{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:30Z","timestamp":1787028570803,"version":"build-2736575974"},"reference-count":55,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chosun University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder affecting 10\u201320% of the population. In this study, we investigate the anti-inflammatory effect on the skin of eight compounds isolated from Digitalis purpurea L., using tumor necrosis factor-\u03b1 (TNF-\u03b1)\/interferon-\u03b3 (IFN-\u03b3)-stimulated human keratinocytes (HaCaT cells) and a three-dimensional (3D) reconstructed human skin model. Among the tested compounds, desrhamnosyl acteoside exhibited the most potent activity, significantly reducing the secretion of pro-inflammatory cytokines (IL-6, IL-8) and chemokines (CCL17, CCL22), suppressing the expression of inflammatory proteins, and modulating key signaling pathways, including NF-\u03baB, JAK2\/STAT1, and MAPK. Notably, this is the first report demonstrating that desrhamnosyl acteoside simultaneously targets all three pathways, indicating a multi-modal mechanism distinct from conventional single-target approaches. In the 3D skin model, desrhamnosyl acteoside further exhibited barrier-protective effects by downregulating inflammatory mediators and upregulating epidermal differentiation markers such as involucrin and loricrin. These findings reveal a previously uncharacterized phytochemical with dual anti-inflammatory and barrier-restorative activities, supporting its potential as a novel therapeutic candidate for AD and other inflammatory skin diseases.<\/jats:p>","DOI":"10.3390\/ijms26167747","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T11:02:09Z","timestamp":1754910129000},"page":"7747","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Anti-Inflammatory Activity of Compounds Isolated from Digitalis purpurea L. in TNF-\u03b1\/IFN-\u03b3-Induced HaCaT Keratinocytes and a Three-Dimensionally Reconstructed Human Skin Model"],"prefix":"10.3390","volume":"26","author":[{"given":"Linsha","family":"Dong","sequence":"first","affiliation":[{"name":"College of Nursing, Qingdao Binhai University, Qingdao 266555, China"},{"name":"Research Institute of Pharmaceutical Sciences (RIPS), College of Pharmacy, Chosun University, Dong-gu, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5015-5949","authenticated-orcid":false,"given":"Hwan","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences (RIPS), College of Pharmacy, Chosun University, Dong-gu, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Liu","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences (RIPS), College of Pharmacy, Chosun University, Dong-gu, Gwangju 61452, Republic of Korea"},{"name":"Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, School of Pharmacy, Yantai University, Yantai 264005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Rhan","family":"Woo","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences (RIPS), College of Pharmacy, Chosun University, Dong-gu, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9234-7567","authenticated-orcid":false,"given":"Dong-Sung","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences (RIPS), College of Pharmacy, Chosun University, Dong-gu, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"486","DOI":"10.2174\/187152811798104935","article-title":"The Pathology and Immunology of Atopic Dermatitis","volume":"10","author":"Ma","year":"2011","journal-title":"Inflamm. Allergy Drug Targets"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/j.1600-065X.2011.01027.x","article-title":"Atopic dermatitis: A disease of altered skin barrier and immune dysregulation","volume":"242","author":"Boguniewicz","year":"2011","journal-title":"Immunol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/S0140-6736(24)02519-4","article-title":"Atopic dermatitis","volume":"405","author":"Guttman","year":"2025","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural Products as Sources of New Drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/978-3-031-54513-9_19","article-title":"The Future of Atopic Dermatitis Treatment","volume":"1447","author":"Lovell","year":"2024","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.abd.2023.03.001","article-title":"JAK-STAT pathway inhibitors in dermatology","volume":"98","author":"Miot","year":"2023","journal-title":"An. Bras. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Calabrese, L., D\u2019Onghia, M., Lazzeri, L., Rubegni, G., and Cinotti, E. (2024). Blocking the IL-4\/IL-13 Axis versus the JAK\/STAT Pathway in Atopic Dermatitis: How Can We Choose?. J. Pers. Med., 14.","DOI":"10.3390\/jpm14070775"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Dabhadkar, M., and Kulkarni, M. (2025). Novel drug delivery systems in topical treatment of atopic dermatitis. Naunyn Schmiedebergs Arch. Pharmacol., 13, Online ahead of print.","DOI":"10.1007\/s00210-025-04002-4"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"106458","DOI":"10.1016\/j.ejps.2023.106458","article-title":"Lipid-based nanoformulation optimization for achieving cutaneous targeting: Niosomes as the potential candidates to fulfill this aim","volume":"186","author":"Lin","year":"2023","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1097\/ACI.0b013e32833e08ae","article-title":"Keratinocytes in allergic skin diseases","volume":"10","author":"Albanesi","year":"2010","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6720","DOI":"10.3390\/ijms14046720","article-title":"Cytokines and the Skin Barrier","volume":"14","author":"Cornelissen","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100131","DOI":"10.1016\/j.xjidi.2022.100131","article-title":"Type 2 inflammation contributes to skin barrier dysfunction in atopic dermatitis","volume":"2","author":"Beck","year":"2022","journal-title":"JID Innov."