{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T02:33:43Z","timestamp":1792550023019,"version":"4.5.0"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T00:00:00Z","timestamp":1711324800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T00:00:00Z","timestamp":1711324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100007670","name":"Dalhousie Medical Research Foundation","doi-asserted-by":"publisher","award":["2019 I3V Studentship"],"award-info":[{"award-number":["2019 I3V Studentship"]}],"id":[{"id":"10.13039\/100007670","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005785","name":"Faculty of Medicine, Dalhousie University","doi-asserted-by":"publisher","award":["Graduate Studentship"],"award-info":[{"award-number":["Graduate Studentship"]}],"id":[{"id":"10.13039\/501100005785","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["THC135230"],"award-info":[{"award-number":["THC135230"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Fibrosis is a destructive, end-stage disease process. In the skin, it is associated with systemic sclerosis and scarring with considerable health burden. Ketotifen is a clinical antihistamine and mast cell stabilizer. Studies have demonstrated mast cell-dependent anti-fibrotic effects of ketotifen but direct effects on fibroblasts have not been determined. Human dermal fibroblasts were treated with pro-fibrotic transforming growth factor-\u03b21 (TGF\u03b2) followed by ketotifen or control treatments to determine direct effects on fibrotic fibroblasts. Ketotifen impaired TGF\u03b2-induced \u03b1-smooth muscle actin gene and protein responses and decreased cytoskeletal- and contractility-associated gene responses associated with fibrosis. Ketotifen reduced Yes-associated protein phosphorylation, transcriptional coactivator with PDZ binding motif transcript and protein levels, and phosphorylation of protein kinase B. In a fibroblast-populated collagen gel contraction assay, ketotifen reduced the contractile activity of TGF\u03b2-activated fibroblasts. In a murine model of bleomycin-induced skin fibrosis, collagen density and dermal thickness were significantly decreased in ketotifen-treated mice supporting in vitro findings. These results support a novel, direct anti-fibrotic activity of ketotifen, reducing pro-fibrotic phenotypic changes in fibroblasts and reducing collagen fibres in fibrotic mouse skin. Together, these findings suggest novel therapeutic potential and a novel mechanism of action for ketotifen in the context of fibrosis.<\/jats:p>","DOI":"10.1038\/s41598-024-57776-7","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T21:40:27Z","timestamp":1711402827000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Ketotifen directly modifies the fibrotic response of human skin fibroblasts"],"prefix":"10.1038","volume":"14","author":[{"given":"Edwin","family":"Leong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haya","family":"Al-Bitar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean S.","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bezuhly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,25]]},"reference":[{"key":"57776_CR1","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1002\/path.2277","volume":"214","author":"TA Wynn","year":"2008","unstructured":"Wynn, T. A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199\u2013210 (2008).","journal-title":"J. Pathol."},{"key":"57776_CR2","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1038\/nm.2807","volume":"18","author":"TA Wynn","year":"2012","unstructured":"Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat. Med. 18, 1028\u20131040 (2012).","journal-title":"Nat. Med."},{"key":"57776_CR3","first-page":"1","volume":"111","author":"L Muhl","year":"2020","unstructured":"Muhl, L. et al. Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination. Nat. Commun. 111, 1\u201318 (2020).","journal-title":"Nat. Commun."},{"key":"57776_CR4","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1172\/JCI93555","volume":"128","author":"MD Lynch","year":"2018","unstructured":"Lynch, M. D. & Watt, F. M. Fibroblast heterogeneity: Implications for human disease. J. Clin. Invest. 