{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T23:53:24Z","timestamp":1784159604129,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,25]],"date-time":"2020-05-25T00:00:00Z","timestamp":1590364800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008783","name":"National Research Council of Science and Technology","doi-asserted-by":"publisher","award":["CCP-13-20-KRICT"],"award-info":[{"award-number":["CCP-13-20-KRICT"]}],"id":[{"id":"10.13039\/501100008783","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dry eye syndrome is the most common eye disease and it is caused by various reasons. As the balance of the tear film that protects the eyes is broken due to various causes, it becomes impossible to properly protect the eyes. In this study, the protective effects and underlying mechanisms of topical (E)-4-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)adamantan-1-carboxamide (KR-67607), a novel selective 11\u03b2-hydroxysteroid dehydrogenase 1 (11\u03b2-HSD1) inhibitor, were investigated in benzalkonium chloride (BAC)-induced dry eye syndrome. BAC-treated rat eyes induced significant increases in ocular surface damage, decreased corneal thickness, corneal basement membrane destruction in the conjunctival epithelium, and expression of pro-inflammatory cytokines tumor necrosis factor-\u03b1 and 11\u03b2-HSD1. These effects of BAC were reversed by topical KR-67607 treatment. Furthermore, KR-67607 decreased 4-hydroxynonenal expression and increased antioxidant and mucus secretion in BAC-treated rat eyes. Taken together, a novel selective 11\u03b2-HSD1 inhibitor can prevent BAC-induced dry eye syndrome by inhibiting pro-inflammatory cytokine and reactive oxygen species expression via the inhibition of both 11\u03b2-HSD1 activity and expression.<\/jats:p>","DOI":"10.3390\/ijms21103729","type":"journal-article","created":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T03:29:10Z","timestamp":1590463750000},"page":"3729","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Novel Selective 11\u03b2-HSD1 Inhibitor, (E)-4-(2-(6-(2,6-Dichloro-4-(Trifluoromethyl)Phenyl)-4-Methyl-1,1-Dioxido-1,2,6-Thiadiazinan-2-yl)Acetamido)Adamantan-1-Carboxamide (KR-67607), Prevents BAC-Induced Dry Eye Syndrome"],"prefix":"10.3390","volume":"21","author":[{"given":"Yoon-Ju","family":"Na","sequence":"first","affiliation":[{"name":"Therapeutics &amp; Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea"},{"name":"Department of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoung Jin","family":"Choi","sequence":"additional","affiliation":[{"name":"Therapeutics &amp; Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won Hoon","family":"Jung","sequence":"additional","affiliation":[{"name":"Therapeutics &amp; Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Bum","family":"Park","sequence":"additional","affiliation":[{"name":"Therapeutics &amp; Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sein","family":"Kang","sequence":"additional","affiliation":[{"name":"Therapeutics &amp; Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6957-6062","authenticated-orcid":false,"given":"Jin Hee","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Therapeutics &amp; Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea"},{"name":"Department of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.12688\/f1000research.16468.1","article-title":"What\u2019s new in dry eye disease diagnosis? Current advances and challenges","volume":"7","author":"Aggarwal","year":"2018","journal-title":"F1000Research"},{"key":"ref_2","first-page":"71","article-title":"The Pathophysiology, Diagnosis, and treatment of dry eye disease","volume":"112","author":"Messmer","year":"2015","journal-title":"Dtsch. Aerzteblatt Online"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s40662-019-0137-2","article-title":"Dry eye disease immune responses and topical therapy","volume":"6","author":"Mcmonnies","year":"2019","journal-title":"Eye Vis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1515\/hmbci-2014-0021","article-title":"Glucocorticoid hormones and energy homeostasis","volume":"19","author":"Rose","year":"2014","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_5","first-page":"99","article-title":"Regulation of glucose homeostasis by glucocorticoids","volume":"872","author":"Kuo","year":"2015","journal-title":"Single Mol. Single Cell Seq."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.cardiores.2004.07.006","article-title":"Does altered glucocorticoid homeostasis increase cardiovascular risk?","volume":"64","author":"Girod","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1097\/MED.0000000000000152","article-title":"Cortisol dysregulation in obesity-related metabolic disorders","volume":"22","author":"Baudrand","year":"2015","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/cts.12618","article-title":"Safety, pharmacokinetics, and pharmacodynamics of ASP3662, a novel 11\u03b2-hydroxysteroid dehydrogenase type 1 inhibitor, in healthy young and elderly subjects","volume":"12","author":"Bellaire","year":"2019","journal-title":"Clin. Transl. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"96263","DOI":"10.18632\/oncotarget.22015","article-title":"11\u03b2-HSD1 inhibition ameliorates diabetes-induced cardiomyocyte hypertrophy and cardiac fibrosis through modulation of EGFR activity","volume":"8","author":"Zou","year":"2017","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1359\/jbmr.2002.17.6.979","article-title":"Osteoblastic 11\u03b2-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure","volume":"17","author":"Cooper","year":"2002","journal-title":"J. Bone Miner. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1210\/en.2011-1398","article-title":"11\u03b2-Hydroxysteroid dehydrogenase type 1, but not type 2, deficiency worsens acute inflammation and experimental arthritis in mice","volume":"153","author":"Coutinho","year":"2012","journal-title":"Endocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.bbrc.2012.01.139","article-title":"Contribution of glucocorticoid-mineralocorticoid receptor pathway on the obesity-related adipocyte dysfunction","volume":"419","author":"Hirata","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1093\/qjmed\/hcg085","article-title":"Inhibition of 11\u03b2-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension","volume":"96","author":"Rauz","year":"2003","journal-title":"QJM"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e000063","DOI":"10.1136\/bmjophth-2016-000063","article-title":"Oral administration of the 11\u03b2-hydroxysteroid-dehydrogenase type 1 inhibitor RO5093151 to patients with glaucoma: An adaptive, randomised, placebo-controlled clinical study","volume":"1","author":"Schwab","year":"2017","journal-title":"BMJ Open Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.cellsig.2012.01.008","article-title":"Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling","volume":"24","author":"Ray","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sharma, P., Jha, A., Shanker Dubey, R., and Pessarakli, M. (2012). Reactive oxygen species, oxidative damage, and antioxidative defense mechanism in plants under stressful conditions. J. Bot., 2012.","DOI":"10.1155\/2012\/217037"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e98","DOI":"10.1097\/MJT.0b013e3181ea31ff","article-title":"Reactive Oxygen Species and the aging eye: Specific role of metabolically active mitochondria in maintaining lens function and in the initiation of the oxidation-induced maturity onset cataract\u2014A novel platform of mitochondria-targeted antioxidants with broad therapeutic potential for redox regulation and detoxification of oxidants in eye diseases","volume":"23","author":"Babizhayev","year":"2016","journal-title":"Am. J. Ther."},{"key":"ref_18","first-page":"637","article-title":"Oxidative stress and its downstream signaling in aging eyes","volume":"9","author":"Nucci","year":"2014","journal-title":"Clin. Interv. Aging"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"DES163","DOI":"10.1167\/iovs.17-23402","article-title":"Potential Role of Oxidative Stress in Ocular Surface Inflammation and Dry Eye Disease","volume":"59","author":"Dogru","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jsbmb.2008.04.003","article-title":"Modification of microsomal 11\u03b2-HSD1 activity by cytosolic compounds: Glutathione and hexose phosphoesters","volume":"111","author":"McCormick","year":"2008","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.bbrc.2015.11.034","article-title":"Protective effect of carbenoxolone on ER stress-induced cell death in hypothalamic neurons","volume":"468","author":"Kim","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1007\/s10495-017-1419-6","article-title":"Protective effects of carbenoxolone, an 11\u03b2-HSD1 inhibitor, against chemical induced dry eye syndrome","volume":"22","author":"Na","year":"2017","journal-title":"Apoptosis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113632","DOI":"10.1016\/j.bcp.2019.113632","article-title":"Protective effect of a novel selective 11\u03b2-HSD1 inhibitor on eye ischemia-reperfusion induced glaucoma","volume":"169","author":"Choi","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1159\/000055579","article-title":"Comparison of the effects of preserved and unpreserved formulations of timolol on the ocular surface of albino rabbits","volume":"32","author":"Pisella","year":"2000","journal-title":"Ophthalmic Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1136\/bjo.59.11.667","article-title":"Effect of benzalkonium chloride on the stability of the precorneal tear film in rabbit and man","volume":"59","author":"Wilson","year":"1975","journal-title":"Br. J. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1136\/bjo.79.4.339","article-title":"Effect of timolol with and without preservative on the basal tear turnover in glaucoma","volume":"79","author":"Kuppens","year":"1995","journal-title":"Br. J. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1097\/00003226-199907000-00002","article-title":"Corneal thickness is reduced in dry eye","volume":"18","author":"Liu","year":"1999","journal-title":"Cornea"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10630","DOI":"10.1038\/srep10630","article-title":"The oxidant role of 4-hydroxynonenal in corneal epithelium","volume":"5","author":"Chen","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"360438","DOI":"10.1155\/2014\/360438","article-title":"Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal","volume":"2014","author":"Ayala","year":"2014","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1167\/iovs.14-15463","article-title":"Role of glutathione peroxidase 4 in conjunctival epithelial cells","volume":"56","author":"Sakai","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1001\/archopht.1984.01040030851031","article-title":"Conjunctival goblet cell densities