{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T13:06:35Z","timestamp":1793451995980,"version":"4.5.0"},"reference-count":49,"publisher":"Elsevier BV","issue":"6","license":[{"start":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T00:00:00Z","timestamp":1748736000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T00:00:00Z","timestamp":1748736000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["jpet.aspetjournals.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"published-print":{"date-parts":[[2025,6]]},"DOI":"10.1016\/j.jpet.2025.103582","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T15:20:50Z","timestamp":1744644050000},"page":"103582","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":5,"title":["Difamilast topically ameliorates pruritus, dermatitis, and barrier dysfunction in atopic dermatitis model mice by inhibiting phosphodiesterase 4, especially the 4B subtype"],"prefix":"10.1016","volume":"392","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8326-649X","authenticated-orcid":false,"given":"Kazuyoshi","family":"Kirima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0878-3503","authenticated-orcid":false,"given":"Yuya","family":"Hoshino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7265-8336","authenticated-orcid":false,"given":"Naoya","family":"Arichika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5600-5538","authenticated-orcid":false,"given":"Takashi","family":"Wadatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2686-8593","authenticated-orcid":false,"given":"Yusuke","family":"Kakumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1320-9916","authenticated-orcid":false,"given":"Masafumi","family":"Shibamori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5238-9172","authenticated-orcid":false,"given":"Hidetaka","family":"Hiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jpet.2025.103582_bib1","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0026-895X(25)09714-7","article-title":"Multiple cyclic nucleotide phosphodiesterases","volume":"46","author":"Beavo","year":"1994","journal-title":"Mol Pharmacol"},{"key":"10.1016\/j.jpet.2025.103582_bib2","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1124\/pr.58.3.5","article-title":"Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use","volume":"58","author":"Bender","year":"2006","journal-title":"Pharmacol Rev"},{"key":"10.1016\/j.jpet.2025.103582_bib3","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41573-021-00266-6","article-title":"Atopic dermatitis: an expanding therapeutic pipeline for a complex disease","volume":"21","author":"Bieber","year":"2022","journal-title":"Nat Rev Drug Discov"},{"key":"10.1016\/j.jpet.2025.103582_bib4","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1146\/annurev.biochem.76.060305.150444","article-title":"Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling","volume":"76","author":"Conti","year":"2007","journal-title":"Annu Rev Biochem"},{"key":"10.1016\/j.jpet.2025.103582_bib5","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2024.1407871","article-title":"PDE4 inhibitors: potential protective effects in inflammation and vascular diseases","volume":"15","author":"Fan","year":"2024","journal-title":"Front Pharmacol"},{"key":"10.1016\/j.jpet.2025.103582_bib6","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.lfs.2004.07.022","article-title":"Scratching of their skin by NC\/Nga mice leads to development of dermatitis","volume":"76","author":"Hashimoto","year":"2004","journal-title":"Life Sci"},{"key":"10.1016\/j.jpet.2025.103582_bib7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1124\/jpet.123.001609","article-title":"Pharmacological profile of difamilast, a novel selective phosphodiesterase 4 inhibitor, for topical treatment of atopic dermatitis","volume":"386","author":"Hiyama","year":"2023","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1016\/j.jpet.2025.103582_bib8","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1538\/expanim.24-0088","article-title":"Long-term application of MC903 in mice prolongs the characteristic symptoms of atopic dermatitis, such as inflammation, skin barrier dysfunction, and itching","volume":"74","author":"Hoshino","year":"2025","journal-title":"Exp Anim"},{"key":"10.1016\/j.jpet.2025.103582_bib9","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jdermsci.2019.08.006","article-title":"Interleukin-33 in atopic dermatitis","volume":"96","author":"Imai","year":"2019","journal-title":"J