{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:11:57Z","timestamp":1788545517861,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T00:00:00Z","timestamp":1554336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetes mellitus (DM) has significant effects on cardiac calcium (Ca2+) and sodium (Na+) regulation. Clinical studies have shown that empagliflozin (Jardiance\u2122) has cardiovascular benefits, however the mechanisms have not been fully elucidated. This study aimed to investigate whether empagliflozin modulates cardiac electrical activity as well as Ca2+\/Na+ homeostasis in DM cardiomyopathy. Electrocardiography, echocardiography, whole-cell patch-clamp, confocal microscopic examinations, and Western blot, were performed in the ventricular myocytes of control and streptozotocin-induced DM rats, with or without empagliflozin (10 mg\/kg for 4 weeks). The results showed that the control and empagliflozin-treated DM rats had smaller left ventricular end-diastolic diameters and shorter QT intervals than the DM rats. In addition, the prolonged action potential duration in the DM rats was attenuated in the empagliflozin-treated DM rats. Moreover, the DM rats had smaller sarcoplasmic reticular Ca2+ contents, intracellular Ca2+ transients, L-type Ca2+, reverse mode Na+-Ca2+exchanger currents, lower protein expressions of sarcoplasmic reticulum ATPase, ryanodine receptor 2 (RyR2), but higher protein expressions of phosphorylated RyR2 at serine 2808 than the control and empagliflozin-treated DM rats. The incidence and frequency of Ca2+ sparks, cytosolic and mitochondrial reactive oxygen species, and late Na+ current and Na+\/hydrogen-exchanger currents were greater in the DM rats than in the control and empagliflozin-treated DM rats. Empagliflozin significantly changed Ca2+ regulation, late Na+ and Na+\/hydrogen-exchanger currents and electrophysiological characteristics in DM cardiomyopathy, which may contribute to its cardioprotective benefits in DM patients.<\/jats:p>","DOI":"10.3390\/ijms20071680","type":"journal-article","created":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T11:31:57Z","timestamp":1554377517000},"page":"1680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":107,"title":["Empagliflozin Attenuates Myocardial Sodium and Calcium Dysregulation and Reverses Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats"],"prefix":"10.3390","volume":"20","author":[{"given":"Ting-I","family":"Lee","sequence":"first","affiliation":[{"name":"Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao-Chang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Kuo","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Chih","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Yu","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei City 22174, Taiwan"},{"name":"School of Medicine, Fu-Jen Catholic University, New Taipei City 22174, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hsun","family":"Kao","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Jen","family":"Chen","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"434","DOI":"10.2337\/diacare.16.2.434","article-title":"Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial","volume":"16","author":"Stamler","year":"1993","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1007\/PL00002934","article-title":"Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes","volume":"44","author":"Morrish","year":"2001","journal-title":"Diabetologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17A","DOI":"10.1016\/j.amjcard.2003.11.004","article-title":"Early myocardial dysfunction in the diabetic heart: Current research and clinical applications","volume":"93","author":"Scognamiglio","year":"2004","journal-title":"Am. J. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1210\/er.2003-0012","article-title":"Diabetic cardiomyopathy: Evidence, mechanisms, and therapeutic implications","volume":"25","author":"Fang","year":"2004","journal-title":"Endocr. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/clpt.2011.16","article-title":"Inhibition of SGLT2: A novel strategy for treatment of type 2 diabetes mellitus","volume":"89","author":"Pfister","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.2337\/dc15-1730","article-title":"Efficacy and Safety of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients with Type 1 Diabetes","volume":"38","author":"Henry","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1080\/14656566.2018.1450387","article-title":"Efficacy of dapagliflozin as an adjunct therapy in patients with inadequately controlled type 1 diabetes mellitus","volume":"19","author":"Caerels","year":"2018","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.2147\/DDDT.S50773","article-title":"Update on developments with SGLT2 inhibitors in the management of type 2 diabetes","volume":"8","author":"Nauck","year":"2014","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1113\/jphysiol.2014.282319","article-title":"Na+\/Ca2+ exchange and Na+\/K+-ATPase in the heart","volume":"593","author":"Shattock","year":"2015","journal-title":"J. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/0022-2828(83)90336-X","article-title":"Altered myocardial response to ouabain in diabetic rats: Mechanics and electrophysiology","volume":"15","author":"Fein","year":"1983","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e002183","DOI":"10.1161\/JAHA.115.002183","article-title":"Intracellular Na+ Concentration ([Na+]i) Is Elevated in Diabetic Hearts Due to Enhanced Na+-Glucose Cotransport","volume":"4","author":"Lambert","year":"2015","journal-title":"J. Am. Heart Assoc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1007\/s00125-014-3171-6","article-title":"Molecular mechanisms of diabetic cardiomyopathy","volume":"57","author":"Bugger","year":"2014","journal-title":"Diabetologia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.ijcard.2011.08.072","article-title":"Rosiglitazone induces arrhythmogenesis in diabetic hypertensive rats with calcium handling alteration","volume":"165","author":"Lee","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5390","DOI":"10.1016\/j.ijcard.2013.08.051","article-title":"The dipeptidyl peptidase-4 inhibitor-sitagliptin modulates calcium dysregulation, inflammation, and PPARs in hypertensive cardiomyocytes","volume":"168","author":"Lee","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.peptides.2016.02.007","article-title":"Glucagon-like peptide-1 regulates calcium homeostasis and electrophysiological activities of HL-1 cardiomyocytes","volume":"78","author":"Huang","year":"2016","journal-title":"Peptides"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.2337\/diabetes.51.4.1166","article-title":"Overexpression of the sarcoplasmic reticulum Ca2+-ATPase improves myocardial contractility in diabetic cardiomyopathy","volume":"51","author":"Trost","year":"2002","journal-title":"Diabetes"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/j.1469-7793.2000.00085.x","article-title":"Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: Implication in Ca2+ overload","volume":"527","author":"Hattori","year":"2000","journal-title":"J. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1006\/jmcc.2000.1107","article-title":"Diminished expression of sarcoplasmic reticulum Ca2+-ATPase and ranodine sensitive Ca2+Channel mRNA in streptozotocin-induced diabetic rat heart","volume":"32","author":"Teshima","year":"2000","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1096\/fj.01-1019fje","article-title":"Transgenic overexpression of the sarcoplasmic reticulum Ca2+ATPase improves reticular Ca2+ handling in normal and diabetic rat hearts","volume":"16","author":"Vetter","year":"2002","journal-title":"FASEB J."},{"key":"ref_21","first-page":"H793","article-title":"Hypertensive-diabetic cardiomyopathy in rats","volume":"258","author":"Fein","year":"1990","journal-title":"Am. J. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1210\/jcem-64-4-751","article-title":"QT interval prolongation and sudden cardiac death in diabetic autonomic neuropathy","volume":"64","author":"Kahn","year":"1987","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/0022-2828(92)91098-P","article-title":"Action potentials and potassium currents in rat ventricular muscle during experimental diabetes","volume":"24","author":"Magyar","year":"1992","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12933-016-0489-z","article-title":"Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes","volume":"16","author":"Habibi","year":"2017","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1046\/j.1365-201x.1999.00538.x","article-title":"Electrophysiological changes in rat ventricular and atrial myocardium at different stages of experimental diabetes","volume":"166","author":"Pacher","year":"1999","journal-title":"Acta Physiol. Scand."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.3389\/fphys.2018.01303","article-title":"Myocyte [Na+]i Dysregulation in Heart Failure and Diabetic Cardiomyopathy","volume":"9","author":"Despa","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"H1398","DOI":"10.1152\/ajpheart.00313.2002","article-title":"Defective intracellular Ca2+ signaling contributes to cardiomyopathy in Type 1 diabetic rats","volume":"283","author":"Choi","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/S0008-6363(00)00062-6","article-title":"Stimulus interval-dependent differences in Ca2+ transients and contractile responses of diabetic rat cardiomyocytes","volume":"46","author":"Kotsanas","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1042\/CS20080500","article-title":"Diabetic cardiomyopathy","volume":"116","author":"Asghar","year":"2009","journal-title":"Clin. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s10557-017-6734-1","article-title":"Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes","volume":"31","author":"Hammoudi","year":"2017","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12632","DOI":"10.14814\/phy2.12632","article-title":"Characterization of L-type calcium channel activity in atrioventricular nodal myocytes from rats with streptozotocin-induced Diabetes mellitus","volume":"3","author":"Yuill","year":"2015","journal-title":"Physiol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"608","DOI":"10.2337\/diabetes.55.03.06.db05-1284","article-title":"Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db\/db type 2 diabetic mice","volume":"55","author":"Pereira","year":"2006","journal-title":"Diabetes"},{"key":"ref_33","first-page":"H1288","article-title":"Abnormalities of K+ and Ca2+ currents in ventricular myocytes from rats with chronic diabetes","volume":"269","author":"Wang","year":"1995","journal-title":"Am. J. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1046\/j.1365-201x.1999.00547.x","article-title":"Decrease in sodium-calcium exchange and calcium currents in diabetic rat ventricular myocytes","volume":"166","author":"Chattou","year":"1999","journal-title":"Acta Physiol. Scand."