{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T21:10:26Z","timestamp":1784581826960,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T00:00:00Z","timestamp":1679616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82204006"],"award-info":[{"award-number":["82204006"]}]},{"name":"National Natural Science Foundation of China","award":["H2020209039"],"award-info":[{"award-number":["H2020209039"]}]},{"name":"National Natural Science Foundation of China","award":["QN2022170"],"award-info":[{"award-number":["QN2022170"]}]},{"name":"National Natural Science Foundation of China","award":["21130208c"],"award-info":[{"award-number":["21130208c"]}]},{"name":"National Natural Science Foundation of China","award":["2020-PT320-005"],"award-info":[{"award-number":["2020-PT320-005"]}]},{"name":"National Natural Science Foundation of China","award":["XMMC-FCTM202202"],"award-info":[{"award-number":["XMMC-FCTM202202"]}]},{"name":"National Natural Science Foundation of Hebei Province","award":["82204006"],"award-info":[{"award-number":["82204006"]}]},{"name":"National Natural Science Foundation of Hebei Province","award":["H2020209039"],"award-info":[{"award-number":["H2020209039"]}]},{"name":"National Natural Science Foundation of Hebei Province","award":["QN2022170"],"award-info":[{"award-number":["QN2022170"]}]},{"name":"National Natural Science Foundation of Hebei Province","award":["21130208c"],"award-info":[{"award-number":["21130208c"]}]},{"name":"National Natural Science Foundation of Hebei Province","award":["2020-PT320-005"],"award-info":[{"award-number":["2020-PT320-005"]}]},{"name":"National Natural Science Foundation of Hebei Province","award":["XMMC-FCTM202202"],"award-info":[{"award-number":["XMMC-FCTM202202"]}]},{"name":"Science and Technology Project of Hebei Education Department","award":["82204006"],"award-info":[{"award-number":["82204006"]}]},{"name":"Science and Technology Project of Hebei Education Department","award":["H2020209039"],"award-info":[{"award-number":["H2020209039"]}]},{"name":"Science and Technology Project of Hebei Education Department","award":["QN2022170"],"award-info":[{"award-number":["QN2022170"]}]},{"name":"Science and Technology Project of Hebei Education Department","award":["21130208c"],"award-info":[{"award-number":["21130208c"]}]},{"name":"Science and Technology Project of Hebei Education Department","award":["2020-PT320-005"],"award-info":[{"award-number":["2020-PT320-005"]}]},{"name":"Science and Technology Project of Hebei Education Department","award":["XMMC-FCTM202202"],"award-info":[{"award-number":["XMMC-FCTM202202"]}]},{"name":"Technology Project of Tangshan","award":["82204006"],"award-info":[{"award-number":["82204006"]}]},{"name":"Technology Project of Tangshan","award":["H2020209039"],"award-info":[{"award-number":["H2020209039"]}]},{"name":"Technology Project of Tangshan","award":["QN2022170"],"award-info":[{"award-number":["QN2022170"]}]},{"name":"Technology Project of Tangshan","award":["21130208c"],"award-info":[{"award-number":["21130208c"]}]},{"name":"Technology Project of Tangshan","award":["2020-PT320-005"],"award-info":[{"award-number":["2020-PT320-005"]}]},{"name":"Technology Project of Tangshan","award":["XMMC-FCTM202202"],"award-info":[{"award-number":["XMMC-FCTM202202"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Science","award":["82204006"],"award-info":[{"award-number":["82204006"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Science","award":["H2020209039"],"award-info":[{"award-number":["H2020209039"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Science","award":["QN2022170"],"award-info":[{"award-number":["QN2022170"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Science","award":["21130208c"],"award-info":[{"award-number":["21130208c"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Science","award":["2020-PT320-005"],"award-info":[{"award-number":["2020-PT320-005"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Science","award":["XMMC-FCTM202202"],"award-info":[{"award-number":["XMMC-FCTM202202"]}]},{"name":"Project of Key Laboratory of Functional and Clinical Translational Medicine","award":["82204006"],"award-info":[{"award-number":["82204006"]}]},{"name":"Project of Key Laboratory of Functional and Clinical Translational Medicine","award":["H2020209039"],"award-info":[{"award-number":["H2020209039"]}]},{"name":"Project of Key Laboratory of Functional and Clinical Translational Medicine","award":["QN2022170"],"award-info":[{"award-number":["QN2022170"]}]},{"name":"Project