128, 26\u201335 (2018).","journal-title":"J. Clin. Invest."},{"key":"57776_CR5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fbioe.2020.00001","volume":"8","author":"M D\u2019Urso","year":"2020","unstructured":"D\u2019Urso, M. & Kurniawan, N. A. Mechanical and physical regulation of fibroblast-myofibroblast transition: From cellular mechanoresponse to tissue pathology. Front. Bioeng. Biotechnol. 8, 1\u201315 (2020).","journal-title":"Front. Bioeng. Biotechnol."},{"key":"57776_CR6","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.biocel.2006.11.005","volume":"39","author":"RJ McAnulty","year":"2007","unstructured":"McAnulty, R. J. Fibroblasts and myofibroblasts: Their source, function and role in disease. Int. J. Biochem. Cell Biol. 39, 666\u2013671 (2007).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"57776_CR7","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1038\/s41584-019-0322-7","volume":"15","author":"JHW Distler","year":"2019","unstructured":"Distler, J. H. W. et al. Shared and distinct mechanisms of fibrosis. Nat. Rev. Rheumatol. 15, 705\u2013730 (2019).","journal-title":"Nat. Rev. Rheumatol."},{"key":"57776_CR8","doi-asserted-by":"publisher","first-page":"1997","DOI":"10.1016\/j.jbiomech.2014.03.031","volume":"47","author":"D Duscher","year":"2014","unstructured":"Duscher, D. et al. Mechanotransduction and fibrosis. J. Biomech. 47, 1997\u20132005 (2014).","journal-title":"J. Biomech."},{"key":"57776_CR9","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1089\/wound.2016.0709","volume":"7","author":"LA Barnes","year":"2018","unstructured":"Barnes, L. A. et al. Mechanical forces in cutaneous wound healing: Emerging therapies to minimize scar formation. Adv. Wound Care 7, 47\u201356 (2018).","journal-title":"Adv. Wound Care"},{"key":"57776_CR10","doi-asserted-by":"publisher","first-page":"1861","DOI":"10.2353\/ajpath.2006.051302","volume":"168","author":"J Varani","year":"2006","unstructured":"Varani, J. et al. Decreased collagen production in chronologically aged skin: Roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am. J. Pathol. 168, 1861\u20131868 (2006).","journal-title":"Am. J. Pathol."},{"key":"57776_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/jcm9051423","volume":"9","author":"B Kuehlmann","year":"2020","unstructured":"Kuehlmann, B., Bonham, C. A., Zucal, I., Prantl, L. & Gurtner, G. C. Mechanotransduction in wound healing and fibrosis. J. Clin. Med. 9, 1\u201319 (2020).","journal-title":"J. Clin. Med."},{"key":"57776_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphys.2021.727451","volume":"12","author":"E Leong","year":"2021","unstructured":"Leong, E., Bezuhly, M. & Marshall, J. S. Distinct metalloproteinase expression and functions in systemic sclerosis and fibrosis: What we know and the potential for intervention. Front. Physiol. 12, 1\u20139 (2021).","journal-title":"Front. Physiol."},{"key":"57776_CR13","doi-asserted-by":"publisher","first-page":"5526","DOI":"10.1021\/acs.biochem.7b00794","volume":"56","author":"R Liu","year":"2017","unstructured":"Liu, R., Hossain, M. M., Chen, X. & Jin, J. P. Mechanoregulation of SM22\u03b1\/Transgelin. Biochemistry. 56, 5526\u20135538 (2017).","journal-title":"Biochemistry."},{"key":"57776_CR14","doi-asserted-by":"publisher","first-page":"L348","DOI":"10.1152\/ajplung.00289.2021","volume":"322","author":"YY Choo","year":"2022","unstructured":"Choo, Y. Y. et al. Calponin 1 contributes to myofibroblast differentiation of human pleural mesothelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 322, L348\u2013L364 (2022).","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"57776_CR15","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1007\/s00403-013-1343-8","volume":"305","author":"E Daimon","year":"2013","unstructured":"Daimon, E., Shibukawa, Y. & Wada, Y. Calponin 3 regulates stress fiber formation in dermal fibroblasts during wound healing. Arch. Dermatol. Res. 305, 571\u2013584 (2013).","journal-title":"Arch. Dermatol. Res."