stress in HSF under hypoxia, mitigating cellular damage. These effects are linked to alterations in Nrf-2/Ho-1 expression, a pathway associated with hypoxic stress. Importantly, our findings indicate that Pd nanocrystals contribute to attenuated scleral matrix remodeling in myopic guinea pigs, effectively slowing myopia progression. This supports the hypothesis that Pd nanocrystals regulate myopia development by controlling oxidative stress associated with hypoxia. Based on these results, we propose that Pd nanocrystals represent a novel and potential treatment avenue for myopia through the modulation of scleral matrix remodeling. This study introduces innovative ideas and directions for the treatment and prevention of myopia., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To explore the phenotype of sclera macrophages in form-deprivation (FD) myopia mice and the effects of M2 macrophage in FD myopia development., Methods: C57BL/6 mice were under 2 weeks of unilateral FD treatment. and they were separated into two groups, including an intraperitoneally injected(IP) vehicle group and Panobinostat (LBH589) (10 mg/kg per body weight) treatment group. All biometric parameters were measured before and after treatments, and the type and density of sclera macrophages were identified by immunofluorescence and RT-qPCR. In vitro, we analyzed the M2 macrophage and primary human sclera fibroblast (HSF) co-culture system by using the transcriptome sequencing method. Gene ontology (GO) and KEGG enrichment analyses were used to pinpoint the biological functions and pathways associated with the identified Differentially Expressed Genes (DEGs). The hub genes were investigated using the STRING database and Cytoscape software and were confirmed using RT-qPCR., Results: We found that the M2-type sclera macrophage density and expression increased in FD-treated eyes. The results showed that LBH589 inhibited the M2 macrophage polarization, and reduced FDM development. GO and KEGG analyses revealed that the DEGs were predominantly involved in the synthesis and breakdown of the extracellular matrix (ECM), as well as in pathways related to ECM-receptor interaction and the PI3K-Akt signaling pathway. Five hub genes (FN-1, MMP-2, COL1A1, CD44, and IL6) were identified, and RT-qPCR validated the variation in expression levels among these genes., Conclusion: M2 macrophage polarization occurred in the sclera in FDM mice. Panobinostat-mediated inhibition of M2 macrophage polarization may decrease FDM progression, as M2 macrophages are crucial in controlling ECM remodeling by HSFs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

VPS13B/COH1 is the only known causative factor for Cohen syndrome, an early-onset autosomal recessive developmental disorder with intellectual inability, developmental delay, joint hypermobility, myopia, and facial dysmorphism as common features, but the molecular basis of VPS13B/COH1 in pathogenesis remains largely unclear. Here, we identify Sec23 interacting protein (Sec23IP) at the ER exit site (ERES) as a VPS13B adaptor that recruits VPS13B to ERES-Golgi interfaces. VPS13B interacts directly with Sec23IP via the VPS13 adaptor binding domain (VAB), and the interaction promotes the association between ERES and the Golgi. Disease-associated missense mutations of VPS13B-VAB impair the interaction with Sec23IP. Knockout of VPS13B or Sec23IP blocks the formation of tubular ERGIC, an unconventional cargo carrier that expedites ER-to-Golgi transport. In addition, depletion of VPS13B or Sec23IP delays ER export of procollagen, suggesting a link between procollagen secretion and joint laxity in patients with Cohen disease. Together, our study reveals a crucial role of VPS13B-Sec23IP interaction at the ERES-Golgi interface in the pathogenesis of Cohen syndrome., (© 2024 Du et al.)

Extreme myopia (EM), defined as a spherical equivalent (SE) ≤ -10.00 diopters (D), is one of the leading causes of sight impairment. Known EM-associated variants only explain limited risk and are inadequate for clinical decision-making. To discover risk genes, we performed a whole-exome sequencing (WES) on 449 EM individuals and 9606 controls. We find a significant excess of rare protein-truncating variants (PTVs) in EM cases, enriched in the retrograde vesicle-mediated transport pathway. Employing single-cell RNA-sequencing (scRNA-seq) and a single-cell polygenic burden score (scPBS), we pinpointed PI16 + /SFRP4+ fibroblasts as the most relevant cell type. We observed that KDELR3 is highly expressed in scleral fibroblast and involved in scleral extracellular matrix (ECM) organization. The zebrafish model revealed that kdelr3 downregulation leads to elongated ocular axial length and increased lens diameter. Together, our study provides insight into the genetics of EM in humans and highlights KDELR3's role in EM pathogenesis., (© 2024. The Author(s).)

