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Small extracellular vesicles (sEVs) are released into different body fluids, including the eye\u2019s aqueous humor. Information about their proteome content and characterization in ocular pathologies is not yet well established. In this study, aqueous humor sEVs from healthy individuals, cataracts, and glaucoma patients were studied, and their specific protein profiles were characterized. Moreover, the potential of identified proteins as diagnostic glaucoma biomarkers was evaluated. The protein content of sEVs from patients\u2019 aqueous humor with cataracts and glaucoma compared to healthy individuals was analyzed by quantitative proteomics. Validation was performed by western blot (WB) and ELISA. A total of 828 peptides and 192 proteins were identified and quantified. After data analysis with the R program, 8 significantly dysregulated proteins from aqueous humor sEVs in cataracts and 16 in glaucoma showed an expression ratio \u2265 1.5. By WB and ELISA using directly aqueous humor samples, the dysregulation of 9 proteins was mostly confirmed. Importantly, GAS6 and SPP1 showed high diagnostic ability of glaucoma, which in combination allowed for discriminating glaucoma patients from control individuals with an area under the curve of 76.1% and a sensitivity of 65.6% and a specificity of 87.7%.<\/jats:p>","DOI":"10.3390\/ijms25136995","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T05:11:39Z","timestamp":1719465099000},"page":"6995","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Proteomics Analyses of Small Extracellular Vesicles of Aqueous Humor: Identification and Validation of GAS6 and SPP1 as Glaucoma Markers"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4614-2536","authenticated-orcid":false,"given":"Raquel","family":"Rejas-Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain"},{"name":"Biochemistry and Molecular Biology Department, Facultad de \u00d3ptica y Optometr\u00eda, Universidad Complutense de Madrid, 28037 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5141-0454","authenticated-orcid":false,"given":"Ana","family":"Montero-Calle","sequence":"additional","affiliation":[{"name":"Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Valverde","sequence":"additional","affiliation":[{"name":"Analytical Chemistry Department, Facultad de CC. Qu\u00edmicas, Universidad Complutense de Madrid, Pza. de las Ciencias 2, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6308-1512","authenticated-orcid":false,"given":"Natalia Pastora","family":"Salvador","sequence":"additional","affiliation":[{"name":"Opthalmology Service, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9 Crespo","family":"Carball\u00e9s","sequence":"additional","affiliation":[{"name":"Opthalmology Service, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Aus\u00edn-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Opthalmology Service, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"S\u00e1nchez-Naves","sequence":"additional","affiliation":[{"name":"Oftalmedic Salv\u00e0, 07013 Palma, Illes Balears, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9928-6613","authenticated-orcid":false,"given":"Susana","family":"Campuzano","sequence":"additional","affiliation":[{"name":"Analytical Chemistry Department, Facultad de CC. 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