},{"key":"57776_CR16","first-page":"1","volume":"119","author":"FJ Alenghat","year":"2002","unstructured":"Alenghat, F. J. & Ingber, D. E. Mechanotransduction: All signals point to cytoskeleton, matrix, and integrins. Sci. STKE 119, 1\u20134 (2002).","journal-title":"Sci. STKE"},{"key":"57776_CR17","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/nrm2594","volume":"101","author":"N Wang","year":"2009","unstructured":"Wang, N., Tytell, J. D. & Ingber, D. E. Mechanotransduction at a distance: Mechanically coupling the extracellular matrix with the nucleus. Nat. Rev. Mol. Cell Biol. 101, 75\u201382 (2009).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"57776_CR18","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/nrm3416","volume":"139","author":"G Halder","year":"2012","unstructured":"Halder, G., Dupont, S. & Piccolo, S. Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat. Rev. Mol. Cell Biol. 139, 591\u2013600 (2012).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"57776_CR19","doi-asserted-by":"publisher","first-page":"L344","DOI":"10.1152\/ajplung.00300.2014","volume":"308","author":"F Liu","year":"2015","unstructured":"Liu, F. et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L344\u2013L357 (2015).","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"57776_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fcell.2021.673599","volume":"9","author":"X Cai","year":"2021","unstructured":"Cai, X., Wang, K. C. & Meng, Z. Mechanoregulation of YAP and TAZ in cellular homeostasis and disease progression. Front. Cell Dev. Biol. 9, 1\u201312 (2021).","journal-title":"Front. Cell Dev. Biol."},{"key":"57776_CR21","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1016\/j.cell.2015.10.044","volume":"163","author":"FX Yu","year":"2015","unstructured":"Yu, F. X., Zhao, B. & Guan, K. L. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163, 811\u2013828 (2015).","journal-title":"Cell"},{"key":"57776_CR22","doi-asserted-by":"publisher","first-page":"L23","DOI":"10.1152\/ajplung.00210.2021","volume":"322","author":"PA Link","year":"2022","unstructured":"Link, P. A. et al. Combined control of the fibroblast contractile program by YAP and TAZ. Am. J. Physiol. Lung Cell. Mol. Physiol. 322, L23\u2013L32 (2022).","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"57776_CR23","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1111\/j.1524-475X.2008.00363.x","volume":"16","author":"CL Gallant-Behm","year":"2008","unstructured":"Gallant-Behm, C. L., Hildebrand, K. A. & Hart, D. A. The mast cell stabilizer ketotifen prevents development of excessive skin wound contraction and fibrosis in red Duroc pigs. Wound Repair Regen. 16, 226\u2013233 (2008).","journal-title":"Wound Repair Regen."},{"key":"57776_CR24","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1302\/2046-3758.96.BJR-2019-0272.R2","volume":"9","author":"ME Tibbo","year":"2020","unstructured":"Tibbo, M. E. et al. Anti-fibrotic effects of the antihistamine ketotifen in a rabbit model of arthrofibrosis. Bone Jt. Res. 9, 302\u2013310 (2020).","journal-title":"Bone Jt. Res."},{"key":"57776_CR25","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1007\/s00011-011-0409-3","volume":"61","author":"MJ Monument","year":"2012","unstructured":"Monument, M. J. et al. The mast cell stabilizer ketotifen reduces joint capsule fibrosis in a rabbit model of post-traumatic joint contractures. Inflamm. Res. 61, 285\u2013292 (2012).","journal-title":"Inflamm. Res."},{"key":"57776_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/cells11132065","volume":"11","author":"MM Mia","year":"2022","unstructured":"Mia, M. M. & Singh, M. K. New insights into Hippo\/YAP signaling in fibrotic diseases. Cells 11, 1\u201322 (2022).","journal-title":"Cells"},{"key":"57776_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1172\/jci.insight.146243","volume":"7","author":"X He","year":"2022","unstructured":"He, X. et al. Myofibroblast YAP\/TAZ activation is a key step in organ fibrogenesis. JCI Insight 7, 1\u201317 (2022).","journal-title":"JCI Insight"},{"key":"57776_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pbio.3000509","volume":"17","author":"N Borreguero-Mu\u00f1oz","year":"2019","unstructured":"Borreguero-Mu\u00f1oz, N. et al. The Hippo pathway integrates PI3K\u2013Akt signals with mechanical and polarity cues to control tissue growth. PLoS Biol. 17, 1\u201331 (2019).","journal-title":"PLoS Biol."