{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T05:57:36Z","timestamp":1777096656997,"version":"3.51.4"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,18]],"date-time":"2023-02-18T00:00:00Z","timestamp":1676678400000},"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>Sodium\u2013glucose cotransporter type 2 inhibitors (SGLT2i) are glycosuric drugs that were originally developed for the treatment of type 2 diabetes mellitus (T2DM). There is a hypothesis that SGLT2i are drugs that are capable of increasing ketone bodies and free fatty acids. The idea is that they could serve as the necessary fuel, instead of glucose, for the purposes of cardiac muscle requirements and could explain antihypertensive effects, which are independent of renal function. The adult heart, under normal conditions, consumes around 60% to 90% of the cardiac energy that is derived from the oxidation of free fatty acids. In addition, a small proportion also comes from other available substrates. In order to meet energy demands with respect to achieving adequate cardiac function, the heart is known to possess metabolic flexibility. This allows it to switch between different available substrates in order to obtain the energy molecule adenosine triphosphate (ATP), thereby rendering it highly adaptive. It must be noted that oxidative phosphorylation in aerobic organisms is the main source of ATP, which is a result of reduced cofactors. These cofactors include nicotine adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which are the result of electron transfer and are used as the enzymatic cofactors that are involved in the respiratory chain. When there is an excessive increase in energy nutrients\u2014such as glucose and fatty acids\u2014which occur in the absence of a parallel increase in demand, a state of nutrient surplus (which is better known as an excess in supply) is created. The use of SGLT2i at the renal level has also been shown to generate beneficial metabolic alterations, which are obtained by reducing the glucotoxicity that is induced by glycosuria. Together with the reduction in perivisceral fat in various organs, such alterations also lead to the use of free fatty acids in the initial stages of the affected heart. Subsequently, this results in an increase in production with respect to ketoacids, which are a more available energy fuel at the cellular level. In addition, even though their mechanism is not fully understood, their vast benefits render them of incredible importance for the purposes of further research.<\/jats:p>","DOI":"10.3390\/ijms24044144","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T04:28:57Z","timestamp":1676867337000},"page":"4144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Renal and Cardiovascular Metabolic Impact Caused by Ketogenesis of the SGLT2 Inhibitors"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3203-3400","authenticated-orcid":false,"given":"Ariana P.","family":"Vargas-Delgado","sequence":"first","affiliation":[{"name":"AtheroThrombosis Research Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA"},{"name":"Instituto Ecuatoriano del Coraz\u00f3n (IECOR), Guayaquil 090513, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Estefania","family":"Arteaga Herrera","sequence":"additional","affiliation":[{"name":"Instituto Ecuatoriano del Coraz\u00f3n (IECOR), Guayaquil 090513, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0544-4255","authenticated-orcid":false,"given":"Cesar","family":"Tumbaco Mite","sequence":"additional","affiliation":[{"name":"Instituto Ecuatoriano del Coraz\u00f3n (IECOR), Guayaquil 090513, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Delgado Cedeno","sequence":"additional","affiliation":[{"name":"Instituto Ecuatoriano del Coraz\u00f3n (IECOR), Guayaquil 090513, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Cristina","family":"Van Loon","sequence":"additional","affiliation":[{"name":"Instituto Ecuatoriano del Coraz\u00f3n (IECOR), Guayaquil 090513, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6780-8771","authenticated-orcid":false,"given":"Juan J.","family":"Badimon","sequence":"additional","affiliation":[{"name":"AtheroThrombosis Research Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,18]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1056\/NEJMoa1812389","article-title":"Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes","volume":"380","author":"Wiviott","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_3","first-page":"547","article-title":"Glucotransportadores (GLUT): Aspectos cl\u00ed-nicos, moleculares y gen\u00e9ticos","volume":"152","year":"2016","journal-title":"Gac. M\u00e9dica M\u00e9xico"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.4067\/S0034-98872010000800014","article-title":"Metabolismo energ\u00e9tico del coraz\u00f3n y sus proyecciones en el tratamiento de la insuficiencia card\u00edaca","volume":"138","author":"Castro","year":"2010","journal-title":"Rev. M\u00e9d. Chile"},{"key":"ref_5","first-page":"924","article-title":"Efecto cardiometab\u00f3lico de los inhibidores del cotransportador sodio glucosa tipo 2 (SGLT2)","volume":"34","year":"2019","journal-title":"Med. Interna M\u00e9xico"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.jacc.2019.11.031","article-title":"Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC state-of-the-art review","volume":"75","author":"Zelniker","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","first-page":"503","article-title":"iS-GLT2 y su potencial efecto nefroprotector en pacientes con diabetes mellitus 2","volume":"33","year":"2017","journal-title":"Med. Interna M\u00e9xico"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1007\/s00125-018-4656-5","article-title":"Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2","volume":"61","author":"Ghezzi","year":"2018","journal-title":"Diabetologia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1007\/s00424-020-02444-8","article-title":"Glucose transporters in cardiovascular system in health and disease","volume":"472","author":"Bertrand","year":"2020","journal-title":"Pflugers Arch."