{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:52:55Z","timestamp":1760147575398,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,12]],"date-time":"2023-02-12T00:00:00Z","timestamp":1676160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health\u2019s (NIH) National Institute of General Medical Sciences (NIGMS), Center of Biomedical Research Excellence (CoBRE) supported Sanford Center for Pediatric Research","award":["2P20GM103620","1R01HL160980"],"award-info":[{"award-number":["2P20GM103620","1R01HL160980"]}]},{"name":"National Heart, Lung and Blood Institute (NHLBI), Cardiovascular Diseases Research","award":["2P20GM103620","1R01HL160980"],"award-info":[{"award-number":["2P20GM103620","1R01HL160980"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Infants exposed to diabetic pregnancy are at higher risk of cardiomyopathy at birth and early onset cardiovascular disease (CVD) as adults. Using a rat model, we showed how fetal exposure to maternal diabetes causes cardiac disease through fuel-mediated mitochondrial dysfunction, and that a maternal high-fat diet (HFD) exaggerates the risk. Diabetic pregnancy increases circulating maternal ketones which can have a cardioprotective effect, but whether diabetes-mediated complex I dysfunction impairs myocardial metabolism of ketones postnatally remains unknown. The objective of this study was to determine whether neonatal rat cardiomyocytes (NRCM) from diabetes- and HFD-exposed offspring oxidize ketones as an alternative fuel source. To test our hypothesis, we developed a novel ketone stress test (KST) using extracellular flux analyses to compare real-time \u00df-hydroxybutyrate (\u03b2HOB) metabolism in NRCM. We also compared myocardial expression of genes responsible for ketone and lipid metabolism. NRCM had a dose-dependent increase in respiration with increasing concentrations of \u03b2HOB, demonstrating that both control and combination exposed NRCM can metabolize ketones postnatally. Ketone treatment also enhanced the glycolytic capacity of combination exposed NRCM with a dose-dependent increase in the glucose-mediated proton efflux rate (PER) from CO2 (aerobic glycolysis) alongside a decreased reliance on PER from lactate (anaerobic glycolysis). Expression of genes responsible for ketone body metabolism was higher in combination exposed males. Findings demonstrate that myocardial ketone body metabolism is preserved and improves fuel flexibility in NRCM from diabetes- and HFD-exposed offspring, which suggests that ketones might serve a protective role in neonatal cardiomyopathy due to maternal diabetes.<\/jats:p>","DOI":"10.3390\/ijms24043684","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T03:28:46Z","timestamp":1676258926000},"page":"3684","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Impact of Prenatal Exposure to Maternal Diabetes and High-Fat Diet on Postnatal Myocardial Ketone Body Metabolism in Rats"],"prefix":"10.3390","volume":"24","author":[{"given":"Prathapan","family":"Ayyappan","sequence":"first","affiliation":[{"name":"Environmental Influences on Health and Disease Group, Sanford Research, Sioux Falls, SD 57104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9015-3929","authenticated-orcid":false,"given":"Tricia D.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Environmental Influences on Health and Disease Group, Sanford Research, Sioux Falls, SD 57104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyler C. T.","family":"Gandy","sequence":"additional","affiliation":[{"name":"Environmental Influences on Health and Disease Group, Sanford Research, Sioux Falls, SD 57104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8741-2240","authenticated-orcid":false,"given":"Eli J.","family":"Louwagie","sequence":"additional","affiliation":[{"name":"Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5966-669X","authenticated-orcid":false,"given":"Michelle L.","family":"Baack","sequence":"additional","affiliation":[{"name":"Environmental Influences on Health and Disease Group, Sanford Research, Sioux Falls, SD 57104, USA"},{"name":"Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.2337\/diab.29.12.1023","article-title":"Banting Lecture 1980: Of pregnancy and progeny","volume":"29","author":"Freinkel","year":"1980","journal-title":"Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E792","DOI":"10.1152\/ajpendo.00078.2006","article-title":"Maternal high-fat diet consumption results in fetal malprogramming predisposing to the onset of metabolic syndrome-like phenotype in adulthood","volume":"291","author":"Srinivasan","year":"2006","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1055\/s-0030-1248303","article-title":"High fat programming induces glucose intolerance in weanling Wistar rats","volume":"42","author":"Cerf","year":"2010","journal-title":"Horm. Metab. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1093\/eurheartj\/ehl416","article-title":"Pathologic ventricular hypertrophy in the offspring of diabetic mothers: A retrospective study","volume":"28","author":"Ullmo","year":"2007","journal-title":"Eur. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1007\/s00246-017-1584-y","article-title":"Subclinical Decrease in Myocardial Function in Asymptomatic Infants of Diabetic Mothers: A Tissue Doppler Study","volume":"38","author":"Zablah","year":"2017","journal-title":"Pediatr. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"l6398","DOI":"10.1136\/bmj.l6398","article-title":"Maternal diabetes during pregnancy and early onset of cardiovascular disease in offspring: Population based cohort study with 40 years of follow-up","volume":"367","author":"Yu","year":"2019","journal-title":"BMJ"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"434","DOI":"10.3109\/07853890.2014.919728","article-title":"Long-term consequences of maternal overweight in pregnancy on offspring later health: Findings from the Helsinki Birth Cohort Study","volume":"46","author":"Eriksson","year":"2014","journal-title":"Ann. