{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T15:13:17Z","timestamp":1784128397965,"version":"3.55.0"},"reference-count":103,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T00:00:00Z","timestamp":1677801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Corneal pathologies may have subtle manifestations in the initial stages, delaying diagnosis and timely treatment. This can lead to irreversible visual loss. Metabolomics is a rapidly developing field that allows the study of metabolites in a system, providing a complementary tool in the early diagnosis and management of corneal diseases. Early identification of biomarkers is key to prevent disease progression. The advancement of nuclear magnetic resonance and mass spectrometry allows the identification of new biomarkers in the analysis of tear, cornea, and aqueous humor. Novel perspectives on disease mechanisms are identified, which provide vital information for potential targeted therapies in the future. Current treatments are analyzed at a molecular level to offer further information regarding their efficacy. In this article, we provide a comprehensive review of the metabolomic studies undertaken in the cornea and various pathologies such as dry eye disease, Sjogren\u2019s syndrome, keratoconus, post-refractive surgery, contact lens wearers, and diabetic corneas. Lastly, we discuss the exciting future that metabolomics plays in cornea research.<\/jats:p>","DOI":"10.3390\/metabo13030380","type":"journal-article","created":{"date-parts":[[2023,3,6]],"date-time":"2023-03-06T03:22:05Z","timestamp":1678072925000},"page":"380","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Metabolomics in Corneal Diseases: A Narrative Review from Clinical Aspects"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0349-6588","authenticated-orcid":false,"given":"Alvin Wei Jun","family":"Teo","sequence":"first","affiliation":[{"name":"Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"GKT School of Medical Education, King\u2019s College London, London SE1 1UL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Applied Biology and Chemical Technology, School of Optometry, Research Centre for SHARP Vision (RCSV), The Hong Kong Polytechnic University, Hong Kong, China"},{"name":"Centre for Eye and Vision Research (CEVR), 17W Hong Kong Science Park, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5408-0382","authenticated-orcid":false,"given":"Yu-Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore"},{"name":"Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore"},{"name":"Cornea and Refractive Surgery Group, Singapore Eye Research Institute, Singapore 169856, Singapore"},{"name":"Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/bs.adgen.2015.11.004","article-title":"Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases","volume":"93","author":"Sun","year":"2016","journal-title":"Adv. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1089\/omi.2012.0121","article-title":"Postgenomics diagnostics: Metabolomics approaches to human blood profiling","volume":"17","author":"Trifonova","year":"2013","journal-title":"OMICS"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s41580-019-0108-4","article-title":"Identification of bioactive metabolites using activity metabolomics","volume":"20","author":"Rinschen","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.2337\/db15-0661","article-title":"Plasma Metabonomic Profiling of Diabetic Retinopathy","volume":"65","author":"Chen","year":"2016","journal-title":"Diabetes"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lains, I., Mendez, K., Nigalye, A., Katz, R., Douglas, V.P., Kelly, R.S., Kim, I.K., Miller, J.B., Vavvas, D.G., and Liang, L. (2022). Plasma Metabolomic Profiles Associated with Three-Year Progression of Age-Related Macular Degeneration. Metabolites, 12.","DOI":"10.3390\/metabo12010032"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"108268","DOI":"10.1016\/j.exer.2020.108268","article-title":"Metabolomic profiling of aqueous humor from glaucoma patients\u2014The metabolomics in surgical ophthalmological patients (MISO) study","volume":"201","author":"Himmelreich","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"587393","DOI":"10.3389\/fimmu.2021.587393","article-title":"Metabolomic Analysis of Aqueous Humor Identifies Aberrant Amino Acid and Fatty Acid Metabolism in Vogt-Koyanagi-Harada and Behcet\u2019s Disease","volume":"12","author":"Xu","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1167\/iovs.62.6.9","article-title":"Metabolomics in Glaucoma: A Systematic Review","volume":"62","author":"Wang","year":"2021","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.aca.2018.01.060","article-title":"Recent advances in the applications of metabolomics in eye research","volume":"1037","author":"Chen","year":"2018","journal-title":"Anal. Chim. