{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T16:35:49Z","timestamp":1771518949513,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T00:00:00Z","timestamp":1701129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CONACyT","award":["CB283225"],"award-info":[{"award-number":["CB283225"]}]},{"name":"CONACyT","award":["300520"],"award-info":[{"award-number":["300520"]}]},{"name":"CONACyT","award":["A1-S-17131"],"award-info":[{"award-number":["A1-S-17131"]}]},{"name":"CONACyT","award":["SIP20231480"],"award-info":[{"award-number":["SIP20231480"]}]},{"name":"CONACyT","award":["SIP20230613"],"award-info":[{"award-number":["SIP20230613"]}]},{"name":"CONACyT","award":["SIP20220900"],"award-info":[{"award-number":["SIP20220900"]}]},{"name":"CONACyT","award":["SIP20220742"],"award-info":[{"award-number":["SIP20220742"]}]},{"name":"CONACyT","award":["SIP20210508"],"award-info":[{"award-number":["SIP20210508"]}]},{"name":"CONACyT","award":["SIP20210700"],"award-info":[{"award-number":["SIP20210700"]}]},{"name":"SIP-IPN","award":["CB283225"],"award-info":[{"award-number":["CB283225"]}]},{"name":"SIP-IPN","award":["300520"],"award-info":[{"award-number":["300520"]}]},{"name":"SIP-IPN","award":["A1-S-17131"],"award-info":[{"award-number":["A1-S-17131"]}]},{"name":"SIP-IPN","award":["SIP20231480"],"award-info":[{"award-number":["SIP20231480"]}]},{"name":"SIP-IPN","award":["SIP20230613"],"award-info":[{"award-number":["SIP20230613"]}]},{"name":"SIP-IPN","award":["SIP20220900"],"award-info":[{"award-number":["SIP20220900"]}]},{"name":"SIP-IPN","award":["SIP20220742"],"award-info":[{"award-number":["SIP20220742"]}]},{"name":"SIP-IPN","award":["SIP20210508"],"award-info":[{"award-number":["SIP20210508"]}]},{"name":"SIP-IPN","award":["SIP20210700"],"award-info":[{"award-number":["SIP20210700"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Candida glabrata and Candida albicans, the most frequently isolated candidiasis species in the world, have developed mechanisms of resistance to treatment with azoles. Among the clinically used antifungal drugs are statins and other compounds that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), resulting in decreased growth and ergosterol levels in yeasts. Ergosterol is a key element for the formation of the yeast cell membrane. However, statins often cause DNA damage to yeast cells, facilitating mutation and drug resistance. The aim of the current contribution was to synthesize seven series of compounds as inhibitors of the HMGR enzyme of Candida ssp., and to evaluate their effect on cellular growth, ergosterol synthesis and generation of petite mutants of C. glabrata and C. albicans. Compared to the reference drugs (fluconazole and simvastatin), some HMGR inhibitors caused lower growth and ergosterol synthesis in the yeast species and generated fewer petite mutants. Moreover, heterologous expression was achieved in Pichia pastoris, and compounds 1a, 1b, 6g and 7a inhibited the activity of recombinant CgHMGR and showed better binding energy values than for \u03b1-asarone and simvastatin. Thus, we believe these are good candidates for future antifungal drug development.<\/jats:p>","DOI":"10.3390\/ijms242316868","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T06:45:35Z","timestamp":1701153935000},"page":"16868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Inhibitors of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Decrease the Growth, Ergosterol Synthesis and Generation of petite Mutants in Candida glabrata and Candida albicans"],"prefix":"10.3390","volume":"24","author":[{"given":"Dulce","family":"Andrade-Pav\u00f3n","sequence":"first","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular de Bacterias y Levaduras, Departamento de Microbiolog\u00eda, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Prolongaci\u00f3n de Carpio y Plan de Ayala S\/N, Col. Santo Tom\u00e1s, Alc. Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6083-4651","authenticated-orcid":false,"given":"Eugenia","family":"S\u00e1nchez-Sandoval","sequence":"additional","affiliation":[{"name":"Core Facilities Department, Gothenburg University, Medicinaregatan 9 A-B, 41390 G\u00f6teborg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joaqu\u00edn","family":"Tamariz","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Prolongaci\u00f3n de Carpio y Plan de Ayala S\/N, Col. Santo Tom\u00e1s, Alc. Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5016-0622","authenticated-orcid":false,"given":"Jose Antonio","family":"Ibarra","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Microbiana, Departamento de Microbiolog\u00eda, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Prolongaci\u00f3n de Carpio y Plan de Ayala S\/N, Col. Santo Tom\u00e1s, Alc. Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2411-9789","authenticated-orcid":false,"given":"C\u00e9sar","family":"Hern\u00e1ndez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular de Bacterias y Levaduras, Departamento de Microbiolog\u00eda, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Prolongaci\u00f3n de Carpio y Plan de Ayala S\/N, Col. Santo Tom\u00e1s, Alc. Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0055-2991","authenticated-orcid":false,"given":"Lourdes","family":"Villa-Tanaca","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular de Bacterias y Levaduras, Departamento de Microbiolog\u00eda, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Prolongaci\u00f3n de Carpio y Plan de Ayala S\/N, Col. Santo Tom\u00e1s, Alc. Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1128\/JCM.39.9.3254-3259.2001","article-title":"International surveillance of bloodstream infections due to Candida species: Frequency of occurrence and in vitro susceptibilities to fluconazole, ravuconazole, and voriconazole of isolates collected from 1997 through 1999 in the SENTRY antimicrobial surveillance program","volume":"39","author":"Pfaller","year":"2001","journal-title":"J. Clin. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1128\/CMR.00029-06","article-title":"Epidemiology of invasive candidiasis: A persistent public health problem","volume":"20","author":"Pfaller","year":"2007","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1128\/JCM.42.10.4419-4431.2004","article-title":"Rare an emerging opportunistic fungal pathogens: Concern for resistance beyond Candida albicans and Aspergillus fumigatus","volume":"42","author":"Pfaller","year":"2004","journal-title":"J. Clin. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9272","DOI":"10.1073\/pnas.142101099","article-title":"Gene order evolution and paleopolyploidy in hemiascomycete yeast","volume":"99","author":"Wong","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1128\/AAC.50.4.1384-1392.2006","article-title":"Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants","volume":"50","author":"Tsai","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","first-page":"23","article-title":"Antifungal resistance: An emerging problem in Mexico","volume":"144","year":"2008","journal-title":"Gac. Med. Mex."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1091\/mbc.7.5.769","article-title":"Different subcellular localization of Saccharomyces cerevisiae HMG-CoA reductase isoenzymes at elevated levels corresponds to distinct endoplasmic reticulum membrane proliferations","volume":"7","author":"Koning","year":"1996","journal-title":"Mol. Biol. Cell."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1002\/(SICI)1097-0061(19960915)12:11<1107::AID-YEA992>3.0.CO;2-E","article-title":"Molecular, functional and evolutionary characterization of the gene encoding HMG-CoA reductase in the fission yeast, Schizosaccharomyces pombe","volume":"12","author":"Lum","year":"1996","journal-title":"Yeast"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1567-1364.2006.00194.x","article-title":"Simvastatin reduces ergosterol levels, inhibits growth and causes loss of mtDNA in Candida glabrata","volume":"7","author":"Westermayer","year":"2007","journal-title":"FEMS. Yeast Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1128\/jb.120.2.779-784.1974","article-title":"Effect of altered sterol composition on growth characteristics of Saccharomyces cerevisiae","volume":"120","author":"Thompson","year":"1990","journal-title":"J. Bacteriol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1128\/jb.145.3.1325-1333.1981","article-title":"Corresponding changes in kynurenine hydroxylase activity, membrane fluidity, and sterol composition in Saccharomyces cerevisiae mitochondria","volume":"145","author":"Parks","year":"1981","journal-title":"J. Bacteriol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1128\/AAC.41.4.850","article-title":"In vitro activity of fluvastatin, a cholesterol-lowering agent, and syntergy with fluconazole and itraconazole against Candida species and Cryptococcus neoformans","volume":"41","author":"Chin","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1099\/0022-1317-51-2-105","article-title":"Effect of fluvastatin and pravastatin, HMG-CoA reductase inhibitors, on fluconazole activity against Candida albicans","volume":"51","author":"Nash","year":"2002","journal-title":"J. Med. Microbiol."