{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:48:13Z","timestamp":1792522093358,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:00:00Z","timestamp":1650412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY026147"],"award-info":[{"award-number":["R01EY026147"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000592","name":"Fulbright commission","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/501100000592","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondation des Aveugles de Guerre","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"Philippe Foundation and the Rothschild Foundation Hospital","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tear hyperosmolarity plays an essential role in the initiation and progression of dry-eye disease. Under a hyperosmotic environment, corneal epithelial cells experience perturbations in endoplasmic reticulum function that can lead to proinflammatory signaling and apoptosis. In this study, we investigated the effect of tauroursodeoxycholic acid (TUDCA), a chemical chaperone known to protect against endoplasmic reticulum stress, on corneal epithelial cells exposed to hyperosmotic conditions. We found that the expression of the genes involved in the activation of the unfolded protein response and the pro-apoptotic transcription factor DDIT3 were markedly upregulated in patients with Sj\u00f6gren\u2019s dry-eye disease and in a human model of corneal epithelial differentiation following treatment with hyperosmotic saline. Experiments in vitro demonstrated that TUDCA prevented hyperosmotically induced cell death by reducing nuclear DNA fragmentation and caspase-3 activation. TUDCA supplementation also led to the transcriptional repression of CXCL8 and IL5, two inflammatory mediators associated with dry-eye pathogenesis. These studies highlight the role of hyperosmotic conditions in promoting endoplasmic reticulum stress in the cornea and identify TUDCA as a potential therapeutic agent for the treatment of dry-eye disease.<\/jats:p>","DOI":"10.3390\/ijms23094528","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T02:04:22Z","timestamp":1650420262000},"page":"4528","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions"],"prefix":"10.3390","volume":"23","author":[{"given":"Damien","family":"Guindolet","sequence":"first","affiliation":[{"name":"Schepens Eye Research Institute of Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114, USA"},{"name":"H\u00f4pital Fondation A. de Rothschild, 25 rue Manin, 75019 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4045-8123","authenticated-orcid":false,"given":"Ashley M.","family":"Woodward","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric E.","family":"Gabison","sequence":"additional","affiliation":[{"name":"H\u00f4pital Fondation A. de Rothschild, 25 rue Manin, 75019 Paris, France"},{"name":"UFR M\u00e9decine, Universit\u00e9 Paris Cit\u00e9, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7321-9503","authenticated-orcid":false,"given":"Pablo","family":"Arg\u00fceso","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.ajo.2008.05.016","article-title":"Advances in understanding and managing dry eye disease","volume":"146","author":"Lemp","year":"2008","journal-title":"Am. J. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1001\/archophthalmol.2009.103","article-title":"Prevalence of dry eye disease among US men: Estimates from the Physicians\u2019 Health Studies","volume":"127","author":"Schaumberg","year":"2009","journal-title":"Arch. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S0002-9394(03)00218-6","article-title":"Prevalence of dry eye syndrome among US women","volume":"136","author":"Schaumberg","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.jtos.2017.08.003","article-title":"TFOS DEWS II Report Executive Summary","volume":"15","author":"Craig","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1016\/j.ajpath.2016.02.004","article-title":"Interferon-\u03b3-Induced Unfolded Protein Response in Conjunctival Goblet Cells as a Cause of Mucin Deficiency in Sj\u00f6gren Syndrome","volume":"186","author":"Coursey","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_6","unstructured":"Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. (2002). The endoplasmic reticulum. Molecular Biology of the Cell, Garland Science. [4th ed.]."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e12169","DOI":"10.14814\/phy2.12169","article-title":"Epithelial sodium channel abundance is decreased by an unfolded protein response induced by hyperosmolality","volume":"2","author":"Crambert","year":"2014","journal-title":"Physiol. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nature07203","article-title":"From endoplasmic-reticulum stress to the inflammatory response","volume":"454","author":"Zhang","year":"2008","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1002\/iub.1576","article-title":"The rise of proteostasis promoters","volume":"68","author":"Vega","year":"2016","journal-title":"IUBMB Life"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kusaczuk, M. (2019). Tauroursodeoxycholate-Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives. Cells, 8.","DOI":"10.3390\/cells8121471"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"119252","DOI":"10.1016\/j.lfs.2021.119252","article-title":"The bile acid TUDCA and neurodegenerative disorders: An overview","volume":"272","author":"Zangerolamo","year":"2021","journal-title":"Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"197","DOI":"10.4161\/pri.28938","article-title":"The therapeutic potential of chemical chaperones in protein folding diseases","volume":"8","author":"Cortez","year":"2014","journal-title":"Prion"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1042\/BJ20101569","article-title":"Beyond the endoplasmic reticulum: Atypical GRP78 in cell viability, signalling and therapeutic targeting","volume":"434","author":"Ni","year":"2011","journal-title":"Biochem. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1167\/iovs.02-0851","article-title":"Mucin gene expression in immortalized human corneal-limbal and conjunctival epithelial cell lines","volume":"44","author":"Gipson","year":"2003","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1167\/iovs.05-0735","article-title":"Mucin characteristics of human corneal-limbal epithelial cells that exclude the rose bengal anionic dye","volume":"47","author":"Argueso","year":"2006","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.1016\/j.bbamcr.2013.06.028","article-title":"ER stress-induced cell death mechanisms","volume":"1833","author":"Sano","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"pdb prot087379","DOI":"10.1101\/pdb.prot087379","article-title":"Crystal violet assay for determining viability of cultured cells","volume":"2016","author":"Feoktistova","year":"2016","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"F1678","DOI":"10.1152\/ajprenal.90424.2008","article-title":"Analysis of DNA breaks, DNA damage response, and apoptosis produced by high NaCl","volume":"295","author":"Dmitrieva","year":"2008","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.neulet.2003.12.080","article-title":"Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12","volume":"357","author":"Hitomi","year":"2004","journal-title":"Neurosci. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7464","DOI":"10.1073\/pnas.93.15.7464","article-title":"In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains","volume":"93","author":"Armstrong","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1097\/ICO.0b013e318030d259","article-title":"Hyperosmolarity-induced apoptosis in human corneal epithelial cells is mediated by cytochrome c and MAPK pathways","volume":"26","author":"Luo","year":"2007","journal-title":"Cornea"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.jtos.2017.05.011","article-title":"TFOS DEWS II pathophysiology report","volume":"15","author":"Bron","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1001\/archophthalmol.2011.364","article-title":"Dry eye disease: An immune-mediated ocular surface disorder","volume":"130","author":"Stevenson","year":"2012","journal-title":"Arch. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.jtos.2013.07.003","article-title":"Role of hyperosmolarity in the pathogenesis and management of dry eye disease: Proceedings of the OCEAN group meeting","volume":"11","author":"Baudouin","year":"2013","journal-title":"Ocul. Surf."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1167\/iovs.18-25583","article-title":"Rapamycin Rescues Endoplasmic Reticulum Stress-Induced Dry Eye Syndrome in Mice","volume":"60","author":"Cho","year":"2019","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1007\/s10495-019-01558-4","article-title":"Hyperosmotic stress promotes endoplasmic reticulum stress-dependent apoptosis in adult rat cardiac myocytes","volume":"24","author":"Burgos","year":"2019","journal-title":"Apoptosis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"14393","DOI":"10.1074\/jbc.RA117.001032","article-title":"TRPM7 channels play a role in high glucose-induced endoplasmic reticulum stress and neuronal cell apoptosis","volume":"293","author":"Huang","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhang, J.Y., Diao, Y.F., Kim, H.R., and Jin, D.I. (2012). Inhibition of endoplasmic reticulum stress improves mouse embryo development. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040433"},{"key":"ref_29","first-page":"860","article-title":"High osmotic pressure increases reactive oxygen species generation in rabbit corneal epithelial cells by endoplasmic reticulum","volume":"8","author":"Wang","year":"2016","journal-title":"Am. J. Transl. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3066","DOI":"10.1101\/gad.1250704","article-title":"CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum","volume":"18","author":"Marciniak","year":"2004","journal-title":"Genes Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1016\/j.celrep.2017.11.027","article-title":"GADD34 Function in Protein Trafficking Promotes Adaptation to Hyperosmotic Stress in Human Corneal Cells","volume":"21","author":"Krokowski","year":"2017","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3671","DOI":"10.1167\/iovs.08-2689","article-title":"A link between tear instability and hyperosmolarity in dry eye","volume":"50","author":"Liu","year":"2009","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1167\/iovs.02-0581","article-title":"Apoptosis of ocular surface cells in experimentally induced dry eye","volume":"44","author":"Yeh","year":"2003","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s12177-009-9030-x","article-title":"Bile acids in treatment of ocular disease","volume":"2","author":"Boatright","year":"2009","journal-title":"J. Ocul. Biol. Dis. Infor."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6087","DOI":"10.1073\/pnas.1031632100","article-title":"Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats","volume":"100","author":"Rodrigues","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3176","DOI":"10.1038\/s41598-018-21621-5","article-title":"Anti-inflammatory effect of Tauroursodeoxycholic acid in RAW 264.7 macrophages, Bone marrow-derived macrophages, BV2 microglial cells, and spinal cord injury","volume":"8","author":"Kim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ajo.2008.08.032","article-title":"Tear cytokine profiles in dysfunctional tear syndrome","volume":"147","author":"Lam","year":"2009","journal-title":"Am. J. Ophthalmol."},{"key":"ref_38","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_39","first-page":"862","article-title":"Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease","volume":"16","author":"Castellanos","year":"2010","journal-title":"Mol. Vis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1097\/00003226-200310000-00008","article-title":"Grading of corneal and conjunctival staining in the context of other dry eye tests","volume":"22","author":"Bron","year":"2003","journal-title":"Cornea"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/978-1-61779-513-8_19","article-title":"Assessing mucin expression and function in human ocular surface epithelia in vivo and in vitro","volume":"842","author":"Argueso","year":"2012","journal-title":"Methods Mol. Biol"},{"key":"ref_42","first-page":"1243","article-title":"Osmoprotectants suppress the production and activity of matrix metalloproteinases induced by hyperosmolarity in primary human corneal epithelial cells","volume":"20","author":"Deng","year":"2014","journal-title":"Mol. Vis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1016\/j.celrep.2015.05.012","article-title":"Acute Lung Injury Results from Innate Sensing of Viruses by an ER Stress Pathway","volume":"11","author":"Hrincius","year":"2015","journal-title":"Cell Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/B978-0-12-385114-7.00004-0","article-title":"Measuring ER stress and the unfolded protein response using mammalian tissue culture system","volume":"490","author":"Oslowski","year":"2011","journal-title":"Methods Enzymol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4528\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:57:10Z","timestamp":1760137030000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4528"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,20]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23094528"],"URL":"https:\/\/doi.org\/10.3390\/ijms23094528","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,20]]}}}