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jtos.2021.12.013","article-title":"In situ metabolic profile and spatial distribution of ocular tissues: New insights into dry eye disease","volume":"24","author":"Chen","year":"2022","journal-title":"Ocul. Surf."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"108734","DOI":"10.1016\/j.exer.2021.108734","article-title":"Identification of potential serum metabolic biomarkers for patient with keratoconus using untargeted metabolomics approach","volume":"211","author":"Jayapalan","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e14984","DOI":"10.1097\/MD.0000000000014984","article-title":"Risk of Parkinson disease in Sj\u00f6gren syndrome administered ineffective immunosuppressant therapies: A nationwide population-based study","volume":"98","author":"Ju","year":"2019","journal-title":"Medicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"108665","DOI":"10.1016\/j.exer.2021.108665","article-title":"Age-related differences in corneal nerve regeneration after SMILE and the mechanism revealed by metabolomics","volume":"209","author":"Li","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/cxo.12918","article-title":"Tear film, contact lenses and tear biomarkers","volume":"102","author":"Willcox","year":"2019","journal-title":"Clin. Exp. Optom."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Padberg, I., Peter, E., Gonz\u00e1lez-Maldonado, S., Witt, H., Mueller, M., Weis, T., Bethan, B., Liebenberg, V., Wiemer, J., and Katus, H.A. (2014). A new metabolomic signature in type-2 diabetes mellitus and its pathophysiology. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0085082"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/eye.2016.37","article-title":"Introduction to metabolomics and its applications in ophthalmology","volume":"30","author":"Tan","year":"2016","journal-title":"Eye"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"333","DOI":"10.3322\/caac.21670","article-title":"Metabolomics in cancer research and emerging applications in clinical oncology","volume":"71","author":"Schmidt","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"D622","DOI":"10.1093\/nar\/gkab1062","article-title":"HMDB 5.0: The Human Metabolome Database for 2022","volume":"50","author":"Wishart","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1469-185X.2010.00157.x","article-title":"An introduction to biological nuclear magnetic resonance spectroscopy","volume":"86","author":"Bothwell","year":"2011","journal-title":"Biol. Rev. Camb. Philos. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/978-1-4939-2377-9_13","article-title":"The strengths and weaknesses of NMR spectroscopy and mass spectrometry with particular focus on metabolomics research","volume":"1277","author":"Emwas","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/978-1-4939-7172-5_13","article-title":"NMR and MS Methods for Metabolomics","volume":"1641","author":"Amberg","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-1-60761-746-4_2","article-title":"A mass spectrometry primer for mass spectrometry imaging","volume":"656","author":"Rubakhin","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_23","first-page":"19","article-title":"Principles and applications of liquid chromatography-mass spectrometry in clinical biochemistry","volume":"30","author":"Pitt","year":"2009","journal-title":"Clin. Biochem. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jpba.2013.06.032","article-title":"Current practice of liquid chromatography-mass spectrometry in metabolomics and metabonomics","volume":"87","author":"Gika","year":"2014","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/00006324-196901000-00003","article-title":"Steady state distribution of oxygen and carbon dioxide in the in vivo cornea of an eye covered by a gas-permeable contact lens","volume":"46","author":"Fatt","year":"1969","journal-title":"Am. J. Optom. Arch. Am. Acad. Optom."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.ebiom.2017.01.004","article-title":"Glutaminolysis is Essential for Energy Production and Ion Transport in Human Corneal Endothelium","volume":"16","author":"Zhang","year":"2017","journal-title":"EBioMedicine"},{"key":"ref_27","unstructured":"Fatt, I., and Weissman, B.A. (1992). Physiology of the Eye, Butterworth-Heinemann. [2nd ed.]."