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.2337\/db06-1629","article-title":"Decreased L-type Ca2+ current in cardiac myocytes of type 1 diabetic Akita mice due to reduced phosphatidylinositol 3-kinase signaling","volume":"56","author":"Lu","year":"2007","journal-title":"Diabetes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1007\/s00125-016-4134-x","article-title":"Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+\/H+ exchanger in rats and rabbits","volume":"60","author":"Baartscheer","year":"2017","journal-title":"Diabetologia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1111\/dme.13629","article-title":"Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: A randomized trial","volume":"35","author":"Laffel","year":"2018","journal-title":"Diabet. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.ceca.2006.08.017","article-title":"Calcium microdomains and oxidative stress","volume":"40","author":"Davidson","year":"2006","journal-title":"Cell Calcium"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1253\/circj.CJ-13-1187","article-title":"Production of reactive oxygen species in the diabetic heart. Roles of mitochondria and NADPH oxidase","volume":"78","author":"Teshima","year":"2014","journal-title":"Circ. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.yjmcc.2009.08.021","article-title":"Cardiac T-type Ca2+ channels in the heart","volume":"48","author":"Ono","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"168264","DOI":"10.5402\/2012\/168264","article-title":"Cardiac autonomic neuropathy measured by heart rate variability and markers of subclinical atherosclerosis in early type 2 diabetes","volume":"2012","author":"Fakhrzadeh","year":"2012","journal-title":"ISRN Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2936","DOI":"10.2337\/diacare.27.12.2936","article-title":"Sympathetic and parasympathetic neuropathy are frequent in both type 1 and type 2 diabetic patients","volume":"27","author":"Freccero","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/j.1365-2362.2010.02318.x","article-title":"Oxidative stress and inflammation modulate peroxisome proliferator-activated receptors with regional discrepancy in diabetic heart","volume":"40","author":"Lee","year":"2010","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1124\/jpet.114.213454","article-title":"The sodium glucose cotransporter type 2 inhibitor empagliflozin preserves beta-cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat","volume":"350","author":"Hansen","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.ijcard.2014.07.077","article-title":"Androgen attenuates cardiac fibroblasts activations through modulations of transforming growth factor-beta and angiotensin II signaling","volume":"176","author":"Chung","year":"2014","journal-title":"Int. J. Cardiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4178","DOI":"10.1016\/j.ijcard.2013.07.111","article-title":"Histone deacetylase inhibition improved cardiac functions with direct antifibrotic activity in heart failure","volume":"168","author":"Kao","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1042\/CS20100529","article-title":"Cardiac peroxisome-proliferator-activated receptor expression in hypertension co-existing with diabetes","volume":"121","author":"Lee","year":"2011","journal-title":"Clin. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s00395-010-0132-1","article-title":"Discrepant electrophysiological characteristics and calcium homeostasis of left atrial anterior and posterior myocytes","volume":"106","author":"Suenari","year":"2011","journal-title":"Basic Res. Cardiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1161\/01.CIR.0000141296.59876.87","article-title":"Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes","volume":"110","author":"Llach","year":"2004","journal-title":"Circulation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1111\/jcmm.12818","article-title":"Colchicine modulates calcium homeostasis and electrical property of HL-1 cells","volume":"20","author":"Lu","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"69231","DOI":"10.18632\/oncotarget.12470","article-title":"Fibroblast growth factor 23 dysregulates late sodium current and calcium homeostasis with enhanced arrhythmogenesis in pulmonary vein cardiomyocytes","volume":"7","author":"Huang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ceca.2004.06.006","article-title":"Inhibition of the Na+-H+ exchanger with cariporide abolishes stretch-induced calcium but not sodium accumulation in mouse ventricular myocytes","volume":"37","author":"Kondratev","year":"2005","journal-title":"Cell Calcium"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1161\/CIRCRESAHA.117.311920","article-title":"Thyroid and Glucocorticoid Hormones Promote Functional T-Tubule Development in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes","volume":"121","author":"Parikh","year":"2017","journal-title":"Circ. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.yjmcc.2014.09.009","article-title":"Intracellular Na+ overload causes oxidation of CaMKII and leads to Ca2+ mishandling in isolated ventricular myocytes","volume":"76","author":"Kornyeyev","year":"2014","journal-title":"J. Mol. Cell. Cardiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1680\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:42:52Z","timestamp":1760186572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1680"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,4]]},"references-count":54,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["ijms20071680"],"URL":"https:\/\/doi.org\/10.3390\/ijms20071680","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,4]]}}}