{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T12:32:23Z","timestamp":1784205143889,"version":"3.55.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T00:00:00Z","timestamp":1637280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Doxorubicin-driven cardiotoxicity could result in dilated cardiomyopathy and heart failure (HF). Previously, we showed that periplocymarin exerted a cardiotonic role by promoting calcium influx and attenuating myocardial fibrosis induced by isoproterenol (ISO) by improving the metabolism of cardiomyocytes. However, the impact of periplocymarin on doxorubicin (DOX)-triggered cardiomyopathy has not been investigated. In the current study, C57BL\/6 mice were randomly divided into three groups, namely, the control, DOX, and DOX+periplocymarin groups. The cardiac function and apoptosis were measured. Our results revealed that periplocymarin administration greatly improved the DOX-induced cardiac dysfunction manifested by the ejection fraction (EF%), fractional shortening (FS%), left ventricular posterior wall thickness (LVPW), left ventricular anterior wall thickness (LVAW), left ventricular (LV) mass, and attenuated DOX-induced cardiomyocyte apoptosis assessed by hematoxylin and eosin (H&amp;amp;E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and western blotting. Further study using H9c2 cells revealed that the pretreatment of periplocymarin suppressed DOX-induced apoptosis evidenced by annexin V staining. Moreover, liquid chromatography with tandem mass spectrometry (LC-MS\/MS) analysis demonstrated that DOX lead to an accumulation in serum ceramide, and the pre-treatment of periplocymarin could reverse this phenomenon. Network pharmacology also demonstrated that ceramide metabolism was involved in the process. Consistently, real-time PCR showed that periplocymarin significantly abolished the induction of the genes involved in the <jats:italic>de novo<\/jats:italic> synthesis of ceramide, i.e., <jats:italic>CerS2, CerS4, CerS5<\/jats:italic>, and <jats:italic>CerS6<\/jats:italic>, and the induction was attributed to the treatment of DOX. Collectively, these results suggested that periplocymarin reduced cardiomyocyte apoptosis to protect hearts from DOX-induced cardiotoxicity and the <jats:italic>de novo<\/jats:italic> synthesis of ceramides was involved in this process.<\/jats:p>","DOI":"10.3389\/fcvm.2021.732554","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T05:14:37Z","timestamp":1637298877000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Periplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides"],"prefix":"10.3389","volume":"8","author":[{"given":"Weijing","family":"Yun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruqiang","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"101394","DOI":"10.1016\/j.redox.2019.101394","article-title":"Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: have we been barking up the wrong tree?","volume":"29","author":"Kalyanaraman","year":"2020","journal-title":"Redox Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/s00109-016-1494-0","article-title":"Doxorubicin-induced chronic dilated cardiomyopathy-the apoptosis hypothesis revisited","volume":"95","author":"Kankeu","year":"2017","journal-title":"J Mol Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1007\/s00109-008-0434-z","article-title":"ARC is a critical cardiomyocyte survival switch in doxorubicin cardiotoxicity","volume":"87","author":"An","year":"2009","journal-title":"J Mol Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.ijcha.2015.11.004","article-title":"Doxorubicin induced heart failure: phenotype and molecular mechanisms","volume":"10","author":"Mitry","year":"2016","journal-title":"Int J Cardiol Heart Vasc."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1834","DOI":"10.1093\/eurheartj\/ehs011","article-title":"Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia\/reperfusion injury","volume":"34","author":"Pu","year":"2013","journal-title":"Eur Heart J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"5115","DOI":"10.2174\/1381612823666170925163427","article-title":"A review of chinese herbal medicine for the treatment of chronic heart failure","volume":"23","author":"Wang","year":"2017","journal-title":"Curr Pharmaceutic Design."},{"key":"B7","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3390\/ijms19113658","article-title":"Ginsenoside rg1 prevents doxorubicin-induced cardiotoxicity through the inhibition of autophagy and endoplasmic reticulum stress in mice","volume":"19","author":"Xu","year":"2018","journal-title":"Int J Mol Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2691","DOI":"10.1038\/s41598-017-02360-5","article-title":"Astragaloside IV alleviates heart failure via activating PPAR\u03b1 to switch glycolysis to fatty acid \u03b2-oxidation","volume":"7","author":"Dong","year":"2017","journal-title":"Scien Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"108599","DOI":"10.1016\/j.biopha.2019.108599","article-title":"Tanshinone IIA protects against heart failure post-myocardial infarction via AMPKs\/mTOR-dependent autophagy pathway","volume":"112","author":"Zhang","year":"2019","journal-title":"Biomed Pharmacotherap."