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/0014-4835(78)90095-7","article-title":"Hexose-monophosphate shunt response to diamide in the component layers of the cornea","volume":"26","author":"Geroski","year":"1978","journal-title":"Exp. Eye Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.optom.2020.12.002","article-title":"A refined model on flow and oxygen consumption in the human cornea depending on the oxygen tension at the interface cornea\/post lens tear film during contact lens wear","volume":"15","author":"Moreno","year":"2022","journal-title":"J. Optom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.preteyeres.2011.07.001","article-title":"Oxygen-deficient metabolism and corneal edema","volume":"30","author":"Leung","year":"2011","journal-title":"Prog. Retin Eye Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/j.1755-3768.2011.02213.x","article-title":"Impact of organ culturing on metabolic profile of human corneas: Preliminary results","volume":"90","author":"Kryczka","year":"2012","journal-title":"Acta Ophthalmol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jtos.2017.05.008","article-title":"TFOS DEWS II Definition and Classification Report","volume":"15","author":"Craig","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Rantamaki, A.H., Seppanen-Laakso, T., Oresic, M., Jauhiainen, M., and Holopainen, J.M. (2011). Human tear fluid lipidome: From composition to function. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019553"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.jtos.2017.05.006","article-title":"TFOS DEWS II Management and Therapy Report","volume":"15","author":"Jones","year":"2017","journal-title":"Ocul Surf."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"158728","DOI":"10.1016\/j.bbalip.2020.158728","article-title":"Lipidomic analysis of epithelial corneal cells following hyperosmolarity and benzalkonium chloride exposure: New insights in dry eye disease","volume":"1865","author":"Magny","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.exer.2012.12.001","article-title":"Betaine stabilizes cell volume and protects against apoptosis in human corneal epithelial cells under hyperosmotic stress","volume":"108","author":"Garrett","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"657","DOI":"10.3109\/02713683.2014.957776","article-title":"Effects of L-carnitine, erythritol and betaine on pro-inflammatory markers in primary human corneal epithelial cells exposed to hyperosmotic stress","volume":"40","author":"Hua","year":"2015","journal-title":"Curr. Eye Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"109168","DOI":"10.1016\/j.exer.2022.109168","article-title":"Preclinical study of a new matrix to help the ocular surface in dry eye disease","volume":"222","author":"Abbate","year":"2022","journal-title":"Exp. Eye Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.ajo.2010.11.003","article-title":"Amino Acid profiles in human tear fluids analyzed by high-performance liquid chromatography and electrospray ionization tandem mass spectrometry","volume":"151","author":"Nakatsukasa","year":"2011","journal-title":"Am. J. Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Arribas-Lopez, E., Zand, N., Ojo, O., Snowden, M.J., and Kochhar, T. (2021). The Effect of Amino Acids on Wound Healing: A Systematic Review and Meta-Analysis on Arginine and Glutamine. Nutrients, 13.","DOI":"10.3390\/nu13082498"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.jtos.2017.11.004","article-title":"Nitrogen mustard-induced corneal injury involves the sphingomyelin-ceramide pathway","volume":"16","author":"Charkoftaki","year":"2018","journal-title":"Ocul. Surf."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.ophtha.2019.08.018","article-title":"Autologous Serum-Based Eye Drops for Treatment of Ocular Surface Disease: A Report by the American Academy of Ophthalmology","volume":"127","author":"Shtein","year":"2020","journal-title":"Ophthalmology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"103155","DOI":"10.1016\/j.transci.2021.103155","article-title":"Metabolomics comparison of cord and peripheral blood-derived serum eye drops for the treatment of dry eye disease","volume":"60","author":"Quartieri","year":"2021","journal-title":"Transfus. Apher. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Choi, J.J., Hwang, J.S., and Shin, Y.J. (2020). Effect of Oral Choline Alfoscerate on Patients with Keratoconjunctivitis Sicca. Nutrients, 12.","DOI":"10.3390\/nu12051526"},{"key":"ref_45","first-page":"CD010846","article-title":"Creatine for women in pregnancy for neuroprotection of the fetus","volume":"2014","author":"Dickinson","year":"2013","journal-title":"Cochrane. Database Syst. