{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T23:01:25Z","timestamp":1778886085290,"version":"3.51.4"},"reference-count":66,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Global Blood Therapeutics (Pfizer)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: In sickle cell disease (SCD), hepatopathy is a cumulative consequence of ischemia\/reperfusion (I\/R) injury from a vaso-occlusive crisis, tissue inflammation, and iron overload due to blood transfusion. Hepatopathy is a major contributing factor of shortened life span in SCD patients. We hypothesized that the voxelotor, a hemoglobin allosteric modifier, ameliorates sickle hepatopathy. Materials and Methods: Townes SCD mice and their controls were treated with either chow containing GBT1118, a voxelotor analog, or normal chow. We evaluated inflammation, fibrosis, apoptosis and ferroptosis in their livers using qPCR, ELISA, histology, and immunohistochemistry. Results: GBT1118 treatment resulted in reduced hemolysis, iron overload and inflammation in the liver of SCD mice. There were significant reductions in the liver enzyme levels and bile acids. Furthermore, GBT1118-treated mice exhibited reduced apoptosis, necrosis, and fibrosis. Increased ferroptosis as evident from elevated 4-hydroxynonenal (4-HNE) staining, malondialdehyde (MDA) levels, and expression of Ptgs2 and Slc7a11 mRNAs, were also significantly reduced after GBT1118 treatment. To explain the increased ferroptosis, we evaluated iron homeostasis markers in livers. SCD mice showed decreased expression of heme oxygenase-1, ferritin, hepcidin, and ferroportin mRNA levels. GBT1118 treatment significantly increased expressions of these genes. Conclusions: Our results suggest GBT1118 treatment in SCD confers the amelioration of sickle hepatopathy by reducing inflammation, fibrosis, apoptosis, iron overload and ferroptosis.<\/jats:p>","DOI":"10.3390\/medicina60101581","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T06:55:52Z","timestamp":1727333752000},"page":"1581","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["GBT1118, a Voxelotor Analog, Ameliorates Hepatopathy in Sickle Cell Disease"],"prefix":"10.3390","volume":"60","author":[{"given":"Elio","family":"Haroun","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seah H.","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8537-2515","authenticated-orcid":false,"given":"Dibyendu","family":"Dutta","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1161\/CIRCRESAHA.116.304577","article-title":"Iron, Inflammation, and Early Death in Adults With Sickle Cell Disease","volume":"116","author":"Yang","year":"2015","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"096368972110465","DOI":"10.1177\/09636897211046559","article-title":"Hematopoietic Stem Cell Transplant for Sickle Cell Disease: PATIENT SELEction and Timing Based on Sickle Cell-Related Multiple Chronic Conditions","volume":"30","author":"Jang","year":"2021","journal-title":"Cell Transpl."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/bjh.16273","article-title":"Intestinal pathophysiological and microbial changes in sickle cell disease: Potential targets for therapeutic intervention","volume":"188","author":"Dutta","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1182\/hematology.2019000037","article-title":"Management of liver complications in sickle cell disease","volume":"2019","author":"Suddle","year":"2019","journal-title":"Hematology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1111\/apt.13347","article-title":"Liver injury is associated with mortality in sickle cell disease","volume":"42","author":"Feld","year":"2015","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"272940","DOI":"10.1155\/2010\/272940","article-title":"Iron Overload in Sickle Cell Disease","volume":"2010","author":"Raghupathy","year":"2010","journal-title":"Adv. Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1002\/hep.31239","article-title":"Impaired Bile Secretion Promotes Hepatobiliary Injury in Sickle Cell Disease","volume":"72","author":"Vats","year":"2020","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1111\/bjh.14214","article-title":"GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease","volume":"175","author":"Oksenberg","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1056\/NEJMoa1903212","article-title":"A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease","volume":"381","author":"Vichinsky","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kanne, C.K., Nebor, D., Pochron, M., Oksenberg, D., and Sheehan, V.A. (2021). Rheological Impact of GBT1118 Cessation in a Sickle Mouse Model. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.742784"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1152\/japplphysiol.00079.2017","article-title":"GBT1118, a compound that increases the oxygen affinity of hemoglobin, improves survival in murine hypoxic acute lung injury","volume":"124","author":"Putz","year":"2018","journal-title":"J. Appl. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"H400","DOI":"10.1152\/ajpheart.00048.2021","article-title":"Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice","volume":"321","author":"Dufu","year":"2021","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4403","DOI":"10.1182\/bloodadvances.2022007809","article-title":"Improvement of hemolytic anemia with GBT1118 is renoprotective in transgenic sickle mice","volume":"6","author":"Ren","year":"2022","journal-title":"Blood Adv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/bjh.18813","article-title":"Effects of GBT1118, a voxelotor analog, on intestinal pathophysiology in sickle cell disease","volume":"202","author":"Haroun","year":"2023","journal-title":"Br. J. Haematol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1111\/bjh.17889","article-title":"Intestinal pathophysiological abnormalities in steady state and after vaso-occlusive crisis in murine sickle cell disease","volume":"196","author":"Poplawska","year":"2022","journal-title":"Br. J. Haematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/S0002-9343(80)80008-8","article-title":"The liver in sickle cell disease. A clinicopathologic study of 70 patients","volume":"69","author":"Bauer","year":"1980","journal-title":"Am. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1080\/17474086.2021.1893688","article-title":"Voxelotor for the treatment of sickle cell disease","volume":"14","author":"Vissa","year":"2021","journal-title":"Expert Rev. Hematol."},{"key":"ref_18","unstructured":"(2021). LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, National Institute of Diabetes and Digestive and Kidney Diseases."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.cld.2018.12.002","article-title":"The Liver in Sickle Cell Disease","volume":"23","author":"Theocharidou","year":"2019","journal-title":"Clin. Liver Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1186\/s12967-021-03074-z","article-title":"Vaso-occlusive crisis in sickle cell disease: A vicious cycle of secondary events","volume":"19","author":"Jang","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lima, B.H.F., Marques, P.E., Gomides, L.F., Mattos, M.S., Kraemer, L., Queiroz-Junior, C.M., Lennon, M., Hirsch, E., Russo, R.C., and Menezes, G.B. (2019). Converging TLR9 and PI3Kgamma signaling induces sterile inflammation and organ damage. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-55504-0"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"844","DOI":"10.4049\/jimmunol.1101736","article-title":"Regulation of the Inflammatory Response: Enhancing Neutrophil Infiltration under Chronic Inflammatory Conditions","volume":"188","author":"Bian","year":"2012","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1182\/blood.2020008455","article-title":"Excess heme upregulates heme oxygenase 1 and promotes cardiac ferroptosis in mice with sickle cell disease","volume":"139","author":"Menon","year":"2022","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1182\/blood-2013-06-427757","article-title":"The liver: Conductor of systemic iron balance","volume":"123","author":"Meynard","year":"2014","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3727\/105221617X15042750874156","article-title":"Hepatic Ischemia\/Reperfusion: Mechanisms of Tissue Injury, Repair, and Regeneration","volume":"17","author":"Konishi","year":"2017","journal-title":"Gene Expr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1182\/blood.2019002907","article-title":"Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis","volume":"136","author":"Yu","year":"2020","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"C537","DOI":"10.1152\/ajpcell.00101.2016","article-title":"4-Hydroxy-2-nonenal: A critical target in oxidative stress?","volume":"311","author":"Breitzig","year":"2016","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1002\/hep.29117","article-title":"Characterization of ferroptosis in murine models of hemochromatosis","volume":"66","author":"Wang","year":"2017","journal-title":"Hepatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4160","DOI":"10.1182\/blood.V99.11.4160","article-title":"Neutrophil activation by heme: Implications for inflammatory processes","volume":"99","author":"Arruda","year":"2002","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3818","DOI":"10.1182\/blood-2013-10-529982","article-title":"Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease","volume":"123","author":"Chen","year":"2014","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1182\/blood-2015-08-663245","article-title":"Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease","volume":"127","author":"Vinchi","year":"2016","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bozza, M.T., and Jeney, V. (2020). Pro-inflammatory Actions of Heme and Other Hemoglobin-Derived DAMPs. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01323"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E4110","DOI":"10.1073\/pnas.1405023111","article-title":"Hemolysis-induced lethality involves inflammasome activation by heme","volume":"111","author":"Dutra","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nature15367","article-title":"Neutrophil ageing is regulated by the microbiome","volume":"525","author":"Zhang","year":"2015","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Gong, J., Tu, W., Liu, J., and Tian, D. (2023). Hepatocytes: A key role in liver inflammation. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1083780"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s12967-019-1938-8","article-title":"Intestinal injury and gut permeability in sickle cell disease","volume":"17","author":"Dutta","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1182\/blood.2022015596","article-title":"Hemolysis, free hemoglobin toxicity, and scavenger protein therapeutics","volume":"140","author":"Vallelian","year":"2022","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Poillerat, V., Gentinetta, T., Leon, J., Wassmer, A., Edler, M., Torset, C., Luo, D., Tuffin, G., and Roumenina, L.T. (2020). Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01684"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2572","DOI":"10.1182\/blood-2005-03-1185","article-title":"Identification of the receptor scavenging hemopexin-heme complexes","volume":"106","author":"Hvidberg","year":"2005","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Schaer, D.J., Vinchi, F., Ingoglia, G., Tolosano, E., and Buehler, P.W. (2014). Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development. Front. Physiol., 5.","DOI":"10.3389\/fphys.2014.00415"},{"key":"ref_41","first-page":"1044","article-title":"Hemopexin deficiency promotes acute kidney injury in sickle cell disease","volume":"135","author":"Hazra","year":"2020","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1161\/CIRCULATIONAHA.112.130179","article-title":"Hemopexin Therapy Improves Cardiovascular Function by Preventing Heme-Induced Endothelial Toxicity in Mouse Models of Hemolytic Diseases","volume":"127","author":"Vinchi","year":"2013","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/bjh.12342","article-title":"Paradoxical protection from atherosclerosis and thrombosis in a mouse model of sickle cell disease","volume":"162","author":"Wang","year":"2013","journal-title":"Br. J. Haematol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41577-020-00491-x","article-title":"Regulation of inflammation by the antioxidant haem oxygenase 1","volume":"21","author":"Campbell","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1042\/BJ20120936","article-title":"Haem oxygenase-1 overexpression alters intracellular iron distribution","volume":"449","author":"Lanceta","year":"2013","journal-title":"Biochem. J."