{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T13:18:31Z","timestamp":1773580711038,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["No. 2020R1A2C2005836"],"award-info":[{"award-number":["No. 2020R1A2C2005836"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Cone of Pinus densiflora (CP), or Korean red pinecone, is a cluster of Pinus densiflora fruit. CP has also been verified in several studies to have anti-oxidation, anti-fungal, anti-bacterial, and anti-melanogenic effects. However, anti-inflammatory effects have not yet been confirmed in the inflammatory responses of pinecones to allergic contact dermatitis. The purpose of this study is to prove the anti-inflammatory effect of CP on allergic contact dermatitis (ACD) in vitro and in vivo. CP inhibited the expression of TSLP, TARC, MCP-1, TNF-\u03b1, and IL-6 in TNF-\u03b1\/IFN-\u03b3-stimulated HaCaT cells and MCP-1, GM-CSF, TNF-\u03b1, IL-6, and IL-8 in PMACI (phorbol-12-myristate-13-acetate plus A23187)-stimulated HMC-1 cells. CP inhibited the phosphorylation of mitogen-activated protein kinase (MAPKs), as well as the translocation of NF-\u03baB on TNF-\u03b1\/IFN-\u03b3 stimulated in HaCaT cells. In vivo, CP decreased major symptoms of ACD, levels of IL-6 in skin lesion, thickening of the epidermis and dermis, infiltration of eosinophils and mast cells, and the infiltration of CD4+ T cells and CD8+ T cells. This result suggests that CP represents a potential alternative medicine to ACD for diseases such as chronic skin inflammation.<\/jats:p>","DOI":"10.3390\/nu13030839","type":"journal-article","created":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T00:39:07Z","timestamp":1614904747000},"page":"839","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Effect of Cone of Pinus densiflora on DNCB-Induced Allergic Contact Dermatitis-Like Skin Lesion in Balb\/c Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Boguen","family":"Kwon","sequence":"first","affiliation":[{"name":"Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soo Yeon","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4671-8400","authenticated-orcid":false,"given":"Eun-Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3593-3049","authenticated-orcid":false,"given":"Jae-Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minsun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0942-7871","authenticated-orcid":false,"given":"Jae Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, Jungwon University, 85, Munmu-ro, Goesan-eup, Goesan-gun, Chungbuk 28024, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2159-1386","authenticated-orcid":false,"given":"Youngjoo","family":"Sohn","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyuk-Sang","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Korean Medicine, Kyung Hee University, 26, Kyunghee dae-ro, Dongdaemun-gu, Seoul 02447, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"ref_1","first-page":"S115","article-title":"Overview of atopic dermatitis","volume":"23","year":"2017","journal-title":"Am. J. Manag. Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1001\/jamadermatol.2013.10271","article-title":"Persistence of mild to moderate atopic dermatitis","volume":"150","author":"Margolis","year":"2014","journal-title":"JAMA Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1152\/physrev.1989.69.4.1316","article-title":"Structure, function, and differentiation of the keratinocyte","volume":"69","author":"Eckert","year":"1989","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s11882-004-0071-8","article-title":"Keratinocytes in atopic dermatitis: Inflammatory signals","volume":"4","author":"Esche","year":"2004","journal-title":"Curr. Allergy Asthma Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1111\/j.1600-0625.2008.00786.x","article-title":"The skin: An indispensable barrier","volume":"17","author":"Proksch","year":"2008","journal-title":"Exp. Derm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7435621","DOI":"10.1155\/2017\/7435621","article-title":"HaCaT cells as a reliable in vitro differentiation model to dissect the inflammatory\/repair response of human keratinocytes","volume":"2017","author":"Colombo","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1007\/s12016-019-08729-w","article-title":"A review of the contribution of mast cells in wound healing: Involved molecular and cellular mechanisms","volume":"58","author":"Komi","year":"2020","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_8","first-page":"035","article-title":"The role of the mast cell in skin aging","volume":"2","author":"Gao","year":"2016","journal-title":"J. Derm. Res. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.7150\/ijbs.26738","article-title":"An investigation of the distribution and location of mast cells affected by the stiffness of substrates as a mechanical niche","volume":"14","author":"Yang","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Marshall, J.S., Portales-Cervantes, L., and Leong, E. (2019). Mast cell responses to viruses and pathogen products. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20174241"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.imbio.2007.10.017","article-title":"Mast cell functions in the innate skin immune system","volume":"213","author":"Metz","year":"2008","journal-title":"Immunobiology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1586\/14789450.2013.814881","article-title":"Epidermal TSLP: A trigger factor for pathogenesis of atopic dermatitis","volume":"10","author":"Indra","year":"2013","journal-title":"Expert Rev. Proteom."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2332\/allergolint.11-RAI-0376","article-title":"Cellular and molecular mechanisms of TSLP function in human allergic disorders-TSLP programs the \u201cTh2 code\u201d in dendritic cells","volume":"61","author":"Ito","year":"2012","journal-title":"Allergol. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/ni805","article-title":"Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP","volume":"3","author":"Soumelis","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.0906-6705.2004.00149.x","article-title":"Thymus-and activation-regulated chemokine (TARC\/CCL17) induces a Th2-dominated inflammatory reaction on intradermal injection in mice","volume":"13","author":"Vestergaard","year":"2004","journal-title":"Exp. Derm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1111\/1523-1747.ep12324061","article-title":"Keratinocyte-derived monocyte chemoattractant protein 1 (MCP-1): Analysis in a transgenic model demonstrates MCP-1 can recruit dendritic and Langerhans cells to skin","volume":"105","author":"Nakamura","year":"1995","journal-title":"J. Investig. Derm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.bbadis.2010.12.014","article-title":"Mast cells and inflammation","volume":"1822","author":"Theoharides","year":"2012","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1007\/s004030100230","article-title":"Enhanced production of CC-chemokines (RANTES, MCP-1, MIP-1\u03b1, MIP-1\u03b2, and eotaxin) in patients with atopic dermatitis","volume":"293","author":"Kaburagi","year":"2001","journal-title":"Arch. Derm. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4311","DOI":"10.4049\/jimmunol.181.6.4311","article-title":"Intradermal administration of thymic stromal lymphopoietin induces a T cell-and eosinophil-dependent systemic Th2 inflammatory response","volume":"181","author":"Jessup","year":"2008","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1089\/jir.2008.0027","article-title":"Monocyte chemoattractant protein-1 (MCP-1): An overview","volume":"29","author":"Deshmane","year":"2009","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.cytogfr.2011.02.003","article-title":"IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer","volume":"22","author":"Neurath","year":"2011","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/sj.cr.7310017","article-title":"Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: What we do and don\u2019t know","volume":"16","author":"Shi","year":"2006","journal-title":"Cell Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1067\/mai.2001.114707","article-title":"Keratinocytes from patients with atopic dermatitis and psoriasis show a distinct chemokine production profile in response to T cell-derived cytokines","volume":"107","author":"Giustizieri","year":"2001","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1159\/000500088","article-title":"Physiological roles of mast cells: Collegium internationale allergologicum update","volume":"179","author":"Varricchi","year":"2019","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1369\/0022155414545334","article-title":"Mast cell function: A new vision of an old cell","volume":"62","author":"Jamur","year":"2014","journal-title":"J. Histochem. Cytochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e24137","DOI":"10.4161\/jkst.24137","article-title":"The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis","volume":"2","author":"Bao","year":"2013","journal-title":"Jak-Stat"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.1016\/j.celrep.2019.05.019","article-title":"Differential roles of the mTOR-STAT3 signaling in dermal \u03b3\u03b4 T cell effector function in skin inflammation","volume":"27","author":"Cai","year":"2019","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.1600-0625.2011.01408.x","article-title":"Involvement of RAGE, MAPK and NF-\u03baB pathways in AGEs-induced MMP-9 activation in HaCaT keratinocytes","volume":"21","author":"Zhu","year":"2012","journal-title":"Exp. Derm."},{"key":"ref_29","first-page":"882","article-title":"PI3K signalling in inflammation","volume":"1851","author":"Hawkins","year":"2015","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Biol. Lipids"},{"key":"ref_30","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_31","doi-asserted-by":"crossref","first-page":"4984","DOI":"10.1016\/j.febslet.2006.08.025","article-title":"Functions of the MAPK family in vertebrate-development","volume":"580","author":"Krens","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1073\/pnas.97.3.1014","article-title":"A nuclear export signal in the N-terminal regulatory domain of I\u03baB\u03b1 controls cytoplasmic localization of inactive NF-\u03baB\/I\u03baB\u03b1 complexes","volume":"97","author":"Huang","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","first-page":"1","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1476-4598-12-86","article-title":"The complexity of NF-\u03baB signaling in inflammation and cancer","volume":"12","author":"Hoesel","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"163","DOI":"10.7732\/kjpr.2016.29.2.163","article-title":"Antioxidant activity and inhibitory effect on oxidative DNA damage of ethyl acetate fractions extracted from cone of red pine (Pinus densiflora)","volume":"29","author":"Jang","year":"2016","journal-title":"Korean J. Plant. Resour."