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1167\/iovs.04-1344","article-title":"D-beta-hydroxybutyrate protects against corneal epithelial disorders in a rat dry eye model with jogging board","volume":"46","author":"Nakamura","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"20855","DOI":"10.1038\/srep20855","article-title":"Randomized, Multicenter, Double-Blind Study of the Safety and Efficacy of 1%D-3-Hydroxybutyrate eye drops for Dry Eye Disease","volume":"6","author":"Kawakita","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1111\/j.1600-0854.2010.01138.x","article-title":"Polarized but differential localization and recruitment of STIM1, Orai1 and TRPC channels in secretory cells","volume":"12","author":"Hong","year":"2011","journal-title":"Traffic"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13953","DOI":"10.1038\/srep13953","article-title":"IP3R deficit underlies loss of salivary fluid secretion in Sj\u00f6gren\u2019s Syndrome","volume":"5","author":"Teos","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Inaba, T., Hisatsune, C., Sasaki, Y., Ogawa, Y., Ebisui, E., Ogawa, N., Matsui, M., Takeuchi, T., Mikoshiba, K., and Tsubota, K. (2014). Mice lacking inositol 1,4,5-trisphosphate receptors exhibit dry eye. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099205"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1080\/15287394.2020.1867274","article-title":"Metabolomics approach to biomarkers of dry eye disease using (1)H-NMR in rats","volume":"84","author":"Lee","year":"2021","journal-title":"J. Toxicol. Environ. Health Part A"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1016\/j.bbagrm.2014.07.013","article-title":"A key role of the mitochondrial citrate carrier (SLC25A1) in TNF\u03b1- and IFN\u03b3-triggered inflammation","volume":"1839","author":"Infantino","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1021\/acs.jproteome.9b00149","article-title":"Integrated Tear Proteome and Metabolome Reveal Panels of Inflammatory-Related Molecules via Key Regulatory Pathways in Dry Eye Syndrome","volume":"18","author":"Chen","year":"2019","journal-title":"J. Proteome Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.biochi.2009.01.008","article-title":"Polyunsaturated fatty acids and inflammatory processes: New twists in an old tale","volume":"91","author":"Calder","year":"2009","journal-title":"Biochimie"},{"key":"ref_55","first-page":"555","article-title":"A metabolomic approach to dry eye disorders. The role of oral supplements with antioxidants and omega 3 fatty acids","volume":"21","author":"Morales","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Hwang, J.S., and Shin, Y.J. (2021). Role of Choline in Ocular Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094733"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jtos.2021.07.006","article-title":"Tear metabolomics highlights new potential biomarkers for differentiating between Sjogren\u2019s syndrome and other causes of dry eye","volume":"22","author":"Urbanski","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"108209","DOI":"10.1016\/j.exer.2020.108209","article-title":"sPLA(2)-IIa participates in ocular surface inflammation in humans with dry eye disease","volume":"201","author":"Wei","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1097\/OPX.0b013e31819f9e70","article-title":"Modeling corneal metabolism and oxygen transport during contact lens wear","volume":"86","author":"Chhabra","year":"2009","journal-title":"Optom. Vis. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.exer.2013.05.010","article-title":"Tear film lipids","volume":"117","author":"Butovich","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/08164622.2022.2083945","article-title":"Silicone hydrogel contact lenses retain and document ocular surface lipid mediator profiles","volume":"5","author":"Gronert","year":"2022","journal-title":"Clin. Exp. Optom."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1080\/08927014.2021.1978433","article-title":"A method for studying lipid adsorption to silicone hydrogel contact lenses","volume":"37","author":"Masoudi","year":"2021","journal-title":"Biofouling"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1167\/iovs.13-12881","article-title":"Evidence of lipid degradation during overnight contact lens wear: Gas chromatography mass spectrometry as the diagnostic tool","volume":"55","author":"Panaser","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.clae.2012.01.003","article-title":"Function of lipids\u2014Their fate in contact lens wear: An interpretive review","volume":"35","author":"Panaser","year":"2012","journal-title":"Cont. Lens Anterior. Eye."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7417","DOI":"10.1167\/iovs.13-12916","article-title":"A comparison of patient matched meibum and tear lipidomes","volume":"54","author":"Brown","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"317","DOI":"10.3928\/1081597X-20200312-01","article-title":"Metabolomic Analysis in Corneal Lenticules from Contact Lens Wearers","volume":"36","author":"Li","year":"2020","journal-title":"J. Refract. Surg."