{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T14:08:44Z","timestamp":1776953324139,"version":"3.51.4"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T00:00:00Z","timestamp":1593043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The molecular etiology of keratoconus (KC), a pathological condition of the human cornea, remains unclear. The aim of this work was to perform profiling of metabolites and identification of features discriminating this pathology from the normal cornea. The combination of gas chromatography and mass spectrometry (GC\/MS) techniques has been applied for profiling and identification of metabolites in corneal buttons from 6 healthy controls and 7 KC patients. An untargeted GC\/MS-based approach allowed the detection of 377 compounds, including 46 identified unique metabolites, whose levels enabled the separation of compared groups of samples in unsupervised hierarchical cluster analysis. There were 13 identified metabolites whose levels differentiated between groups of samples. Downregulation of several carboxylic acids, fatty acids, and steroids was observed in KC when compared to the normal cornea. Metabolic pathways associated with compounds that discriminated both groups were involved in energy production, lipid metabolism, and amino acid metabolism. An observed signature may reflect cellular processes involved in the development of KC pathology, including oxidative stress and inflammation.<\/jats:p>","DOI":"10.3390\/molecules25122933","type":"journal-article","created":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T10:36:54Z","timestamp":1593081414000},"page":"2933","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Metabolomic Signature Discriminates Normal Human Cornea from Keratoconus\u2014A Pilot GC\/MS Study"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4541-1239","authenticated-orcid":false,"given":"Anna","family":"Wojakowska","sequence":"first","affiliation":[{"name":"European Centre for Bioinformatics and Genomics, Institute of Bioorganic Chemistry Polish Academy of Sciences, Noskowskiego12\/14, 61-704 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9317-7822","authenticated-orcid":false,"given":"Monika","family":"Pietrowska","sequence":"additional","affiliation":[{"name":"Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5099-4726","authenticated-orcid":false,"given":"Piotr","family":"Widlak","sequence":"additional","affiliation":[{"name":"Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8768-1691","authenticated-orcid":false,"given":"Dariusz","family":"Dobrowolski","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology &amp; Tissue and Cells Bank, St. Barbara Hospital, Trauma Center, Plac Medyk\u00f3w 1, 41-200 Sosnowiec, Poland"},{"name":"Chair and Clinical Department of Ophthalmology, Division of Medical Science in Zabrze, Medical University of Silesia, Panewnicka 65, 40-760 Katowice, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5950-2425","authenticated-orcid":false,"given":"Edward","family":"Wyl\u0119ga\u0142a","sequence":"additional","affiliation":[{"name":"Chair and Clinical Department of Ophthalmology, Division of Medical Science in Zabrze, Medical University of Silesia, Panewnicka 65, 40-760 Katowice, Poland"},{"name":"Department of Ophthalmology, District Railway Hospital, Panewnicka 65, 40-760 Katowice, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0520-9589","authenticated-orcid":false,"given":"Dorota","family":"Tarnawska","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, District Railway Hospital, Panewnicka 65, 40-760 Katowice, Poland"},{"name":"Faculty of Science and Technology, Silesian Center for Education and Interdisciplinary Research, University of Silesia, 75 Pu\u0142ku Piechoty 1A, 41-500 Chorz\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1001\/archopht.1992.01080220071023","article-title":"Changing trends in the indications for penetrating keratoplasty","volume":"110","author":"Mamalis","year":"1992","journal-title":"Arch. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1097\/00003226-199711000-00004","article-title":"Indications for penetrating keratoplasty and associated procedures, 1989\u20131995","volume":"16","author":"Lois","year":"1997","journal-title":"Cornea"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1097\/00003226-200001000-00002","article-title":"Three decades of corneal transplantation: Indications and patient characteristics","volume":"19","author":"Maeno","year":"2000","journal-title":"Cornea"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/0002-9394(86)90817-2","article-title":"A 48-year clinical and epidemiologic study of keratoconus","volume":"101","author":"Kennedy","year":"1986","journal-title":"Am. J. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.ajo.2016.12.015","article-title":"Age-specific Incidence and Prevalence of Keratoconus: A Nationwide Registration Study","volume":"175","author":"Godefrooij","year":"2017","journal-title":"Am. J. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.ajo.2009.06.024","article-title":"Prevalence and Associations of Keratoconus in Rural Maharashtra in Central India: The Central India Eye and Medical Study","volume":"148","author":"Jonas","year":"2009","journal-title":"Am. J. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/sj.eye.6700652","article-title":"Influence of ethnic origin on the incidence of keratoconus and associated atopic disease in Asians and white patients","volume":"18","author":"Georgiou","year":"2004","journal-title":"Eye"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1097\/00003226-199809000-00002","article-title":"Changing indications for penetrating keratoplasty: Histopathology of 1250 corneal buttons","volume":"17","author":"Cursiefen","year":"1998","journal-title":"Cornea"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1167\/iovs.04-0549","article-title":"Increased Levels of Catalase and Cathepsin V\/L2 but Decreased TIMP-1 in Keratoconus Corneas: Evidence that Oxidative Stress Plays a Role in This Disorder","volume":"46","author":"Kenney","year":"2005","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8592","DOI":"10.1167\/iovs.11-7732","article-title":"Oxidative Stress in Keratoconus?","volume":"52","author":"Arnal","year":"2011","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.exer.2012.09.005","article-title":"Changes in lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas","volume":"104","author":"Dudakova","year":"2012","journal-title":"Exp. Eye Res."