{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T05:06:42Z","timestamp":1772341602753,"version":"3.50.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100024786","name":"Instituto Oswaldo Cruz","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100024786","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The epithelial-mesenchymal transition (EMT) is a biological process in which epithelial cells change into mesenchymal cells with fibroblast-like characteristics. EMT plays a crucial role in the progression of fibrosis. Classical inducers associated with the maintenance of EMT, such as TGF-\u03b21, have become targets of several anti-EMT therapeutic strategies. Natural products from the pentacyclic triterpene class have emerged as promising elements in inhibiting EMT. Uvaol is a pentacyclic triterpene found in olive trees (<jats:italic>Olea europaea<\/jats:italic> L.) known for its anti-inflammatory, antioxidant, and antiproliferative properties. Yet, its effect on the TGF-\u03b21-induced EMT in alveolar epithelial cells is unknown. The present study aimed to investigate the impact of uvaol upon TGF-\u03b21-induced EMT in a cultured A549 human alveolar epithelial cell line, a classic <jats:italic>in vitro<\/jats:italic> model for studies of EMT. Changes in cell shape were measured using phase-contrast and confocal microscopy, whereas protein expression levels were measured using immunofluorescence, flow cytometry, and Western blotting. We also performed wound scratch experiments to explore its effects on cell migration. Uvaol had no significant cytotoxic effects on A549 cells. By contrast, the changes in the cell morphology consistent with TGF-\u03b21-induced EMT were largely suppressed by treatment with uvaol. In addition, increased contents of mesenchymal markers, namely, vimentin, N-cadherin, and fibronectin in TGF-\u03b21-induced A549 cells, were downregulated by uvaol treatment. Furthermore, the TGF-\u03b21-induced migration of A549 cells was significantly suppressed by uvaol. Mechanistically, uvaol prevented the nuclear translocation of \u03b2-catenin and reduced the TGF-\u03b21-induced levels of ZEB1 in A549 cells. These results provide compelling evidence that uvaol inhibits EMT by regulating proteins related to the mesenchymal profile in human alveolar epithelial cells, likely by modulating \u03b2-catenin and ZEB1 levels.<\/jats:p>","DOI":"10.3389\/fphar.2024.1504556","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T07:36:24Z","timestamp":1736235384000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Uvaol attenuates TGF-\u03b21-induced epithelial-mesenchymal transition in human alveolar epithelial cells by modulating expression and membrane localization of \u03b2-catenin"],"prefix":"10.3389","volume":"15","author":[{"given":"Liliane","family":"Patr\u00edcia Gon\u00e7alves Ten\u00f3rio","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felipe Henrique da Cunha","family":"Xavier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00f4nica","family":"Silveira Wagner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayo","family":"Moreira Bagri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erick Gabriel","family":"Alves Ferreira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romulo","family":"Galvani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Mermelstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana Cesar","family":"Bonomo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wilson","family":"Savino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emiliano","family":"Barreto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.ejphar.2016.03.056","article-title":"Uvaol attenuates pleuritis and eosinophilic inflammation in ovalbumin-induced allergy in mice","volume":"780","author":"Agra","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1038\/NCOMMS1734","article-title":"Activation of canonical Wnt signalling is required for TGF-\u03b2-mediated fibrosis","volume":"3","author":"Akhmetshina","year":"2012","journal-title":"Nat. Commun."},{"key":"B3","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1021\/JF102319Y","article-title":"Antioxidant, antiproliferative, and pro-apoptotic capacities of pentacyclic triterpenes found in the skin of olives on MCF-7 human breast cancer cells and their effects on DNA damage","volume":"59","author":"Allouche","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"7668","DOI":"10.3390\/MOLECULES27227668","article-title":"Can natural products targeting EMT serve as the future anticancer therapeutics?","volume":"27","author":"Anwar","year":"2022","journal-title":"Molecules"},{"key":"B5","doi-asserted-by":"publisher","first-page":"4254","DOI":"10.3390\/MOLECULES25184254","article-title":"Antiproliferative and pro-apoptotic effect of uvaol in human hepatocarcinoma HepG2 cells by affecting G0\/G1 cell cycle arrest, ROS production and AKT\/PI3K signaling pathway","volume":"25","author":"Bonel-P\u00e9rez","year":"2020","journal-title":"Mol. Basel, Switz."