{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:16:20Z","timestamp":1786979780862,"version":"build-2736575974"},"reference-count":84,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T00:00:00Z","timestamp":1757030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Republic of Korea (NRF)","doi-asserted-by":"publisher","award":["NRF-2017R1A2B4004758"],"award-info":[{"award-number":["NRF-2017R1A2B4004758"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Republic of Korea (NRF)","doi-asserted-by":"publisher","award":["NRF-2020R1I1A1A01072862"],"award-info":[{"award-number":["NRF-2020R1I1A1A01072862"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Republic of Korea (NRF)","doi-asserted-by":"publisher","award":["RS-2024-00463346"],"award-info":[{"award-number":["RS-2024-00463346"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Polyhexamethylene guanidine phosphate (PHMG-p), a widely used disinfectant component in household humidifiers, has been implicated in various health issues, including pulmonary toxicity. Many people use humidifiers to improve dry eye disease (DED). The current study was performed to elucidate the effect of PHMG-p on eye dryness in a rat model using metabolomics. Male Sprague Dawley rats were exposed to PHMG-p (0.1% and 0.3%) following a previously established DED induction model using scopolamine hydrobromide and desiccation stress. Ocular surface damage was assessed using corneal fluorescein staining, tear volume measurement, and tear break-up time (TBUT). Plasma and urine samples were analyzed using 1H-NMR-based metabolomics to identify metabolic alterations associated with PHMG-P-p exposure and DED pathogenesis. PHMG-p exposure exacerbated DED symptoms, as evidenced by a significant reduction in tear volume, shorter TBUT, and increased corneal damage compared to the control group. Metabolomic profiling identified distinct metabolic changes in PHMG-p-exposed groups, including alterations in glutamate, glycine, citrate, and succinate metabolism. These metabolic changes correlated with increased levels of inflammatory cytokines such as IL-1\u03b2, IL-6, and TNF-\u03b1 in the corneal and lacrimal gland tissues. Our findings suggest that PHMG-p exposure contributes to DED pathophysiology by inducing metabolic disturbances and inflammatory responses in the ocular surface. This study highlights the need for further investigation into the potential risks of PHMG-p exposure on ocular health and provides novel insights into the metabolic underpinnings of DED.<\/jats:p>","DOI":"10.3390\/ijms26178660","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T12:18:18Z","timestamp":1757074698000},"page":"8660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effects of Exposure of PHMG-p, a Humidifier Disinfectant Component, on Eye Dryness: A Study on a Rat Model Based on 1H-NMR Metabolomics"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0714-8596","authenticated-orcid":false,"given":"Jung Dae","family":"Lee","sequence":"first","affiliation":[{"name":"College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea"},{"name":"Center for Human Risk Assessment, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3203-462X","authenticated-orcid":false,"given":"Hyang Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea"},{"name":"Center for Human Risk Assessment, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Bean","family":"Oh","sequence":"additional","affiliation":[{"name":"College of Medicine, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3846-4260","authenticated-orcid":false,"given":"Hyeyoon","family":"Goo","sequence":"additional","affiliation":[{"name":"College of Medicine, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyong Jin","family":"Cho","sequence":"additional","affiliation":[{"name":"College of Medicine, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1357-1633","authenticated-orcid":false,"given":"Gi-Wook","family":"Hwang","sequence":"additional","affiliation":[{"name":"Division of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhkmann","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Center for Proteome Biophysics, and Chemistry Institute for Functional Materials, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2139-2296","authenticated-orcid":false,"given":"Kyu-Bong","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea"},{"name":"Center for Human Risk