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.4103\/1673-5374.308666","article-title":"Corneal neuromediator profiles following laser refractive surgery","volume":"16","author":"Yang","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"653","DOI":"10.3928\/1081597X-20200730-01","article-title":"Cross-sectional Study on Corneal Denervation in Contralateral Eyes Following SMILE Versus LASIK","volume":"36","author":"Liu","year":"2020","journal-title":"J. Refract. Surg."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"731462","DOI":"10.3389\/fmed.2021.731462","article-title":"Lipidomics Analysis of the Tears in the Patients Receiving LASIK, FS-LASIK, or SBK Surgery","volume":"8","author":"Gao","year":"2021","journal-title":"Front. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1089\/jop.2017.0008","article-title":"Antioxidant and Osmoprotecting Activity of Taurine in Dry Eye Models","volume":"34","author":"Bucolo","year":"2018","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1002\/sctm.16-0441","article-title":"Ascorbic Acid Promotes the Stemness of Corneal Epithelial Stem\/Progenitor Cells and Accelerates Epithelial Wound Healing in the Cornea","volume":"6","author":"Chen","year":"2017","journal-title":"Stem. Cells Transl. Med."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Qiu, Y., Yang, X., Wang, L., Gao, K., and Jiang, Z. (2019). L-Arginine Inhibited Inflammatory Response and Oxidative Stress Induced by Lipopolysaccharide via Arginase-1 Signaling in IPEC-J2 Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071800"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.jss.2013.10.002","article-title":"Diverse effects of parenteral arginine on systemic and local oxidant-antioxidant homeostasis and nitrosative stress in rats with subacute peritonitis","volume":"187","author":"Chen","year":"2014","journal-title":"J. Surg. Res."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Teo, A.W.J., Mansoor, H., Sim, N., Lin, M.T., and Liu, Y.C. (2022). In Vivo Confocal Microscopy Evaluation in Patients with Keratoconus. J. Clin. Med., 11.","DOI":"10.3390\/jcm11020393"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4608","DOI":"10.1038\/srep04608","article-title":"In vitro model suggests oxidative stress involved in keratoconus disease","volume":"4","author":"Karamichos","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exer.2015.01.007","article-title":"Tear metabolite changes in keratoconus","volume":"132","author":"Karamichos","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Wojakowska, A., Pietrowska, M., Widlak, P., Dobrowolski, D., Wylegala, E., and Tarnawska, D. (2020). Metabolomic Signature Discriminates Normal Human Cornea from Keratoconus-A Pilot GC\/MS Study. Molecules, 25.","DOI":"10.3390\/molecules25122933"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"305","DOI":"10.3109\/02713683.2012.754904","article-title":"Metabolic profile of keratoconic cornea","volume":"38","author":"Kryczka","year":"2013","journal-title":"Curr. Eye Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1007\/s11306-017-1281-0","article-title":"Quantitative metabolomic analysis of the human cornea and aqueous humor","volume":"13","author":"Snytnikova","year":"2017","journal-title":"Metabolomics"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"760","DOI":"10.3390\/jfb3040760","article-title":"Novel in Vitro Model for Keratoconus Disease","volume":"3","author":"Karamichos","year":"2012","journal-title":"J. Funct. Biomater."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.3945\/jn.117.256404","article-title":"Proline Precursors and Collagen Synthesis: Biochemical Challenges of Nutrient Supplementation and Wound Healing","volume":"147","author":"Albaugh","year":"2017","journal-title":"J. Nutr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"639500","DOI":"10.3389\/fsurg.2021.639500","article-title":"Application of Collagen I and IV in Bioengineering Transparent Ocular Tissues","volume":"8","author":"Song","year":"2021","journal-title":"Front. Surg."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"McKay, T.B., Priyadarsini, S., Rowsey, T., and Karamichos, D. (2021). Arginine Supplementation Promotes Extracellular Matrix and Metabolic Changes in Keratoconus. Cells, 10.","DOI":"10.3390\/cells10082076"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/S0002-9394(02)02220-1","article-title":"Riboflavin\/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus","volume":"135","author":"Wollensak","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1038\/s41433-018-0075-6","article-title":"Effects of collagen cross-linking on the keratoconus metabolic network","volume":"32","author":"Sharif","year":"2018","journal-title":"Eye"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"S122","DOI":"10.1097\/ICL.0000000000000644","article-title":"Tear Organic Acid Analysis After Corneal Collagen Crosslinking in Keratoconus","volume":"46","author":"Koyuncu","year":"2020","journal-title":"Eye Contact Lens."