Background: The aqueous humor, a transparent fluid secreted by the ciliary body, supports the lens of the eyeball. In this study, we analyzed the cytokine and chemokine profiles within the aqueous humor of the contralateral eye post-implantation of an implantable collamer lens (ICL) to evaluate potential subclinical inflammation in the second eye subsequent to ICL implantation in the first eye., Methods: Aqueous humor samples were procured from both eyes of 40 patients (totaling 80 eyes) prior to bilateral ICL insertion. Subsequently, a comprehensive statistical analysis was conducted using the Luminex assay to quantify 30 different cytokines in these samples., Results: Compared to the first eye, the aqueous humor of the second eye demonstrated decreased concentrations of IFN-γ (P = 0.038), IL-13 (P = 0.027), IL-17/IL-17 A (P = 0.012), and IL-4 (P = 0.025). No significant differences were observed in other cytokine levels between the two groups. Patients were then categorized based on the postoperative rise in intraocular pressure (IOP) in the first eye. The group with elevated IOP displayed elevated levels of EGF in the aqueous humor of the first eye (P = 0.013) and higher levels of PDGF-AB/BB in the aqueous humor of the second eye (P = 0.032) compared to the group with normal IOP. Within the elevated IOP group, the levels of EGF (P = 0.013) and IL-17/IL-17 A (P = 0.016) in the aqueous humor were lower in the second eye than in the first eye. In the normal IOP group, cytokine levels did not differ notably between eyes., Conclusion: Following sequential ICL implantation, it appears that a protective response may be activated to mitigate subclinical inflammation in the second eye induced by the initial implantation in the first eye. Additionally, the increase in IOP subsequent to surgery in the first eye may correlate with the presence of inflammatory mediators in the aqueous humor., Competing Interests: Declaration of competing interest None of the authors have any financial disclosure or conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to identify potential drug targets for myopia and explore underlying mechanisms., Methods: Mendelian randomization (MR) was implemented to assess the effect of 2684 pharmacologically targetable genes in the blood and retina on the risk of myopia from a genomewide association study (GWAS) for age-at-onset of spectacle wearing-inferred mean spherical equivalent (MSE; discovery cohort, N = 287,448, European), which was further validated in a GWAS for autorefraction-measured MSE (replication cohort, N = 95,619, European). The reliability of the identified significant potential targets was strengthened by colocalization analysis. Additionally, enrichment analysis, protein-protein interaction network, and molecular docking were performed to explore the functional roles and the druggability of these targets., Results: This systematic drug target identification has unveiled 6 putative genetically causal targets for myopia-CD34, CD55, Wnt3, LCAT, BTN3A1, and TSSK6-each backed by colocalization evidence in adult blood eQTL datasets. Functional analysis found that dopaminergic neuron differentiation, cell adhesion, Wnt signaling pathway, and plasma lipoprotein-associated pathways may be involved in myopia pathogenesis. Finally, drug prediction and molecular docking corroborated the pharmacological value of these targets with LCAT demonstrating the strongest binding affinity., Conclusions: Our study not only opens new avenues for the development of therapeutic interventions for myopia but may also help to understand the underlying mechanisms of myopia.

Purpose: To assess the long-term (1-year) effect of myopic femtosecond laser-assisted in situ keratomileusis (FSLASIK) on clinical characteristics and tear film biomarkers., Methods: Eighty eyes from 80 patients who underwent FSLASIK were evaluated. Ocular surface symptoms and signs were evaluated using specific questionnaires and tests. The corneal nerves and dendritic cells were examined using in vivo confocal microscopy. Corneal sensitivity was evaluated using a Cochet-Bonnet esthesiometer. Tear inflammatory cytokines and neuropeptides were evaluated using Luminex immunoassay. These examinations were performed preoperatively and at 1, 3, 6, and 12 months postoperatively., Results: Seventy-three participants completed all follow-up visits. Following FS-LASIK, ocular symptoms and signs (except Schirmer I test) worsened at 1 month but corneal and conjunctival stainings improved by 3 months. The numbers of dendritic cells and activated dendritic cells increased at the 3-month postoperative visit and recovered to preoperative levels by the 6-month visit. Ocular symptoms and corneal sensitivity recovered to preoperative levels at the 12-month visit. Tear break-up time and corneal nerve morphology were not recovered to preoperative status at the 12-month visit. Interleukin (IL)-1β, IL-17A, tumor necrosis factor-α, and substance P tear levels significantly increased at all postoperative visits compared to preoperative levels. Corneal staining scores positively correlated with tear IL-1β and IL-17A levels, whereas corneal nerve morphology positively correlated with corneal sensitivity and negatively correlated with substance P levels., Conclusions: Although most clinical variables improved at 12 months postoperatively, some tear inflammatory cytokines and substance P remain altered beyond 12 months, indicating that ocular homeostasis is not completely recovered. [ J Refract Surg . 2024;40(8):e508-e519.] .