},{"key":"ref_12","first-page":"2293","article-title":"Superoxide dismutase isoenzymes in the normal and diseased human cornea","volume":"42","author":"Behndig","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1177\/002215540205000306","article-title":"Evidence of Oxidative Stress in Human Corneal Diseases","volume":"50","author":"Buddi","year":"2002","journal-title":"J. Histochem. Cytochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/00003226-200001000-00019","article-title":"Apoptosis in UV-exposed rabbit corneas","volume":"19","author":"Podskochy","year":"2000","journal-title":"Cornea"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1167\/iovs.05-0828","article-title":"Increased Stress-Induced Generation of Reactive Oxygen Species and Apoptosis in Human Keratoconus Fibroblasts","volume":"47","author":"Chwa","year":"2006","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_16","first-page":"893","article-title":"The role of oxidative stress in corneal diseases and injuries","volume":"30","year":"2015","journal-title":"Histol. Histopathol."},{"key":"ref_17","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_18","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_19","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.preteyeres.2018.11.002","article-title":"Metabolomics in the study of retinal health and disease","volume":"69","author":"Gantner","year":"2019","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_20","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_21","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_22","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1194\/jlr.M067264","article-title":"Analysis of sphingolipids in human corneal fibroblasts from normal and keratoconus patients","volume":"58","author":"Qi","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/eye.2015.63","article-title":"Keratoconus: An inflammatory disorder?","volume":"29","author":"Galvis","year":"2015","journal-title":"Eye"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1136\/bjo.83.12.1364","article-title":"Cell subpopulations in failed human corneal grafts","volume":"83","author":"Lumsden","year":"1999","journal-title":"Br. J. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.jtos.2015.04.006","article-title":"Cytokine Expression in Keratoconus and its Corneal Microenvironment: A Systematic Review","volume":"13","author":"Wisse","year":"2015","journal-title":"Ocul. Surf."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S1367-0484(03)00022-5","article-title":"The cascade hypothesis of keratoconus","volume":"26","author":"Kenney","year":"2003","journal-title":"Cont. Lens Anterior Eye"},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.exer.2012.07.010","article-title":"Tear fluid small molecular antioxidants profiling shows lowered glutathione in keratoconus","volume":"103","author":"Saijyothi","year":"2012","journal-title":"Exp. Eye Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/S0014-4835(89)80040-5","article-title":"Phosphatic metabolites in keratoconus","volume":"49","author":"Greiner","year":"1989","journal-title":"Exp. Eye Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.exer.2015.03.008","article-title":"Metabolomic composition of normal aged and cataractous human lenses","volume":"134","author":"Tsentalovich","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_31","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_32","doi-asserted-by":"crossref","unstructured":"Wojakowska, A., Marczak, \u0141., Jelonek, K., Polanski, K., Widlak, P., and Pietrowska, M. (2015). An optimized method of metabolite extraction from formalin-fixed paraffin-embedded tissue for GC\/MS analysis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136902"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1097\/00003226-199501000-00015","article-title":"The effects of age on phosphatic metabolites of the human cornea","volume":"14","author":"Lass","year":"1995","journal-title":"Cornea"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1755-3768.2011.02271.x","article-title":"Influence of donor age, post-mortem time and cold storage on metabolic profile of human cornea","volume":"91","author":"Kryczka","year":"2013","journal-title":"Acta Ophthalmol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"546192","DOI":"10.1155\/2014\/546192","article-title":"NMR spectroscopy of human eye tissues: A new insight into ocular biochemistry","volume":"2014","author":"Kryczka","year":"2014","journal-title":"Sci. World J."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wang, H., Muehlbauer, M., O\u2019Neal, S., Newgard, C., Hauser, E., Bain, J., and Shah, S. (2017). Recommendations for Improving Identification and Quantification in Non-Targeted, GC-MS-Based Metabolomic Profiling of Human Plasma. Metabolites, 7.","DOI":"10.3390\/metabo7030045"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1136\/bjo.2008.144253","article-title":"Subclinical keratoconus and inflammatory molecules from tears","volume":"93","author":"Lema","year":"2009","journal-title":"Br. J. Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"25534","DOI":"10.1038\/srep25534","article-title":"Endocrine and Metabolic Pathways Linked to Keratoconus: Implications for the Role of Hormones in the Stromal Microenvironment","volume":"6","author":"McKay","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/WOX.0b013e3182439613","article-title":"Oxidative Stress and Antioxidant Defense","volume":"5","author":"Birben","year":"2012","journal-title":"World Allergy Organ. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1001\/archopht.1966.03850010405020","article-title":"Lipid analysis of the human cornea with and without arcus senilis","volume":"76","author":"Tschetter","year":"1966","journal-title":"Arch. Ophthalmol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1194\/jlr.R001347","article-title":"Significance of lipid mediators in corneal injury and repair","volume":"51","author":"Kenchegowda","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3109\/02713688509000847","article-title":"Inflammation-induced stimulation of the synthesis of prostaglandins and lipoxygenase-reaction products in rabbit cornea","volume":"4","author":"Bazan","year":"1985","journal-title":"Curr. Eye Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4396","DOI":"10.1167\/iovs.12-9724","article-title":"Anti-Inflammatory Effects of Alpha Linolenic Acid on Human Corneal Epithelial Cells","volume":"53","author":"Erdinest","year":"2012","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrc2981","article-title":"Regulation of cancer cell metabolism","volume":"11","author":"Cairns","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"C409","DOI":"10.1152\/ajpcell.1985.249.5.C409","article-title":"Role of glucose in corneal metabolism","volume":"249","author":"Thies","year":"1985","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_46","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":"2015","journal-title":"Sci. Rep."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/12\/2933\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:42:59Z","timestamp":1760175779000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/12\/2933"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,25]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["molecules25122933"],"URL":"https:\/\/doi.org\/10.3390\/molecules25122933","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,25]]}}}