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.yjmcc.2018.01.017","article-title":"Decreased ATP production and myocardial contractile reserve in metabolic heart disease","volume":"116","author":"Luptak","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.2337\/dc16-0330","article-title":"CV Protection in the EMPA-REG outcome Trial: A \u201cThrifty Substrate\u201d Hypothesis","volume":"39","author":"Ferrannini","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_12","unstructured":"K\u00f6hler, F.B., Bevacqua, R.J., and Perrone, S.V. (2022, November 30). Inhibidores del Cotransportador de Sodio-Glucosa Tipo 2 en la Insuficiencia Card\u00edaca. Available online: http:\/\/www.insuficienciacardiaca.org\/pdf\/v16n4_21\/v16n4a02.pdf."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Ropero, \u00c1., Vargas-Delgado, A.P., Santos-Gallego, C.G., and Badimon, J.J. (2019). Inhibition of Sodium Glucose Cotransporters Improves Cardiac Performance. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133289"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1093\/cvr\/cvz104","article-title":"Ketone body can be a fuel substrate for failing heart","volume":"115","author":"Nakamura","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12968-018-0491-6","article-title":"Cardiac work is related to creatine kinase energy supply in human heart failure: A cardiovascular magnetic resonance spectroscopy study","volume":"20","author":"Gabr","year":"2018","journal-title":"J. Cardiovasc. Magn. Reson."},{"key":"ref_16","first-page":"218","article-title":"Cambios en el metabolismo card\u00edaco y su posible aprovechamiento en la terap\u00e9utica (Parte I)","volume":"73","author":"Guarner","year":"2003","journal-title":"Arch. Cardiol. M\u00e9xico"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3293","DOI":"10.1074\/jbc.M608337200","article-title":"Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricar-boxylic acid cycle intermediates","volume":"282","author":"Hewitson","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4524","DOI":"10.1074\/jbc.M610415200","article-title":"Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: Possible links between cell metabolism and stabilization of HIF","volume":"282","author":"Koivunen","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"41928","DOI":"10.1074\/jbc.M508718200","article-title":"Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1","volume":"280","author":"Lu","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.cmet.2015.08.007","article-title":"PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer","volume":"22","author":"Dupuy","year":"2015","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11635","DOI":"10.1038\/ncomms11635","article-title":"HIF-1alpha-PDK1 axis-induced active glycolysis plays an essential role in macrophage mi-gratory capacity","volume":"7","author":"Semba","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.cmet.2006.02.002","article-title":"HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia","volume":"3","author":"Kim","year":"2006","journal-title":"Cell Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"32529","DOI":"10.1074\/jbc.271.51.32529","article-title":"Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1","volume":"271","author":"Semenza","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/ejhf.1320","article-title":"Treating oxidative stress in heart failure: Past, present and future: Treating oxidative stress in heart failure","volume":"21","author":"Voors","year":"2019","journal-title":"Eur. J. Heart Fail."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"523.e1","DOI":"10.1016\/j.recesp.2021.11.027","article-title":"Gu\u00eda ESC 2021 sobre el diagn\u00f3stico y tratamiento de la insuficiencia cardiaca aguda y cr\u00f3nica","volume":"75","author":"McDonagh","year":"2022","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1056\/NEJMoa1611925","article-title":"Canvas","volume":"377","author":"Neal","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s10557-018-06850-0","article-title":"Rationale and Design of the EMPA-TROPISM Trial (ATRU-4): Are the \u201cCardiac Benefits\u201d of Empagliflozin Independent of its Hypoglycemic Activity?","volume":"33","author":"Mancini","year":"2019","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1161\/CIRCULATIONAHA.117.030117","article-title":"Class Effect for Sodium Glucose-Cotransporter-2 Inhibitors in Cardiovascular Outcomes","volume":"137","author":"Bethel","year":"2018","journal-title":"Circulation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/S2213-8587(18)30141-4","article-title":"Canagliflozin and renal outcomes in type 2 diabetes: Results from the CANVAS Program randomised clinical trials","volume":"6","author":"Perkovic","year":"2018","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_30","first-page":"243","article-title":"Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction","volume":"77","author":"Mancini","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1056\/NEJMoa2022190","article-title":"Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure","volume":"383","author":"Packer","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1161\/CIRCULATIONAHA.122.059755","article-title":"Effects of Empagliflozin in Women and Men with Heart Failure and Preserved Ejection Fraction","volume":"146","author":"Butler","year":"2022","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fneph.2022.867075","article-title":"SGLT2 Inhibitors: A Broad Impact Therapeutic Option for the Nephrologist","volume":"2","author":"Granata","year":"2022","journal-title":"Front. Nephrol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"145","DOI":"10.18566\/medupb.v41n2.a07","article-title":"Evidencia molecular y cl\u00ednica del beneficio cardiovascular de los inhibidores SGLT2: Estado del arte","volume":"41","author":"Negrete","year":"2022","journal-title":"Med. UPB"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1007\/s00125-018-4670-7","article-title":"SGLT2 