{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T14:08:24Z","timestamp":1768831704641,"version":"3.49.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T00:00:00Z","timestamp":1583971200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T00:00:00Z","timestamp":1583971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["108-2314-B-715 -002"],"award-info":[{"award-number":["108-2314-B-715 -002"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Pharmacol Toxicol"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Despite the fact that histone deacetylase (HDAC) inhibitors have been tested to treat various cardiovascular diseases, the effects of selective HDAC6 inhibitor ACY1215 on infarct size during cardiac ischemia-reperfusion (IR) injury still remain unknown. In the present study we aimed to investigate the effects of ACY1215 on infarct size in rats with cardiac IR injury, as well as to examine the association between HDAC6 inhibitors and the gene expression of hypoxia inducible factor-1\u03b1 (HIF-1\u03b1), a key regulator of cellular responses to hypoxia.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>By using computational analysis of high-throughput expression profiling dataset, the association between HDAC inhibitors (pan-HDAC inhibitors panobinostat and vorinostat, and HDAC6 inhibitor ISOX) and their effects on HIF-1\u03b1 gene-expression were evaluated. The male Wistar rats treated with ligation of left coronary artery followed by reperfusion were used as a cardiac IR model. ACY1215 (50\u2009mg\/kg), pan-HDAC inhibitor MPT0E028 (25\u2009mg\/kg), and vehicle were intraperitoneally injected within 5\u2009min before reperfusion. The infarct size in rat myocardium was determined by 2,3,5-triphenyltetrazolium chloride staining. The serum levels of transforming growth factor-\u03b2 (TGF-\u03b2) and C-reactive protein (CRP) were also determined.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The high-throughput gene expression assay showed that treatment of ISOX was associated with a more decreased gene expression of HIF-1\u03b1 than that of panobinostat and vorinostat. Compared to control rats, ACY1215-treated rats had a smaller infarct size (49.75\u2009\u00b1\u20099.36% vs. 19.22\u2009\u00b1\u20091.70%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), while MPT0E028-treated rats had a similar infarct size to control rats. ACY-1215- and MPT0E028-treated rats had a trend in decreased serum TGF-\u03b2 levels, but not statistically significant. ACY1215-treated rats also had higher serum CRP levels compared to control rats (641.6\u2009\u03bcg\/mL vs. 961.37\u2009\u00b1\u200964.94\u2009\u03bcg\/mL, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our research indicated that HDAC6 inhibition by ACY1215 might reduce infarct size in rats with cardiac IR injury possibly through modulating HIF-1\u03b1 expression. TGF-\u03b2 and CRP should be useful biomarkers to monitor the use of ACY1215 in cardiac IR injury.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40360-020-0400-0","type":"journal-article","created":{"date-parts":[[2020,3,16]],"date-time":"2020-03-16T16:03:41Z","timestamp":1584374621000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Investigating the potential effects of selective histone deacetylase 6 inhibitor ACY1215 on infarct size in rats with cardiac ischemia-reperfusion injury"],"prefix":"10.1186","volume":"21","author":[{"given":"Chao-Feng","family":"Lin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai-Cheng","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Chun","family":"HuangFu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tony