This review examines the pivotal role of photoreceptor cells in ocular refraction development, focusing on dopamine (DA) as a key neurotransmitter. Contrary to the earlier view favoring cone cells, recent studies have highlighted the substantial contributions of both rod and cone cells to the visual signaling pathways that influence ocular refractive development. Notably, rod cells appeared to play a central role. Photoreceptor cells interact intricately with circadian rhythms, color vision pathways, and other neurotransmitters, all of which are crucial for the complex mechanisms driving the development of myopia. This review emphasizes that ocular refractive development results from a coordinated interplay between diverse cell types, signaling pathways, and neurotransmitters. This perspective has significant implications for unraveling the complex mechanisms underlying myopia and aiding in the development of more effective prevention and treatment strategies., Competing Interests: Declaration of competing interest The authors declare they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Myopia is one of the most common eye diseases in children and adolescents worldwide, and scleral remodeling plays a role in myopia progression. However, the identity of the initiating factors and signaling pathways that induce myopia-associated scleral remodeling is still unclear. This study aimed to identify biomarkers of scleral remodeling to elucidate the pathogenesis of myopia., Methods: The gene expression omnibus (GEO) and comparative toxicogenomics database (CTD) mining were used to identify the miRNA-mRNA regulatory network related to scleral remodeling in myopia. Real-time quantitative PCR (RT-qPCR), Western blot, immunofluorescence, H&E staining, Masson staining, and flow cytometry were used to detect the changes in the FOXO signaling pathway, fibrosis, apoptosis, cell cycle, and other related factors in scleral remodeling., Results: miR-15b-5p/miR-379-3p can regulate the FOXO signaling pathway. Confirmatory studies confirmed that the axial length of the eye was significantly increased, the scleral thickness was thinner, the levels of miR-15b-5p, miR-379-3p, PTEN, p-PTEN, FOXO3a, cyclin-dependent kinase (CDK) inhibitor 1B (CDKN1B) were increased, and the levels of IGF1R were decreased in Len-induced myopia (LIM) group. CDK2, cyclin D1 (CCND1), and cell cycle block assessed by flow cytometry indicated G1/S cell cycle arrest in myopic sclera. The increase in BAX level and the decrease in BCL-2 level indicated enhanced apoptosis of the myopic sclera. In addition, we found that the levels of transforming growth factor-β1 (TGF-β1), collagen type 1 (COL-1), and α-smooth muscle actin (α-SMA) were decreased, suggesting scleral remodeling occurred in myopia., Conclusions: miR-15b-5p/miR-379-3p can regulate the scleral cell cycle and apoptosis through the IGF1R/PTEN/FOXO signaling pathway, thereby promoting scleral remodeling in myopia progression., (© 2024. The Author(s).)