inhibitors and mechanisms of cardiovascular benefit: A state-of-the-art review","volume":"61","author":"Verma","year":"2018","journal-title":"Diabetologia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e016173","DOI":"10.1161\/JAHA.119.016173","article-title":"Acute and Chronic Effects of SGLT2 Inhibitor Empagliflozin on Renal Oxygenation and Blood Pressure Control in Nondiabetic Normotensive Subjects: A Randomized, Placebo-Controlled Trial","volume":"9","author":"Zanchi","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_38","first-page":"e26313","article-title":"A Systematic Review of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors and Sympathetic Nervous System Inhibition: An Underrated Mechanism of Cardiorenal Protection","volume":"14","author":"Raza","year":"2022","journal-title":"Cureus"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"E40","DOI":"10.1093\/eurheartj\/suab094","article-title":"Surprises in cardiology: Efficacy of gliflozines in heart failure even in the absence of diabetes","volume":"23","author":"Bragagni","year":"2021","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"112515","DOI":"10.1016\/j.biopha.2021.112515","article-title":"Empagliflozin reduces oxidative stress through inhibition of the novel inflammation\/NHE\/[Na+]c\/ROS-pathway in human endothelial cells","volume":"146","author":"Uthman","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.2174\/0929867324666170710121145","article-title":"Metabolic Syndrome: Sex-Related Cardiovascular Risk and Therapeutic Approach","volume":"24","author":"Santilli","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"107841","DOI":"10.1016\/j.jdiacomp.2020.107841","article-title":"Sex-related differences in diabetic kidney disease: A review on the mechanisms and potential therapeutic implications","volume":"35","author":"Piani","year":"2021","journal-title":"J. Diabetes Complicat."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.cmet.2020.06.020","article-title":"SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition","volume":"32","author":"Tomita","year":"2020","journal-title":"Cell Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1056\/NEJMoa2024816","article-title":"Dapagliflozin in Patients with Chronic Kidney Disease","volume":"383","author":"Heerspink","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.kint.2022.06.008","article-title":"KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease","volume":"102","author":"Rossing","year":"2022","journal-title":"Kidney Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.2337\/dc16-0542","article-title":"Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis","volume":"39","author":"Mudaliar","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1161\/CIRCULATIONAHA.122.060805","article-title":"SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism","volume":"146","author":"Mayr","year":"2022","journal-title":"Circulation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1093\/cvr\/cvz045","article-title":"Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency","volume":"115","author":"Ho","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2017.04.011","article-title":"Sodium-Glucose Co-transporters and Their Inhibition: Clinical Physiology","volume":"26","author":"Ferrannini","year":"2017","journal-title":"Cell Metab."},{"key":"ref_50","first-page":"22","article-title":"Mecanismos de acci\u00f3n de los inhibidores de cotransportador de sodio y glucosa tipo 2 \u2014SGLT2\u2014: M\u00e1s all\u00e1 del control de la glicemia","volume":"27","year":"2020","journal-title":"Rev. Colomb. Cardiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1016\/j.jacc.2019.01.056","article-title":"Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics","volume":"73","author":"Antonio","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.jacbts.2018.07.006","article-title":"Empagliflozin Increases Cardiac Energy Production in Diabetes: Novel translational insights into the heart failure benefits of SGLT2 inhibitors","volume":"3","author":"Verma","year":"2018","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_53","first-page":"363","article-title":"Inhibidores del cotransportador de sodio y glucosa tipo 2 (SGLT2), el ri\u00f1\u00f3n como objetivo en el control gluc\u00e9mico de la diabetes mellitus tipo 2","volume":"33","year":"2017","journal-title":"Med. Interna M\u00e9xico"},{"key":"ref_54","first-page":"1","article-title":"Documento de consenso sobre el uso de los iSGLT2 en el tratamiento de pacientes con diabetes mellitus tipo 2","volume":"158","year":"2022","journal-title":"Gac. Med. Mex."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1136\/heartjnl-2020-318060","article-title":"Sodium-glucose co-transporter 2 inhibitor therapy: Mechanisms of action in heart failure","volume":"107","author":"Joshi","year":"2021","journal-title":"Heart"},{"key":"ref_56","first-page":"618","article-title":"Inhibidores del cotransportador sodio-glucosa tipo 2 (SGLT2): De la glucosuria renal familiar al tratamiento de la diabetes mellitus tipo 2","volume":"30","year":"2010","journal-title":"Nefrolog\u00eda"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Gliflozinas: M\u00e1s Que Antidiab\u00e9ticos Orales (2021). Una Breve Revisi\u00f3n de la Literatura. Rev. Urug. Cardiol., 36, e3611.","DOI":"10.29277\/cardio.36.1.14"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.medcli.2019.05.028","article-title":"Efecto de dapagliflozina sobre la rigidez arterial en pacientes con diabetes mellitus tipo 2","volume":"154","year":"2020","journal-title":"Med. Cl\u00ednica"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/4144\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:36:14Z","timestamp":1760121374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/4144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,18]]},"references-count":58,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24044144"],"URL":"https:\/\/doi.org\/10.3390\/ijms24044144","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,18]]}}}