Eight","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han-Li","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiow-Lin","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,3,12]]},"reference":[{"issue":"4","key":"400_CR1","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.mcna.2007.03.005","volume":"91","author":"AP Burke","year":"2007","unstructured":"Burke AP, Virmani R. Pathophysiology of acute myocardial infarction. Med Clin North Am. 2007;91(4):553\u201372 ix.","journal-title":"Med Clin North Am"},{"issue":"11","key":"400_CR2","first-page":"774","volume":"38","author":"G Heusch","year":"2017","unstructured":"Heusch G, Gersh BJ. The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J. 2017;38(11):774\u201384.","journal-title":"Eur Heart J"},{"issue":"3","key":"400_CR3","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1007\/s00441-016-2431-9","volume":"365","author":"V Talman","year":"2016","unstructured":"Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res. 2016;365(3):563\u201381.","journal-title":"Cell Tissue Res"},{"issue":"3","key":"400_CR4","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/j.cardiores.2004.07.017","volume":"64","author":"M Ikeuchi","year":"2004","unstructured":"Ikeuchi M, Tsutsui H, Shiomi T, Matsusaka H, Matsushima S, Wen J, et al. Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction. Cardiovasc Res. 2004;64(3):526\u201335.","journal-title":"Cardiovasc Res"},{"key":"400_CR5","doi-asserted-by":"crossref","unstructured":"Sui X, Wei H, Wang D. Novel mechanism of cardiac protection by valsartan: synergetic roles of TGF-beta1 and HIF-1alpha in Ang II-mediated fibrosis after myocardial infarction. J Cell Mol Med. 2015;19(8):1773\u201382.","DOI":"10.1111\/jcmm.12551"},{"key":"400_CR6","doi-asserted-by":"crossref","unstructured":"Saito S, Zhuang Y, Shan B, Danchuk S, Luo F, Korfei M, et al. Tubastatin ameliorates pulmonary fibrosis by targeting the TGFbeta-PI3K-Akt pathway. PLoS One. 2017;12(10):e0186615.","DOI":"10.1371\/journal.pone.0186615"},{"key":"400_CR7","doi-asserted-by":"publisher","first-page":"8797206","DOI":"10.1155\/2016\/8797206","volume":"2016","author":"EE Hull","year":"2016","unstructured":"Hull EE, Montgomery MR, Leyva KJ. HDAC inhibitors as epigenetic regulators of the immune system: impacts on Cancer therapy and inflammatory diseases. Biomed Res Int. 2016;2016:8797206.","journal-title":"Biomed Res Int"},{"issue":"5","key":"400_CR8","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1016\/j.jacbts.2018.05.003","volume":"3","author":"MB Felisbino","year":"2018","unstructured":"Felisbino MB, McKinsey TA. Epigenetics in cardiac fibrosis: emphasis on inflammation and fibroblast activation. JACC Basic Transl Sci. 2018;3(5):704\u201315.","journal-title":"JACC Basic Transl Sci"},{"issue":"1","key":"400_CR9","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.jmb.2004.02.006","volume":"338","author":"IV Gregoretti","year":"2004","unstructured":"Gregoretti IV, Lee YM, Goodson HV. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol. 2004;338(1):17\u201331.","journal-title":"J Mol Biol"},{"issue":"8","key":"400_CR10","doi-asserted-by":"publisher","first-page":"e43645","DOI":"10.1371\/journal.pone.0043645","volume":"7","author":"HL Huang","year":"2012","unstructured":"Huang HL, Lee HY, Tsai AC, Peng CY, Lai MJ, Wang JC, et al. Anticancer activity of MPT0E028, a novel potent histone deacetylase inhibitor, in human colorectal cancer HCT116 cells in vitro and in vivo. PLoS One. 2012;7(8):e43645.","journal-title":"PLoS One"},{"issue":"1","key":"400_CR11","doi-asserted-by":"publisher","first-page":"2","DOI":"10.21037\/atm.2018.11.48","volume":"7","author":"Y Tan","year":"2019","unstructured":"Tan Y, Zhang S, Zhu H, Chu Y, Zhou H, Liu D, et al. Histone deacetylase 6 selective inhibitor ACY1215 inhibits cell proliferation and enhances the chemotherapeutic effect of 5-fluorouracil in HCT116 cells. Ann Transl Med. 2019;7(1):2.","journal-title":"Ann Transl Med"},{"issue":"1","key":"400_CR12","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1161\/01.RES.75.1.105","volume":"75","author":"JR Teerlink","year":"1994","unstructured":"Teerlink JR, Pfeffer JM, Pfeffer MA. Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats. Circ Res. 1994;75(1):105\u201313.","journal-title":"Circ Res"},{"key":"400_CR13","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/1479-5876-11-80","volume":"11","author":"P Gupta","year":"2013","unstructured":"Gupta P, Kanwal A, Putcha UK, Bulani Y, Sojitra B, Khatua TN, et al. Cardioprotective effect of ritonavir, an antiviral drug, in isoproterenol induced myocardial necrosis: a new therapeutic implication. J Transl Med. 2013;11:80.","journal-title":"J Transl Med"},{"key":"400_CR14","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.yrtph.2016.03.005","volume":"76","author":"M Kumar","year":"2016","unstructured":"Kumar M, Kasala ER, Bodduluru LN, Dahiya V, Sharma D, Kumar V, et al. Animal models of myocardial infarction: mainstay in clinical translation. Regul Toxicol Pharmacol. 2016;76:221\u201330.","journal-title":"Regul Toxicol Pharmacol"},{"issue":"2","key":"400_CR15","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.bbamcr.2014.11.015","volume":"1853","author":"AV Kuznetsov","year":"2015","unstructured":"Kuznetsov AV, Javadov S, Sickinger S, Frotschnig S, Grimm M. H9c2 and HL-1 cells demonstrate distinct features of energy metabolism, mitochondrial function and sensitivity to hypoxia-reoxygenation. Biochim Biophys Acta. 2015;1853(2):276\u201384.","journal-title":"Biochim Biophys Acta"},{"issue":"10","key":"400_CR16","doi-asserted-by":"publisher","first-page":"3549","DOI":"10.1096\/fj.08-108548","volume":"22","author":"A Granger","year":"2008","unstructured":"Granger A, Abdullah I, Huebner F, Stout A, Wang T, Huebner T, et al. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J. 2008;22(10):3549\u201360.","journal-title":"FASEB J"},{"key":"400_CR17","doi-asserted-by":"crossref","unstructured":"Zhao TC, Du J, Zhuang S, Liu P, Zhang LX. HDAC inhibition elicits myocardial protective effect through modulation of MKK3\/Akt-1. PLoS One. 2013;8(6):e65474.","DOI":"10.1371\/journal.pone.0065474"},{"key":"400_CR18","doi-asserted-by":"crossref","unstructured":"Subramanian A, Narayan R, Corsello SM, Peck DD, Natoli TE, Lu X, et al. A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell. 2017;171(6):1437\u201352.e17.","DOI":"10.1016\/j.cell.2017.10.049"},{"key":"400_CR19","doi-asserted-by":"crossref","unstructured":"Hughes TR, Marton MJ, Jones AR, Roberts CJ, Stoughton R, Armour CD, et al. Functional discovery via a compendium of expression profiles. Cell. 2000;102(1):109\u201326.","DOI":"10.1016\/S0092-8674(00)00015-5"},{"key":"400_CR20","doi-asserted-by":"crossref","unstructured":"Enache OM, Lahr DL, Natoli TE, Litichevskiy L, Wadden D, Flynn C, et al. The GCTx format and cmap{Py, R, M, J} packages: resources for optimized storage and integrated traversal of annotated dense matrices. Bioinformatics. 2019;35(8):1427\u201329.","DOI":"10.1093\/bioinformatics\/bty784"},{"issue":"5","key":"400_CR21","doi-asserted-by":"publisher","first-page":"11482","DOI":"10.3390\/ijms160511482","volume":"16","author":"H Nural-Guvener","year":"2015","unstructured":"Nural-Guvener H, Zakharova L, Feehery L, Sljukic S, Gaballa M. Anti-fibrotic effects of class I HDAC inhibitor, Mocetinostat is associated with IL-6\/Stat3 signaling in ischemic heart failure. Int J Mol Sci. 2015;16(5):11482\u201399.","journal-title":"Int J Mol Sci"},{"key":"400_CR22","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.yjmcc.2014.03.005","volume":"72","author":"SE Aune","year":"2014","unstructured":"Aune SE, Herr DJ, Mani SK, Menick DR. Selective inhibition of class I but not class IIb histone deacetylases exerts cardiac protection from ischemia reperfusion. J Mol Cell Cardiol. 