Among the environmental factors contributing to myopia, the role of correlated color temperature (CCT) of ambient light emerges as a key element warranting in-depth investigation. The choroid, a highly vascularized and dynamic structure, often undergoes thinning during the progression of myopia, though the precise mechanism remains elusive. The retinal pigment epithelium (RPE), the outermost layer of the retina, plays a pivotal role in regulating the transport of ion and fluid between the subretinal space and the choroid. A hypothesis suggests that variations in choroidal thickness (ChT) may be modulated by transepithelial fluid movement across the RPE. Our experimental results demonstrate that high CCT illumination significantly compromised the integrity of tight junctions in the RPE and disrupted chloride ion transport. This functional impairment of the RPE may lead to a reduction in fluid transfer across the RPE, consequently resulting in choroidal thinning and potentially accelerating axial elongation. Our findings provide support for the crucial role of the RPE in regulating ChT. Furthermore, we emphasize the potential hazards posed by high CCT artificial illumination on the RPE, the choroid, and refractive development, underscoring the importance of developing eye-friendly artificial light sources to aid in the prevention and control of myopia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The world-wide prevalence of myopia (nearsightedness) is increasing, but its pathogenesis is incompletely understood. Among many putative mechanisms, laboratory and clinical findings have implicated circadian biology in the etiology of myopia. Consistent with a circadian hypothesis, we recently reported a marked variability in diurnal patterns of gene expression in two crucial tissues controlling post-natal refractive development - the retina and choroid-at the onset of form-deprivation myopia in chick, a widely studied and validated model. To extend these observations, we assayed gene expression by RNA-Seq in retina and choroid during the progression of established unilateral form-deprivation myopia of chick. We assayed gene expression every 4 hours during a single day from myopic and contralateral control eyes. Retinal and choroidal gene expression in myopic vs. control eyes during myopia progression differed strikingly at discrete times during the day. Very few differentially expressed genes occurred at more than one time in either tissue during progressing myopia. Similarly, Gene Set Enrichment Analysis pathways varied markedly by time during the day. Some of the differentially expressed genes in progressing myopia coincided with candidate genes for human myopia, but only partially corresponded with genes previously identified at myopia onset. Considering other laboratory findings and human genetics and epidemiology, these results further link circadian biology to the pathogenesis of myopia; but they also point to important mechanistic differences between the onset of myopia and the progression of established myopia. Future laboratory and clinical investigations should systematically incorporate circadian mechanisms in studying the etiology of myopia and in seeking more effective treatments to normalize eye growth in children., Competing Interests: The authors have read the journal’s policy and have the following competing interests: RAS serves as an advisor to iView Therapeutics, Inc. (https://www.iviewtherapeutics.com/). PMI serves as an advisor to Spave Science, Inc. (https://www.spavescience.com/) and to NeuroRays, LLC (https://neurorays.com). This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2024 Stone et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: To investigate the levels of angiogenesis and inflammatory cytokines in individuals with myopic choroidal neovascularization (mCNV) and the changes in these factors following intravitreal anti-VEGF injection., Methods: Aqueous humor samples were gathered from eyes with mCNV, those with single macular bleeding (SMB) without mCNV in highly myopic eyes, and those with age-related cataracts. Using a multiplex bead immunoassay, we analyzed 28 angiogenesis and inflammatory factors in the aqueous humor. Furthermore, clinical data were documented for correlation analysis., Results: In this study, the levels of vascular endothelial growth factor A (VEGF-A), interleukin 8 (IL-8), and fibroblast growth factors 1 (FGF-1) were significantly elevated in mCNV compared to SMB eyes (p < 0.05). Their odds ratios for mCNV occurrence were 1.05, 3.45, and 2.64, respectively. Hepatocyte growth factor (HGF) and VEGF-C were notably higher in mCNV than in cataract patients (p < 0.05), and VEGF-C correlated to the degree of myopic atrophic maculopathy (p = 0.024). Axial length exhibited a negative correlation with VEGF-A and positive correlations with VEGF-C, HGF, and MCP-1 (p < 0.01). Following anti-VEGF treatment, a reduction in VEGF-A, endothelin-1, and FGF-2 was noted in mCNV patients (p < 0.05), but MCP-1 levels increased., Conclusion: Our findings highlight the predominant role of angiogenesis and inflammation factors in mCNV pathogenesis. VEGF-C's correlation with axial length and atrophy suggests its involvement in the process of myopic atrophic maculopathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Myopia is regarded as a worldwide epidemic ocular disease, has been proved related to inflammation. CD55, also known as decay-accelerating factor (DAF) can modulate the activation of complement through inhibiting the formation of complement 3 convertase and its dysregulation is involved in various inflammatory diseases. To investigate the association between CD55 and myopia, and to test whether CD55 can inhibit myopia development by suppressing inflammation in the eye, we use three different animal models including monocular form-deprivation myopia, myopia induced by TNF-α administration and allergic conjunctivitis animal model to reveal the CD55 in myopia development. The tears of thirty-eight participants with different spherical equivalents were collected and CD55 in the tears were also analyzed. Complement 3 and complement 5 levels increased while CD55 levels decreased in allergic conjunctivitis and myopic eyes. After anti-inflammatory drugs administration, CD55 expression was increased in monocular form-deprivation myopia model. We also found inflammatory cytokines TGF-β, IL-6, TNF-α, and IL-1β may enhance complement 3 and complement 5 activation while CD55 level was suppressed contrary. Moreover, lower CD55 levels were found in the tears of patients with myopia with decreased diopter values. Finally, CD55-Fc administration on the eyelids can inhibit the elongation of axial length and change of refractive error. CD55-Fc application also suppress myopia development subsequent to complement 3 and complement 5 reduction and can lower myopia-specific (MMP-2 and TGF-β) cytokine expression in TNF-α induced myopia animal model. This suggests that CD55 can inhibit myopia development by suppression of complement activation and eventual down-regulation of inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study was to evaluate pupillary light reflex (PLR) to chromatic flashes in patients with early-onset high-myopia (eoHM) without (myopic controls = M-CTRL) and with (female-limited myopia-26 = MYP-26) genetic mutations in the ARR3 gene encoding the cone arrestin., Methods: Participants were 26 female subjects divided into 3 groups: emmetropic controls (E-CTRL, N = 12, mean age = 28.6 ± 7.8 years) and 2 myopic (M-CTRL, N = 7, mean age = 25.7 ± 11.5 years and MYP-26, N = 7, mean age = 28.3 ± 15.4 years) groups. In addition, one hemizygous carrier and one control male subject were examined. Direct PLRs were recorded after 10-minute dark adaptation. Stimuli were 1-second red (peak wavelength = 621 nm) and blue (peak wavelength = 470 nm) flashes at photopic luminance of 250 cd/m². A 2-minute interval between the flashes was introduced. Baseline pupil diameter (BPD), peak pupil constriction (PPC), and postillumination pupillary response (PIPR) were extracted from the PLR. Group comparisons were performed with ANOVAs., Results: Dark-adapted BPD was comparable among the groups, whereas PPC to the red light was slightly reduced in patients with myopia (P = 0.02). PIPR at 6 seconds elicited by the blue flash was significantly weaker (P < 0.01) in female patients with MYP-26, whereas it was normal in the M-CTRL group and the asymptomatic male carrier., Conclusions: L/M-cone abnormalities due to ARR3 gene mutation is currently claimed to underlie the pathological eye growth in MYP-26. Our results suggest that malfunction of the melanopsin system of intrinsically photosensitive retinal ganglion cells (ipRGCs) is specific to patients with symptomatic MYP-26, and may therefore play an additional role in the pathological eye growth of MYP-26.