},{"key":"ref_14","first-page":"16","article-title":"The effect of lovastatin on sterol synthesis and yeast resistance to polyene antibiotics","volume":"38","author":"Kreiner","year":"1993","journal-title":"Antibiot. Khimioter."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"455","DOI":"10.2174\/156800605774962086","article-title":"Cholesterol absortion blockade with ezetimibe","volume":"5","author":"Toth","year":"2005","journal-title":"Curr. Drug Targets Cardiovasc. Haematol. Disord."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.bcp.2006.01.016","article-title":"Hydroxymethylglutaryl-coenzyme A reductase inhibitors induce apoptosis in human cardiac myocytes in vitro","volume":"71","author":"Demyanets","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1016\/j.bcp.2004.02.037","article-title":"Apoptotic injury in cultured human hepatocytes induced by HMG-CoA reductase inhibitors","volume":"67","author":"Kubota","year":"2004","journal-title":"Biochem. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4238","DOI":"10.1016\/j.bmc.2010.04.096","article-title":"Design, synthesis, and docking of highly hypolipidemic agents: Schizosaccharomyces pombe as a new model for evaluating hypolipidemic activity of a-asarone-based HMG-CoA reductase inhibitors","volume":"18","author":"Mendieta","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5871","DOI":"10.1016\/j.bmc.2014.09.022","article-title":"Synthesis and highly potent hypolipidemic activity of alpha-asarone- and fibrate-based 2-acyl and 2-alkyl phenols as HMG-CoA reductase inhibitors","volume":"22","author":"Mendieta","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.riam.2013.10.004","article-title":"The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi (HMGRf): A proposal as a therapeutic target and as a study model","volume":"31","author":"Ibarra","year":"2014","journal-title":"Rev. Iberoam. Micol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e01642-21","DOI":"10.1128\/spectrum.01642-21","article-title":"Antifungal activity of fibrate-based compounds and substituted pyrroles that inhibit the enzyme 3-hydroxy-methyl-glutaryl-CoA reductase of Candida glabrata (CgHMGR), thus decreasing yeast viability and ergosterol synthesis","volume":"10","author":"Escalante","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1007\/s12010-017-2412-9","article-title":"Recombinant 3-hydroxy 3-methyl glutaryl-CoA reductase from Candida glabrata (Rec-CgHMGR) obtained by heterologous expression, as a novel therapeutic target model for testing synthetic drugs","volume":"182","author":"Ibarra","year":"2017","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jbiotec.2019.01.008","article-title":"Inhibition of recombinant enzyme 3-hydroxy-3-methylglutaryl-CoA reductase from Candida glabrata by \u03b1-asarone-based synthetic compounds as antifungal agents","volume":"292","author":"Tamariz","year":"2019","journal-title":"J. Biotechnol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/nrd1552","article-title":"Functional genomics to new drug targets","volume":"3","author":"Kramer","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1078\/0944-7113-00274","article-title":"Alpha-asarone inhibits HMG-CoA reductase, lowers serum LDL-cholesterol levels and reduces biliary CSI in hypercholesterolemic rats","volume":"10","author":"Baeza","year":"2003","journal-title":"Phytomedicine"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Friesen, J.A., and Rodwell, V.W. (2004). The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases. Genome Biol., 5.","DOI":"10.1186\/gb-2004-5-11-248"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1021\/ci500588j","article-title":"Data warrior: An open-source program for chemistry aware data visualization and analysis","volume":"55","author":"Sander","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1099\/0022-1317-49-11-977","article-title":"In-vivo selection of an azole-resistant petite mutant of Candida glabrata","volume":"49","author":"Bouchara","year":"2000","journal-title":"J. Med. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3332","DOI":"10.1128\/JCM.37.10.3332-3337.1999","article-title":"Quantitation of ergosterol content: Novel method for determination of fluconazole susceptibility of Candida albicans","volume":"37","author":"Jadi","year":"1999","journal-title":"J. Clin. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1128\/AAC.34.9.1660","article-title":"Effects of lovastatin (mevinolin) on sterol levels and on activity of azoles in Saccharomyces cerevisiae","volume":"34","author":"Lorenz","year":"1990","journal-title":"Antimicrob. Agents. Chemother."},{"key":"ref_31","first-page":"3","article-title":"The growth of Rhodotorula rubra yeasts and their synthesis of ergosterol on media with lovastatin","volume":"41","author":"Baranova","year":"1996","journal-title":"Antibiot. Khimioter."},{"key":"ref_32","first-page":"3","article-title":"Lovastatin effect on ergosterol production and growth of Tolypocladium inflatum 106","volume":"49","author":"Bibikova","year":"2004","journal-title":"Antibiot. Khimioter."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.riam.2018.05.004","article-title":"Simvastatin and other inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase of Ustilago maydis (Um-Hmgr) affect the viability of the fungos, its synthesis of sterols and noting","volume":"36","author":"Mendieta","year":"2019","journal-title":"Rev. Iberoam. Micol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/0278-6915(84)90196-0","article-title":"Metabolism of anethole. I. Pathways of metabolism in the rat and mouse","volume":"22","author":"Sangster","year":"1984","journal-title":"Food Chem. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1080\/10425170500226474","article-title":"Cloning and sequence analysis of myostatin promoter in sheep","volume":"16","author":"Du","year":"2005","journal-title":"DNA Seq."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1093\/bioinformatics\/14.4.378","article-title":"SOSUI: Classification and secondary structure prediction system for membrane protein","volume":"14","author":"Hirokawa","year":"1998","journal-title":"Bioinformatics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0968-0004(98)01336-X","article-title":"PSORT: A program for detecting the sorting signals of proteins and predicting their subcellular localization","volume":"24","author":"Nakai","year":"1999","journal-title":"Trends Biochem. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1093\/nar\/gks1067","article-title":"New and continuing developments at PROSITE","volume":"41","author":"Sigrist","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3644","DOI":"10.1128\/AAC.46.11.3644-3647.2002","article-title":"Comparative evaluation of NCCLS M27-A and EUCAST broth microdilution procedures for antifungal susceptibility testing of Candida species","volume":"46","author":"Ciblak","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1093\/jac\/dki402","article-title":"Antimicrobial peptides enhance the candidacidal activity of antifungal drugs by promoting the efflux of ATP from Candida cells","volume":"57","author":"Tanida","year":"2006","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1128\/AAC.48.5.1600-1613.2004","article-title":"Functional genomic analysis of fluconazole susceptibility in the pathogenic yeast Candida glabrata: Roles of calcium signaling and mitochondria","volume":"48","author":"Kaur","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_42","unstructured":"Sambrook, J., Fritsch, E.F., and Maniatis, T. (1989). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/227680a0","article-title":"Cleavage of structural proteins during the assembly of the head of bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1128\/jb.178.1.19-23.1996","article-title":"3-Hydroxy-3-methylglutaryl-coenzyme A reductase from Haloferax volcanii: Purification, characterization, and expression in Escherichia coli","volume":"178","author":"Bischoff","year":"1995","journal-title":"J. Bacteriol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"Autodock4 and AutoDockTools4: Automated docking with selective receptor flexiblity","volume":"16","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_47","first-page":"5","article-title":"Comparative protein structure modeling using Modeller","volume":"54","author":"Webb","year":"2014","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminf."},{"key":"ref_49","unstructured":"Biovia, D.S. (2017). BIOVIA Pipeline Pilot, Dassault Syst\u00e8mes."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16868\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:32:29Z","timestamp":1760131949000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16868"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,28]]},"references-count":49,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242316868"],"URL":"https:\/\/doi.org\/10.3390\/ijms242316868","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,28]]}}}