},{"key":"ref_13","first-page":"35","article-title":"Atopic dermatitis: An overview","volume":"86","author":"Berke","year":"2012","journal-title":"Am. Fam. Physician."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"643","DOI":"10.3920\/BM2017.0162","article-title":"Effect of Lactobacillus strains on thymus and chemokine expression in keratinocytes and development of atopic dermatitis-like symptoms","volume":"15","author":"Kawahara","year":"2018","journal-title":"Benef. Microbes."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.det.2007.06.003","article-title":"Keratinocyte cytokine and chemokine receptors","volume":"25","author":"Antonov","year":"2007","journal-title":"Dermatol. Clin."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.clindermatol.2007.08.011","article-title":"The cytokine and chemokine network in psoriasis","volume":"25","author":"Nickoloff","year":"2007","journal-title":"Clin. Dermatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.1111\/all.15089","article-title":"Advances and highlights in biomarkers of allergic diseases","volume":"76","author":"Ogulur","year":"2021","journal-title":"Allergy"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, C.C., Hsiao, C.Y., Hsu, Y.J., Ko, H.H., Chang, D.C., and Hung, C.F. (2022). Anti-Inflammatory Effects of Cycloheterophyllin on Dinitrochlorobenzene-Induced Atopic Dermatitis in HaCaT Cells and BALB\/c Mice. Molecules, 27.","DOI":"10.3390\/molecules27092610"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/j.jaci.2023.02.012","article-title":"Keratinocyte signaling in atopic dermatitis: Investigations in organotypic skin models toward clinical application","volume":"151","author":"Meesters","year":"2023","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9521","DOI":"10.1007\/s00210-024-03285-3","article-title":"\u201cCardiac glycosides\u201d\u2014quo vaditis?\u2014past, present, and future?","volume":"397","author":"Fender","year":"2024","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1056\/NEJM198802113180606","article-title":"Digitalis: Mechanisms of action and clinical use","volume":"318","author":"Smith","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1211\/0022357056451","article-title":"Effects of phenylethanoid glycosides from Digitalis purpurea L. on the expression of inducible nitric oxide synthase","volume":"57","author":"Oh","year":"2005","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Grebenciucova, E., and VanHaerents, S. (2023). Interleukin-6: At the Interface of Human Health and Disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1255533"},{"key":"ref_24","first-page":"50","article-title":"Serum Levels of IL-8, Tnf-\u03b1 and IL-6 in Children with Atopic Dermatitis","volume":"10","author":"Aral","year":"2012","journal-title":"J. Curr. Pediatr."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Clausen, M.L., Kezic, S., Olesen, C.M., and Agner, T. (2020). Cytokine concentration across the stratum corneum in atopic dermatitis and healthy controls. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-78943-6"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"57","DOI":"10.5483\/BMBRep.2016.49.1.141","article-title":"2,3-Dimethoxy-2\u2032-hydroxychalcone ameliorates TNF-\u03b1-induced ICAM-1 expression and subsequent monocyte adhesiveness via NF-kappaB inhibition and HO-1 induction in HaCaTs","volume":"49","author":"Kim","year":"2016","journal-title":"BMB Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"494","DOI":"10.4049\/jimmunol.162.1.494","article-title":"IL-17 is produced by nickel-specific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: Synergistic or antagonist effects with IFN-gamma and TNF-alpha","volume":"162","author":"Albanesi","year":"1999","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chen, Y., Ye, X., Escames, G., Lei, W., Zhang, X., Li, M., Jing, T., Yao, Y., Qiu, Z., and Wang, Z. (2023). The NLRP3 inflammasome: Contributions to inflammation-related diseases. Cell Mol. Biol. Lett., 28.","DOI":"10.1186\/s11658-023-00462-9"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1002\/JLB.2MR0220-549R","article-title":"ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis","volume":"108","author":"Bui","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3622","DOI":"10.2174\/0929867327999200917150939","article-title":"Natural cox-2 inhibitors as promising anti-inflammatory agents: An update","volume":"28","author":"Cui","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0090-6980(02)00029-1","article-title":"Distinct functions of COX-1 and COX-2","volume":"68","author":"Morita","year":"2002","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.clim.2007.11.006","article-title":"Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6","volume":"126","author":"Kim","year":"2008","journal-title":"Clin. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.jsps.2017.04.034","article-title":"Acitretin modulates HaCaTs proliferation through STAT1- and STAT3-dependent signaling","volume":"25","author":"Qin","year":"2017","journal-title":"Saudi Pharm. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"118092","DOI":"10.1016\/j.jep.2024.118092","article-title":"Yu-Ping-Feng-San alleviates inflammation in atopic dermatitis mice by TLR4\/MyD88\/NF-\u03baB pathway","volume":"329","author":"Nie","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1007\/s13258-021-01081-4","article-title":"Glabridin attenuates atopic dermatitis progression through downregulating the TLR4\/MyD88\/NF-\u03baB signaling pathway","volume":"43","author":"Chang","year":"2021","journal-title":"Genes Genom."