},{"key":"57776_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.celrep.2022.111230","volume":"40","author":"M Eyres","year":"2022","unstructured":"Eyres, M. et al. Spatially resolved deconvolution of the fibrotic niche in lung fibrosis. Cell Rep. 40, 1\u201322 (2022).","journal-title":"Cell Rep."},{"key":"57776_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.rmed.2019.105803","volume":"159","author":"S Cerri","year":"2019","unstructured":"Cerri, S. et al. Real-life comparison of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis: A 24-month assessment. Respir. Med. 159, 1\u20136 (2019).","journal-title":"Respir. Med."},{"key":"57776_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fmolb.2020.581828","volume":"7","author":"P Cameli","year":"2020","unstructured":"Cameli, P. et al. Long-term follow-up of patients with idiopathic pulmonary fibrosis treated with pirfenidone or nintedanib: A real-life comparison study. Front. Mol. Biosci. 7, 1\u20138 (2020).","journal-title":"Front. Mol. Biosci."},{"key":"57776_CR32","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.ejps.2014.02.014","volume":"58","author":"E Conte","year":"2014","unstructured":"Conte, E. et al. Effect of pirfenidone on proliferation, TGF-\u03b2-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts. Eur. J. Pharm. Sci. 58, 13\u201319 (2014).","journal-title":"Eur. J. Pharm. Sci."},{"key":"57776_CR33","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1183\/09031936.00174914","volume":"45","author":"L Wollin","year":"2015","unstructured":"Wollin, L. et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur. Respir. J. 45, 1434\u20131445 (2015).","journal-title":"Eur. Respir. J."},{"key":"57776_CR34","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1001\/archopht.121.5.626","volume":"121","author":"MB Abelson","year":"2003","unstructured":"Abelson, M. B., Chapin, M. J., Kapik, B. M. & Shams, N. B. K. Efficacy of Ketotifen fumarate 0.025% ophthalmic solution compared with placebo in the conjunctival allergen challenge model. Arch. Ophthalmol. 121, 626\u2013630 (2003).","journal-title":"Arch. Ophthalmol."},{"key":"57776_CR35","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.anai.2013.10.003","volume":"111","author":"KC Sokol","year":"2013","unstructured":"Sokol, K. C., Amar, N. K., Starkey, J. & Grant, J. A. Ketotifen in the management of chronic urticaria: Resurrection of an old drug. Ann. Allergy Asthma Immunol. 111, 433\u2013436 (2013).","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"57776_CR36","doi-asserted-by":"publisher","first-page":"196","DOI":"10.3109\/08977194.2011.595714","volume":"29","author":"A Biernacka","year":"2011","unstructured":"Biernacka, A., Dobaczewski, M. & Frangogiannis, N. G. TGF-\u03b2 signaling in fibrosis. Growth Factors 29, 196\u2013202 (2011).","journal-title":"Growth Factors"},{"key":"57776_CR37","first-page":"1","volume":"91","author":"A Vall\u00e9e","year":"2019","unstructured":"Vall\u00e9e, A. & Lecarpentier, Y. TGF-\u03b2 in fibrosis by acting as a conductor for contractile properties of myofibroblasts. Cell Biosci. 91, 1\u201315 (2019).","journal-title":"Cell Biosci."},{"key":"57776_CR38","doi-asserted-by":"publisher","first-page":"2508","DOI":"10.1091\/mbc.e02-11-0729","volume":"14","author":"B Hinz","year":"2003","unstructured":"Hinz, B., Dugina, V., Ballestrem, C., Wehrle-Haller, B. & Chaponnier, C. \u03b1-smooth muscle actin is crucial for focal adhesion maturation in myofibroblasts. Mol. Biol. Cell. 14, 2508\u20132519 (2003).","journal-title":"Mol. Biol. Cell."},{"key":"57776_CR39","doi-asserted-by":"publisher","first-page":"2730","DOI":"10.1091\/mbc.12.9.2730","volume":"12","author":"B Hinz","year":"2001","unstructured":"Hinz, B., Celetta, G., Tomasek, J. J., Gabbiani, G. & Chaponnier, C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol. Biol. Cell. 12, 2730\u20132741 (2001).","journal-title":"Mol. Biol. Cell."