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.12659\/MSM.915194","article-title":"Qishen yiqi dropping pills ameliorates doxorubicin-induced cardiotoxicity in mice via enhancement of cardiac angiogenesis","volume":"25","author":"Wang","year":"2019","journal-title":"Med Sci Monit."},{"key":"B11","doi-asserted-by":"publisher","first-page":"153443","DOI":"10.1016\/j.phymed.2020.153443","article-title":"The discovery of Q-markers of Qiliqiangxin Capsule, a traditional Chinese medicine prescription in the treatment of chronic heart failure, based on a novel strategy of multi-dimensional \u201cradar chart\u201d mode evaluation","volume":"82","author":"He","year":"2021","journal-title":"Phytomedicine."},{"key":"B12","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jchromb.2018.05.014","article-title":"Systematic screening and characterization of Qi-Li-Qiang-Xin capsule-related xenobiotics in rats by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry","volume":"1090","author":"Yun","year":"2018","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1007\/s00280-009-0929-5","article-title":"Pro-apoptotic and cytostatic activity of naturally occurring cardenolides","volume":"64","author":"Bloise","year":"2009","journal-title":"Cancer Chemother Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/bdd.1884","article-title":"Periplocymarin is a potential natural compound for drug development: highly permeable with absence of P-glycoprotein efflux and cytochrome P450 inhibitions","volume":"35","author":"Martey","year":"2014","journal-title":"Biopharm Drug Dispos."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.3389\/fphar.2020.01292","article-title":"Periplocymarin plays an efficacious cardiotonic role via promoting calcium influx","volume":"11","author":"Yun","year":"2020","journal-title":"Frontiers in pharmacology."},{"key":"B16","doi-asserted-by":"publisher","first-page":"111562","DOI":"10.1016\/j.biopha.2021.111562","article-title":"Periplocymarin protects against myocardial fibrosis induced by \u03b2-adrenergic activation in mice","volume":"139","author":"Yun","year":"2021","journal-title":"Biomed Pharmacotherapy."},{"key":"B17","doi-asserted-by":"publisher","first-page":"H795","DOI":"10.1152\/ajpheart.00253.2017","article-title":"Vitamin C mitigates oxidative\/nitrosative stress and inflammation in doxorubicin-induced cardiomyopathy","volume":"313","author":"Akolkar","year":"2017","journal-title":"Heart Circulat Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1210\/er.2007-0025","article-title":"Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism","volume":"29","author":"Holland","year":"2008","journal-title":"Endocrine Rev."},{"key":"B19","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.jacbts.2017.12.005","article-title":"Plasma ceramides as prognostic biomarkers and their arterial and myocardial tissue correlates in acute myocardial infarction","volume":"3","author":"de Carvalho","year":"2018","journal-title":"JACC"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41569-021-00536-1","article-title":"Ceramides and other sphingolipids as drivers of cardiovascular disease","volume":"36","author":"Choi","year":"2021","journal-title":"Nat Rev Cardiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e005708","DOI":"10.1161\/CIRCHEARTFAILURE.118.005708","article-title":"Plasma ceramides and sphingomyelins in relation to heart failure risk","volume":"12","author":"Lemaitre","year":"2019","journal-title":"Circul"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2250","DOI":"10.1161\/01.CIR.0000035650.05921.50","article-title":"Dual effect of ceramide on human endothelial cells: induction of oxidative stress and transcriptional upregulation of endothelial nitric oxide synthase","volume":"106","author":"Li","year":"2002","journal-title":"Circul."},{"key":"B23","first-page":"1257","article-title":"Ceramide is involved in triggering of cardiomyocyte apoptosis induced by ischemia and reperfusion","volume":"151","author":"Bielawska","year":"1997","journal-title":"Am J Pathol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2854","DOI":"10.1172\/JCI119114","article-title":"Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. involvement of the sphingolipid signaling cascade in cardiac cell death","volume":"98","author":"Krown","year":"1996","journal-title":"J Clinic Investigat."