Dermatol Sci"},{"key":"10.1016\/j.jpet.2025.103582_bib10","doi-asserted-by":"crossref","first-page":"7628","DOI":"10.1073\/pnas.122041599","article-title":"Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses","volume":"99","author":"Jin","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.jpet.2025.103582_bib11","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1016\/j.jaci.2010.08.014","article-title":"Phosphodiesterase 4B is essential for TH2-cell function and development of airway hyperresponsiveness in allergic asthma","volume":"126","author":"Jin","year":"2010","journal-title":"J Allergy Clin Immunol"},{"key":"10.1016\/j.jpet.2025.103582_bib12","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.4049\/jimmunol.175.3.1523","article-title":"Specific role of phosphodiesterase 4B in lipopolysaccharide-induced signaling in mouse macrophages","volume":"175","author":"Jin","year":"2005","journal-title":"J Immunol"},{"key":"10.1016\/j.jpet.2025.103582_bib13","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.3390\/cells10061392","article-title":"Current insights into immunology and novel therapeutics of atopic dermatitis","volume":"10","author":"Kader","year":"2021","journal-title":"Cells"},{"key":"10.1016\/j.jpet.2025.103582_bib14","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0142755","article-title":"Simple genome editing of rodent intact embryos by electroporation","volume":"10","author":"Kaneko","year":"2015","journal-title":"PLoS One"},{"key":"10.1016\/j.jpet.2025.103582_bib15","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/j.jid.2019.02.014","article-title":"Research techniques made simple: mouse models of atopic dermatitis","volume":"139","author":"Kim","year":"2019","journal-title":"J Invest Dermatol"},{"key":"10.1016\/j.jpet.2025.103582_bib16","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S0140-6736(20)31286-1","article-title":"Atopic dermatitis","volume":"396","author":"Langan","year":"2020","journal-title":"Lancet"},{"key":"10.1016\/j.jpet.2025.103582_bib17","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1111\/bjd.19580","article-title":"The global burden of atopic dermatitis: lessons from the Global Burden of Disease Study 1990\u20132017","volume":"184","author":"Laughter","year":"2021","journal-title":"Br J Dermatol"},{"key":"10.1016\/j.jpet.2025.103582_bib18","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1038\/sj.bjp.0702911","article-title":"Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B","volume":"128","author":"Manning","year":"1999","journal-title":"Br J Pharmacol"},{"key":"10.1016\/j.jpet.2025.103582_bib19","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1111\/all.16009","article-title":"Treatment of atopic dermatitis: recently approved drugs and advanced clinical development programs","volume":"79","author":"M\u00fcller","year":"2024","journal-title":"Allergy"},{"key":"10.1016\/j.jpet.2025.103582_bib20","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.1016\/j.jid.2018.06.168","article-title":"Eosinophils determine dermal thickening and water loss in an MC903 model of atopic dermatitis","volume":"138","author":"Naidoo","year":"2018","journal-title":"J Invest Dermatol"},{"key":"10.1016\/j.jpet.2025.103582_bib21","doi-asserted-by":"crossref","DOI":"10.1016\/j.cyto.2021.155664","article-title":"Novel pathogenesis of atopic dermatitis from the view of cytokines in mice and humans","volume":"148","author":"Nakajima","year":"2021","journal-title":"Cytokine"},{"key":"10.1016\/j.jpet.2025.103582_bib22","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.jaci.2021.02.018","article-title":"Basophils promote barrier dysfunction and resolution in the atopic skin","volume":"148","author":"Pellefigues","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"10.1016\/j.jpet.2025.103582_bib23","doi-asserted-by":"crossref","first-page":"4820","DOI":"10.4049\/jimmunol.178.8.4820","article-title":"Differential expression and function of phosphodiesterase 4 (PDE4) subtypes in human primary CD4+ T cells: predominant role of PDE4D","volume":"178","author":"Peter","year":"2007","journal-title":"J Immunol"},{"key":"10.1016\/j.jpet.2025.103582_bib24","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s41232-017-0044-7","article-title":"The etiopathogenesis of atopic dermatitis: barrier disruption, immunological derangement, and pruritus","volume":"37","author":"Rerknimitr","year":"2017","journal-title":"Inflamm