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1016\/J.BBAGEN.2019.06.012","article-title":"Biomechanical and functional properties of trophoblast cells exposed to Group B Streptococcus in vitro and the beneficial effects of uvaol treatment","volume":"1863","author":"Botelho","year":"2019","journal-title":"Biochimica Biophysica Acta (BBA) - General Subj."},{"key":"B7","doi-asserted-by":"publisher","first-page":"13644","DOI":"10.1038\/s41598-018-28968-9","article-title":"Inhibition of Wnt\/\u03b2-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis","volume":"8","author":"Cao","year":"2018","journal-title":"Sci. Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"4982","DOI":"10.3390\/MOLECULES25214982","article-title":"Uvaol improves the functioning of fibroblasts and endothelial cells and accelerates the healing of cutaneous wounds in mice","volume":"25","author":"Carmo","year":"2020","journal-title":"Mol. Basel, Switz."},{"key":"B9","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1002\/cbin.11967","article-title":"Epithelial-to-mesenchymal transition as a learning paradigm of cell biology","volume":"47","author":"Carvalho Le\u00e3o","year":"2023","journal-title":"Cell Biol. Int."},{"key":"B10","doi-asserted-by":"publisher","first-page":"3261","DOI":"10.1002\/jcp.25797","article-title":"Epithelial\u2013mesenchymal transition (EMT): a biological process in the development, stem cell differentiation, and tumorigenesis","volume":"232","author":"Chen","year":"2017","journal-title":"J. Cell. Physiology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4285","DOI":"10.3892\/ol.2019.10140","article-title":"Effect of asiatic acid on epithelial-mesenchymal transition of human alveolar epithelium A549 cells induced by TGF-\u03b21","volume":"17","author":"Cui","year":"2019","journal-title":"Oncol. Lett."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1882","DOI":"10.3390\/CANCERS13081882","article-title":"Cytoskeletal dynamics in epithelial-mesenchymal transition: insights into therapeutic targets for cancer metastasis","volume":"13","author":"Datta","year":"2021","journal-title":"Cancers"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1844","DOI":"10.1021\/acs.jnatprod.4c00581","article-title":"Natural products have increased rates of clinical trial success throughout the drug development process","volume":"87","author":"Domingo-Fern\u00e1ndez","year":"2024","journal-title":"J. Nat. Prod."},{"key":"B14","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41580-018-0080-4","article-title":"New insights into the mechanisms of epithelial\u2013mesenchymal transition and implications for cancer","volume":"20","author":"Dongre","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3799","DOI":"10.1083\/JCB.201704053","article-title":"Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin","volume":"216","author":"Erdogan","year":"2017","journal-title":"J. Cell Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"440118","DOI":"10.3389\/fphar.2019.00388","article-title":"Therapeutic targeting of fibrotic epithelial-mesenchymal transition\u2013an outstanding challenge","volume":"10","author":"Fintha","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e74","DOI":"10.1002\/CPCY.74","article-title":"Acquisition of high-quality spectral flow cytometry data","volume":"93","author":"Fox","year":"2020","journal-title":"Curr. Protoc. Cytom."},{"key":"B18","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1111\/1440-1681.13047","article-title":"miR-375-3p\/YWHAZ\/\u03b2-catenin axis regulates migration, invasion, EMT in gastric cancer cells","volume":"46","author":"Guo","year":"2019","journal-title":"Clin. Exp. Pharmacol. Physiology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1642","DOI":"10.1681\/ASN.2010101079","article-title":"Targeted inhibition of \u03b2-catenin\/CBP signaling ameliorates renal interstitial fibrosis","volume":"22","author":"Hao","year":"2011","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"B21","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1002\/DVDY.24541","article-title":"Epithelial\u2013mesenchymal transition, a spectrum of states: role in lung development, homeostasis, and disease","volume":"247","author":"Jolly","year":"2018","journal-title":"Dev. Dyn."