{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:46:58Z","timestamp":1790887618951,"version":"4.1.0"},"reference-count":91,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T00:00:00Z","timestamp":1649808000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Aryl hydrocarbon receptor (AhR) activation by environmental agents and microbial metabolites is potentially implicated in a series of skin diseases. Hence, it would be very important to identify natural compounds that could inhibit the AhR activation by ligands of microbial origin as 6-formylindolo[3,2-b]carbazole (FICZ), indirubin (IND) and pityriazepin (PZ) or the prototype ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Five different dry Rosmarinus officinalis L. extracts (ROEs) were assayed for their activities as antagonists of AhR ligand binding with guinea pig cytosol in the presence of [3H]TCDD. The methanolic ROE was further assayed towards CYP1A1 mRNA induction using RT-PCR in human keratinocytes against TCDD, FICZ, PZ, and IND. The isolated metabolites, carnosic acid, carnosol, 7-O-methyl-epi-rosmanol, 4\u2032,7-O-dimethylapigenin, and betulinic acid, were assayed for their agonist and antagonist activity in the presence and absence of TCDD using the gel retardation assay (GRA). All assayed ROE extracts showed similar dose-dependent activities with almost complete inhibition of AhR activation by TCDD at 100 ppm. The methanol ROE at 10 ppm showed 99%, 50%, 90%, and 85% inhibition against TCDD, FICZ, IND, and PZ, respectively, in human keratinocytes. Most assayed metabolites exhibited dose-dependent antagonist activity. ROEs inhibit AhR activation by TCDD and by the Malassezia metabolites FICZ, PZ, and IND. Hence, ROE could be useful for the prevention or treatment of skin diseases mediated by activation of AhR.<\/jats:p>","DOI":"10.3390\/molecules27082499","type":"journal-article","created":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T23:07:16Z","timestamp":1649891236000},"page":"2499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Rosmarinus officinalis L. Leaf Extracts and Their Metabolites Inhibit the Aryl Hydrocarbon Receptor (AhR) Activation In Vitro and in Human Keratinocytes: Potential Impact on Inflammatory Skin Diseases and Skin Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Panagiotis","family":"Kallimanis","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Chinou","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeliki","family":"Panagiotopoulou","sequence":"additional","affiliation":[{"name":"Institute of Biosciences and Applications, National Centre for Scientific Research \u201cDemokritos\u201d, Patr. Gregoriou E & 27 Neapoleos Str., Agia Paraskevi, 15310 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anatoly A.","family":"Soshilov","sequence":"additional","affiliation":[{"name":"Department of Environmental Toxicology, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guochun","family":"He","sequence":"additional","affiliation":[{"name":"Department of Environmental Toxicology, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Denison","sequence":"additional","affiliation":[{"name":"Department of Environmental Toxicology, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0399-5344","authenticated-orcid":false,"given":"Prokopios","family":"Magiatis","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"},{"name":"Department of Environmental Toxicology, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.bcp.2008.10.003","article-title":"AhR protein trafficking and function in the skin","volume":"77","author":"Ikuta","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/toxsci\/kfr218","article-title":"Exactly the same but different: Promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor","volume":"124","author":"Denison","year":"2011","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.immuni.2014.04.019","article-title":"Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions","volume":"40","author":"Duarte","year":"2014","journal-title":"Immunity"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.mehy.2018.05.001","article-title":"Aryl hydrocarbon receptor (AhR) a possible target for the treatment of skin disease","volume":"116","author":"Napolitano","year":"2018","journal-title":"Med. Hypotheses"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s00403-014-1481-7","article-title":"Role of AhR\/ARNT system in skin homeostasis","volume":"306","author":"Furue","year":"2014","journal-title":"Arch. Dermatol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8851","DOI":"10.1073\/pnas.0701764104","article-title":"Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation","volume":"104","author":"Fritsche","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9360","DOI":"10.1128\/MCB.25.21.9360-9368.2005","article-title":"Constitutive Expression of Aryl Hydrocarbon Receptor in Keratinocytes Causes Inflammatory Skin Lesions","volume":"25","author":"Tauchi","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1111\/j.1600-0625.2006.00476.x","article-title":"Dioxin-induced chloracne--reconstructing the cellular and molecular mechanisms of a classic environmental disease","volume":"15","author":"Panteleyev","year":"2006","journal-title":"Exp. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1038\/sj.jid.5701252","article-title":"AhR ligands, malassezin, and indolo [3,2-b]carbazole are selectively produced by Malassezia furfur strains isolated from seborrheic dermatitis","volume":"128","author":"Gaitanis","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jdermsci.2009.07.014","article-title":"Eczema, respiratory allergies, and traffic-related air pollution in birth cohorts from small-town areas","volume":"56","author":"Sugiri","year":"2009","journal-title":"J. Dermatol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1038\/jid.2013.92","article-title":"Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin","volume":"133","author":"Magiatis","year":"2013","journal-title":"J. Investig. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1016\/j.jid.2017.05.004","article-title":"Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans","volume":"137","author":"Smith","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1093\/carcin\/9.9.1677","article-title":"Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the Syrian golden hamster","volume":"9","author":"Rao","year":"1988","journal-title":"Carcinogenesis"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1073\/pnas.97.2.779","article-title":"Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor","volume":"97","author":"Shimizu","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1093\/carcin\/23.11.1861","article-title":"Indolo [3,2-b]carbazole inhibits gap junctional intercellular communication in rat primary hepatocytes and acts as a potential tumor promoter","volume":"23","author":"Herrmann","year":"2002","journal-title":"Carcinogenesis"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1515\/BC.2006.143","article-title":"The aryl hydrocarbon receptor and light","volume":"387","author":"Rannug","year":"2006","journal-title":"Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1021\/es062793g","article-title":"Aryl hydrocarbon receptor plays a significant role in mediating airborne particulate-induced carcinogenesis in mice","volume":"41","author":"Matsumoto","year":"2007","journal-title":"Environ. Sci. Technol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.mehy.2011.03.020","article-title":"Could Malassezia yeasts be implicated in skin carcinogenesis through the production of aryl-hydrocarbon receptor ligands?","volume":"77","author":"Gaitanis","year":"2011","journal-title":"Med. Hypotheses"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2572","DOI":"10.1038\/jid.2015.285","article-title":"The Janus-Faced Role of Aryl Hydrocarbon Receptor Signaling in the Skin: Consequences for Prevention and Treatment of Skin Disorders","volume":"135","author":"Esser","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.cotox.2017.02.002","article-title":"AHR in the skin: From the mediator of chloracne to a therapeutic panacea?","volume":"2","author":"Merches","year":"2017","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1038\/s41418-018-0160-1","article-title":"The AHR represses nucleotide excision repair and apoptosis and contributes to UV-induced skin carcinogenesis","volume":"25","author":"Pollet","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"194","DOI":"10.3389\/fmed.2019.00194","article-title":"Aryl Hydrocarbon Receptor Modulates Carcinogenesis and Maintenance of Skin Cancers","volume":"6","author":"Hidaka","year":"2019","journal-title":"Front. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.toxlet.2013.10.039","article-title":"AhR signalling and dioxin toxicity","volume":"230","author":"Sorg","year":"2014","journal-title":"Toxicol. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1126\/science.7732381","article-title":"Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor","volume":"268","author":"Pineau","year":"1995","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1046\/j.1365-2443.1997.1490345.x","article-title":"Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor","volume":"2","author":"Mimura","year":"1997","journal-title":"Genes Cells Devoted Mol. Cell. Mech."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Furue, M., Fuyuno, Y., Mitoma, C., Uchi, H., and Tsuji, G. (2018). Therapeutic Agents with AHR Inhibiting and NRF2 Activating Activity for Managing Chloracne. Antioxidants, 7.","DOI":"10.3390\/antiox7070090"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/j.1600-0625.2010.01204.x","article-title":"2,3,7,8-Tetrachlorodibenzo-p-dioxin alters sebaceous gland cell differentiation in vitro","volume":"20","author":"Ju","year":"2011","journal-title":"Exp. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.it.2009.06.005","article-title":"The aryl hydrocarbon receptor in immunity","volume":"30","author":"Esser","year":"2009","journal-title":"Trends Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1111\/j.1365-2133.2012.11014.x","article-title":"Malassezia-derived indoles activate the aryl hydrocarbon receptor and inhibit Toll-like receptor-induced maturation in monocyte-derived dendritic cells","volume":"167","author":"Vlachos","year":"2012","journal-title":"Br. J. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.abb.2015.02.023","article-title":"Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast","volume":"571","author":"Mexia","year":"2015","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.tifs.2015.07.015","article-title":"A novel insight on an ancient aromatic plant: The rosemary (Rosmarinus officinalis L.)","volume":"45","author":"Cavaleiro","year":"2015","journal-title":"Trends Food Sci. Technol."},{"key":"ref_32","first-page":"701","article-title":"Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid","volume":"54","author":"Huang","year":"1994","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cattaneo, L., Cicconi, R., Mignogna, G., Giorgi, A., Mattei, M., Graziani, G., Ferracane, R., Grosso, A., Aducci, P., and Schinin\u00e0, M.E. (2015). Anti-Proliferative Effect of Rosmarinus officinalis L. Extract on Human Melanoma A375 Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132439"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1158\/1940-6207.CAPR-12-0002","article-title":"Carnosol, a constituent of Zyflamend, inhibits aryl hydrocarbon receptor-mediated activation of CYP1A1 and CYP1B1 transcription and mutagenesis","volume":"5","author":"Mohebati","year":"2012","journal-title":"Cancer Prev. Res."},{"key":"ref_35","unstructured":"Kallimanis, P.G. (2017). Rosemary and Sage Extracts for Skin Diseases: Compositions and Treatments. (GR1009073), Method. Patent."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.yfrne.2010.07.002","article-title":"Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance","volume":"31","author":"Lensu","year":"2010","journal-title":"Front. Neuroendocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11903","DOI":"10.1021\/acs.est.5b02906","article-title":"Development of Species-Specific Ah Receptor-Responsive Third Generation CALUX Cell Lines with Enhanced Responsiveness and Improved Detection Limits","volume":"49","author":"Brennan","year":"2015","journal-title":"Environ. Sci. Technol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zhao, B., Bohonowych, J.E., Timme-Laragy, A., Jung, D., Affatato, A.A., Rice, R.H., Di Giulio, R.T., and Denison, M.S. (2013). Common commercial and consumer products contain activators of the aryl hydrocarbon (dioxin) receptor. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056860"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1111\/j.1749-6632.1993.tb35928.x","article-title":"Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction","volume":"685","author":"Nebert","year":"1993","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1111\/j.1365-2567.2009.03054.x","article-title":"The aryl hydrocarbon receptor: A perspective on potential roles in the immune system","volume":"127","author":"Stevens","year":"2009","journal-title":"Immunology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cotox.2017.01.001","article-title":"Canonical and non-canonical aryl hydrocarbon receptor signaling pathways","volume":"2","author":"Wright","year":"2017","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.drudis.2012.11.014","article-title":"The AhR twist: Ligand-dependent AhR signaling and pharmaco-toxicological implications","volume":"18","author":"Guyot","year":"2013","journal-title":"Drug Discov. Today"},{"key":"ref_43","first-page":"231","article-title":"The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways","volume":"99","author":"Ma","year":"2009","journal-title":"EXS"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.bcp.2008.08.031","article-title":"The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways","volume":"77","author":"Puga","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1021\/tx300169e","article-title":"Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR)","volume":"25","author":"Bengtsson","year":"2012","journal-title":"Chem. Res. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1021\/acs.chemrestox.9b00270","article-title":"A Biomimetic, One-Step Transformation of Simple Indolic Compounds to Malassezia-Related Alkaloids with High AhR Potency and Efficacy","volume":"32","author":"Mexia","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1093\/toxsci\/kfj065","article-title":"Sunlight generates multiple tryptophan photoproducts eliciting high efficacy CYP1A induction in chick hepatocytes and in vivo","volume":"90","author":"Labitzke","year":"2006","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1074\/jbc.M808321200","article-title":"The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo [3,2-b]carbazole is present in humans","volume":"284","author":"Wincent","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.jaad.2003.12.034","article-title":"Skin diseases associated with Malassezia species","volume":"51","author":"Gupta","year":"2004","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Boekhout, T., Gueho, E., Mayser, P., and Velegraki, A. (2010). Physiology and Biochemistry. Malassezia and the Skin. Science and Clinical Practice, Springer.","DOI":"10.1007\/978-3-642-03616-3"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/ni.3614","article-title":"The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin","volume":"18","author":"Hidaka","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/exd.12350","article-title":"Increased expression of the aryl hydrocarbon receptor in patients with chronic inflammatory skin diseases","volume":"23","author":"Kim","year":"2014","journal-title":"Exp. Dermatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7359806","DOI":"10.1155\/2017\/7359806","article-title":"Rosemary Extracts Upregulate Nrf2, Sestrin2, and MRP2 Protein Level in Human Hepatoma HepG2 Cells","volume":"2017","author":"Tong","year":"2017","journal-title":"Evid.