Regen"},{"key":"10.1016\/j.jpet.2025.103582_bib25","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/bjd.20655","article-title":"Difamilast, a selective phosphodiesterase 4 inhibitor, ointment in paediatric patients with atopic dermatitis: a phase III randomized double-blind, vehicle-controlled trial","volume":"186","author":"Saeki","year":"2022","journal-title":"Br J Dermatol"},{"key":"10.1016\/j.jpet.2025.103582_bib26","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/1346-8138.15137","volume":"47","author":"Saeki","year":"2020","journal-title":"J Dermatol"},{"key":"10.1016\/j.jpet.2025.103582_bib27","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1007\/s13555-022-00751-9","article-title":"Difamilast ointment in Japanese adult and pediatric patients with atopic dermatitis: a phase III, long-term, open-label study","volume":"12","author":"Saeki","year":"2022","journal-title":"Dermatol Ther (Heidelb)"},{"key":"10.1016\/j.jpet.2025.103582_bib28","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jaad.2021.10.027","article-title":"Difamilast ointment in adult patients with atopic dermatitis: a phase 3 randomized, double-blind, vehicle-controlled trial","volume":"86","author":"Saeki","year":"2022","journal-title":"J Am Acad Dermatol"},{"key":"10.1016\/j.jpet.2025.103582_bib29","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1007\/s13555-024-01236-7","article-title":"An interim report of a phase 3, long-term, open-label study to evaluate efficacy and safety of difamilast ointment in Japanese infants with atopic dermatitis","volume":"14","author":"Saeki","year":"2024","journal-title":"Dermatol Ther (Heidelb)"},{"key":"10.1016\/j.jpet.2025.103582_bib30","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1007\/s10753-019-01086-y","article-title":"Interference of skin scratching attenuates accumulation of neutrophils in murine allergic contact dermatitis model","volume":"42","author":"Sakai","year":"2019","journal-title":"Inflammation"},{"key":"10.1016\/j.jpet.2025.103582_bib31","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.cellsig.2016.01.007","article-title":"Phosphodiesterase 4 in inflammatory diseases: effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4\/CD271 complex","volume":"28","author":"Schafer","year":"2016","journal-title":"Cell Signal"},{"key":"10.1016\/j.jpet.2025.103582_bib32","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.3390\/ijms23031209","article-title":"Clinical implication of phosphodiesterase-4-inhibition","volume":"23","author":"Schick","year":"2022","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.jpet.2025.103582_bib33","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.jid.2023.10.019","article-title":"Genetic and immunological pathogenesis of atopic dermatitis","volume":"144","author":"Schuler","year":"2024","journal-title":"J Invest Dermatol"},{"key":"10.1016\/j.jpet.2025.103582_bib34","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1016\/j.jaci.2016.04.031","article-title":"Opposing functions of thymic stromal lymphopoietin-responsive basophils and dendritic cells in a mouse model of atopic dermatitis","volume":"138","author":"Schwartz","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"10.1016\/j.jpet.2025.103582_bib35","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.jid.2021.09.023","article-title":"A new era with the development of cytokine-based therapy for pruritus","volume":"142","author":"Shibuya","year":"2022","journal-title":"J Invest Dermatol"},{"key":"10.1016\/j.jpet.2025.103582_bib36","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.anai.2018.07.006","article-title":"Patient burden and quality of life in atopic dermatitis in US adults: a population-based cross-sectional study","volume":"121","author":"Silverberg","year":"2018","journal-title":"Ann Allergy Asthma Immunol"},{"key":"10.1016\/j.jpet.2025.103582_bib37","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.2165\/00003495-200363230-00002","article-title":"Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease","volume":"63","author":"Spina","year":"2003","journal-title":"Drugs"},{"key":"10.1016\/j.jpet.2025.103582_bib38","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1056\/NEJMra2023911","article-title":"Atopic dermatitis","volume":"384","author":"St\u00e4nder","year":"2021","journal-title":"N Engl J Med"},{"key":"10.1016\/j.jpet.2025.103582_bib39","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1016\/j.jaci.2022.03.010","article-title":"Neuroimmune