2014;72:138\u201345.","journal-title":"J Mol Cell Cardiol"},{"key":"400_CR23","doi-asserted-by":"publisher","first-page":"9494052","DOI":"10.1155\/2018\/9494052","volume":"2018","author":"Y Leng","year":"2018","unstructured":"Leng Y, Wu Y, Lei S, Zhou B, Qiu Z, Wang K, et al. Inhibition of HDAC6 activity alleviates myocardial ischemia\/reperfusion injury in diabetic rats: potential role of Peroxiredoxin 1 acetylation and redox regulation. Oxidative Med Cell Longev. 2018;2018:9494052.","journal-title":"Oxidative Med Cell Longev"},{"issue":"9","key":"400_CR24","doi-asserted-by":"publisher","first-page":"e107832","DOI":"10.1371\/journal.pone.0107832","volume":"9","author":"J Si","year":"2014","unstructured":"Si J, Wang N, Wang H, Xie J, Yang J, Yi H, et al. HIF-1alpha signaling activation by post-ischemia treatment with astragaloside IV attenuates myocardial ischemia-reperfusion injury. PLoS One. 2014;9(9):e107832.","journal-title":"PLoS One"},{"issue":"5","key":"400_CR25","doi-asserted-by":"publisher","first-page":"H867","DOI":"10.1152\/ajpheart.00875.2014","volume":"309","author":"G Nanayakkara","year":"2015","unstructured":"Nanayakkara G, Alasmari A, Mouli S, Eldoumani H, Quindry J, McGinnis G, et al. Cardioprotective HIF-1alpha-frataxin signaling against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2015;309(5):H867\u201379.","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"2","key":"400_CR26","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1111\/apha.12874","volume":"221","author":"P Xie","year":"2017","unstructured":"Xie P, Yang L, Talaiti A, Wu JJ, Yu J, Yu T, et al. Deferoxamine-activated hypoxia-inducible factor-1 restores cardioprotective effects of sevoflurane postconditioning in diabetic rats. Acta Physiol (Oxf). 2017;221(2):98\u2013114.","journal-title":"Acta Physiol (Oxf)"},{"key":"400_CR27","doi-asserted-by":"publisher","first-page":"66","DOI":"10.3389\/fphys.2015.00066","volume":"6","author":"G Euler","year":"2015","unstructured":"Euler G. Good and bad sides of TGFbeta-signaling in myocardial infarction. Front Physiol. 2015;6:66.","journal-title":"Front Physiol"},{"issue":"1","key":"400_CR28","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.cardiores.2005.02.021","volume":"67","author":"D Schneiders","year":"2005","unstructured":"Schneiders D, Heger J, Best P, Michael Piper H, Taimor G. SMAD proteins are involved in apoptosis induction in ventricular cardiomyocytes. Cardiovasc Res. 2005;67(1):87\u201396.","journal-title":"Cardiovasc Res"},{"issue":"1","key":"400_CR29","doi-asserted-by":"publisher","first-page":"e30","DOI":"10.1111\/j.1755-5922.2010.00228.x","volume":"30","author":"AJ Edgley","year":"2012","unstructured":"Edgley AJ, Krum H, Kelly DJ. Targeting fibrosis for the treatment of heart failure: a role for transforming growth factor-beta. Cardiovasc Ther. 2012;30(1):e30\u201340.","journal-title":"Cardiovasc Ther"},{"issue":"1","key":"400_CR30","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1159\/000438781","volume":"133","author":"H Tao","year":"2016","unstructured":"Tao H, Yang JJ, Hu W, Shi KH, Li J. HDAC6 promotes cardiac fibrosis progression through suppressing RASSF1A expression. Cardiology. 2016;133(1):18\u201326.","journal-title":"Cardiology."},{"issue":"11","key":"400_CR31","doi-asserted-by":"publisher","first-page":"5828","DOI":"10.1210\/en.2008-0165","volume":"149","author":"LJ Ellmers","year":"2008","unstructured":"Ellmers LJ, Scott NJ, Medicherla S, Pilbrow AP, Bridgman PG, Yandle TG, et al. Transforming growth factor-beta blockade down-regulates the renin-angiotensin system and modifies cardiac remodeling after myocardial infarction. Endocrinology. 