Artificial light can affect eyeball development and increase myopia rate. Matrix metalloproteinase 2 (MMP-2) degrades the extracellular matrix, and induces its remodeling, while tissue inhibitor of matrix MMP-2 (TIMP-2) inhibits active MMP-2. The present study aimed to look into how refractive development and the expression of MMP-2 and TIMP-2 in the guinea pigs' remodeled sclerae are affected by artificial light with varying spectral compositions. Three weeks old guinea pigs were randomly assigned to groups exposed to five different types of light: natural light, LED light with a low color temperature, three full spectrum artificial lights, i.e. E light (continuous spectrum in the range of ~390-780 nm), G light (a blue peak at 450 nm and a small valley 480 nm) and F light (continuous spectrum and wavelength of 400 nm below filtered). A-scan ultrasonography was used to measure the axial lengths of their eyes, every two weeks throughout the experiment. Following twelve weeks of exposure to light, the sclerae were observed by optical and transmission electron microscopy. Immunohistochemistry, Western blot and RT-qPCR were used to detect the MMP-2 and TIMP-2 protein and mRNA expression levels in the sclerae. After four, six, eight, ten, and twelve weeks of illumination, the guinea pigs in the LED and G light groups had axial lengths that were considerably longer than the animals in the natural light group while the guinea pigs in the E and F light groups had considerably shorter axial lengths than those in the LED group. Following twelve weeks of exposure to light, the expression of the scleral MMP-2 protein and mRNA were, from low to high, N group, E group, F group, G group, LED group; however, the expression of the scleral TIMP-2 protein and mRNA were, from high to low, N group, E group, F group, G group, LED group. The comparison between groups was statistically significant (p<0.01). Continuous, peaks-free or valleys-free artificial light with full-spectrum preserves remodeling of scleral extracellular matrix in guinea pigs by downregulating MMP-2 and upregulating TIMP-2, controlling eye axis elongation, and inhibiting the onset and progression of myopia.

With the increasing prevalence of myopia among adolescents, the pathogenesis of this condition has garnered significant attention. Studies have discovered the expression of various hormone receptors in ocular tissues of both animals and humans. Additionally, changes in hormone levels accompany the development of myopia, although the exact relationships remain inconclusive. This article reviews the potential influences and mechanisms of action of endogenous hormones such as melatonin, serotonin, insulin, glucagon, sex hormones, vitamin D, and prostaglandins in ocular tissues including the retina, choroid, and sclera. It elaborates on the relationship between fluctuations in these hormone levels and the progression of myopia, aiming to provide guidance for exploring targets for myopia prevention and control.