of Key Laboratory of Functional and Clinical Translational Medicine","award":["21130208c"],"award-info":[{"award-number":["21130208c"]}]},{"name":"Project of Key Laboratory of Functional and Clinical Translational Medicine","award":["2020-PT320-005"],"award-info":[{"award-number":["2020-PT320-005"]}]},{"name":"Project of Key Laboratory of Functional and Clinical Translational Medicine","award":["XMMC-FCTM202202"],"award-info":[{"award-number":["XMMC-FCTM202202"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Rosacea is a chronic inflammatory skin disease whose late manifestations have not yet been clearly reported in animal models. The objective of this study is to describe the skin lesions and major histopathological changes in a rosacea-like phenotype in mice induced by prolonged LL-37 administration and furthermore, to assess the potential of long-term LL-37 administration in inducing irreversible rosacea-like skin lesion models. Balb\/c mice were continuously injected intradermally with LL-37 every 12 h to induce a rosacea-like phenotype. After LL-37 injections were administered for 20 consecutive days, the area of rosacea-like lesions gradually expanded in the first 13 days, then entered a stable phase. Haematoxylin and eosin (H&amp;E) and Van Gieson\u2019s staining showed a high degree of inflammatory cell aggregation, thickening of the epidermis and dermis, and collagen deposition in large quantities. The results of immunofluorescence staining and Western blotting showed that the expression of \u03b1-SMA, TNF-\u03b1, vimentin, and COL1 in the skin of mice was significantly upregulated. Short-term LL-37 administration induced rosacea-like lesions that only featured the aggregation of inflammatory factors and thickening of the epidermis, whereas no collagen hyperplasia was observed, and a full recovery was noticed. However, rosacea-like skin lesions induced by long-term LL-37 administration did not completely recover. Our study compares rosacea-like lesions induced by short-term versus long-term LL-37 administration, and the results suggest that irreversible rosacea-like lesions can be induced by long-term LL-37 administration.<\/jats:p>","DOI":"10.3390\/cimb45040177","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T04:31:05Z","timestamp":1679632265000},"page":"2703-2716","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Long-Term Administration of LL-37 Can Induce Irreversible Rosacea-like Lesion"],"prefix":"10.3390","volume":"45","author":[{"given":"Chuanxi","family":"Zhang","sequence":"first","affiliation":[{"name":"Clinical Medical College, North China University of Science and Technology, Tangshan 063210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumeng","family":"Kang","sequence":"additional","affiliation":[{"name":"Clinical Medical College, North China University of Science and Technology, Tangshan 063210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinical Medical College, North China University of Science and Technology, Tangshan 063210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heliang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Public Health, North China University of Science and Technology, Tangshan 063210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3655-3833","authenticated-orcid":false,"given":"Hong","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Public Health, North China University of Science and Technology, Tangshan 063210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchen","family":"Cai","sequence":"additional","affiliation":[{"name":"School of Public Health, North China University of Science and Technology, Tangshan 063210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemin","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Public Health, North China University of Science and Technology, Tangshan 063210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yang","sequence":"additional","affiliation":[{"name":"Clinical Medical College, North China University of Science and Technology, Tangshan 063210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s40257-021-00595-7","article-title":"Rosacea: New Concepts in Classification and Treatment","volume":"22","author":"Arents","year":"2021","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.12688\/f1000research.16537.1","article-title":"Recent advances in understanding and managing rosacea","volume":"7","author":"Buddenkotte","year":"2018","journal-title":"F1000Research"},{"key":"ref_3","first-page":"1","article-title":"Rosacea: An Update in Diagnosis, Classification and Management","volume":"26","author":"Kang","year":"2021","journal-title":"Skin Ther. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e175","DOI":"10.1111\/ijd.14757","article-title":"Rosacea: A wholistic review and update from pathogenesis to diagnosis and therapy","volume":"59","author":"Marson","year":"2020","journal-title":"Int. J. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/j.jaad.2020.01.077","article-title":"Standard management options for rosacea: The 2019 update by the National Rosacea Society Expert Committee","volume":"82","author":"Thiboutot","year":"2020","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1361574","DOI":"10.1080\/19381980.2017.1361574","article-title":"Rosacea: Epidemiology, pathogenesis, and treatment","volume":"9","author":"Rainer","year":"2017","journal-title":"Derm. -Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1016\/j.jaad.2018.08.049","article-title":"Global epidemiology and clinical spectrum of rosacea, highlighting skin of color: Review and clinical practice experience","volume":"80","author":"Alexis","year":"2019","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.jaad.2014.05.036","article-title":"The psychological impact of rosacea and the influence of current management options","volume":"71","author":"Moustafa","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1089\/sur.2018.194","article-title":"Antimicrobial Peptides","volume":"19","author":"Fry","year":"2018","journal-title":"Surg. Infect."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bin Hafeez, A., Jiang, X., Bergen, P.J., and Zhu, Y. (2021). Antimicrobial Peptides: An Update on Classifications and Databases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111691"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"638494","DOI":"10.3389\/fbioe.2021.638494","article-title":"Cathelicidin LL37 Promotes Osteogenic Differentiation in vitro and Bone Regeneration in vivo","volume":"9","author":"Li","year":"2021","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.peptides.2011.06.005","article-title":"Wound healing activity of the human antimicrobial peptide LL37","volume":"32","author":"Ramos","year":"2011","journal-title":"Peptides"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1042\/BJ20131048","article-title":"Native oligomerization determines the mode of action and biological activities of human cathelicidin LL-37","volume":"457","author":"Xhindoli","year":"2014","journal-title":"Biochem. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s00005-009-0057-2","article-title":"Cathelicidin LL-37: A multitask antimicrobial peptide","volume":"58","author":"Bucki","year":"2010","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100029","DOI":"10.1016\/j.jtauto.2019.100029","article-title":"Cathelicidin LL-37: A new important molecule in the pathophysiology of systemic lupus erythematosus","volume":"3","year":"2020","journal-title":"J. Transl. Autoimmun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"857","DOI":"10.3389\/fimmu.2019.00857","article-title":"Antimicrobial Peptide LL-37 Facilitates Intracellular Uptake of RNA Aptamer Apt 21-2 Without Inducing an Inflammatory or Interferon Response","volume":"10","author":"Macleod","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Luo, Y., and Song, Y. (2021). Mechanism of Antimicrobial Peptides: Antimicrobial, Anti-Inflammatory and Antibiofilm Activities. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111401"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2885","DOI":"10.1016\/j.jid.2021.02.745","article-title":"Antimicrobial Peptide LL-37 Drives Rosacea-Like Skin Inflammation in an NLRP3-Dependent Manner","volume":"141","author":"Yoon","year":"2021","journal-title":"J. Investig. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1038\/nm1616","article-title":"Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea","volume":"13","author":"Yamasaki","year":"2007","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1016\/j.jid.2021.04.024","article-title":"Cathelicidin LL-37 Ignites Primed NLRP3 Inflammasomes in Rosacea","volume":"141","author":"Croitoru","year":"2021","journal-title":"J. Investig. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1111\/jocd.14164","article-title":"Murine models of rosacea: A review","volume":"21","author":"Zhang","year":"2022","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"618","DOI":"10.3892\/etm.2022.11555","article-title":"Development of an animal model for rosacea-like skin lesions caused by Demodex","volume":"24","author":"Luo","year":"2022","journal-title":"Exp. Ther. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/j.jid.2020.08.013","article-title":"Paired Transcriptomic and Proteomic Analysis Implicates IL-1\u03b2 in the Pathogenesis of Papulopustular Rosacea Explants","volume":"141","author":"Harden","year":"2021","journal-title":"J. Investing. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1111\/exd.13381","article-title":"Inhibition of mast cell infiltration in an LL-37-induced rosacea mouse model using topical brimonidine tartrate 0.33% gel","volume":"26","author":"Kim","year":"2017","journal-title":"Exp. Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.jdermsci.2018.12.004","article-title":"Botulinum toxin blocks mast cells and prevents rosacea like inflammation","volume":"93","author":"Choi","year":"2019","journal-title":"J. Dermatol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"106178","DOI":"10.1016\/j.intimp.2019.106178","article-title":"Hydroxychloroquine is a novel therapeutic approach for rosacea","volume":"79","author":"Li","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lee, J., Jung, Y., Jeong, S., Jeong, G., Moon, G., and Kim, M. (2021). Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-like Mouse Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020931"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1002\/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H","article-title":"TNF alpha and the TNF receptor superfamily: Structure-function relationship(s)","volume":"50","author":"Idriss","year":"2000","journal-title":"Microsc. Res. Tech."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/j.1600-0781.2010.00522.x","article-title":"Ultraviolet B-induced apoptosis of human skin fibroblasts involves activation of caspase-8 and -3 with increased expression of vimentin","volume":"26","author":"Xu","year":"2010","journal-title":"Photodermatol. Photoimmunol. Photomed."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"114091","DOI":"10.1016\/j.biopha.2022.114091","article-title":"Dietary supplementation of n-3 PUFAs ameliorates LL37-induced rosacea-like skin inflammation via inhibition of TLR2\/MyD88\/NF-\u03baB pathway","volume":"157","author":"Shen","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"166563","DOI":"10.1016\/j.bbadis.2022.166563","article-title":"Lithocholic acid promotes rosacea-like skin inflammation via G protein-coupled bile acid receptor 1. Biochimica et biophysica acta","volume":"1868","author":"Xiao","year":"2022","journal-title":"Mol. Basis Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"109181","DOI":"10.1016\/j.biopha.2019.109181","article-title":"Artemisinin, a potential option to inhibit inflammation and angiogenesis in rosacea","volume":"117","author":"Yuan","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4127","DOI":"10.2147\/DDDT.S393122","article-title":"Thalidomide Attenuates Skin Lesions and Inflammation in Rosacea-like Mice Induced by Long-Term Exposure of LL-37","volume":"16","author":"Kang","year":"2022","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Li, X., Zhai, Y., Xi, B., Ma, W., Zhang, J., Ma, X., Miao, Y., Zhao, Y., Ning, W., and Zhou, H. (2021). Pinocembrin Ameliorates Skin Fibrosis via Inhibiting TGF-\u03b21 Signaling Pathway. Biomolecules, 11.","DOI":"10.3390\/biom11081240"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11290","DOI":"10.1111\/jcmm.17055","article-title":"MicroRNA-411-3p inhibits bleomycin-induced skin fibrosis by regulating transforming growth factor-\u03b2\/Smad ubiquitin regulatory factor-2 signalling","volume":"25","author":"Zhang","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"609615","DOI":"10.3389\/fimmu.2021.609615","article-title":"A Novel Mechanism of Carvedilol Efficacy for Rosacea Treatment: Toll-like Receptor 2 Inhibition in Macrophages","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Immunol."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/4\/177\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:02:04Z","timestamp":1760122924000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/4\/177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,24]]},"references-count":36,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["cimb45040177"],"URL":"https:\/\/doi.org\/10.3390\/cimb45040177","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,24]]}}}