},{"key":"57776_CR40","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.bbadis.2016.11.006","volume":"1863","author":"AV Shinde","year":"2017","unstructured":"Shinde, A. V., Humeres, C. & Frangogiannis, N. G. The role of \u03b1-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 298\u2013309 (2017).","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"57776_CR41","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1016\/j.ajpath.2012.02.004","volume":"180","author":"B Hinz","year":"2012","unstructured":"Hinz, B. et al. Recent developments in myofibroblast biology: Paradigms for connective tissue remodeling. Am. J. Pathol. 180, 1340\u20131355 (2012).","journal-title":"Am. J. Pathol."},{"key":"57776_CR42","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.copbio.2003.08.006","volume":"14","author":"B Hinz","year":"2003","unstructured":"Hinz, B. & Gabbiani, G. Mechanisms of force generation and transmission by myofibroblasts. Curr. Opin. Biotechnol. 14, 538\u2013546 (2003).","journal-title":"Curr. Opin. Biotechnol."},{"key":"57776_CR43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/biom11081095","volume":"11","author":"Y Tai","year":"2021","unstructured":"Tai, Y. et al. Myofibroblasts: Function, formation, and scope of molecular therapies for skin fibrosis. Biomolecules 11, 1\u201327 (2021).","journal-title":"Biomolecules"},{"key":"57776_CR44","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.trsl.2011.05.004","volume":"158","author":"N Sandbo","year":"2011","unstructured":"Sandbo, N. & Dulin, N. The actin cytoskeleton in myofibroblast differentiation: Ultrastructure defining form and driving function. Transl. Res. 158, 181\u2013196 (2011).","journal-title":"Transl. Res."},{"key":"57776_CR45","doi-asserted-by":"publisher","first-page":"41","DOI":"10.4331\/wjbc.v3.i3.41","volume":"3","author":"X Guo","year":"2012","unstructured":"Guo, X., Chen Xia Guo, S.-Y. & Chen, S.-Y. Transforming growth factor-\u03b2 and smooth muscle differentiation. World. J. Biol. Chem. 3, 41\u201352 (2012).","journal-title":"World. J. Biol. Chem."},{"key":"57776_CR46","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1016\/j.yjmcc.2003.09.002","volume":"35","author":"P Qiu","year":"2003","unstructured":"Qiu, P., Feng, X. H. & Li, L. Interaction of Smad3 and SRF-associated complex mediates TGF-\u03b21 signals to regulate SM22 transcription during myofibroblast differentiation. J. Mol. Cell. Cardiol. 35, 1407\u20131420 (2003).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"57776_CR47","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.gene.2016.02.040","volume":"585","author":"R Liu","year":"2016","unstructured":"Liu, R. & Jin, J. P. Calponin isoforms CNN1, CNN2 and CNN3: Regulators for actin cytoskeleton functions in smooth muscle and non-muscle cells. Gene 585, 143\u2013153 (2016).","journal-title":"Gene"},{"key":"57776_CR48","doi-asserted-by":"publisher","first-page":"e2321","DOI":"10.1038\/cddis.2016.196","volume":"7","author":"M Elsafadi","year":"2016","unstructured":"Elsafadi, M. et al. Transgelin is a TGF\u03b2-inducible gene that regulates osteoblastic and adipogenic differentiation of human skeletal stem cells through actin cytoskeleston organization. Cell Death Dis. 7, e2321\u2013e2321 (2016).","journal-title":"Cell Death Dis."},{"key":"57776_CR49","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/S0014-5793(04)00220-0","volume":"562","author":"A Zeidan","year":"2004","unstructured":"Zeidan, A. et al. Ablation of SM22\u03b1 decreases contractility and actin contents of mouse vascular smooth muscle. FEBS Lett. 562, 141\u2013146 (2004).","journal-title":"FEBS Lett."},{"key":"57776_CR50","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.yjmcc.2019.01.026","volume":"129","author":"HZ Feng","year":"2019","unstructured":"Feng, H. Z., Wang, H., Takahashi, K. & Jin, J. P. Double deletion of calponin 1 and calponin 2 in mice decreases systemic blood pressure with blunted length-tension response of aortic smooth muscle. J. Mol. Cell. Cardiol. 129, 49\u201357 (2019).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"57776_CR51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fmed.2021.752316","volume":"8","author":"JJ Gokey","year":"2021","unstructured":"Gokey, J. J., Patel, S. D. & Kropski, J. A. The role of hippo\/YAP signaling in alveolar repair and pulmonary fibrosis. Front. Med. 8, 1\u20137 (2021).","journal-title":"Front. Med."