{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:34:08Z","timestamp":1787168048364,"version":"build-2736575974"},"reference-count":53,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T00:00:00Z","timestamp":1647216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Federal Ministry for Economic Affairs and Energy for the central innovation program (ZIM, grant)","award":["ZF4399503MD7"],"award-info":[{"award-number":["ZF4399503MD7"]}]},{"name":"Wilhelm Doerenkamp-Stiftung (Natvantage grant)","award":["1027085801"],"award-info":[{"award-number":["1027085801"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>We demonstrated the anti-inflammatory and anti-oxidative effects of Humulus lupulus (HL) extract on solar simulator-irradiated primary human keratinocytes (PHKs) by analyzing ERK and p38 MAPK phosphorylation and production of IL-6 and IL-8. The anti-inflammatory effect of topically applied HL was further tested in vivo on human skin. To this end, we developed an oil-in-water (O\/W) and a water-in-oil (W\/O) cream with a lipid content of 40%. The anti-inflammatory effect of 1% HL extract incorporated in these two vehicles was assessed in a randomized, prospective, placebo controlled, double-blind UVB erythema study with 40 healthy volunteers. Hydrocortisone acetate (HCA) in the corresponding vehicle served as positive control. Surprisingly, both HL and HCA were only effective in the O\/W system but not in the W\/O formulation. Release studies using vertical diffusion cells (Franz cells) revealed that HCA was released in much higher amounts from the O\/W cream compared to the W\/O formulation. In summary, we have shown that 1% HL extract exerts anti-inflammatory effects comparable to 1% HCA, but only when incorporated in our O\/W cream. Our findings confirm the critical role of the vehicle in topical anti-inflammatory systems.<\/jats:p>","DOI":"10.3390\/ph15030350","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T02:56:20Z","timestamp":1647312980000},"page":"350","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The Anti-Inflammatory Effect of Humulus lupulus Extract In Vivo Depends on the Galenic System of the Topical Formulation"],"prefix":"10.3390","volume":"15","author":[{"given":"Zita","family":"Hurth","sequence":"first","affiliation":[{"name":"Research Center Skinitial, Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Luise","family":"Faber","sequence":"additional","affiliation":[{"name":"Research Center Skinitial, Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Gendrisch","sequence":"additional","affiliation":[{"name":"Research Center Skinitial, Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2602-8293","authenticated-orcid":false,"given":"Martin","family":"Holzer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmaceutical Sciences, Faculty of Chemistry and Pharmacy, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Haarhaus","sequence":"additional","affiliation":[{"name":"Research Center Skinitial, Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Cawelius","sequence":"additional","affiliation":[{"name":"Flavex Naturextrakte GmbH, 66780 Rehlingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay","family":"Schwabe","sequence":"additional","affiliation":[{"name":"BSI-Beauty Science Intelligence GmbH, 30855 Langenhagen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph Mathis","family":"Schempp","sequence":"additional","affiliation":[{"name":"Research Center Skinitial, Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0093-560X","authenticated-orcid":false,"given":"Ute","family":"W\u00f6lfle","sequence":"additional","affiliation":[{"name":"Research Center Skinitial, Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gendrisch, F., Haarhaus, B., Krieger, N., Quirin, K.-W., Schempp, C.M., and W\u00f6lfle, U. (2021). The Effect of Herbal Medicinal Products on Psoriasis-Like Keratinocytes. Biomolecules, 11.","DOI":"10.3390\/biom11030371"},{"key":"ref_2","first-page":"376","article-title":"S2k guidelines for the use of topical preparations on the skin","volume":"16","author":"Wohlrab","year":"2018","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gendrisch, F., Nov\u00e1\u010dkov\u00e1, A., Sochorov\u00e1, M., Haarhaus, B., V\u00e1vrov\u00e1, K., Schempp, C.M., and W\u00f6lfle, U. (2020). Gentiana lutea Extract Modulates Ceramide Synthesis in Primary and Psoriasis-Like Keratinocytes. Molecules, 25.","DOI":"10.3390\/molecules25081832"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/cod.12073","article-title":"Eczema and ceramides: An update","volume":"69","author":"Jungersted","year":"2013","journal-title":"Contact Dermat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.clindermatol.2011.08.022","article-title":"Abnormal epidermal barrier in the pathogenesis of psoriasis","volume":"30","author":"Wolf","year":"2012","journal-title":"Clin. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jtv.2016.03.006","article-title":"Skin care products: What do they promise, what do they deliver","volume":"26","author":"Surber","year":"2017","journal-title":"J. Tissue Viability"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/j.1610-0387.2007.06321.x","article-title":"Galenics of dermal products\u2014Vehicles, properties and drug release","volume":"5","author":"Daniels","year":"2007","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/jdv.12204","article-title":"Beer and beer compounds: Physiological effects on skin health","volume":"28","author":"Chen","year":"2014","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"699666","DOI":"10.3389\/fnut.2021.699666","article-title":"Myrcene\u2014What Are the Potential Health Benefits of This Flavouring and Aroma Agent?","volume":"8","author":"Surendran","year":"2021","journal-title":"Front. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1142\/S0192415X17500604","article-title":"Myrcene, an Aromatic Volatile Compound, Ameliorates Human Skin Extrinsic Aging via Regulation of MMPs Production","volume":"45","author":"Hwang","year":"2017","journal-title":"Am. J. Chin. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ejmech.2018.07.076","article-title":"Medicinal properties of terpenes found in Cannabis sativa and Humulus lupulus","volume":"157","author":"Nuutinen","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1111\/1541-4337.12201","article-title":"Biologically Active Compounds from Hops and Prospects for Their Use","volume":"15","year":"2016","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1530\/rep.0.1230235","article-title":"Oestrogenic activity of the hop phyto-oestrogen, 8-prenylnaringenin","volume":"123","author":"Milligan","year":"2002","journal-title":"Reproduction"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1271\/bbb.59.740","article-title":"Antioxidative activity of hop bitter acids and their analogues","volume":"59","author":"Tagashira","year":"1995","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1021\/np800740m","article-title":"Hop (Humulus lupulus)-Derived Bitter Acids as Multipotent Bioactive Compounds","volume":"72","author":"Cattoor","year":"2009","journal-title":"J. Nat. Prod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.phymed.2008.12.021","article-title":"In Vitro evaluation of antibacterial, anticollagenase, and antioxidant activities of hop components (Humulus lupulus) addressing acne vulgaris","volume":"16","author":"Yamaguchi","year":"2009","journal-title":"Phytomedicine"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Weber, N., Biehler, K., Schwabe, K., Haarhaus, B., Quirin, K.-W., Frank, U., Schempp, C.M., and W\u00f6lfle, U. (2019). Hop Extract Acts as an Antioxidant with Antimicrobial Effects against PropionibacteriumAcnes and Staphylococcus Aureus. Molecules, 24.","DOI":"10.3390\/molecules24020223"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1093\/carcin\/bgm054","article-title":"Humulone inhibits phorbol ester-induced COX-2 expression in mouse skin by blocking activation of NF-kappaB and AP-1: IkappaB kinase and c-Jun-N-terminal kinase as respective potential upstream targets","volume":"28","author":"Lee","year":"2007","journal-title":"Carcinogenesis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1006\/bbrc.2001.5934","article-title":"Inhibition of Angiogenesis by Humulone, a Bitter Acid from Beer Hop","volume":"289","author":"Shimamura","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","first-page":"289","article-title":"Antiangiogenic properties of lupulone, a bitter acid of hop cones","volume":"28","author":"Siegel","year":"2008","journal-title":"Anticancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/emm.2005.25","article-title":"Curcumin inhibits the expression of COX-2 in UVB-irradiated human keratinocytes (HaCaT) by inhibiting activation of AP-1: p38 MAP kinase and JNK as potential upstream targets","volume":"37","author":"Cho","year":"2005","journal-title":"Exp. Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1111\/j.0022-202X.2005.23747.x","article-title":"Role of p38 MAPK in UVB-induced inflammatory responses in the skin of SKH-1 hairless mice","volume":"124","author":"Kim","year":"2005","journal-title":"J. Investig. Dermatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1080\/09629359791677","article-title":"Ionizing radiation enhances IL-6 and IL-8 production by human endothelial cells","volume":"6","author":"Meeren","year":"1997","journal-title":"Mediat. Inflamm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1111\/1523-1747.ep12371677","article-title":"IL-8 Gene Expression and Production in Human Keratinocytes and Their Modulation by UVB","volume":"101","author":"Kondo","year":"1993","journal-title":"J. Investig. Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1208\/s12249-008-9107-z","article-title":"Control of Transdermal Permeation of Hydrocortisone Acetate from Hydrophilic and Lipophilic Formulations","volume":"9","author":"Fini","year":"2008","journal-title":"AAPS PharmSciTech"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1081\/PDT-100101373","article-title":"Evaluation of the test system used for in vitro release of drugs for topical dermatological drug products","volume":"4","author":"Shah","year":"1999","journal-title":"Pharm. Dev. Technol."},{"key":"ref_27","first-page":"85","article-title":"Physical Chemical analysis of Percutaneous Absorption Process from Creams and Ointments","volume":"11","author":"Higuchi","year":"1960","journal-title":"J. Soc. Cosmet. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/exd.13336","article-title":"Systemic immune mechanisms in atopic dermatitis and psoriasis with implications for treatment","volume":"27","author":"Krueger","year":"2018","journal-title":"Exp. Dermatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e12932","DOI":"10.1111\/dth.12932","article-title":"Biologics in dermatology: What does the future hold?","volume":"32","author":"Yavuz","year":"2019","journal-title":"Dermatol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1002\/ptr.6032","article-title":"Antiproliferation of keratinocytes and alleviation of psoriasis by the ethanol extract of Artemisia capillaris","volume":"32","author":"Lee","year":"2018","journal-title":"Phytother. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hoffmann, J., Gendrisch, F., Schempp, C.M., and W\u00f6lfle, U. (2020). New Herbal Biomedicines for the Topical Treatment of Dermatological Disorders. Biomedicines, 8.","DOI":"10.3390\/biomedicines8020027"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1002\/mnfr.200800493","article-title":"Hop bitter acids efficiently block inflammation independent of GR\u03b1, PPAR\u03b1, or PPAR\u03b3","volume":"53","author":"Cleemput","year":"2009","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1055\/s-2007-981583","article-title":"Sage extract rich in phenolic diterpenes inhibits ultraviolet-induced erythema in vivo","volume":"73","author":"Reuter","year":"2007","journal-title":"Planta Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hoffmann, J., Casetti, F., Bullerkotte, U., Haarhaus, B., Vagedes, J., Schempp, C.M., and W\u00f6lfle, U. (2016). Anti-Inflammatory Effects of Agrimoniin-Enriched Fractions of Potentilla erecta. Molecules, 21.","DOI":"10.3390\/molecules21060792"},{"key":"ref_35","first-page":"156","article-title":"Humulon, a Bitter in the Hop, Inhibits Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate in Two-Stage Carcinogenesis in Mouse Skin","volume":"52","author":"Yasukawa","year":"1995","journal-title":"OCL"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"W\u00f6lfle, U., Haarhaus, B., Seiwerth, J., Cawelius, A., Schwabe, K., Quirin, K.-W., and Schempp, C.M. (2017). The Herbal Bitter Drug Gentiana lutea Modulates Lipid Synthesis in Human Keratinocytes In Vitro and In Vivo. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081814"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"111883","DOI":"10.1016\/j.marpolbul.2020.111883","article-title":"Worldwide actions against plastic pollution from microbeads and microplastics in cosmetics focusing on European policies. Has the issue been handled effectively?","volume":"162","author":"Anagnosti","year":"2021","journal-title":"Mar. Pollut. Bull."