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1128\/MMBR.68.2.320-344.2004","article-title":"ERK and p38 MAPK-activated protein kinases: A family of protein kinases with diverse biological functions","volume":"68","author":"Roux","year":"2004","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lee, K.S., Lee, S., Wang, H., Lee, G., Kim, S., Ryu, Y.-H., Chang, N.H., and Kang, Y.-W. (2023). Analysis of Skin Regeneration and Barrier-Improvement Efficacy of Polydeoxyribonucleotide Isolated from Panax Ginseng (C.A. Mey.) Adventitious Root. Molecules., 28.","DOI":"10.3390\/molecules28217240"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hwang, J.H., Lee, S., Lee, H.G., Choi, D., and Lim, K.M. (2022). Evaluation of Skin Irritation of Acids Commonly Used in Cleaners in 3D-Reconstructed Human Epidermis Model, KeraSkinTM. Toxics, 10.","DOI":"10.3390\/toxics10100558"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"104725","DOI":"10.1016\/j.yrtph.2020.104725","article-title":"Me-too validation study for in vitro skin irritation test with a reconstructed human epidermis model, KeraSkin\u2122 for OECD test guideline 439","volume":"117","author":"Han","year":"2020","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"114942","DOI":"10.1016\/j.fct.2024.114942","article-title":"Round Robin Study for Evaluation an in vitro skin irritation test for medical device extracts using KeraSkinTM in Korea","volume":"192","author":"Kim","year":"2024","journal-title":"Food Chem. Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Afshari, M., Kolackova, M., Rosecka, M., \u010celakovsk\u00e1, J., and Krejsek, J. (2024). Unraveling the skin; a comprehensive review of atopic dermatitis, current understanding, and approaches. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1361005"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Amiri, F., Moghadam, A., Tahmasebi, A., and Niazi, A. (2023). Identification of key genes involved in secondary metabolite biosynthesis in Digitalis purpurea. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0277293"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"624","DOI":"10.2174\/0113816128295053240207090928","article-title":"The Potential of Natural Products in the Management of Cardiovascular Disease","volume":"30","author":"Singhai","year":"2024","journal-title":"Curr. Pharm. Des."},{"key":"ref_44","first-page":"86","article-title":"Of mixed vegetables and cardiac arrhythmias\u2014Digitalis purpurea confused with Borago officinalis: A case series of accidental digitoxin intoxications","volume":"28","author":"Iraci","year":"2023","journal-title":"J. Cardiol. Cases"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1111\/wrr.13217","article-title":"Polyphenol hydroxytyrosol present olive oil improves skin wound healing of diabetic mice","volume":"32","author":"Duarte","year":"2024","journal-title":"Wound Repair Regen."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1080\/09637486.2021.1996542","article-title":"Dietary polyphenol oleuropein and its metabolite hydroxytyrosol are moderate skin permeable elastase and collagenase inhibitors with synergistic cellular antioxidant effects in human skin fibroblasts","volume":"73","author":"Li","year":"2022","journal-title":"Int. J. Food Sci. Nutr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13020-021-00555-7","article-title":"Compound traditional Chinese medicine dermatitis ointment ameliorates inflammatory responses and dysregulation of itch-related molecules in atopic dermatitis","volume":"17","author":"Zhang","year":"2022","journal-title":"Chin. Med."},{"key":"ref_48","first-page":"335","article-title":"Targeting Skin Barrier Function in Atopic Dermatitis","volume":"111","author":"Elias","year":"2023","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.jid.2024.03.006","article-title":"Skin Barrier in Atopic Dermatitis","volume":"144","author":"Schmuth","year":"2024","journal-title":"J. Investig. Dermatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"154200","DOI":"10.1016\/j.phymed.2022.154200","article-title":"Therapeutic effects of myricetin on atopic dermatitis in vivo and in vitro","volume":"102","author":"Hou","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00432-020-03460-y","article-title":"MAPK signaling pathway-targeted marine compounds in cancer therapy","volume":"147","author":"Wei","year":"2021","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_52","first-page":"999","article-title":"A human 3D skin model based on KeraSkin\u2122 for screening skin irritation of chemicals","volume":"43","author":"Park","year":"2020","journal-title":"Arch. Pharm. Res."},{"key":"ref_53","unstructured":"OECD (2021). Test No. 439: In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method. OECD Guidelines for the Testing of Chemicals, OECD. Section 4."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.5012\/bkcs.2011.32.5.1721","article-title":"Phenylethanoid Glycosides from Digitalis purpurea L.","volume":"32","author":"Jin","year":"2011","journal-title":"Bull. Korean Chem. Soc."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1007\/s11373-005-9028-8","article-title":"Chrysoeriol potently inhibits the induction of nitric oxide synthase by blocking AP-1 activation","volume":"12","author":"Choi","year":"2005","journal-title":"J. Biomed. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7747\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:24:39Z","timestamp":1760034279000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,11]]},"references-count":55,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26167747"],"URL":"https:\/\/doi.org\/10.3390\/ijms26167747","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,11]]}}}