},{"key":"57776_CR52","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.1093\/cvr\/cvab205","volume":"118","author":"MM Mia","year":"2022","unstructured":"Mia, M. M. et al. Loss of Yap\/Taz in cardiac fibroblasts attenuates adverse remodelling and improves cardiac function. Cardiovasc. Res. 118, 1785\u20131804 (2022).","journal-title":"Cardiovasc. Res."},{"key":"57776_CR53","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1161\/CIRCRESAHA.121.319373","volume":"131","author":"G Garoffolo","year":"2022","unstructured":"Garoffolo, G. et al. Reduction of cardiac fibrosis by interference with YAP-dependent transactivation. Circ. Res. 131, 239\u2013257 (2022).","journal-title":"Circ. Res."},{"key":"57776_CR54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep42595","volume":"7","author":"S Noguchi","year":"2017","unstructured":"Noguchi, S. et al. TAZ contributes to pulmonary fibrosis by activating profibrotic functions of lung fibroblasts. Sci. Rep. 7, 1\u201311 (2017).","journal-title":"Sci. Rep."},{"key":"57776_CR55","doi-asserted-by":"publisher","first-page":"14902","DOI":"10.1074\/jbc.M117.780502","volume":"292","author":"MZ Miranda","year":"2017","unstructured":"Miranda, M. Z. et al. TGF-\u03b21 regulates the expression and transcriptional activity of TAZ protein via a Smad3-independent, myocardin-related transcription factor-mediated mechanism. J. Biol. Chem. 292, 14902\u201314920 (2017).","journal-title":"J. Biol. Chem."},{"key":"57776_CR56","doi-asserted-by":"publisher","first-page":"3117","DOI":"10.1681\/ASN.2015050499","volume":"27","author":"SG Szeto","year":"2016","unstructured":"Szeto, S. G. et al. YAP\/TAZ are mechanoregulators of TGF-b-smad signaling and renal fibrogenesis. J. Am. Soc. Nephrol. 27, 3117\u20133128 (2016).","journal-title":"J. Am. Soc. Nephrol."},{"key":"57776_CR57","doi-asserted-by":"publisher","first-page":"2747","DOI":"10.1101\/gad.1602907","volume":"21","author":"B Zhao","year":"2007","unstructured":"Zhao, B. et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747\u20132761 (2007).","journal-title":"Genes Dev."},{"key":"57776_CR58","doi-asserted-by":"publisher","first-page":"61","DOI":"10.15252\/embr.201642683","volume":"18","author":"S Moon","year":"2017","unstructured":"Moon, S. et al. Phosphorylation by NLK inhibits YAP -14-3-3-interactions and induces its nuclear localization. EMBO Rep. 18, 61\u201371 (2017).","journal-title":"EMBO Rep."},{"key":"57776_CR59","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1016\/j.cmet.2016.09.016","volume":"24","author":"X Wang","year":"2016","unstructured":"Wang, X. et al. Hepatocyte TAZ\/WWTR1 promotes inflammation and fibrosis in Nonalcoholic steatohepatitis. Cell Metab. 24, 848\u2013862 (2016).","journal-title":"Cell Metab."},{"key":"57776_CR60","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1128\/JVI.00617-17","volume":"91","author":"J Morrison","year":"2017","unstructured":"Morrison, J. et al. Transcriptional profiling confirms the therapeutic effects of mast cell stabilization in a dengue disease model. J. Virol. 91, 617\u2013634 (2017).","journal-title":"J. Virol."},{"key":"57776_CR61","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.jid.2017.08.024","volume":"138","author":"T Toyama","year":"2018","unstructured":"Toyama, T. et al. Therapeutic targeting of TAZ and YAP by dimethyl fumarate in systemic sclerosis fibrosis. J. Invest. Dermatol. 138, 78\u201388 (2018).","journal-title":"J. Invest. Dermatol."},{"key":"57776_CR62","doi-asserted-by":"publisher","first-page":"16364","DOI":"10.1074\/jbc.RA118.004073","volume":"293","author":"Y Gui","year":"2018","unstructured":"Gui, Y. et al. Yap\/Taz mediates mTORC2-stimulated fibroblast activation and kidney fibrosis. J. Biol. Chem. 293, 16364\u201316375 (2018).","journal-title":"J. Biol. Chem."},{"key":"57776_CR63","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-017-14612-5","volume":"7","author":"HS Hsu","year":"2017","unstructured":"Hsu, H. S. et al. Involvement of ER stress, PI3K\/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Sci. Rep. 7, 1\u201311 (2017).","journal-title":"Sci. Rep."