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Novel Corneal Protein Biomarker Candidates Reveal Iron Metabolic Disturbance in High Myopia Eyes

ABSTRACT: Myopia is a major public health concern with increasing global prevalence and is the leading cause of vision loss and complications. The potential role of the cornea, a substantial component of refractive power and the protective fortress of the eye, has been underestimated in the development of myopia. Our study acquired corneal stroma tissues from myopic patients undergoing femtosecond laser-assisted small incision lenticule extraction (SMILE) surgery and investigated the differential expression of circulating proteins between subjects with low and high myopia by means of high-throughput proteomic approaches—the quantitative tandem mass tag (TMT) labeling method and parallel reaction monitoring (PRM) validation. Across all corneal stroma tissue samples, a total of 2,455 proteins were identified qualitatively and quantitatively, 103 of which were differentially expressed between those with low and high myopia. The differentially abundant proteins (DAPs) between the groups of stroma samples mostly demonstrated catalytic activity and molecular function regulator and transporter activity and participated in metabolic processes, biological regulation, response to stimulus, and so forth. Pathway enrichment showed that mineral absorption, ferroptosis, and HIF-1 signaling pathways were activated in the human myopic cornea. Furthermore, TMT analysis and PRM validation revealed that the expression of ferritin light chain (FTL, P02792) and ferritin heavy chain (FTH1, P02794) was negatively associated with myopia development, while the expression of serotransferrin (TF, P02787) was positively related to myopia status. Overall, our results indicated that subjects with low and high myopia could have different proteomic profiles or signatures in the cornea. These findings revealed disturbances in iron metabolism and corneal oxidative stress in the more myopic eyes. Iron metabolic proteins could serve as an essential modulator in the pathogenesis of myopia.

SUBMITTER: Chen J

PROVIDER: S-EPMC8517150 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHigh myopia and cataracts are major causes of blindness in East and Southeast Asia. Corneal astigmatism is a major contributor to uncorrected poor vision after cataract surgery in patients with high myopia. The purpose of the present study was to evaluate the demographic characteristics and distribution of preoperative corneal astigmatism in Chinese cataract surgery candidates with high myopia.MethodsSwept-source optical coherence tomography-based optical biometry was performed preoperatively in consecutive cataract surgery candidates who were classified by axial length (AL) into a high myopia group (defined as AL ≥26.0 mm) and a control group (normal ALs). The demographics, ALs, and keratometry values were recorded.ResultsAmong 15,063 cataract surgery candidates (15,063 eyes), 1,921 patients (12.8%, 1,921 eyes) in the high myopia group and 11,880 patients (11,880 eyes) in the control group were enrolled. In the high myopia group, the mean age was 59.8±12.6 (standard deviation) years, which was younger than that in the control group (69.1±11.0 years, P<0.001). In the high myopia group, the mean corneal astigmatism was 1.20±0.83 dioptre (D), which was greater than that in the control group (0.93±0.69 D, P<0.001). In the high myopia group, 82.2% had corneal astigmatism ≥0.50 D, 51.4% ≥1.00 D, 27.4% ≥1.50 D and 14.4% ≥2.00 D, all of which were higher than the respective proportions in the control group (P<0.001 for all). In the high myopia group, 66.8% had moderate to high corneal astigmatism, and 42.8% had "with-the-rule" astigmatism, and both of these proportions were higher than the respective proportions in the control group (P<0.001 for both). In the high myopia group, corneal astigmatism tended to increase with increasing age (r =0.134, P<0.001) after the age of 50, which was consistent with the tendency in the control group.ConclusionsA significant burden of preoperative corneal astigmatism was observed in Chinese cataract surgery candidates with high myopia. Moderate to high corneal astigmatism was more common in highly myopic eyes than in normal AL eyes.