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Chiang, S.-K., Chen, S.-E., and Chang, L.-C. (2018). A Dual Role of Heme Oxygenase-1 in Cancer Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010039"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7811","DOI":"10.1074\/jbc.M008923200","article-title":"A New Mouse Liver-specific Gene, Encoding a Protein Homologous to Human Antimicrobial Peptide Hepcidin, Is Overexpressed during Iron Overload","volume":"276","author":"Pigeon","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3204","DOI":"10.1182\/blood-2006-06-027631","article-title":"Interleukin-6 induces hepcidin expression through STAT3","volume":"108","author":"Wrighting","year":"2006","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.cmet.2015.09.006","article-title":"Ironing out Ferroportin","volume":"22","author":"Drakesmith","year":"2015","journal-title":"Cell Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"19906","DOI":"10.1074\/jbc.M000713200","article-title":"A Novel Mammalian Iron-regulated Protein Involved in Intracellular Iron Metabolism","volume":"275","author":"Abboud","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Sangokoya, C., Doss, J.F., and Chi, J.-T. (2013). Iron-Responsive miR-485-3p Regulates Cellular Iron Homeostasis by Targeting Ferroportin. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003408"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1038\/nm.2507","article-title":"Ischemia and reperfusion\u2014From mechanism to translation","volume":"17","author":"Eltzschig","year":"2011","journal-title":"Nat. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/B978-0-12-394309-5.00006-7","article-title":"Cell biology of ischemia\/reperfusion injury","volume":"298","author":"Kalogeris","year":"2012","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3324\/haematol.2010.028506","article-title":"Abnormal modulation of cell protective systems in response to ischemic\/reperfusion injury is important in the development of mouse sickle cell hepatopathy","volume":"96","author":"Siciliano","year":"2011","journal-title":"Haematologica"},{"key":"ref_55","first-page":"3091","article-title":"Macrophage metabolic rewiring improves heme-suppressed efferocytosis and tissue damage in sickle cell disease","volume":"141","author":"Sharma","year":"2023","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41392-020-00428-9","article-title":"Ferroptosis: Mechanisms and links with diseases","volume":"6","author":"Yan","year":"2021","journal-title":"Sig. Transduct. Target. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41422-020-00441-1","article-title":"Ferroptosis: Molecular mechanisms and health implications","volume":"31","author":"Tang","year":"2021","journal-title":"Cell Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11455","DOI":"10.1074\/jbc.274.17.11455","article-title":"Cloning and Expression of a Plasma Membrane Cystine\/Glutamate Exchange Transporter Composed of Two Distinct Proteins","volume":"274","author":"Sato","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"L163","DOI":"10.1152\/ajplung.1989.257.4.L163","article-title":"Regulation of cellular glutathione","volume":"257","author":"Deneke","year":"1989","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Telorack, M., Meyer, M., Ingold, I., Conrad, M., Bloch, W., and Werner, S. (2016). A Glutathione-Nrf2-Thioredoxin Cross-Talk Ensures Keratinocyte Survival and Efficient Wound Repair. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005800"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/0891-5849(95)02182-5","article-title":"Lipid metabolite involvement in the activation of the human heme oxygenase-1 gene","volume":"20","author":"Tyrrell","year":"1996","journal-title":"Free Radic. Biol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3400147I","DOI":"10.1155\/2023\/3400147","article-title":"Organelle-Specific Mechanisms in Crosstalk between Apoptosis and Ferroptosis","volume":"2023","author":"Wu","year":"2023","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Yu, S., Ji, G., and Zhang, L. (2022). The role of p53 in liver fibrosis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1057829"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/s41418-022-00943-y","article-title":"p53 in ferroptosis regulation: The new weapon for the old guardian","volume":"29","author":"Liu","year":"2022","journal-title":"Cell Death Differ."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1038\/s41418-020-0528-x","article-title":"Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia\/reperfusion-induced acute lung injury","volume":"27","author":"Li","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/ajh.20809","article-title":"Morbidity and mortality in chronically transfused subjects with thalassemia and sickle cell disease: A report from the multi-center study of iron overload","volume":"82","author":"Fung","year":"2007","journal-title":"Am. J. Hematol."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/10\/1581\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:03:56Z","timestamp":1760112236000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/10\/1581"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,26]]},"references-count":66,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["medicina60101581"],"URL":"https:\/\/doi.org\/10.3390\/medicina60101581","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,26]]}}}