Purpose: Interphotoreceptor retinoid-binding protein's (IRBP) role in eye growth and its involvement in cell homeostasis remain poorly understood. One hypothesis proposes early conditional deletion of the IRBP gene could lead to a myopic response with retinal degeneration, whereas late conditional deletion (after eye size is determined) could cause retinal degeneration without myopia. Here, we sought to understand if prior myopia was required for subsequent retinal degeneration in the absence of IRBP. This study investigates if any cell type or developmental stage is more important in myopia or retinal degeneration., Methods: IBRPfl/fl mice were bred with 5 Cre-driver lines: HRGP-Cre, Chx10-Cre, Rho-iCre75, HRGP-Cre Rho-iCre75, and Rx-Cre. Mice were analyzed for IRBP gene expression through digital droplet PCR (ddPCR). Young adult (P30) mice were tested for retinal degeneration and morphology using spectral-domain optical coherence tomography (SD-OCT) and hematoxylin and eosin (H&E) staining. Function was analyzed using electroretinograms (ERGs). Eye sizes and axial lengths were compared through external eye measurements and whole eye biometry., Results: Across all outcome measures, when bred to IRBPfl/fl, HRGP-Cre and Chx10-Cre lines showed no differences from IRBPfl/fl alone. With the Rho-iCre75 line, small but significant reductions were seen in retinal thickness with SD-OCT imaging and postmortem H&E staining without increased axial length. Both the HRGP-Cre+Rho-iCre75 and the Rx-Cre lines showed significant decreases in retinal thickness and outer nuclear layer cell counts. Using external eye measurements and SD-OCT imaging, both lines showed an increase in eye size. Finally, function in both lines was roughly halved across scotopic, photopic, and flicker ERGs., Conclusions: Our studies support hypotheses that for both eye size determination and retinal homeostasis, there are two critical timing windows when IRBP must be expressed in rods or cones to prevent myopia (P7-P12) and degeneration (P21 and later). The rod-specific IRBP knockout (Rho-iCre75) showed significant retinal functional losses without myopia, indicating that the two phenotypes are independent. IRBP is needed for early development of photoreceptors and eye size, whereas Rho-iCre75 IRBPfl/fl knockout results in retinal degeneration without myopia.

Myopia represents a significant public health concern worldwide, particularly affecting the ocular health of children and adolescents. The escalating prevalence of myopia in recent years underscores its urgency as a health issue among this demographic. Research indicates a profound connection between the onset of myopia, inflammatory processes and fibrosis. Individuals with inflammatory conditions like allergic conjunctivitis, choroiditis, systemic lupus erythematosus, and diabetes exhibit a heightened susceptibility to myopia. Conversely, myopic patients are at an increased risk of developing ocular inflammatory disorders, notably idiopathic multifocal choroiditis. We postulate that the expression of inflammatory markers, including NF-κB, TGF-β, IL-1β, IL-6, IL-8, and TNF-α, may contribute to the chronic inflammatory state observed in myopia. This paper highlights a substantial correlation between myopia and inflammation, suggesting the potential efficacy of anti-inflammatory agents in managing inflammation and slowing myopia progression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: To explore the biomechanical proteins different between low myopic corneas and moderate to high myopic corneas., Methods: A total of 27 myopic corneas were used for the Tandem Mass Tag (TMT) proteomics analysis. Differentially expressed proteins (DEPs) were clustered with fold changes > 1.20 or < 0.83 and p < 0.05. Proteins and Proteins Interactions (PPIs) were conducted to find hub proteins; Uniprot database was to screen proteins with biomechanical functions, and Parallel Reaction Monitoring (PRM) was performed to verify the TMT results. Pearson analysis was used to reveal the correlations between myopic degrees and biomechanical proteins. The Immunofluorescence (IF) staining was used to observe the protein distributions., Results: In total, 34 DEPs were observed between moderate myopic corneas and low myopic corneas; 103 DEPs were observed between high myopic corneas and low myopic corneas, 20 proteins overlapped. The PPIs analysis showed keratin 2, keratins 10 and PRSS1 were hub proteins. The Uniprot function analysis suggested keratin 2 and keratin 10 exhibited biomechanical functions. The PRM demonstrated keratin 2 and keratin 10 levels were significantly lower in moderate and high myopic corneas, which was consistent with the TMT proteomics results. IF staining also demonstrated keratin 2 and keratin 10 were less distributed in moderate and high myopic corneas than in low myopic corneas., Conclusions: The levels of biomechanical proteins keratin 2 and keratin 10 are significantly lower in moderate and high myopic corneas than in low myopic corneas., (Copyright © 2024 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Myopia, the most prevalent eye condition, has sparked notable interest regarding its origin and prevention. MicroRNAs (miRNAs) are short, non-coding RNA strands typically consisting of 18-24 nucleotides. They play a central role in post-transcriptional gene regulation and are closely associated with both normal and pathological processes in organisms. Recent advances in next-generation sequencing and bioinformatics have provided novel insights into miRNA expression and its regulatory role in myopia. This review discusses the distinct expression patterns, regulatory functions, and potential pathways of miRNAs involved in the onset and progression of myopia. The primary objective of this review was to provide valuable insights into molecular mechanisms underlying myopia and the contribution of miRNAs. These insights are expected to pave the way for further exploration of the molecular mechanisms, diagnosis, treatment, and clinical applications of myopia., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Myopia is one of the eye diseases that can damage the vision of young people. This study aimed to explore the protective role of miR-92b-3p against DNA damage and apoptosis in retinal tissues of negative lens-induced myopic (LIM) guinea pigs by targeting BTG2., Methods: Biometric measurements of ocular parameters, flash electroretinogram (FERG), and retinal thickness (RT) were performed after miR-92b-3p intravitreal injection in LIM guinea pigs. The apoptotic rate was detected by Annexin V-FITC/PI double staining, and the change in mitochondrial membrane potential was measured by JC-1 staining. Retinal apoptosis and expression of p53, BTG2, and CDK2 were explored by TdT-mediated dUTP-biotin nick labeling (TUNEL) and immunofluorescence staining assays, respectively. BTG2 and its upstream and downstream molecules at gene and protein levels in retinal tissues were measured by real-time quantitative PCR (qPCR) and Western blotting., Results: Compared with normal controls (NC), the ocular axial length of LIM guinea pig significantly increased, whereas refraction decreased. Meanwhile, dMax-a and -b wave amplitudes of ERG declined, retinal thickness was decreased, the number of apoptotic cells and apoptotic rate in LIM eyes was exaggerated, and the mitochondrial membrane potential significantly decreased. In addition, results of qPCR and Western blot assays showed that the expression levels of p53, BTG2, CDK2, and BAX in LIM guinea pigs were higher than the levels of the NC group, whereas the BCL-2 expression level was decreased. By contrast, the miR-92b-3p intravitreal injection in LIM guinea pigs could significantly inhibit axial elongation, alleviate DNA damage and apoptosis, and thus protect guinea pigs against myopia., Conclusion: In conclusion, p53 and BTG2 were activated in the retinal tissue of myopic guinea pigs, and the activated BTG2 could elevate the expression of CDK2 and BAX, and attenuate the expression of BCL-2, which in turn promote apoptosis and eventually lead to retinal thinning and impaired visual function in myopic guinea pigs. The miR-92b-3p intravitreal injection can attenuate the elongation of ocular length and retinal thickness, and inhibit the CDK2, BAX, and p53 expression by targeting BTG2, thereby ameliorating DNA damage and apoptosis in LIM guinea pigs and protecting ocular tissues., (© 2024. The Author(s).)

Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration. One well-studied rhodopsin point mutant, G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization. However, the nature of this constitutive activity and its precise molecular source have not been resolved for almost 30 y. In this study, we made a knock-in (KI) mouse line with a very low expression of G90D-Rho (equal in amount to ~0.1% of normal rhodopsin, WT-Rho, in WT rods), with the remaining WT-Rho replaced by REY-Rho, a mutant with a very low efficiency of activating transducin due to a charge reversal of the highly conserved ERY motif to REY. We observed two kinds of constitutive noise: one being spontaneous isomerization (R*) of G90D-Rho at a molecular rate (R* s -1 ) 175-fold higher than WT-Rho and the other being G90D-Rho-generated dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s -1 from WT-Rho. Neither noise type originated from G90D-Opsin because exogenous 11- cis -retinal had no effect. Extrapolating the above observations at low (0.1%) expression of G90D-Rho to normal disease exhibited by a KI mouse model with Rho G90D/WT and Rho G90D/G90D genotypes predicts the disease condition very well quantitatively. Overall, the continuous noise from G90D-Rho therefore predominates, constituting the major equivalent background light causing rod desensitization in CSNB., Competing Interests: Competing interests statement:The authors declare no competing interest.

The annual increase in myopia prevalence poses a significant economic and health challenge. Our study investigated the effect of calcitriol role in myopia by inducing the condition in guinea pigs through form deprivation for four weeks. Untargeted metabolomics methods were used to analyze the differences in metabolites in the vitreous body, and the expression of vitamin D receptor (VDR) in the retina was detected. Following form deprivation, the guinea pigs received intraperitoneal injections of calcitriol at different concentrations. We assessed myopia progression using diopter measurements and biometric analysis after four weeks. Results indicated that form deprivation led to a pronounced shift towards myopia, characterized by reduced choroidal and scleral thickness, disorganized collagen fibers, and decreased scleral collagen fiber diameter. Notably, a reduction in calcitriol expression in vitreous body, diminished vitamin D and calcitriol levels in the blood, and decreased VDR protein expression in retinal tissues were observed in myopic guinea pigs. Calcitriol administration effectively slowed myopia progression, preserved choroidal and scleral thickness, and prevented the reduction of scleral collagen fiber diameter. Our findings highlight a significant decrease in calcitriol and VDR expressions in myopic guinea pigs and demonstrate that exogenous calcitriol supplementation can halt myopia development, enhancing choroidal and scleral thickness and scleral collagen fiber diameter., (© 2024. The Author(s).)