Assessment, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,5]]},"reference":[{"key":"ref_1","unstructured":"Golden, M.I., Meyer, J.J., Zeppieri, M., and Patel, B.C. (2025, March 21). Dry Eye Syndrome, StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK470411\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.exer.2003.09.003","article-title":"The Role of the Lacrimal Functional Unit in the Pathophysiology of Dry Eye","volume":"78","author":"Stern","year":"2004","journal-title":"Exp. Eye Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.4103\/IJO.IJO_796_23","article-title":"Dry Eye Disease = DED = A Disease Eluding Diagnosis","volume":"71","author":"Honavar","year":"2023","journal-title":"Indian J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s43188-025-00282-3","article-title":"Short-term Health Effects of Tear Agents Chlorobenzylidenemalonitrile and Oleoresin Capsicum During the Civil Riots of Santiago de Chile in 2019\u20132020","volume":"41","author":"Bravo","year":"2025","journal-title":"Toxicol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Inomata, T., Iwagami, M., Hiratsuka, Y., Fujimoto, K., Okumura, Y., Shiang, T., and Murakami, A. (2018). Maximum Blink Interval Is Associated with Tear Film Breakup Time: A New Simple, Screening Test for Dry Eye Disease. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-31814-7"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Research Subcommittee of the International Dry Eye WorkShop (2007). Research in Dry Eye: Report of the Research Subcommittee of the International Dry Eye WorkShop. Ocul. Surf., 5, 179\u2013193.","DOI":"10.1016\/S1542-0124(12)70086-1"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8763","DOI":"10.3892\/mmr.2017.7754","article-title":"Evaluation of a Novel Dry Eye Model Induced by Oral Administration of Finasteride","volume":"16","author":"Li","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_8","first-page":"1356","article-title":"Flow Cytometric Analysis of Inflammatory Markers in Conjunctival Epithelial Cells of Patients with Dry Eyes","volume":"41","author":"Brignole","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1167\/iovs.05-1364","article-title":"Conjunctival Cytokine Expression in Symptomatic Moderate Dry Eye Subjects","volume":"47","author":"Narayanan","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S211","DOI":"10.1016\/S0039-6257(00)00200-9","article-title":"The Pathology of Dry Eye","volume":"45","author":"Baudouin","year":"2001","journal-title":"Surv. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/S1542-0124(12)70148-9","article-title":"Inflammation in Dry Eye","volume":"2","author":"Stern","year":"2004","journal-title":"Ocul. Surf."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1097\/ICO.0b013e31803dcda2","article-title":"Interleukin-6 and Tumor Necrosis Factor-Alpha Levels in Tears of Patients with Dry Eye Syndrome","volume":"26","author":"Yoon","year":"2007","journal-title":"Cornea"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4302","DOI":"10.1167\/iovs.04-0299","article-title":"Stimulation of Matrix Metalloproteinases by Hyperosmolarity via a JNK Pathway in Human Corneal Epithelial Cells","volume":"45","author":"Li","year":"2004","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.exer.2005.08.019","article-title":"JNK and ERK MAP Kinases Mediate Induction of IL-1\u03b2, TNF-\u03b1 and IL-8 Following Hyperosmolar Stress in Human Limbal Epithelial Cells","volume":"82","author":"Li","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.jtos.2023.08.004","article-title":"TNF Is a Critical Cytokine in Age-Related Dry Eye Disease","volume":"30","author":"Kelagere","year":"2023","journal-title":"Ocul. Surf."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5665","DOI":"10.12998\/wjcc.v12.i25.5665","article-title":"Analyze Interleukin-1\u03b2, Interleukin-6, and Tumor Necrosis Factor-Alpha Levels in Dry Eye and the Therapeutic Effect of Cyclosporine A","volume":"12","author":"Wu","year":"2024","journal-title":"World J. Clin. Cases"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7557","DOI":"10.1167\/iovs.12-11515","article-title":"Neutralization of Ocular Surface TNF-Alpha Reduces Ocular Surface and Lacrimal Gland Inflammation Induced by In Vivo Dry Eye","volume":"54","author":"Ji","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_18","unstructured":"HIRA (Health Insurance Review and Assessment Service) (2025, March 21). Information on Statistical Illnesses: Statistics on Diseases. Available online: https:\/\/www.hira.or.kr\/ra\/stcIlnsInfm\/stcIlnsInfmView.do?pgmid=HIRAA030502000000&sortSno=192&utm_source=chatgpt.com."