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.4103\/1673-5374.327364","article-title":"Diabetic corneal neuropathy as a surrogate marker for diabetic peripheral neuropathy","volume":"17","author":"Liu","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"15173","DOI":"10.1038\/s41598-018-33169-5","article-title":"Exosomes from normal and diabetic human corneolimbal keratocytes differentially regulate migration, proliferation and marker expression of limbal epithelial cells","volume":"8","author":"Leszczynska","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s13167-022-00272-7","article-title":"Metabolic phenotyping of tear fluid as a prognostic tool for personalised medicine exemplified by T2DM patients","volume":"13","author":"Brunmair","year":"2022","journal-title":"EPMA J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1210\/clinem\/dgz240","article-title":"Metabolomics Signatures in Type 2 Diabetes: A Systematic Review and Integrative Analysis","volume":"105","author":"Sun","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/nm.2307","article-title":"Metabolite profiles and the risk of developing diabetes","volume":"17","author":"Wang","year":"2011","journal-title":"Nat. Med."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Yoon, M.S. (2016). The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism. Nutrients, 8.","DOI":"10.3390\/nu8070405"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1159\/000484283","article-title":"Uric Acid as a Cause of the Metabolic Syndrome","volume":"192","author":"King","year":"2018","journal-title":"Contrib. Nephrol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/978-1-4615-0717-8_87","article-title":"Different concentrations of amino acids in tears of normal and human dry eyes","volume":"506","author":"ChenZhuo","year":"2002","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1206808","DOI":"10.1155\/2018\/1206808","article-title":"Assessment of Ocular Surface Damage during the Course of Type 2 Diabetes Mellitus","volume":"2018","author":"He","year":"2018","journal-title":"J. Ophthalmol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Sak, D., Erdenen, F., M\u00fcderrisoglu, C., Altunoglu, E., Sozer, V., Gungel, H., Guler, P.A., Sak, T., and Uzun, H. (2019). The Relationship between Plasma Taurine Levels and Diabetic Complications in Patients with Type 2 Diabetes Mellitus. Biomolecules, 9.","DOI":"10.3390\/biom9030096"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.exer.2016.10.010","article-title":"Complete metabolome and lipidome analysis reveals novel biomarkers in the human diabetic corneal stroma","volume":"153","author":"Priyadarsini","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Guitton, J., Bandet, C.L., Mariko, M.L., Tan-Chen, S., Bourron, O., Benomar, Y., Hajduch, E., and Le Stunff, H. (2020). Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity\/Type 2 Diabetes. Cells, 9.","DOI":"10.3390\/cells9071682"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Matysik-Wo\u017aniak, A., Turski, W., Turska, M., Paduch, R., \u0141a\u0144cut, M., Piwowarczyk, P., Czuczwar, M., and Rejdak, R. (2021). Kynurenic Acid Accelerates Healing of Corneal Epithelium In Vitro and In Vivo. Pharmaceuticals, 14.","DOI":"10.3390\/ph14080753"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.pharep.2017.02.020","article-title":"Effects of tryptophan, kynurenine and kynurenic acid exerted on human reconstructed corneal epithelium in vitro","volume":"69","author":"Paduch","year":"2017","journal-title":"Pharmacol. Rep."},{"key":"ref_101","first-page":"1312","article-title":"Function of the tryptophan metabolite, L-kynurenine, in human corneal endothelial cells","volume":"15","author":"Serbecic","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1167\/iovs.09-3860","article-title":"Human corneal fibrosis: An in vitro model","volume":"51","author":"Karamichos","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"13627","DOI":"10.1038\/s41598-021-93164-1","article-title":"Nerve influence on the metabolism of type I and type II diabetic corneal stroma: An in vitro study","volume":"11","author":"Whelchel","year":"2021","journal-title":"Sci. Rep."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/3\/380\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:47:13Z","timestamp":1760122033000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/3\/380"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,3]]},"references-count":103,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["metabo13030380"],"URL":"https:\/\/doi.org\/10.3390\/metabo13030380","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,3]]}}}