{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T12:58:12Z","timestamp":1777640292261,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T00:00:00Z","timestamp":1673395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-028424 (CARTILFACTORY)"],"award-info":[{"award-number":["POCI-01-0145-FEDER-028424 (CARTILFACTORY)"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/04539\/2020"],"award-info":[{"award-number":["UIDP\/04539\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["LA\/P\/0058\/2020"],"award-info":[{"award-number":["LA\/P\/0058\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/79600\/2011"],"award-info":[{"award-number":["SFRH\/79600\/2011"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>To explore the molecular mechanisms underlying the anti-inflammatory activity of (R)-(-)-carvone, we evaluated its ability to inhibit the signaling pathways involving the mitogen-activated protein kinases (MAPKs) and the transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB). (R)-(-)-carvone significantly decreased c-Jun N-terminal kinase (JNK) 1phosphorylation, but not that of the other MAPKs, induced by bacterial lipopolysaccharides (LPS) in the RAW 264.7 macrophage cell line. Although (R)-(-)-carvone significantly inhibited resynthesis of the inhibitor of NF-\u03baB (I\u03baB)-\u03b1 induced by LPS, it did not interfere with the canonical NF-\u03baB activation pathway, suggesting that it may interfere with its transcriptional activity. (R)-(-)-carvone also showed a tendency to decrease the levels of acetylated NF-\u03baB\/p65 in the nucleus, without affecting the activity and protein levels of Sirtuin-1, the major NF-\u03baB\/p65 deacetylating enzyme. Interestingly, the nuclear protein levels of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the expression of its target,, heme oxygenase-1 (HO-1), an antioxidant enzyme, also showed a tendency to increase in the presence of (R)-(-)-carvone. Taken together, these results suggest that the ability of (R)-(-)-carvone to inhibit JNK1 and to activate Nrf2 can underlie its capacity to inhibit the transcriptional activity of NF-\u03baB and the expression of its target genes. This study highlights the diversity of molecular mechanisms that can be involved in the anti-inflammatory activity of monoterpenes.<\/jats:p>","DOI":"10.3390\/pharmaceutics15010249","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T04:59:58Z","timestamp":1673413198000},"page":"249","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Molecular Mechanisms Underlying the Anti-Inflammatory Properties of (R)-(-)-Carvone: Potential Roles of JNK1, Nrf2 and NF-\u03baB"],"prefix":"10.3390","volume":"15","author":[{"given":"C\u00e1tia","family":"Sousa","sequence":"first","affiliation":[{"name":"Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7391-3124","authenticated-orcid":false,"given":"Bruno Miguel","family":"Neves","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences and Institute of Biomedicine\u2013\u2013iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3895-9631","authenticated-orcid":false,"given":"Alcino Jorge","family":"Leit\u00e3o","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5511-7132","authenticated-orcid":false,"given":"Alexandrina Ferreira","family":"Mendes","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Azab, A., Nassar, A., and Azab, A. (2016). Anti-Inflammatory Activity of Natural Products. Molecules, 21.","DOI":"10.3390\/molecules21101321"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.3390\/molecules18011227","article-title":"A Review on Anti-Inflammatory Activity of Monoterpenes","volume":"18","author":"Andrade","year":"2013","journal-title":"Molecules"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9252","DOI":"10.3390\/molecules15129252","article-title":"Antioxidant and Anti-Inflammatory Activities of Essential Oils: A Short Review","volume":"15","author":"Miguel","year":"2010","journal-title":"Molecules"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.3389\/fphys.2018.01741","article-title":"Editorial: The Physiology of Inflammation\u2014The Final Common Pathway to Disease","volume":"9","author":"Mendes","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1038\/s41591-019-0675-0","article-title":"Chronic Inflammation in the Etiology of Disease across the Life Span","volume":"25","author":"Furman","year":"2019","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7204","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory Responses and Inflammation-Associated Diseases in Organs","volume":"9","author":"Chen","year":"2018","journal-title":"Oncotarget"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1021\/np400828x","article-title":"Anti-Inflammatory and Chondroprotective Activity of (+)-\u03b1-Pinene: Structural and Enantiomeric Selectivity","volume":"77","author":"Rufino","year":"2014","journal-title":"J. Nat. Prod."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ejphar.2015.01.018","article-title":"Evaluation of the Anti-Inflammatory, Anti-Catabolic and pro-Anabolic Effects of E-Caryophyllene, Myrcene and Limonene in a Cell Model of Osteoarthritis","volume":"750","author":"Rufino","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_9","first-page":"1220","article-title":"Differential Effects of the Essential Oils of Lavandula Luisieri and Eryngium Duriaei Subsp","volume":"53","author":"Rufino","year":"2015","journal-title":"Juresianum in Cell Models of Two Chronic Inflammatory Diseases. Pharm. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7199","DOI":"10.1038\/s41598-020-64032-1","article-title":"Standardised Comparison of Limonene-Derived Monoterpenes Identifies Structural Determinants of Anti-Inflammatory Activity","volume":"10","author":"Sousa","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sousa, C., Neves, B.M., Leit\u00e3o, A.J., and Mendes, A.F. (2021). Elucidation of the Mechanism Underlying the Anti-Inflammatory Properties of (S)-(+)-Carvone Identifies a Novel Class of Sirtuin-1 Activators in a Murine Macrophage Cell Line. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070777"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1080\/10799893.2016.1203943","article-title":"Assessment of Cell Line Competence for Studies of Pharmacological GPR30 Modulation","volume":"37","author":"Sousa","year":"2017","journal-title":"J. Recept. Signal Transduct."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nri3495","article-title":"Mitogen-Activated Protein Kinases in Innate Immunity","volume":"13","author":"Arthur","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mulero, M.C., Huxford, T., and Ghosh, G. (2019). NF-\u039aB, I\u03baB, and IKK: Integral Components of Immune System Signaling. Structural Immunology, Springer.","DOI":"10.1007\/978-981-13-9367-9_10"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/bs.ircmb.2017.07.007","article-title":"NF-\u039aB and the Transcriptional Control of Inflammation","volume":"335","author":"Mitchell","year":"2018","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5630","DOI":"10.4049\/jimmunol.170.11.5630","article-title":"IKK\u03b2 Plays an Essential Role in the Phosphorylation of RelA\/P65 on Serine 536 Induced by Lipopolysaccharide","volume":"170","author":"Yang","year":"2003","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"30353","DOI":"10.1074\/jbc.274.43.30353","article-title":"I\u03baB Kinases Phosphorylate NF-\u039aB P65 Subunit on Serine 536 in the Transactivation Domain","volume":"274","author":"Sakurai","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.cellsig.2010.03.017","article-title":"Posttranslational Modifications of NF-\u039aB: Another Layer of Regulation for NF-\u039aB Signaling Pathway","volume":"22","author":"Huang","year":"2010","journal-title":"Cell. Signal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1084\/jem.188.6.1055","article-title":"Functional Redundancy of the Nuclear Factor \u039aB Inhibitors I\u03baB\u03b1 and I\u03baB\u03b2","volume":"188","author":"Cheng","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6539","DOI":"10.1093\/emboj\/cdf660","article-title":"Acetylation of RelA at Discrete Sites Regulates Distinct Nuclear Functions of NF-KappaB","volume":"21","author":"Chen","year":"2002","journal-title":"EMBO J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1038\/sj.emboj.7600244","article-title":"Modulation of NF-\u039aB-Dependent Transcription and Cell Survival by the SIRT1 Deacetylase","volume":"23","author":"Yeung","year":"2004","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1042\/BST20150014","article-title":"Dissecting Molecular Cross-Talk between Nrf2 and NF-\u039aB Response Pathways","volume":"43","author":"Wardyn","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1055\/s-2006-961480","article-title":"Anethofuran, Carvone, and Limonene: Potential Cancer Chemoprotective Agents from Dill Weed Oil and Caraway Oil","volume":"58","author":"Zheng","year":"1992","journal-title":"Planta Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8261","DOI":"10.1073\/pnas.85.21.8261","article-title":"Identification of a Common Chemical Signal Regulating the Induction of Enzymes That Protect against Chemical Carcinogenesis","volume":"85","author":"Talalay","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2774","DOI":"10.1073\/pnas.93.7.2774","article-title":"Activation of C-Jun N-Terminal Kinase in Bacterial Lipopolysaccharide-Stimulated Macrophages","volume":"93","author":"Hambleton","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1007\/s13238-011-1113-3","article-title":"C-Jun, at the Crossroad of the Signaling Network","volume":"2","author":"Meng","year":"2011","journal-title":"Protein Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0167-4889(02)00320-8","article-title":"Summary and Comparison of the Signaling Mechanisms of the Toll\/Interleukin-1 Receptor Family","volume":"1592","author":"Martin","year":"2002","journal-title":"Biochim. Biophys. Acta-Mol. Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0898-6568(00)00149-2","article-title":"LPS Induction of Gene Expression in Human Monocytes","volume":"13","author":"Guha","year":"2001","journal-title":"Cell. Signal."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4407","DOI":"10.1128\/MCB.00535-07","article-title":"C-Jun Controls Histone Modifications, NF-\u039aB Recruitment, and RNA Polymerase II Function To Activate the Ccl2 Gene","volume":"28","author":"Wolter","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s10787-018-0483-z","article-title":"In Vitro Anti-Inflammatory Activity of Terpenes via Suppression of Superoxide and Nitric Oxide Generation and the NF-\u039aB Signalling Pathway","volume":"27","author":"Marques","year":"2019","journal-title":"Inflammopharmacology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1002\/jcb.10428","article-title":"Differential Roles of Hydrogen Peroxide and Superoxide in Mediating IL-1-Induced NF-?B Activation and INOS Expression in Bovine Articular Chondrocytes","volume":"88","author":"Mendes","year":"2003","journal-title":"J. Cell. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1023\/B:CBTO.0000003730.21261.fa","article-title":"Hydrogen Peroxide Mediates Interleukin-1\u03b2-Induced AP-1 Activation in Articular Chondrocytes: Implications for the Regulation of INOS Expression","volume":"19","author":"Caramona","year":"2003","journal-title":"Cell Biol. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/nrd2829","article-title":"Targeting Innate Immunity Protein Kinase Signalling in Inflammation","volume":"8","author":"Gaestel","year":"2009","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"945","DOI":"10.2174\/138955706777934937","article-title":"Naturally Occurring NF-KB Inhibitors","volume":"6","author":"Nam","year":"2006","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1007\/s11926-012-0288-9","article-title":"Intersection of Inflammation and Herbal Medicine in the Treatment of Osteoarthritis","volume":"14","author":"Mobasheri","year":"2012","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"117362","DOI":"10.1016\/j.lfs.2020.117362","article-title":"Resveratrol Protects against CIH-Induced Myocardial Injury by Targeting Nrf2 and Blocking NLRP3 Inflammasome Activation","volume":"245","author":"Sun","year":"2020","journal-title":"Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sousa, C., and Mendes, A.F. (2022). Monoterpenes as Sirtuin-1 Activators: Therapeutic Potential in Aging and Related Diseases. Biomolecules, 12.","DOI":"10.3390\/biom12070921"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"39","DOI":"10.21315\/mjms2020.27.6.5","article-title":"Hypolipidaemic and Insulin Secretagogue Activities of (R)-(\u2212)-Carvone","volume":"27","author":"Abbas","year":"2020","journal-title":"Malaysian J. Med. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"98","DOI":"10.4274\/balkanmedj.galenos.2019.2019.7.117","article-title":"R-(-)-Carvone Attenuated Doxorubicin Induced Cardiotoxicity In Vivo and Potentiated Its Anticancer Toxicity In Vitro","volume":"37","author":"Abbas","year":"2020","journal-title":"Balkan Med. J."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ribeiro-Filho, J., da Silva Brandi, J., Ferreira Costa, H., Carla de Paula Medeiros, K., Alves Leite, J., Pergentino de Sousa, D., and Regina Piuvezam, M. (2020). Carvone Enantiomers Differentially Modulate IgE-Mediated Airway Inflammation in Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239209"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.bbadis.2016.11.005","article-title":"Nrf2 Signaling Pathway: Pivotal Roles in Inflammation","volume":"1863","author":"Ahmed","year":"2017","journal-title":"Biochim. Biophys. Acta-Mol. Basis Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"R167","DOI":"10.1186\/ar3127","article-title":"Chondroprotective Effects and Mechanisms of Resveratrol in Advanced Glycation End Products-Stimulated Chondrocytes","volume":"12","author":"Liu","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"791376","DOI":"10.3389\/fphar.2022.791376","article-title":"Deferoxamine Alleviates Osteoarthritis by Inhibiting Chondrocyte Ferroptosis and Activating the Nrf2 Pathway","volume":"13","author":"Guo","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10513","DOI":"10.18632\/aging.102474","article-title":"Astaxanthin Protects against Osteoarthritis via Nrf2: A Guardian of Cartilage Homeostasis","volume":"11","author":"Sun","year":"2019","journal-title":"Aging"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/ddr.21509","article-title":"Curcumin Reduces Inflammation in Knee Osteoarthritis Rats through Blocking TLR4 \/MyD88\/NF-\u03baB Signal Pathway","volume":"80","author":"Zhang","year":"2019","journal-title":"Drug Dev. Res."},{"key":"ref_46","first-page":"1493","article-title":"Resveratrol Ameliorates Inflammatory Damage and Protects against Osteoarthritis in a Rat Model of Osteoarthritis","volume":"17","author":"Wei","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1142\/S0192415X15500457","article-title":"Alpha-Pinene Exhibits Anti-Inflammatory Activity Through the Suppression of MAPKs and the NF-\u039aB Pathway in Mouse Peritoneal Macrophages","volume":"43","author":"Kim","year":"2015","journal-title":"Am. J. Chin. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"105743","DOI":"10.1016\/j.intimp.2019.105743","article-title":"Carvacrol Suppresses LPS-Induced pro-Inflammatory Activation in RAW 264.7 Macrophages through ERK1\/2 and NF-KB Pathway","volume":"75","author":"Somensi","year":"2019","journal-title":"Int. Immunopharmacol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/1\/249\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:03:02Z","timestamp":1760119382000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/1\/249"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,11]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["pharmaceutics15010249"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15010249","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,11]]}}}