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Choi, J.H., and Kim, K. (2024). Polyhexamethylene Guanidine Phosphate Enhanced Procoagulant Activity through Oxidative-Stress-Mediated Phosphatidylserine Exposure in Platelets. Toxics, 12.","DOI":"10.3390\/toxics12010050"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1111\/j.1365-2672.2005.02664.x","article-title":"Cationic Antiseptics: Diversity of Action under a Common Epithet","volume":"99","author":"Gilbert","year":"2005","journal-title":"J. Appl. Microbiol."},{"key":"ref_21","unstructured":"(2025, March 21). The Special Investigation Commission on Humidifier Disinfectant Disaster and Sewol Ferry Disaster. Available online: https:\/\/socialdisasterscommission.co.kr\/."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"415","DOI":"10.2131\/jts.44.415","article-title":"Polyhexamethylene Guanidine Phosphate-Induced ROS-Mediated DNA Damage Caused Cell Cycle Arrest and Apoptosis in Lung Epithelial Cells","volume":"44","author":"Park","year":"2019","journal-title":"J. Toxicol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1007\/s00204-020-02657-x","article-title":"Integration of Transcriptomics, Proteomics and Metabolomics Identifies Biomarkers for Pulmonary Injury by Polyhexamethylene Guanidine Phosphate (PHMG-P-p), a Humidifier Disinfectant, in Rats","volume":"94","author":"Lee","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jeong, M.H., Jeon, M.S., Kim, G.E., and Kim, H.R. (2021). Polyhexamethylene Guanidine Phosphate Induces Apoptosis through Endoplasmic Reticulum Stress in Lung Epithelial Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031215"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jeong, S.H., Lee, H., Nam, Y.J., Kang, J.Y., Lee, H., Choi, J.Y., Lee, Y.S., Kim, J., Park, Y.H., and Park, S.A. (2024). Longitudinal Long Term Follow-Up Investigation on the Carcinogenic Impact of Polyhexamethylene Guanidine Phosphate in Rat Models. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-57605-x"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s43188-024-00269-6","article-title":"Effect of CTMP1 Gene on Pulmonary Fibrosis","volume":"41","author":"Nguyen","year":"2025","journal-title":"Toxicol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxlet.2022.03.009","article-title":"Polyhexamethylene Guanidine Phosphate-Induced Necrosis May Be Linked to Pulmonary Fibrosis","volume":"362","author":"Kang","year":"2022","journal-title":"Toxicol. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"694","DOI":"10.3390\/toxics10110694","article-title":"Hematotoxic Effect of Respiratory Exposure to PHMG-P-p and Its Integrated Genetic Analysis","volume":"10","author":"Sung","year":"2022","journal-title":"Toxics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1097\/OPX.0000000000001136","article-title":"Randomized Trial of Desktop Humidifier for Dry Eye Relief in Computer Users","volume":"94","author":"Wang","year":"2017","journal-title":"Optom. Vis. Sci."},{"key":"ref_30","unstructured":"HIRA (Health Insurance Review and Assessment Service) (2025, March 21). Dry Eye Syndrome\u2019 Cannot Be Relieved even in Spring and Summer. Available online: https:\/\/www.hira.or.kr\/bbsDummy.do?pgmid=HIRAA020041000100&brdScnBltNo=4&brdBltNo=8709&pageIndex=1."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15287394.2021.1967821","article-title":"Metabolomics profiling of valproic acid-induced symptoms resembling autism spectrum disorders using 1H NMR spectral analysis in rat model","volume":"85","author":"Kim","year":"2022","journal-title":"J. Toxicol. Environ. Health A"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1093\/toxres\/tfad008","article-title":"Integration of serum metabolomics and network pharmacology reveals the immunoenhancing mechanisms of Qishenbuqi capsules","volume":"12","author":"Zhao","year":"2023","journal-title":"Toxicol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Al-Sulaiti, H., Almaliti, J., Naman, C.B., Al Thani, A.A., and Yassine, H.M. (2023). Metabolomics approaches for the diagnosis, treatment, and better disease management of viral infections. Metabolites, 13.","DOI":"10.3390\/metabo13080948"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Vo, D.K., and Trinh, K.T.L. (2024). Emerging biomarkers in metabolomics: Advancements in precision health and disease diagnosis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252313190"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e792","DOI":"10.1002\/mco2.792","article-title":"Metabolomics-driven approaches for identifying therapeutic targets in drug discovery","volume":"5","author":"Pan","year":"2024","journal-title":"MedComm (2020)"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"290","DOI":"10.4103\/epj.epj_10_19","article-title":"Metabolomics applications in disease diagnosis, treatment, and drug discovery","volume":"18","author":"Ghanem","year":"2019","journal-title":"Egypt. Pharm. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/joim.20090","article-title":"Metabolomics in cardiometabolic diseases: Key biomarkers and therapeutic implications for insulin resistance and diabetes","volume":"297","author":"Henderson","year":"2025","journal-title":"J. Intern. Med."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Gonzalez-Covarrubias, V., Mart\u00ednez-Mart\u00ednez, E., and Del Bosque-Plata, L. (2022). The Potential of Metabolomics in Biomedical Applications. Metabolites, 12.","DOI":"10.3390\/metabo12020194"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6563","DOI":"10.1021\/acs.analchem.4c06061","article-title":"Beyond targeted newborn screening: A nontargeted metabolomics workflow to investigate birthweight-metabolome correlations","volume":"97","author":"Asef","year":"2025","journal-title":"Anal. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Hasan, M.R., Suleiman, M., and P\u00e9rez-L\u00f3pez, A. (2021). Metabolomics in the Diagnosis and Prognosis of COVID-19. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.721556"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Rahman, M., and Schellhorn, H.E. (2023). Metabolomics of infectious diseases in the era of personalized medicine. Front. Mol. Biosci., 10.","DOI":"10.3389\/fmolb.2023.1120376"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Jiang, Y., Yang, C., Zheng, Y., Liu, Y., and Chen, Y. (2020). A Set of Global Metabolomic Biomarker Candidates to Predict the Risk of Dry Eye Disease. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00344"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.ophtha.2016.12.011","article-title":"A Metabolome-Wide Study of Dry Eye Disease Reveals Serum Androgens as Biomarkers","volume":"124","author":"Vehof","year":"2017","journal-title":"Ophthalmology"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Fineide, F.A., Tashbayev, B., Elgst\u00f8en, K.B.P., Sand\u00e5s, E.M., Rootwelt, H., Hynne, H., Chen, X., R\u00e6der, S., Vehof, J., and Dartt, D. (2023). Tear and Saliva Metabolomics in Evaporative Dry Eye Disease in Females. Metabolites, 13.","DOI":"10.3390\/metabo13111125"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1080\/15287394.2020.1867274","article-title":"Metabolomics approach to biomarkers of dry eye disease using 1H-NMR in rats","volume":"84","author":"Lee","year":"2021","journal-title":"J. Toxicol. Environ. Health A"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1080\/15287394.2024.2393770","article-title":"Mass Spectrometry (MS)-Based Metabolomics of Plasma and Urine in Dry Eye Disease (DED)-Induced Rat Model","volume":"88","author":"Kim","year":"2025","journal-title":"J. Toxicol. Environ. Health A"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41392-024-02119-1","article-title":"Identification of glutamine as a potential therapeutic target in dry eye disease","volume":"10","author":"Chen","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Xia, J., and Wishart, D.S. (2016). Using MetaboAnalyst 3.0 for comprehensive metabolomics data analysis. Curr. Protoc. Bioinform., 55.","DOI":"10.1002\/cpbi.11"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e2021009","DOI":"10.5620\/eaht.2021009","article-title":"Fibrosis as a Result of Polyhexamethylene Guanide Exposure in Cultured Statens Seruminstitut Rabbit Cornea (SIRC) Cells","volume":"36","author":"Lee","year":"2021","journal-title":"Environ. Anal. Health Toxicol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e2019004","DOI":"10.5620\/eht.e2019004","article-title":"Eye Irritation Tests of Polyhexamethylene Guanidine Phosphate (PHMG) and Chloromethylisothiazolinone\/Methylisothiazolinone (CMIT\/MIT) Using a Tissue Model of Reconstructed Human Cornea-Like Epithelium","volume":"34","author":"Park","year":"2019","journal-title":"Environ. Health Toxicol."