-Based Complement. Altern. Med. Ecam"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ejphar.2018.08.024","article-title":"Betulinic acid alleviates myocardial hypoxia\/reoxygenation injury via inducing Nrf2\/HO-1 and inhibiting p38 and JNK pathways","volume":"838","author":"Wang","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1111\/j.1471-4159.2007.05039.x","article-title":"Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1\/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1","volume":"104","author":"Satoh","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e2499","DOI":"10.1038\/cddis.2016.389","article-title":"Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2\/ARE pathway in Alzheimer\u2019s disease models","volume":"7","author":"Lipton","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Mimura, J., Inose-Maruyama, A., Taniuchi, S., Kosaka, K., Yoshida, H., Yamazaki, H., Kasai, S., Harada, N., Kaufman, R.J., and Oyadomari, S. (2019). Concomitant Nrf2- and ATF4-activation by Carnosic Acid Cooperatively Induces Expression of Cytoprotective Genes. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071706"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Li, X., Zhang, Q., Hou, N., Li, J., Liu, M., Peng, S., Zhang, Y., Luo, Y., Zhao, B., and Wang, S. (2019). Carnosol as a Nrf2 Activator Improves Endothelial Barrier Function through Antioxidative Mechanisms. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040880"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/aps.2010.181","article-title":"Upregulation of NF-E2-related factor-2-dependent glutathione by carnosol provokes a cytoprotective response and enhances cell survival","volume":"32","author":"Chen","year":"2011","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15761\/IMM.1000335","article-title":"Carnosol, a dietary diterpene from rosemary (Rosmarinus officinalis) activates Nrf2 leading to sestrin 2 induction in colon cells","volume":"5","author":"Yan","year":"2018","journal-title":"Integr. Mol. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/jid.2011.359","article-title":"The AhR-Nrf2 pathway in keratinocytes: On the road to chemoprevention?","volume":"132","author":"Abel","year":"2012","journal-title":"J. Investig. Dermatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"94743","DOI":"10.18632\/oncotarget.21889","article-title":"Combination of betulinic acid and chidamide inhibits acute myeloid leukemia by suppression of the HIF1\u03b1 pathway and generation of reactive oxygen species","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1039\/C6FO01810F","article-title":"Mechanisms and therapeutic prospects of polyphenols as modulators of the aryl hydrocarbon receptor","volume":"8","author":"Xue","year":"2017","journal-title":"Food Funct."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/toxsci\/kfy075","article-title":"Structure-Dependent Modulation of Aryl Hydrocarbon Receptor-Mediated Activities by Flavonoids","volume":"164","author":"Jin","year":"2018","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"key":"ref_65","first-page":"120","article-title":"Epidemiology of skin cancer","volume":"810","author":"Leiter","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"12048","DOI":"10.1038\/ncomms12048","article-title":"Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma","volume":"7","author":"Chahal","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nature08658","article-title":"A comprehensive catalogue of somatic mutations from a human cancer genome","volume":"463","author":"Pleasance","year":"2010","journal-title":"Nature"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1111\/exd.13944","article-title":"Malassezia derived aryl hydrocarbon receptor ligands enhance the CCL20\/Th17\/soluble CD163 pathogenic axis in extra-mammary Paget\u2019s disease","volume":"28","author":"Sato","year":"2019","journal-title":"Exp. Dermatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/jid.2013.362","article-title":"The new aryl hydrocarbon receptor antagonist E\/Z-2-benzylindene-5,6-dimethoxy-3,3-dimethylindan-1-one protects against UVB-induced signal transduction","volume":"134","author":"Tigges","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_70","first-page":"331","article-title":"Modulatory influence of Rosmarinus officinalis on DMBA-induced mouse skin tumorigenesis","volume":"7","author":"Sancheti","year":"2006","journal-title":"Asian Pac. J. Cancer Prev. APJCP"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1002\/ptr.1989","article-title":"Effect of Rosmarinus officinalis in modulating 7,12-dimethylbenz(a)anthracene induced skin tumorigenesis in mice","volume":"20","author":"Sancheti","year":"2006","journal-title":"Phytother. Res. PTR"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s00394-011-0289-x","article-title":"Anti-angiogenic properties of carnosol and carnosic acid, two major dietary compounds from rosemary","volume":"52","author":"Medina","year":"2013","journal-title":"Eur. J. Nutr."