Pou6f2 is a genetic connection between central corneal thickness (CCT) in the mouse and a risk factor for developing primary open-angle glaucoma. POU6F2 is also a risk factor for several conditions in humans, including glaucoma, myopia, and dyslexia. Recent findings demonstrate that POU6F2-positive retinal ganglion cells (RGCs) comprise a number of RGC subtypes in the mouse, some of which also co-stain for Cdh6 and Hoxd10. These POU6F2-positive RGCs appear to be novel of ON-OFF directionally selective ganglion cells (ooDSGCs) that do not co-stain with CART or SATB2 (typical ooDSGCs markers). These POU6F2-positive cells are sensitive to damage caused by elevated intraocular pressure. In the DBA/2J mouse glaucoma model, heavily-labeled POU6F2 RGCs decrease by 73% at 8 months of age compared to only 22% loss of total RGCs (labeled with RBPMS). Additionally, Pou6f2 -/- mice suffer a significant loss of acuity and spatial contrast sensitivity along with an 11.4% loss of total RGCs. In the rhesus macaque retina, POU6F2 labels the large parasol ganglion cells that form the magnocellular (M) pathway. The association of POU6F2 with the M-pathway may reveal in part its role in human glaucoma, myopia, and dyslexia., (© 2024. The Author(s).)

The mechanisms underlying myopia remain not fully understood. We proposed to examine the function and underlying mechanisms of miR-204-5p in myopia development. The miR-204-5p expression level was assessed in the vitreous humor (VH) of a cohort consisting of 11 patients with high myopia (HM) and 16 control patients undergoing vitrectomy. Then the functional implications of miR-204-5p in ARPE-19 cells were assessed. Thioredoxin-interacting protein (TXNIP) was found as a possible target of miR-204-5p through mRNA sequencing, and its interaction with miR-204-5p was confirmed employing luciferase assay and western blotting. Furthermore, the miR-204-5p function in regulating oxidative stress was examined by measuring reactive oxygen species (ROS) accumulation. The results indicated a significant reduction of miR-204-5p in the VH of HM patients. Overexpression of miR-204-5p suppressed cell proliferation, migration, invasion, and apoptosis in ARPE-19 cells. The direct targeting of miR-204-5p on TXNIP has been confirmed, and its downregulation mediated the miR-204-5p impacts on ARPE-19 cells. Moreover, miR-204-5p overexpression significantly reduced ROS accumulation by targeting TXNIP. Our findings revealed the possible contribution of the miR-204-5p/TXNIP axis in myopia development by regulating oxidative stress, which may provide new targets to combat this prevalent and debilitating condition., (© 2024. The Author(s).)

Background: High myopia is a common cause of vision loss. Age is an important factor in the development of high myopia. However, the effect of age on aqueous humor proteins in the context of high myopia is unknown. This study explored the effect of age on the aqueous humor protein of humans with high myopia., Methods: The aqueous humor of high myopia patients of different ages with implantable collamer lens implantation (ICL) was collected. Data-independent acquisition proteomic analysis was employed to explore differentially expressed proteins (DEPs). Two different bioinformatics analysis methods were used to interpret the proteomic results. Furthermore, three proteins were confirmed by enzyme-linked immunosorbent assay (ELISA)., Results: The study showed 18 upregulated and 20 downregulated proteins. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the upregulated DEPs were highly enriched in coagulation and complement cascades. Weighted gene coexpression network analysis showed that the blue module was identified as a key module for high myopia and that the plasminogen (PLG) protein is a hub protein. ELISA confirmed that the expression levels of Alpha-1-antitrypsin were significantly upregulated in the aqueous humor of older patients presenting with high myopia., Conclusions: This is the first study to investigate the effect of age on the level of aqueous humor protein in high myopia. Our study provided a comprehensive data set on the overall protein changes of different ages of human high myopia, shedding light on its potential molecular mechanism in high myopia damage to the eyeball., (Copyright © 2024 Molecular Vision.)