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1161\/HYPERTENSIONAHA.115.05920","article-title":"Maternal Obesity During Pregnancy Associates With Premature Mortality and Major Cardiovascular Events in Later Life","volume":"66","author":"Lee","year":"2015","journal-title":"Hypertension"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"H681","DOI":"10.1152\/ajpheart.00795.2015","article-title":"Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction","volume":"310","author":"Mdaki","year":"2016","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Louwagie, E.J., Larsen, T.D., Wachal, A.L., Gandy, T.C.T., and Baack, M.L. (2021). Mitochondrial Transfer Improves Cardiomyocyte Bioenergetics and Viability in Male Rats Exposed to Pregestational Diabetes. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052382"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/pr.2017.288","article-title":"Placental lipid processing in response to a maternal high-fat diet and diabetes in rats","volume":"83","author":"Louwagie","year":"2017","journal-title":"Pediatr. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Larsen, T.D., Sabey, K.H., Knutson, A.J., Gandy, T.C.T., Louwagie, E.J., Lauterboeck, L., Mdaki, K.S., and Baack, M.L. (2019). Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20123090"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101746","DOI":"10.1016\/j.isci.2020.101746","article-title":"Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity","volume":"23","author":"Louwagie","year":"2020","journal-title":"iScience"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mdaki, K.S., Larsen, T.D., Weaver, L.J., and Baack, M.L. (2016). Age Related Bioenergetics Profiles in Isolated Rat Cardiomyocytes Using Extracellular Flux Analyses. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0149002"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4581","DOI":"10.2147\/DMSO.S280851","article-title":"Effect of Elevated Ketone Body on Maternal and Infant Outcome of Pregnant Women with Abnormal Glucose Metabolism During Pregnancy","volume":"13","author":"Qian","year":"2020","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1161\/CIRCULATIONAHA.115.017355","article-title":"The Failing Heart Relies on Ketone Bodies as a Fuel","volume":"133","author":"Aubert","year":"2016","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"H1060","DOI":"10.1152\/ajpheart.00646.2012","article-title":"Ketone body metabolism and cardiovascular disease","volume":"304","author":"Cotter","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e000433","DOI":"10.1161\/JAHA.113.000433","article-title":"Taking diabetes to heart--deregulation of myocardial lipid metabolism in diabetic cardiomyopathy","volume":"2","author":"Bayeva","year":"2013","journal-title":"J. Am. Heart Assoc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/j.bbalip.2016.03.020","article-title":"Cardiac fatty acid oxidation in heart failure associated with obesity and diabetes","volume":"1861","author":"Fukushima","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1161\/CIRCULATIONAHA.115.017545","article-title":"Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure","volume":"133","author":"Bedi","year":"2016","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e013039","DOI":"10.1161\/JAHA.119.013039","article-title":"Increased Glucose Availability Attenuates Myocardial Ketone Body Utilization","volume":"9","author":"Brahma","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"570846","DOI":"10.3389\/fendo.2020.570846","article-title":"Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts","volume":"11","author":"Preston","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.cmet.2005.05.004","article-title":"Metabolic control through the PGC-1 family of transcription coactivators","volume":"1","author":"Lin","year":"2005","journal-title":"Cell Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"29","DOI":"10.21775\/cimb.028.029","article-title":"PGC-1: The Energetic Regulator in Cardiac Metabolism","volume":"28","author":"Di","year":"2018","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wagner, N., and Wagner, K.D. (2020). The Role of PPARs in Disease. Cells, 9.","DOI":"10.3390\/cells9112367"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1159\/000492091","article-title":"High Fat Diet Upregulates Fatty Acid Oxidation and Ketogenesis via Intervention of PPAR-\u03b3","volume":"48","author":"Sikder","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.plipres.2015.11.004","article-title":"Carnitine palmitoyltransferase 1C: From cognition to cancer","volume":"61","author":"Casals","year":"2016","journal-title":"Prog. Lipid Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/j.1467-789X.2009.00642.x","article-title":"Regulatory enzymes of mitochondrial beta-oxidation as targets for treatment of the metabolic syndrome","volume":"11","author":"Schreurs","year":"2010","journal-title":"Obes. Rev. Off. J. Int. Assoc. Study Obes."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1161\/CIRCRESAHA.121.318241","article-title":"Cardiac Energy Metabolism in Heart Failure","volume":"128","author":"Lopaschuk","year":"2021","journal-title":"Circ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"681513","DOI":"10.3389\/fragi.2021.681513","article-title":"Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts","volume":"2","author":"Chu","year":"2021","journal-title":"Front. Aging"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1152\/physrev.00015.2009","article-title":"Myocardial fatty acid metabolism in health and disease","volume":"90","author":"Lopaschuk","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"886393","DOI":"10.3389\/fcell.2022.886393","article-title":"Energy Metabolism on Mitochondrial Maturation and Its Effects on Cardiomyocyte Cell Fate","volume":"10","author":"Persad","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"H751","DOI":"10.1152\/ajpheart.00260.2021","article-title":"Why the diabetic heart is energy inefficient: A ketogenesis and ketolysis perspective","volume":"321","author":"Mishra","year":"2021","journal-title":"Am. J. Physiology. Heart Circ. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"789458","DOI":"10.3389\/fcvm.2021.789458","article-title":"Ketone Body Metabolism in the Ischemic Heart","volume":"8","author":"Kolwicz","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Vijay, V., Han, T., Moland, C.L., Kwekel, J.C., Fuscoe, J.C., and Desai, V.G. (2015). Sexual dimorphism in the expression of mitochondria-related genes in rat heart at different ages. PloS ONE, 10.","DOI":"10.1371\/journal.pone.0117047"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jsbmb.2014.11.009","article-title":"Significant role of estrogen in maintaining cardiac mitochondrial functions","volume":"147","author":"Rattanasopa","year":"2015","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.placenta.2017.06.001","article-title":"Effects of maternal diabetes and fetal sex on human placenta mitochondrial biogenesis","volume":"57","author":"Jiang","year":"2017","journal-title":"Placenta"},{"key":"ref_39","first-page":"20192713","article-title":"Developmental programming of mitochondrial biology: A conceptual framework and review","volume":"287","author":"Gyllenhammer","year":"2020","journal-title":"Proc. Biol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"919","DOI":"10.3389\/fendo.2019.00919","article-title":"Female Heart Health: Is GPER the Missing Link?","volume":"10","author":"Groban","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/s41569-021-00569-6","article-title":"PPAR control of metabolism and cardiovascular functions","volume":"18","author":"Montaigne","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/eurheartj\/ehy903","article-title":"Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy","volume":"40","author":"Costantino","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.1172\/JCI30335","article-title":"Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice","volume":"117","author":"Son","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3389\/fcvm.2020.00002","article-title":"Multiple Levels of PGC-1\u03b1 Dysregulation in Heart Failure","volume":"7","author":"Oka","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/aps.2010.198","article-title":"17\u03b2-Estradiol inhibition of PPAR\u03b3-induced adipogenesis and adipocyte-specific gene expression","volume":"32","author":"Jeong","year":"2011","journal-title":"Acta Pharmacol. Sin"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"31292","DOI":"10.1074\/jbc.M110.147850","article-title":"Estrogen receptor-{beta}-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice","volume":"285","author":"Yepuru","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s11789-013-0056-z","article-title":"Genes and hormones: Sex differences in myocardial hypertrophy","volume":"8","author":"Seeland","year":"2013","journal-title":"Clin. Res. Cardiol. Suppl."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1006\/jmcc.2000.1304","article-title":"Differential regulation of carnitine palmitoyltransferase-I gene isoforms (CPT-I alpha and CPT-I beta) in the rat heart","volume":"33","author":"Cook","year":"2001","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.bbaexp.2004.06.006","article-title":"Peroxisomal proliferator activated receptor gamma coactivator (PGC-1alpha) stimulates carnitine palmitoyltransferase I (CPT-Ialpha) through the first intron","volume":"1679","author":"Song","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.reprotox.2014.03.013","article-title":"Hyperglycemia induces embryopathy, even in the absence of systemic maternal diabetes: An in vivo test of the fuel mediated teratogenesis hypothesis","volume":"46","author":"Baack","year":"2014","journal-title":"Reprod. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Sussman, D., van Eede, M., Wong, M.D., Adamson, S.L., and Henkelman, M. (2013). Effects of a ketogenic diet during pregnancy on embryonic growth in the mouse. BMC Pregnancy Childbirth, 13.","DOI":"10.1186\/1471-2393-13-109"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1161\/CIRCULATIONAHA.118.036459","article-title":"Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients","volume":"139","author":"Nielsen","year":"2019","journal-title":"Circulation"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1126\/science.abc8861","article-title":"Comprehensive quantification of fuel use by the failing and nonfailing human heart","volume":"370","author":"Murashige","year":"2020","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1210\/jc.2015-1884","article-title":"SGLT2 Inhibitors May Predispose to Ketoacidosis","volume":"100","author":"Taylor","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.2337\/db15-1356","article-title":"Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes","volume":"65","author":"Ferrannini","year":"2016","journal-title":"Diabetes"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Baack, M.L., Forred, B.J., Larsen, T.D., Jensen, D.N., Wachal, A.L., Khan, M.A., and Vitiello, P.F. (2016). Consequences of a Maternal High-Fat Diet and Late Gestation Diabetes on the Developing Rat Lung. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160818"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"7189","DOI":"10.1074\/jbc.M116.774471","article-title":"Quantifying intracellular rates of glycolytic and oxidative ATP production and consumption using extracellular flux measurements","volume":"292","author":"Mookerjee","year":"2017","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3684\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:32:18Z","timestamp":1760121138000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3684"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,12]]},"references-count":57,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043684"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043684","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,2,12]]}}}