in ocular surface disease","volume":"102","author":"Nelson","year":"1984","journal-title":"Arch. Ophthalmol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0161-6420(97)30330-3","article-title":"Correlation of goblet cell density and mucosal epithelial membrane mucin expression with rose bengal staining in patients with ocular irritation","volume":"104","author":"Pflugfelder","year":"1997","journal-title":"Ophthalmology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7545","DOI":"10.1167\/iovs.15-17627","article-title":"Aqueous Tear Deficiency Increases Conjunctival Interferon-gamma (IFN-gamma) Expression and Goblet Cell Loss","volume":"56","author":"Pflugfelder","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1089\/jop.2008.0120","article-title":"In vivo evaluation of 11\u03b2-hydroxysteroid dehydrogenase activity in the rabbit eye","volume":"25","author":"Anderson","year":"2009","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0303-7207(00)00403-2","article-title":"Immunohistochemical distribution of 11\u03b2-hydroxysteroid dehydrogenase in human eye","volume":"173","author":"Suzuki","year":"2001","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3164734","DOI":"10.1155\/2016\/3164734","article-title":"The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults","volume":"2016","author":"Nita","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2887","DOI":"10.1038\/cddis.2017.272","article-title":"Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells","volume":"8","author":"Wang","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2927","DOI":"10.1039\/C7SC05476A","article-title":"ROS scavenging Mn3O4 nanozymes for in vivo anti-inflammation","volume":"9","author":"Yao","year":"2018","journal-title":"Chem. Sci."},{"key":"ref_39","first-page":"3293","article-title":"Ascorbic acid concentration and total antioxidant activity of human tear fluid measured using the FRASC assay","volume":"41","author":"Choy","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5081","DOI":"10.1167\/iovs.14-14483","article-title":"Antioxidant and inflammatory cytokine in tears of patients with dry eye syndrome treated with preservative-free versus preserved eye drops","volume":"55","author":"Jee","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1167\/iovs.07-0720","article-title":"A rabbit dry eye model induced by topical medication of a preservative benzalkonium chloride","volume":"49","author":"Xiong","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1001\/archopht.1992.01080190090035","article-title":"What is actually stained by rose bengal?","volume":"110","author":"Feenstra","year":"1992","journal-title":"Arch. Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1111\/j.1755-3768.2009.01610.x","article-title":"Morphological evaluation of normal human corneal epithelium","volume":"88","author":"Ehlers","year":"2010","journal-title":"Acta Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6390","DOI":"10.1167\/iovs.13-12547","article-title":"The corneal epithelial basement membrane: Structure, function, and disease","volume":"54","author":"Torricelli","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"BIO151","DOI":"10.1167\/iovs.17-21436","article-title":"Oxidative stress measures of lipid and dna damage in human tears","volume":"58","author":"Haworth","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s10522-013-9463-2","article-title":"Role of antioxidant enzymes and small molecular weight antioxidants in the pathogenesis of age-related macular degeneration (AMD)","volume":"14","author":"Tokarz","year":"2013","journal-title":"Biogerontology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1080\/15569527.2017.1291664","article-title":"Sodium perbarate and benzalkonium chloride induce DNA damage in Chang conjunctival epithelial cells","volume":"36","author":"Zhang","year":"2017","journal-title":"Cutan. Ocul. Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6174","DOI":"10.1167\/iovs.10-7022","article-title":"Effect of tear hyperosmolarity and signs of clinical ocular surface pathology upon conjunctival goblet cell function in the human ocular surface","volume":"52","author":"Moore","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_49","first-page":"165","article-title":"Effects of matrine on airway inflammation and early airway remodeling in asthmatic mice","volume":"32","author":"Lei","year":"2009","journal-title":"Chin. J. Tuberc. Respir. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Shirai, K., and Saika, S. (2015). Ocular surface mucins and local inflammation\u2014Studies in genetically modified mouse lines. BMC Ophthalmol., 15.","DOI":"10.1186\/s12886-015-0137-5"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1136\/bjophthalmol-2011-301448","article-title":"A randomised, double-masked comparison study of diquafosol versus sodium hyaluronate ophthalmic solutions in dry eye patients","volume":"96","author":"Takamura","year":"2012","journal-title":"Br. J. Ophthalmol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/10\/3729\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:32:27Z","timestamp":1760175147000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/10\/3729"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,25]]},"references-count":51,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["ijms21103729"],"URL":"https:\/\/doi.org\/10.3390\/ijms21103729","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,25]]}}}