},{"key":"B22","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1007\/s13205-022-03360-7","article-title":"A systems biology investigation of curcumin potency against TGF-\u03b2-induced EMT signaling in lung cancer","volume":"12","author":"Kandagalla","year":"2022","journal-title":"3 Biotech."},{"key":"B23","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3389\/fphar.2014.00123","article-title":"Fibroblasts in fibrosis: novel roles and mediators","author":"Kendall","year":"2014","journal-title":"Front. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1038\/ncb3513","article-title":"The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer","volume":"19","author":"Krebs","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.7150\/IJBS.44943","article-title":"Mechanical tumor microenvironment and transduction: cytoskeleton mediates cancer cell invasion and metastasis","volume":"16","author":"Li","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1036329","DOI":"10.3389\/fchem.2022.1036329","article-title":"Natural products in drug discovery and development: synthesis and medicinal perspective of leonurine","volume":"17","author":"Li","year":"2022","journal-title":"Front. Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41392-021-00762-6","article-title":"Wnt\/\u03b2-catenin signalling: function, biological mechanisms, and therapeutic opportunities","volume":"7","author":"Liu","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.3390\/CELLS8101118","article-title":"The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges","volume":"8","author":"Loh","year":"2019","journal-title":"Cells"},{"key":"B29","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1002\/EMMM.200900043","article-title":"Inflammation and EMT: an alliance towards organ fibrosis and cancer progression","volume":"1","author":"L\u00f3pez-Nouoa","year":"2009","journal-title":"EMBO Mol. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1681\/ASN.2014121188","article-title":"Paracrine wnt1 drives interstitial fibrosis without inflammation by tubulointerstitial cross-talk","volume":"27","author":"Maarouf","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e5975","DOI":"10.1371\/JOURNAL.PONE.0005975","article-title":"Natural triterpenic diols promote apoptosis in astrocytoma cells through ROS-mediated mitochondrial depolarization and JNK activation","volume":"4","author":"Mart\u00edn","year":"","journal-title":"PloS One"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e5975","DOI":"10.1371\/JOURNAL.PONE.0005975","article-title":"Natural triterpenic diols promote apoptosis in astrocytoma cells through ROS-mediated mitochondrial depolarization and JNK activation","volume":"4","author":"Mart\u00edn","year":"","journal-title":"PLOS ONE"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e41545","DOI":"10.1371\/JOURNAL.PONE.0041545","article-title":"DIOL triterpenes block profibrotic effects of angiotensin II and protect from cardiac hypertrophy","volume":"7","author":"Mart\u00edn","year":"2012","journal-title":"PLOS ONE"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e0143526","DOI":"10.1371\/JOURNAL.PONE.0143526","article-title":"Kaempferol inhibits endoplasmic reticulum stress-associated mucus hypersecretion in airway epithelial cells and ovalbumin-sensitized mice","volume":"10","author":"Park","year":"2015","journal-title":"PLoS ONE"},{"key":"B36","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1002\/path.6240","article-title":"A partial epithelial-mesenchymal transition signature for highly aggressive colorectal cancer cells that survive under nutrient restriction","volume":"262","author":"Pastorino","year":"2024","journal-title":"J. Pathol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"12173","DOI":"10.1021\/JF403154E","article-title":"Bioactive properties of the main triterpenes found in olives, virgin olive oil, and leaves of Olea europaea","volume":"61","author":"S\u00e1nchez-Quesada","year":"2013","journal-title":"J. Agric. Food Chem."