},{"key":"B25","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.yjmcc.2018.08.008","article-title":"Protease-activated receptor 1 activation enhances doxorubicin-induced cardiotoxicity","volume":"122","author":"Antoniak","year":"2018","journal-title":"J Mol Cell Cardiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.lfs.2017.10.034","article-title":"Sustained \u03b2-AR stimulation induces synthesis and secretion of growth factors in cardiac myocytes that affect on cardiac fibroblast activation","volume":"193","author":"Nuamnaichati","year":"2018","journal-title":"Life Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.3389\/fphar.2019.01135","article-title":"Salsolinol attenuates doxorubicin-induced chronic heart failure in rats and improves mitochondrial function in h9c2 cardiomyocytes","volume":"10","author":"Wen","year":"2019","journal-title":"Front Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e138505","DOI":"10.1172\/jci.insight.138505","article-title":"Endothelial cell prostaglandin E2 receptor EP4 is essential for blood pressure homeostasis","volume":"5","author":"Xu","year":"2020","journal-title":"JCI insight."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1038\/nm.2919","article-title":"Identification of the molecular basis of doxorubicin-induced cardiotoxicity","volume":"18","author":"Zhang","year":"2012","journal-title":"Nat Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2672","DOI":"10.1073\/pnas.1821022116","article-title":"Ferroptosis as a target for protection against cardiomyopathy","volume":"116","author":"Fang","year":"2019","journal-title":"Proceed Nat Acad Sci USA."},{"key":"B31","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1093\/cvr\/cvm029","article-title":"Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis","volume":"77","author":"Parra","year":"2008","journal-title":"Cardiovascul Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1172\/jci.insight.82922","article-title":"Increased de novo ceramide synthesis and accumulation in failing myocardium","volume":"2","author":"Ji","year":"2017","journal-title":"JCI Insight."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1096\/fj.201700300R","article-title":"Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes","volume":"32","author":"Law","year":"2018","journal-title":"FASEB J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/S0008-6363(99)00142-X","article-title":"Doxorubicin induces slow ceramide accumulation and late apoptosis in cultured adult rat ventricular myocytes","volume":"43","author":"Delpy","year":"1999","journal-title":"Cardiovascul Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1161\/ATVBAHA.118.311199","article-title":"Plasma ceramides","volume":"38","author":"Meeusen","year":"2018","journal-title":"Arterioscler Thromb Vascul Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e013050","DOI":"10.1161\/JAHA.119.013050","article-title":"Association of circulating ceramides with cardiac structure and function in the community: the framingham heart study","volume":"8","author":"Nwabuo","year":"2019","journal-title":"J Am Heart Assoc."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.007931","article-title":"Ceramide remodeling and risk of cardiovascular events and mortality","volume":"7","author":"Peterson","year":"2018","journal-title":"J Am Heart Assoc."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2028","DOI":"10.1161\/CIRCULATIONAHA.116.024261","article-title":"Plasma ceramides, mediterranean diet, and incident cardiovascular disease in the predimed trial (prevenci\u00f3n con dieta mediterr\u00e1nea)","volume":"135","author":"Wang","year":"2017","journal-title":"Circulation."},{"key":"B39","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.molmed.2018.10.009","article-title":"Ceramides as novel disease biomarkers","volume":"25","author":"Kurz","year":"2019","journal-title":"Trends Mol Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.prostaglandins.2006.10.004","article-title":"Pioglitazone induces de novo ceramide synthesis in the rat heart","volume":"83","author":"Baranowski","year":"2007","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"B41","doi-asserted-by":"publisher","first-page":"158630","DOI":"10.1016\/j.bbalip.2020.158630","article-title":"Novel signaling aspects of ceramide 1-phosphate","volume":"1865","author":"Presa","year":"2020","journal-title":"Biochimica et biophysica acta."},{"key":"B42","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.plipres.2014.01.004","article-title":"Ceramide: a simple sphingolipid with unique biophysical properties","volume":"54","author":"Castro","year":"2014","journal-title":"Progress Lipid Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.bbadis.2018.10.010","article-title":"Vitamin E alleviates non-alcoholic fatty liver disease in phosphatidylethanolamine N-methyltransferase deficient mice","volume":"1865","author":"Presa","year":"2019","journal-title":"Biochimica et biophysica acta"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.732554\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T05:14:43Z","timestamp":1637298883000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.732554\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,19]]},"references-count":43,"alternative-id":["10.3389\/fcvm.2021.732554"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2021.732554","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,19]]},"article-number":"732554"}}