{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T14:55:57Z","timestamp":1774968957522,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T00:00:00Z","timestamp":1669680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and ICT(MSIT)","award":["KSN1812101"],"award-info":[{"award-number":["KSN1812101"]}]},{"name":"Ministry of Science and ICT(MSIT)","award":["KSN2022230"],"award-info":[{"award-number":["KSN2022230"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We determined the effects of two extracts from Acer palmatum Thumb. leaves (hot water extract KIOM-2015EW and 25% ethanol extract KIOM-2015EE) in a benzalkonium chloride (BAC)-induced dry eye mouse model. Dry eye was induced by 0.2% BAC for 2 weeks, followed by treatment three times (eye drop) or once (oral administration) daily with KIOM-2015E for 2 weeks. Treatment with both KIOM-2015EE and KIOM-2015EW resulted in a marked increase in tear volume production for the 4 days of treatment. The Lissamine Green staining score, TUNEL-positive cells, and inflammatory index were significantly decreased after 2 weeks. Topical KIOM-2015EE administration exhibited a greater improvement in decreasing the ocular surface staining scores, inflammation, dead cells, and increasing tear production in a dose-dependent manner compared with the other groups. Furthermore, KIOM-2015E significantly reduced the phosphorylation of NF-\u03baB, which was activated in the BAC-treated cornea. Topical administration was much more effective than oral administration for KIOM-2015E and KIOM-2015EE was more effective than KIOM-2015EW. Application of KIOM-2015E resulted in clinical improvement, inhibited the inflammatory response, and alleviated signs of dry eye. These results indicate that KIOM-2015E has potential as a therapeutic agent for the clinical treatment of dry eye.<\/jats:p>","DOI":"10.3390\/ijms232314964","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T01:52:20Z","timestamp":1669773140000},"page":"14964","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Therapeutic Effects of Acer palmatum Thumb. Leaf Extract (KIOM-2015E) on Benzalkonium Chloride-Induced Dry Eye in a Mouse Model"],"prefix":"10.3390","volume":"23","author":[{"given":"Nam-Hui","family":"Yim","sequence":"first","affiliation":[{"name":"Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), 70, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunhee","family":"Park","sequence":"additional","affiliation":[{"name":"Helixmith, 21, Magokjungang 8-ro 7-gil, Gangseo-gu, Seoul 07794, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6425-5748","authenticated-orcid":false,"given":"Won-Kyung","family":"Cho","sequence":"additional","affiliation":[{"name":"Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), 70, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2815-5886","authenticated-orcid":false,"given":"Yeoun-Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"R&D Center, Etnova Therapeutics Corp., 198, Saneop-ro, Gwonseon-gu, Suwon-si 13207, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin Yeul","family":"Ma","sequence":"additional","affiliation":[{"name":"Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), 70, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,29]]},"reference":[{"key":"ref_1","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_2","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_3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1097\/01.ICL.0000162759.79740.46","article-title":"Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface","volume":"31","author":"Luo","year":"2005","journal-title":"Eye Contact Lens"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1293\/tox.2013-0022","article-title":"Ocular toxicity of benzalkonium chloride homologs compared with their mixtures","volume":"26","author":"Okahara","year":"2013","journal-title":"J. Toxicol. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6314","DOI":"10.1167\/iovs.12-10725","article-title":"A mouse model of limbal stem cell deficiency induced by topical medication with the preservative benzalkonium chloride","volume":"54","author":"Lin","year":"2013","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1080\/02713689808951223","article-title":"Histopathological effects of topical ophthalmic preservatives on rat corneoconjunctival surface","volume":"17","author":"Becquet","year":"1998","journal-title":"Curr. Eye Res."},{"key":"ref_7","first-page":"308","article-title":"Preservative cytotoxic threshold for benzalkonium chloride and chlorhexidine digluconate in cat and rabbit corneas","volume":"19","author":"Burstein","year":"1980","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.preteyeres.2010.03.001","article-title":"Preservatives in eyedrops: The good, the bad and the ugly","volume":"29","author":"Baudouin","year":"2010","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_9","first-page":"257","article-title":"A mouse dry eye model induced by topical administration of benzalkonium chloride","volume":"17","author":"Lin","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"(2007). The definition and classification of dry eye disease: Report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul. Surf., 5, 75\u201392.","DOI":"10.1016\/S1542-0124(12)70081-2"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3950","DOI":"10.4049\/jimmunol.176.7.3950","article-title":"Desiccating stress induces T cell-mediated Sjogren\u2019s Syndrome-like lacrimal keratoconjunctivitis","volume":"176","author":"Niederkorn","year":"2006","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.cyto.2004.03.007","article-title":"Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory Smad7 by a negative feedback mechanism","volume":"26","author":"Zhu","year":"2004","journal-title":"Cytokine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1097\/00003226-199303000-00004","article-title":"Artificial tear composition and promotion of recovery of the damaged corneal epithelium","volume":"12","author":"Ubels","year":"1993","journal-title":"Cornea"},{"key":"ref_14","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_15","first-page":"2283","article-title":"Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease","volume":"42","author":"Solomon","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1076\/ceyr.19.3.201.5309","article-title":"Altered cytokine balance in the tear fluid and conjunctiva of patients