},{"key":"57776_CR64","doi-asserted-by":"publisher","first-page":"4045","DOI":"10.1007\/s11010-021-04219-w","volume":"476","author":"W Qin","year":"2021","unstructured":"Qin, W., Cao, L. & Massey, I. Y. Role of PI3K\/Akt signaling pathway in cardiac fibrosis. Mol. Cell. Biochem. 476, 4045\u20134059 (2021).","journal-title":"Mol. Cell. Biochem."},{"key":"57776_CR65","doi-asserted-by":"publisher","first-page":"5699","DOI":"10.3892\/mmr.2016.5960","volume":"14","author":"XL Zhang","year":"2016","unstructured":"Zhang, X. L., Xing, R. G., Chen, L., Liu, C. R. & Miao, Z. G. PI3K\/Akt signaling is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis via regulation of epithelial-mesenchymal transition. Mol. Med. Rep. 14, 5699\u20135706 (2016).","journal-title":"Mol. Med. Rep."},{"key":"57776_CR66","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1165\/rcmb.2009-0002OC","volume":"42","author":"Y Lu","year":"2010","unstructured":"Lu, Y. et al. Phosphatidylinositol-3-kinase\/Akt regulates bleomycin-induced fibroblast proliferation and collagen production. Am. J. Respir. Cell Mol. Biol. 42, 432\u2013441 (2010).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"57776_CR67","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1038\/jid.2008.39","volume":"128","author":"AM Bujor","year":"2008","unstructured":"Bujor, A. M. et al. Akt blockade downregulates collagen and upregulates MMP1 in human dermal fibroblasts. J. Invest. Dermatol. 128, 1906\u20131914 (2008).","journal-title":"J. Invest. Dermatol."},{"key":"57776_CR68","doi-asserted-by":"publisher","first-page":"3018","DOI":"10.4049\/jimmunol.1502482","volume":"197","author":"F Morin","year":"2016","unstructured":"Morin, F. et al. Niclosamide prevents systemic sclerosis in a reactive oxygen species-induced mouse model. J. Immunol. 197, 3018\u20133028 (2016).","journal-title":"J. Immunol."},{"key":"57776_CR69","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1002\/jor.22676","volume":"32","author":"KA Hildebrand","year":"2014","unstructured":"Hildebrand, K. A., Zhang, M., Befus, A. D., Salo, P. T. & Hart, D. A. A myofibroblast\u2013mast cell\u2013neuropeptide axis of fibrosis in post-traumatic joint contractures: An in vitro analysis of mechanistic components. J. Orthop. Res. 32, 1290\u20131296 (2014).","journal-title":"J. Orthop. Res."},{"key":"57776_CR70","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.2106\/JBJS.I.00684","volume":"92","author":"MJ Monument","year":"2010","unstructured":"Monument, M. J. et al. The mast cell stabilizer ketotifen fumarate lessens contracture severity and myofibroblast hyperplasia: A study of a rabbit model of posttraumatic joint contractures. J. Bone Jt. Surg. 92, 1468\u20131477 (2010).","journal-title":"J. Bone Jt. Surg."},{"key":"57776_CR71","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1042\/bj2600463","volume":"260","author":"AS Narayanan","year":"1989","unstructured":"Narayanan, A. S., Page, R. C. & Swanson, J. Collagen synthesis by human fibroblasts Regulation by transforming growth factor-fl in the presence of other inflammatory mediators. Biochem. J. 260, 463\u2013469 (1989).","journal-title":"Biochem. J."},{"key":"57776_CR72","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1001\/archderm.144.5.666","volume":"144","author":"GJ Fisher","year":"2008","unstructured":"Fisher, G. J., Varani, J. & Voorhees, J. J. Looking older: Fibroblast collapse and therapeutic implications. Arch. Dermatol. 144, 666\u2013672 (2008).","journal-title":"Arch. Dermatol."},{"key":"57776_CR73","first-page":"57","volume":"17","author":"M Walker","year":"1990","unstructured":"Walker, M., Harley, R. & Leroy, E. C. Ketotifen prevents skin fibrosis in the tight skin mouse. J. Rheumatol. 17, 57\u201359 (1990).","journal-title":"J. Rheumatol."},{"key":"57776_CR74","doi-asserted-by":"publisher","first-page":"33483","DOI":"10.1074\/jbc.M113.504290","volume":"288","author":"M Abdalla","year":"2013","unstructured":"Abdalla, M., Goc, A., Segar, L. & Somanath, P. R. Akt1 mediates \u03b1-smooth muscle actin expression and myofibroblast differentiation via myocardin and serum response factor. J. Biol. Chem. 288, 33483\u201333493 (2013).","journal-title":"J. Biol. Chem."