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jphotobiol.2015.03.008","article-title":"Synthesis and characterization of nanosilver with antibacterial properties using Pinus densiflora young cone extract","volume":"147","author":"Velmurugan","year":"2015","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"45","DOI":"10.5764\/TCF.2014.26.1.45","article-title":"Anti-bacterial effects of aqueous extract purified from the immature cone of red pine (Pinus densiflora)","volume":"26","author":"Jeong","year":"2014","journal-title":"Text. Coloration Finish."},{"key":"ref_38","first-page":"275","article-title":"Inhibitory Effects of Pine Cone (Pinus densiflora) on Melanogenesis in B16F10 Melanoma Cells","volume":"32","author":"Lee","year":"2019","journal-title":"Plant. Resour. Soc. Korea"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"301","DOI":"10.20402\/ajbc.2016.0055","article-title":"Anti-oxidant and anti-melanogenic activity of the methanol extract of pine cone","volume":"14","author":"Lee","year":"2016","journal-title":"Asian J. Beauty Cosmetol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ha, T.K.Q., Lee, B.W., Nguyen, N.H., Cho, H.M., Venkatesan, T., Doan, T.P., Kim, E., and Oh, W.K. (2020). Antiviral Activities of Compounds Isolated from Pinus densiflora (Pine Tree) against the Influenza A Virus. Biomolecules, 10.","DOI":"10.3390\/biom10050711"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Guo, D., Chen, J., Tan, L., Jin, M., Ju, F., Cao, Z., Deng, F., Wang, L., Gu, Y., and Deng, Y. (2019). Terpene glycosides from Sanguisorba officinalis and their anti-inflammatory effects. Molecules, 24.","DOI":"10.3390\/molecules24162906"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5319","DOI":"10.2174\/092986712803833335","article-title":"Terpene compounds in nature: A review of their potential antioxidant activity","volume":"19","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.intimp.2005.02.002","article-title":"Ginkgo terpene component has an anti-inflammatory effect on Candida albicans-caused arthritic inflammation","volume":"5","author":"Han","year":"2005","journal-title":"Int. Immunopharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.cbi.2019.01.037","article-title":"Penta-O-galloyl-\u03b2-d-glucose, a hydrolysable tannin from Radix Paeoniae Alba, inhibits adipogenesis and TNF-\u03b1-mediated inflammation in 3T3-L1 cells","volume":"302","author":"Peng","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kim, H.J., Baek, J., Lee, J.R., Roh, J.Y., and Jung, Y. (2018). Optimization of cytokine milieu to reproduce atopic dermatitis-related gene expression in HaCaT keratinocyte cell line. Immune Netw., 18.","DOI":"10.4110\/in.2018.18.e9"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/jid.2008.106","article-title":"Animal models of atopic dermatitis","volume":"129","author":"Jin","year":"2009","journal-title":"J. Investig. Derm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"R19","DOI":"10.1016\/j.jaci.2009.07.015","article-title":"Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis","volume":"124","author":"Jensen","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_48","first-page":"1191","article-title":"Atopic dermatitis: A review of diagnosis and treatment","volume":"60","author":"Correale","year":"1999","journal-title":"Am. Fam. Physician"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1111\/j.1398-9995.2004.00476.x","article-title":"Eosinophils and atopic dermatitis","volume":"59","author":"Simon","year":"2004","journal-title":"Allergy"},{"key":"ref_50","unstructured":"OECD (2017). Test No. 402: Acute Dermal Toxicity, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0165-2427(96)05763-7","article-title":"Immunophenotyping of skin-infiltrating T-cell subsets in dogs with atopic dermatitis","volume":"57","author":"Sinke","year":"1997","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/ni1040","article-title":"Duration of TCR signaling controls CD4-CD8 lineage differentiation in vivo","volume":"5","author":"Liu","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S0952-7915(01)00287-4","article-title":"T-cell subpopulations in the development of atopic and contact allergy","volume":"13","author":"Girolomoni","year":"2001","journal-title":"Curr. Opin. Immunol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/3\/839\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:33:00Z","timestamp":1760160780000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/3\/839"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,4]]},"references-count":53,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["nu13030839"],"URL":"https:\/\/doi.org\/10.3390\/nu13030839","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,4]]}}}