with Sjogren\u2019s syndrome keratoconjunctivitis sicca","volume":"19","author":"Pflugfelder","year":"1999","journal-title":"Curr. Eye Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1097\/ICO.0b013e318033a729","article-title":"Strain-related cytokine profiles on the murine ocular surface in response to desiccating stress","volume":"26","author":"Corrales","year":"2007","journal-title":"Cornea"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1097\/01.ICL.0000092064.05514.04","article-title":"Recombinant human tumor necrosis factor receptor Fc fusion protein (Etanercept): Experience as a therapy for sight-threatening scleritis and sterile corneal ulceration","volume":"30","author":"Tozman","year":"2004","journal-title":"Eye Contact Lens"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/S0161-6420(99)90171-9","article-title":"Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren syndrome","volume":"106","author":"Marsh","year":"1999","journal-title":"Ophthalmology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.optm.2009.02.010","article-title":"Advancements in anti-inflammatory therapy for dry eye syndrome","volume":"80","author":"McCabe","year":"2009","journal-title":"Optometry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jep.2016.04.021","article-title":"Traditional uses, phytochemistry, and pharmacology of the genus Acer (maple): A review","volume":"189","author":"Bi","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3390\/nu10030282","article-title":"Anti-Inflammatory and Anti-Apoptotic Effects of Acer Palmatum Thumb. Extract, KIOM-2015EW, in a Hyperosmolar-Stress-Induced In Vitro Dry Eye Model","volume":"10","author":"Kim","year":"2018","journal-title":"Nutrients"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1097\/ICL.0b013e318184bdb6","article-title":"Topical apolipoprotein A-1 may have a beneficial effect on the corneal epithelium in a mouse model of dry eye: A pilot study","volume":"34","author":"Nyunt","year":"2008","journal-title":"Eye Contact Lens"},{"key":"ref_24","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. Opthalmol. Vis. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"244","DOI":"10.3109\/09273941003721926","article-title":"Dry eye disease as an inflammatory disorder","volume":"18","author":"Calonge","year":"2010","journal-title":"Ocul. Immunol. Inflamm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ajo.2003.10.036","article-title":"Antiinflammatory therapy for dry eye","volume":"137","author":"Pflugfelder","year":"2004","journal-title":"Am. J. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1097\/IAE.0b013e3181b32cfd","article-title":"Visual loss caused by corticosteroid-induced glaucoma: How to avoid it","volume":"29","author":"Spaeth","year":"2009","journal-title":"Retina"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.jcrs.2010.10.051","article-title":"Risk factors for steroid response among cataract patients","volume":"37","author":"Chang","year":"2011","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1167\/iovs.15-16595","article-title":"Quercetin and Resveratrol Decrease the Inflammatory and Oxidative Responses in Human Ocular Surface Epithelial Cells","volume":"56","author":"Calonge","year":"2015","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"794","DOI":"10.3109\/08923973.2012.656273","article-title":"Spirodela polyrhiza (L.) Sch. ethanolic extract inhibits LPS-induced inflammation in RAW264.7 cells","volume":"34","author":"Seo","year":"2012","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9658030","DOI":"10.1155\/2017\/9658030","article-title":"Comparison of Anti-Inflammatory Effects of Flavonoid-Rich Common and Tartary Buckwheat Sprout Extracts in Lipopolysaccharide-Stimulated RAW 264.7 and Peritoneal Macrophages","volume":"2017","author":"Nam","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"562","DOI":"10.3389\/fphar.2017.00562","article-title":"Anti-inflammatory and Analgesic Effects of Polygonum orientale L. Extracts","volume":"8","author":"Gou","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/978-1-4615-0717-8_104","article-title":"Dry eye and delayed tear clearance: \u201cA call to arms\u201d","volume":"506","author":"Pflugfelder","year":"2002","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4309","DOI":"10.1167\/iovs.05-1504","article-title":"Tear film osmolarity: Determination of a referent for dry eye diagnosis","volume":"47","author":"Tomlinson","year":"2006","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4293","DOI":"10.1167\/iovs.03-1145","article-title":"Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface","volume":"45","author":"Luo","year":"2004","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_36","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-1beta, TNF-alpha and IL-8 following hyperosmolar stress in human limbal epithelial cells","volume":"82","author":"Li","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_37","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":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5401","DOI":"10.1167\/iovs.14-13924","article-title":"Topical administration of lacritin is a novel therapy for aqueous-deficient dry eye disease","volume":"55","author":"Vijmasi","year":"2014","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1097\/ICO.0000000000000695","article-title":"Comparison of the Efficacy of Fluorometholone With and Without Benzalkonium Chloride in Ocular Surface Disease","volume":"35","author":"Kim","year":"2016","journal-title":"Cornea"},{"key":"ref_40","first-page":"3510","article-title":"The phenol red thread tear test: A cross-cultural study","volume":"34","author":"Sakamoto","year":"1993","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1097\/ICO.0000000000000477","article-title":"Cyclosporine A Downregulates MMP-3 and MMP-13 Expression in Cultured Pterygium Fibroblasts","volume":"34","author":"Kim","year":"2015","journal-title":"Cornea"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/23\/14964\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:29:32Z","timestamp":1760146172000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/23\/14964"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,29]]},"references-count":41,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232314964"],"URL":"https:\/\/doi.org\/10.3390\/ijms232314964","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,29]]}}}