Project description:Pleural effusion is a common respiratory disease worldwide; however, rapid and accurate diagnoses of tuberculosis pleural effusion (TPE) and malignancy pleural effusion (MPE) remain challenging. Although extracellular vesicles (EVs) have been confirmed as promising sources of disease biomarkers, little is known about the metabolite compositions of its subpopulations and their roles in the diagnosis of pleural effusion. Here, we performed metabolomics and lipidomics analysis to investigate the metabolite characteristics of two EV subpopulations derived from pleural effusion by differential ultracentrifugation, namely large EVs (lEVs, pelleted at 20,000 × g) and small EVs (sEVs, pelleted at 110,000 × g), and assessed their metabolite differences between tuberculosis and malignancy. A total of 579 metabolites, including amino acids, acylcarnitines, organic acids, steroids, amides and various lipid species, were detected. The results showed that the metabolic profiles of lEVs and sEVs overlapped with and difference from each other but significantly differed from those of pleural effusion. Additionally, different type of vesicles and pleural effusion showed unique metabolic enrichments. Furthermore, lEVs displayed more significant and larger metabolic alterations between the tuberculosis and malignancy groups, and their differential metabolites were more closely related to clinical parameters than those of sEV. Finally, a panel of four biomarker candidates, including phenylalanine, leucine, phosphatidylcholine 35:0, and sphingomyelin 44:3, in pleural lEVs was defined based on the comprehensive discovery and validation workflow. This panel showed high performance for distinguishing TPE and MPE, particularly in patients with delayed or missed diagnosis, such as the area under the receiver-operating characteristic curve (AUC) >0.95 in both sets. We conducted comprehensive metabolic profiling analysis of EVs, and further explored the metabolic reprogramming of tuberculosis and malignancy at the level of metabolites in lEVs and sEVs, providing insight into the mechanism of pleural effusion, and identifying novel biomarkers for diagnosing TPE and MPE.

Project description:PurposeTo assess whether topical application of VEGFR1R2 Trap after corneal transplantation can impair corneal (lymph)angiogenesis and promote murine corneal allograft survival in eyes at high risk of rejection.MethodsWe used the murine model of suture-induced neovascularization and subsequent keratoplasty in eyes at high risk of rejection, which is an established model for local drug application. After transplantation, the mice were treated with either VEGFR1R2 Trap (aflibercept) or human IgG Fc as eye drops for 2 weeks (three times/d). Deposition of VEGFR1R2 Trap in corneal tissue was detected by immunohistochemistry. Two and 8 weeks after transplantation, corneal (lymph)angiogenesis was assessed morphometrically. Dendritic cells (DCs) and regulatory T cells (Tregs) in the draining lymph nodes (dLNs) were examined by flow cytometry. Allograft survival was determined by corneal graft opacity scores.ResultsTopically applied VEGFR1R2 Trap penetrated into corneal host and graft stroma after keratoplasty in eyes at high risk of rejection. Additional postsurgical corneal hemangiogenesis (P < 0.0001) and lymphangiogenesis (P < 0.01) as well as infiltrating CD45+ leukocytes (P < 0.001) and macrophages (P < 0.01) were significantly reduced in the VEGFR1R2 Trap group compared to controls. VEGFR1R2 Trap eye drops significantly decreased the frequency of total CD11c+ DCs (P < 0.01), as well as activated CD11c+MHC II+ DCs (P < 0.01) and CD11c+CD40+ DCs (P < 0.05). In contrast, the frequency of CD200R+ regulatory DCs (P < 0.05) and Tregs in dLNs (P < 0.01) was enhanced. Moreover, long-term allograft survival was also improved (P < 0.05).ConclusionsTemporary, topical application of VEGFR1R2 Trap after corneal transplantation can achieve sufficient anti-VEGF activity, inhibit additional (lymph)angiogenesis, and significantly improve corneal allograft survival in eyes at high risk of rejection.Translational relevanceVEGFR1R2 Trap eye drops after transplantation present a new therapeutic option for patients undergoing corneal transplantation and are at high risk of graft rejection.

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Novel Corneal Protein Biomarker Candidates Reveal Iron Metabolic Disturbance in High Myopia Eyes

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