},{"key":"B38","doi-asserted-by":"publisher","first-page":"19204","DOI":"10.1073\/pnas.1108977108","article-title":"\u03b2-catenin\/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness","volume":"108","author":"S\u00e1nchez-Till\u00f3","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B39","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/J.ADDR.2018.01.020","article-title":"Integrins in wound healing, fibrosis and tumor stroma: high potential targets for therapeutics and drug delivery","volume":"129","author":"Schnittert","year":"2018","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2040622320936023","DOI":"10.1177\/2040622320936023","article-title":"Integrin alpha-5 silencing leads to myofibroblastic differentiation in IPF-derived human lung fibroblasts","volume":"11","author":"Shochet","year":"2020","journal-title":"Ther. Adv. Chronic Dis."},{"key":"B58","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1016\/j.cellsig.2014.01.005","article-title":"Docosahexaenoic acid reverses angiotensin II-induced RECK suppression and cardiac fibroblast migration","volume":"26","author":"Siddesha","year":"2014","journal-title":"Cell. Signal."},{"key":"B41","doi-asserted-by":"publisher","first-page":"766382","DOI":"10.3389\/fphys.2021.766382","article-title":"Uvaol prevents group B streptococcus-induced trophoblast cells inflammation and possible endothelial dysfunction","volume":"12","author":"Silva","year":"2021","journal-title":"Front. Physiology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1321973","DOI":"10.1155\/2019\/1321973","article-title":"Resveratrol suppresses epithelial-mesenchymal transition in GBM by regulating smad-dependent signaling","volume":"2019","author":"Song","year":"2019","journal-title":"BioMed Res. Int."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e15207","DOI":"10.7717\/peerj.15207","article-title":"Epithelial to mesenchymal transition in mammary gland tissue fibrosis and insights into drug therapeutics","volume":"11","author":"Syed","year":"2023","journal-title":"PeerJ"},{"key":"B49","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/S13205-023-03461-X","article-title":"Capparis zeylanica L. root extract promotes apoptosis and cell cycle arrest, inhibits epithelial-to-mesenchymal transition and triggers E-cadherin expression in breast cancer cell lines","volume":"13","author":"Venkataswamy","year":"2023","journal-title":"3 Biotech."},{"key":"B59","doi-asserted-by":"publisher","first-page":"e0178619","DOI":"10.1371\/journal.pone.0178619","article-title":"Imatinib attenuates cardiac fibrosis by inhibiting platelet-derived growth factor receptors activation in isoproterenol induced model","volume":"12","author":"Wang","year":"2017","journal-title":"PLoS One"},{"key":"B50","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1248\/BPB.B18-00613","article-title":"Ursolic acid inhibits tumor growth via epithelial-to-mesenchymal transition in colorectal cancer cells","volume":"42","author":"Wang","year":"2019","journal-title":"Biol. and Pharm. Bull."},{"key":"B51","doi-asserted-by":"publisher","first-page":"F567","DOI":"10.1152\/AJPRENAL.00212.2006","article-title":"The characterization of alpha5-integrin expression on tubular epithelium during renal injury","volume":"292","author":"White","year":"2007","journal-title":"Am. J. Physiology. Ren. Physiology"},{"key":"B54","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1080\/13880209.2019.1577464","article-title":"Ursolic acid inhibits epithelial-mesenchymal transition in vitro and in vivo","volume":"57","author":"Xu","year":"2019","journal-title":"Pharm. Biol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/s41580-020-0237-9","article-title":"Guidelines and definitions for research on epithelial\u2013mesenchymal transition","volume":"21","author":"Yang","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s40635-015-0039-0","article-title":"Shape descriptors of the \u201cnever resting\u201d microglia in three different acute brain injury models in mice","volume":"3","author":"Zanier","year":"2015","journal-title":"Intensive Care Med. Exp."},{"key":"B57","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.3892\/or.2015.4213","article-title":"Ursolic acid inhibits the proliferation of human ovarian cancer stem-like cells through epithelial-mesenchymal transition","volume":"34","author":"Zhang","year":"2015","journal-title":"Oncol. Rep."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1504556\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T07:36:28Z","timestamp":1736235388000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1504556\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,7]]},"references-count":50,"alternative-id":["10.3389\/fphar.2024.1504556"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1504556","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,7]]},"article-number":"1504556"}}