},{"key":"57776_CR75","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1111\/j.1524-475X.2010.00643.x","volume":"19","author":"J Paterno","year":"2011","unstructured":"Paterno, J. et al. Akt-mediated mechanotransduction in murine fibroblasts during hypertrophic scar formation. Wound Repair Regen. 19, 49\u201358 (2011).","journal-title":"Wound Repair Regen."},{"key":"57776_CR76","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1038\/labinvest.2016.48","volume":"96","author":"G Li","year":"2016","unstructured":"Li, G., Li, Y. Y., Sun, J. E., Lin, W. H. & Zhou, R. X. ILK\u2013PI3K\/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast. Lab. Investig. 96, 741\u2013751 (2016).","journal-title":"Lab. Investig."},{"key":"57776_CR77","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13045-021-01137-8","volume":"14","author":"H Hua","year":"2021","unstructured":"Hua, H. et al. Targeting Akt in cancer for precision therapy. J. Hematol. Oncol. 14, 1\u201325 (2021).","journal-title":"J. Hematol. Oncol."},{"key":"57776_CR78","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphar.2021.662232","volume":"12","author":"F Martorana","year":"2021","unstructured":"Martorana, F. et al. AKT inhibitors: New weapons in the fight against breast cancer?. Front. Pharmacol. 12, 1\u201313 (2021).","journal-title":"Front. Pharmacol."},{"key":"57776_CR79","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1158\/1535-7163.MCT-09-1012","volume":"9","author":"H Hirai","year":"2010","unstructured":"Hirai, H. et al. MK-2206, an allosteric akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol. Cancer Ther. 9, 1956\u20131967 (2010).","journal-title":"Mol. Cancer Ther."},{"key":"57776_CR80","doi-asserted-by":"publisher","first-page":"7391","DOI":"10.1038\/sj.onc.1209100","volume":"24","author":"JR Testa","year":"2005","unstructured":"Testa, J. R. & Tsichlis, P. N. AKT signaling in normal and malignant cells. Oncogene 24, 7391\u20137393 (2005).","journal-title":"Oncogene"},{"key":"57776_CR81","first-page":"105","volume":"2","author":"KM Vasudevan","year":"2010","unstructured":"Vasudevan, K. M. & Garraway, L. A. AKT signaling in physiology and disease. Curr. Top. Microbiol. Immunol. 2, 105\u2013133 (2010).","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"57776_CR82","first-page":"14904","volume":"10","author":"Y Chen","year":"2017","unstructured":"Chen, Y., Yu, Q. & Xu, C. B. A convenient method for quantifying collagen fibers in atherosclerotic lesions by imagej software. Int. J. Clin. Exp. Med. 10, 14904\u201314910 (2017).","journal-title":"Int. J. Clin. Exp. Med."},{"key":"57776_CR83","doi-asserted-by":"publisher","first-page":"803E","DOI":"10.1097\/PRS.0000000000006173","volume":"144","author":"A Murphy","year":"2019","unstructured":"Murphy, A. et al. Angiotensin II type i receptor blockade is associated with decreased cutaneous scar formation in a rat model. Plast. Reconstr. Surg. 144, 803E-813E (2019).","journal-title":"Plast. Reconstr. Surg."},{"key":"57776_CR84","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/978-1-62703-505-7_3","volume":"1037","author":"HP Ehrlich","year":"2013","unstructured":"Ehrlich, H. P. & Moyer, K. E. Cell-populated collagen lattice contraction model for the investigation of fibroblast collagen interactions. Methods Mol. Biol. 1037, 45\u201358 (2013).","journal-title":"Methods Mol. Biol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-57776-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-57776-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-57776-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T00:46:34Z","timestamp":1731631594000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-57776-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,25]]},"references-count":84,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["57776"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-57776-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,25]]},"assertion":[{"value":"26 October 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7076"}}