},{"key":"ref_51","first-page":"153","article-title":"Toxicity and Safety Analysis of Polyhexamethylene Guanidine: A Comprehensive Systematic Review","volume":"3","author":"Ivanov","year":"2024","journal-title":"Sci. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1167\/iovs.07-0069","article-title":"Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-gamma","volume":"48","author":"Villarreal","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1167\/tvst.12.12.22","article-title":"Noninvasive Imaging of Conjunctival Goblet Cells as a Method for Diagnosing Dry Eye Disease in an Experimental Mouse Model","volume":"12","author":"Kim","year":"2023","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1097\/ICO.0b013e3181a16578","article-title":"Analysis of Inflammatory Cytokines in the Tears of Dry Eye Patients","volume":"28","author":"Massingale","year":"2009","journal-title":"Cornea"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Roda, M., Corazza, I., Bacchi Reggiani, M.L., Pellegrini, M., Taroni, L., Giannaccare, G., and Versura, P. (2020). Dry Eye Disease and Tear Cytokine Levels\u2014A Meta-Analysis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093111"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1074\/mcp.M111.016006","article-title":"Urine Metabolomics Analysis for Biomarker Discovery and Detection of Jaundice Syndrome in Patients with Liver Disease","volume":"11","author":"Wang","year":"2012","journal-title":"Mol. Cell Proteom."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Xu, J., Chen, Y., Zhang, R., He, J., Song, Y., Wang, J., Wang, H., Wang, L., Zhan, Q., and Abliz, Z. (2016). Global Metabolomics Reveals Potential Urinary Biomarkers of Esophageal Squamous Cell Carcinoma for Diagnosis and Staging. Sci. Rep., 6.","DOI":"10.1038\/srep35010"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Anesi, A., Rubert, J., Oluwagbemigun, K., Orozco-Ruiz, X., N\u00f6thlings, U., Breteler, M.M.B., and Mattivi, F. (2019). Metabolic Profiling of Human Plasma and Urine, Targeting Tryptophan, Tyrosine and Branched Chain Amino Acid Pathways. Metabolites, 9.","DOI":"10.3390\/metabo9110261"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1074\/mcp.M800165-MCP200","article-title":"Urine Metabolomics Analysis for Kidney Cancer Detection and Biomarker Discovery","volume":"8","author":"Kim","year":"2009","journal-title":"Mol. Cell Proteom."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1038\/nprot.2010.82","article-title":"Combining Genetic Diversity, Informatics and Metabolomics to Facilitate Annotation of Plant Gene Function","volume":"5","author":"Tohge","year":"2010","journal-title":"Nat. Protoc."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Villas-Boas, S.G., Nielsen, J., Smedsgaard, J., Hansen, M.A.E., and Roessner-Tunali, U. (2007). Metabolomics in humans and other mammals. Metabolome Analysis: An Introduction, John Wiley and Sons.","DOI":"10.1002\/0470105518"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Cruzat, V., Macedo Rogero, M., Keane, K.N., Curi, R., and Newsholme, P. (2018). Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients, 10.","DOI":"10.20944\/preprints201809.0459.v1"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/npp.2016.199","article-title":"Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders","volume":"42","author":"Haroon","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Zheng, X., Zhu, Y., Zhao, Z., Chu, Y., and Yang, W. (2023). The Role of Amino Acid Metabolism in Inflammatory Bowel Disease and Other Inflammatory Diseases. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1284133"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"C1399","DOI":"10.1152\/ajpcell.00386.2005","article-title":"Glutamate Induces Oxidative Stress and Apoptosis in Cerebral Vascular Endothelial Cells: Contributions of HO-1 and HO-2 to Cytoprotection","volume":"290","author":"Parfenova","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.ejphar.2008.09.047","article-title":"Glycine regulates the production of pro-inflammatory cytokines in lean and monosodium glutamate-obese mice","volume":"599","author":"Blancas","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Aguayo-Cer\u00f3n, K.A., S\u00e1nchez-Mu\u00f1oz, F., Gutierrez-Rojas, R.A., Acevedo-Villavicencio, L.N., Flores-Zarate, A.V., Huang, F., Giacoman-Martinez, A., Villafa\u00f1a, S., and Romero-Nava, R. (2023). Glycine: The Smallest Anti-Inflammatory Micronutrient. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411236"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/s41419-019-1877-6","article-title":"Lactate and Pyruvate Promote Oxidative Stress Resistance Through Hormetic ROS Signaling","volume":"10","author":"Tauffenberger","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2006.11.032","article-title":"Pyruvate Protects Mitochondria from Oxidative Stress in Human Neuroblastoma SK-N-SH Cells","volume":"1132","author":"Wang","year":"2007","journal-title":"Brain Res."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Choi, I., Son, H., and Baek, J.H. (2021). Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses. Life, 11.","DOI":"10.3390\/life11010069"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Williams, N.C., and O\u2019Neill, L.A.J. (2018). A Role for the Krebs Cycle Intermediate Citrate in Metabolic Reprogramming in Innate Immunity and Inflammation. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00141"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00726-008-0210-y","article-title":"Arginine Metabolism and Nutrition in Growth, Health and Disease","volume":"37","author":"Wu","year":"2009","journal-title":"Amino Acids"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e70009","DOI":"10.1002\/jimd.70009","article-title":"Amino Acid Metabolism and Immune Dysfunction in Urea Cycle Disorders: T and B Cell Perspectives","volume":"48","author":"Kiykim","year":"2025","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_74","first-page":"87","article-title":"Is Citrate a Critical Signal in Immunity and Inflammation?","volume":"1","author":"Zotta","year":"2020","journal-title":"J. Cell Signal."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41467-019-13668-3","article-title":"Mitochondrial TCA Cycle Metabolites Control Physiology and Disease","volume":"11","author":"Chandel","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/JLB.3MIR1118-415R","article-title":"Regulation of Leukocyte Function by Citric Acid Cycle Intermediates","volume":"106","author":"Patil","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s42255-018-0014-7","article-title":"Coupling Krebs Cycle Metabolites to Signalling in Immunity and Cancer","volume":"1","author":"Ryan","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Ramendra, R., Mancini, M., Ayala, J.M., Tung, L.T., Isnard, S., Lin, J., Routy, J.P., Nijnik, A., and Langlais, D. (2021). Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1\u21923)-\u03b2-D-Glucan. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.694152"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.immuni.2017.03.019","article-title":"Glutathione Primes T Cell Metabolism for Inflammation","volume":"46","author":"Mak","year":"2017","journal-title":"Immunity"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1007\/s00417-008-0784-9","article-title":"Time Course of Ocular Surface and Lacrimal Gland Changes in a New Scopolamine-Induced Dry Eye Model","volume":"246","author":"Viau","year":"2008","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1007\/s00417-009-1080-z","article-title":"Efficacy of a 2-Month Dietary Supplementation with Polyunsaturated Fatty Acids in Dry Eye Induced by Scopolamine in a Rat Model","volume":"247","author":"Viau","year":"2009","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"S25","DOI":"10.1097\/ICO.0b013e31826a80ea","article-title":"Effectiveness of Topical Infliximab in a Mouse Model of Experimental Dry Eye","volume":"31","author":"Li","year":"2012","journal-title":"Cornea"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1167\/iovs.12-10648","article-title":"Therapeutic Effect of Topical Adiponectin in a Mouse Model of Desiccating Stress-Induced Dry Eye","volume":"54","author":"Li","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"7267","DOI":"10.1167\/iovs.11-7231","article-title":"Tear production and ocular surface changes in experimental dry eye after elimination of desiccating stress","volume":"52","author":"Yoon","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8660\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:40:15Z","timestamp":1760035215000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8660"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,5]]},"references-count":84,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178660"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178660","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,5]]}}}