communication regulating pruritus in atopic dermatitis","volume":"149","author":"Steinhoff","year":"2022","journal-title":"J Allergy Clin Immunol"},{"key":"10.1016\/j.jpet.2025.103582_bib40","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/j.jid.2023.09.272","article-title":"Topical application of a PDE4 inhibitor ameliorates atopic dermatitis through inhibition of basophil IL-4 production","volume":"144","author":"Takahashi","year":"2024","journal-title":"J Invest Dermatol"},{"key":"10.1016\/j.jpet.2025.103582_bib41","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1164\/ajrccm.157.2.9708012","article-title":"Phosphodiesterase isozymes: molecular targets for novel antiasthma agents","volume":"157","author":"Torphy","year":"1998","journal-title":"Am J Respir Crit Care Med"},{"key":"10.1016\/j.jpet.2025.103582_bib42","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.jaci.2021.09.014","article-title":"IL-33 signaling in sensory neurons promotes dry skin itch","volume":"149","author":"Trier","year":"2022","journal-title":"J Allergy Clin Immunol"},{"key":"10.1016\/j.jpet.2025.103582_bib43","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jdermsci.2023.04.007","article-title":"PDE4 inhibition by difamilast regulates filaggrin and loricrin expression via keratinocyte proline-rich protein in human keratinocytes","volume":"110","author":"Tsuji","year":"2023","journal-title":"J Dermatol Sci"},{"key":"10.1016\/j.jpet.2025.103582_bib44","doi-asserted-by":"crossref","DOI":"10.3390\/ijms241914633","article-title":"Regulatory mechanism of the IL-33-IL-37 axis via aryl hydrocarbon receptor in atopic dermatitis and psoriasis","volume":"24","author":"Tsuji","year":"2023","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.jpet.2025.103582_bib45","doi-asserted-by":"crossref","first-page":"7910","DOI":"10.3390\/ijms25147910","article-title":"Difamilast, a topical phosphodiesterase 4 inhibitor, produces soluble ST2 via the AHR-NRF2 axis in human keratinocytes","volume":"25","author":"Tsuji","year":"2024","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.jpet.2025.103582_bib46","doi-asserted-by":"crossref","first-page":"4001","DOI":"10.3390\/jcm13144001","article-title":"A comprehensive review of biologics in phase III and IV clinical trials for atopic dermatitis","volume":"13","author":"Walig\u00f3ra-Dziwak","year":"2024","journal-title":"J Clin Med"},{"key":"10.1016\/j.jpet.2025.103582_bib47","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/s00403-008-0912-8","article-title":"Contribution of itch-associated scratch behavior to the development of skin lesions in Dermatophagoides farinae-induced dermatitis model in NC\/Nga mice","volume":"301","author":"Yamamoto","year":"2009","journal-title":"Arch Dermatol Res"},{"key":"10.1016\/j.jpet.2025.103582_bib48","article-title":"Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human","volume":"11","author":"Yamamura","year":"2024","journal-title":"Front Med (Lausanne)"},{"key":"10.1016\/j.jpet.2025.103582_bib49","doi-asserted-by":"crossref","first-page":"125","DOI":"10.4049\/jimmunol.2300629","article-title":"Diminished \u03b3\u03b4 T cells during murine allergic skin inflammation is mediated by IL-4 signaling in keratinocytes","volume":"213","author":"Zhang","year":"2024","journal-title":"J Immunol"}],"container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356525397958?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356525397958?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T10:18:19Z","timestamp":1751019499000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0022356525397958"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6]]},"references-count":49,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["S0022356525397958"],"URL":"https:\/\/doi.org\/10.1016\/j.jpet.2025.103582","relation":{},"ISSN":["0022-3565"],"issn-type":[{"value":"0022-3565","type":"print"}],"subject":[],"published":{"date-parts":[[2025,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Difamilast topically ameliorates pruritus, dermatitis, and barrier dysfunction in atopic dermatitis model mice by inhibiting phosphodiesterase 4, especially the 4B subtype","name":"articletitle","label":"Article Title"},{"value":"The Journal of Pharmacology and Experimental Therapeutics","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jpet.2025.103582","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"103582"}}