2008;149(11):5828\u201334.","journal-title":"Endocrinology."},{"issue":"2","key":"400_CR32","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/ejhf.696","volume":"19","author":"M Gyongyosi","year":"2017","unstructured":"Gyongyosi M, Winkler J, Ramos I, Do QT, Firat H, McDonald K, et al. Myocardial fibrosis: biomedical research from bench to bedside. Eur J Heart Fail. 2017;19(2):177\u201391.","journal-title":"Eur J Heart Fail"},{"issue":"1","key":"400_CR33","doi-asserted-by":"publisher","first-page":"57","DOI":"10.2353\/ajpath.2008.070974","volume":"173","author":"M Bujak","year":"2008","unstructured":"Bujak M, Dobaczewski M, Chatila K, Mendoza LH, Li N, Reddy A, et al. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling. Am J Pathol. 2008;173(1):57\u201367.","journal-title":"Am J Pathol"},{"issue":"12","key":"400_CR34","doi-asserted-by":"publisher","first-page":"e0167195","DOI":"10.1371\/journal.pone.0167195","volume":"11","author":"MH Hartman","year":"2016","unstructured":"Hartman MH, Vreeswijk-Baudoin I, Groot HE, van de Kolk KW, de Boer RA, Mateo Leach I, et al. Inhibition of Interleukin-6 receptor in a murine model of myocardial ischemia-reperfusion. PLoS One. 2016;11(12):e0167195.","journal-title":"PLoS One"},{"issue":"10","key":"400_CR35","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1016\/j.amjcard.2009.12.059","volume":"105","author":"A Abbate","year":"2010","unstructured":"Abbate A, Kontos MC, Grizzard JD, Biondi-Zoccai GG, Van Tassell BW, Robati R, et al. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra remodeling trial [VCU-ART] pilot study). Am J Cardiol. 2010;105(10):1371\u20137 e1.","journal-title":"Am J Cardiol"},{"issue":"10","key":"400_CR36","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1016\/j.amjcard.2013.01.287","volume":"111","author":"A Abbate","year":"2013","unstructured":"Abbate A, Van Tassell BW, Biondi-Zoccai G, Kontos MC, Grizzard JD, Spillman DW, et al. Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth University-Anakinra remodeling trial (2) (VCU-ART2) pilot study]. Am J Cardiol. 2013;111(10):1394\u2013400.","journal-title":"Am J Cardiol"},{"key":"400_CR37","doi-asserted-by":"publisher","first-page":"286","DOI":"10.3389\/fonc.2017.00286","volume":"7","author":"L Iommarini","year":"2017","unstructured":"Iommarini L, Porcelli AM, Gasparre G, Kurelac I. Non-canonical mechanisms regulating hypoxia-inducible factor 1 alpha in Cancer. Front Oncol. 2017;7:286.","journal-title":"Front Oncol"}],"container-title":["BMC Pharmacology and Toxicology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s40360-020-0400-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s40360-020-0400-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s40360-020-0400-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:07:19Z","timestamp":1615507639000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcpharmacoltoxicol.biomedcentral.com\/articles\/10.1186\/s40360-020-0400-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,12]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["400"],"URL":"https:\/\/doi.org\/10.1186\/s40360-020-0400-0","relation":{},"ISSN":["2050-6511"],"issn-type":[{"value":"2050-6511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,12]]},"assertion":[{"value":"13 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All animal experimental procedures in the present study were performed under protocols approved by the Institutional Animal Care and Use Committee of Taipei Medical University (IACUC approved No. LAC-2017-0167).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"21"}}