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.scitotenv.2019.05.163","article-title":"Combined effects of polystyrene microplastics and natural organic matter on the accumulation and toxicity of copper in zebrafish","volume":"682","author":"Qiao","year":"2019","journal-title":"Sci. Total Environ."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"978","DOI":"10.3389\/fendo.2021.724989","article-title":"A Review of Human Exposure to Microplastics and Insights Into Microplastics as Obesogens","volume":"12","author":"Kannan","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/1523-1747.ep12533356","article-title":"Percutaneous Absorption. On the Relevance of in Vitro Data","volume":"64","author":"Franz","year":"1975","journal-title":"J. Investig. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1152\/physrev.1971.51.4.702","article-title":"Permeability of the skin","volume":"51","author":"Scheuplein","year":"1971","journal-title":"Physiol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0928-0987(01)00167-1","article-title":"Novel mechanisms and devices to enable successful transdermal drug delivery","volume":"14","author":"Barry","year":"2001","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4671","DOI":"10.2174\/092986712803306358","article-title":"Transdermal drug delivery in vitro using diffusion cells","volume":"19","author":"Bartosova","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1034\/j.1600-0625.2000.009003165.x","article-title":"The 500 Dalton rule for the skin penetration of chemical compounds and drugs","volume":"9","author":"Bos","year":"2000","journal-title":"Exp. Dermatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1016\/j.bbamem.2006.06.021","article-title":"The skin barrier in healthy and diseased state","volume":"1758","author":"Bouwstra","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1021\/mp400675d","article-title":"An insight into the skin penetration enhancement mechanism of N-methylpyrrolidone","volume":"11","author":"Cilurzo","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Sugibayashi, K. (2017). Related Topic: Skin Permeation of Topical Formulations. Skin Permeation and Disposition of Therapeutic and Cosmeceutical Compounds, Springer.","DOI":"10.1007\/978-4-431-56526-0"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1002\/jps.2600751013","article-title":"Glucocorticoids: Binding affinity and lipophilicity","volume":"75","author":"Ponec","year":"1986","journal-title":"J. Pharm. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Casiraghi, A., Musazzi, U.M., Centin, G., Franz\u00e8, S., and Minghetti, P. (2020). Topical Administration of Cannabidiol: Influence of Vehicle-Related Aspects on Skin Permeation Process. Pharmaceuticals, 13.","DOI":"10.3390\/ph13110337"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0092-8674(75)80001-8","article-title":"Serial cultivation of strains of human epidermal keratinocytes: The formation of keratinizing colonies from single cells","volume":"6","author":"Rheinwald","year":"1975","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1046\/j.1365-2133.2000.03482.x","article-title":"Topical application of St John\u2019s wort (Hypericum perforatum L.) and of its metabolite hyperforin inhibits the allostimulatory capacity of epidermal cells","volume":"142","author":"Schempp","year":"2000","journal-title":"Br. J. Dermatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0378-5173(89)90361-X","article-title":"Determination of in vitro drug release from hydrocortisone creams","volume":"53","author":"Shah","year":"1989","journal-title":"Int. J. Pharm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"37","DOI":"10.14227\/DT170410P37","article-title":"Technical Note: Hydrocortisone as a Performance Verification Test Reference Standard for In Vitro Release Testing","volume":"17","author":"Klein","year":"2010","journal-title":"Dissolution Technol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/3\/350\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:36:03Z","timestamp":1760135763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/3\/350"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,14]]},"references-count":53,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ph15030350"],"URL":"https:\/\/doi.org\/10.3390\/ph15030350","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,14]]}}}