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"12698","DOI":"10.3390\/ijms150712698","article-title":"Carnosic acid inhibits the epithelial-mesenchymal transition in B16F10 melanoma cells: A possible mechanism for the inhibition of cell migration","volume":"15","author":"Park","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"12455","DOI":"10.1073\/pnas.182429899","article-title":"Topical applications of caffeine or (-)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice","volume":"99","author":"Lu","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1021\/tx025672c","article-title":"Identification of potential aryl hydrocarbon receptor antagonists in green tea","volume":"16","author":"Palermo","year":"2003","journal-title":"Chem. Res. Toxicol."},{"key":"ref_76","first-page":"1193","article-title":"Chemoprevention of skin cancer by grape constituent resveratrol: Relevance to human disease?","volume":"19","author":"Aziz","year":"2005","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4775","DOI":"10.1038\/s41467-018-06951-2","article-title":"Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma","volume":"9","author":"Corre","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.ccell.2018.02.005","article-title":"Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation","volume":"33","author":"Liu","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_79","first-page":"1","article-title":"Use of rosemary extracts as a food additive\u2013Scientific opinion of the panel on food additives, flavourings, processing aids and materials in contact with food","volume":"721","author":"Aguilar","year":"2008","journal-title":"EFSA J."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.canlet.2015.07.005","article-title":"Diterpenes from rosemary (Rosmarinus officinalis): Defining their potential for anti-cancer activity","volume":"367","author":"Petiwala","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4956","DOI":"10.3390\/molecules19044956","article-title":"Characterization of natural aryl hydrocarbon receptor agonists from cassia seed and rosemary","volume":"19","author":"Amakura","year":"2014","journal-title":"Molecules"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10600-018-2359-2","article-title":"Chemical constituents of Euscaphis japonica","volume":"54","author":"Ding","year":"2018","journal-title":"Chem. Nat. Compd."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1016\/j.bmc.2013.02.019","article-title":"Structure activity relationship of phenolic diterpenes from Salvia officinalis as activators of the nuclear factor E2-related factor 2 pathway","volume":"21","author":"Fischedick","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1021\/np010565o","article-title":"Semisynthesis of rosmanol and its derivatives. Easy access to abietatriene diterpenes isolated from the genus Salvia with biological activities","volume":"65","author":"Marrero","year":"2002","journal-title":"J. Nat. Prod."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"30","DOI":"10.53879\/id.49.10.p0030","article-title":"Apigenin-4\u2032, 7-dimethyl ether from Aquilaria agallocha roxb","volume":"49","author":"Saraswathy","year":"2012","journal-title":"Indian Drugs"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3987","DOI":"10.1016\/S0021-9258(17)35611-9","article-title":"Structure and function of the Ah receptor for 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. Species difference in molecular properties of the receptors from mouse and rat hepatic cytosols","volume":"261","author":"Denison","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4.8.1","DOI":"10.1002\/0471140856.tx0408s11","article-title":"Analysis of the aryl hydrocarbon receptor (AhR) signal transduction pathway","volume":"11","author":"Denison","year":"2002","journal-title":"Curr. Protoc. Toxicol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1128\/MCB.01183-13","article-title":"Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis","volume":"34","author":"Soshilov","year":"2014","journal-title":"Mol. Cell. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1038\/sj.jid.5700424","article-title":"Spontaneous immortalization of human epidermal cells with naturally elevated telomerase","volume":"126","author":"Rea","year":"2006","journal-title":"J. Investig. Dermatol."},{"key":"ref_90","unstructured":"Yan, A., and Caldwell, G.W. (2013). Cell-based assays for identification of aryl hydrocarbon (Ah) receptor activators. Optimization of Drug Discovery: In Vitro Methods, Humana Press. [2nd ed.]."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"75","DOI":"10.2144\/05391RV01","article-title":"Real-time PCR for mRNA quantitation","volume":"39","author":"Wong","year":"2005","journal-title":"BioTechniques"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/8\/2499\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:52:57Z","timestamp":1760136777000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/8\/2499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,13]]},"references-count":91,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["molecules27082499"],"URL":"https:\/\/doi.org\/10.3390\/molecules27082499","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,13]]}}}