{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:03:13Z","timestamp":1760148193209,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Social Fund","award":["09.33-LMT-K-712","DOTSUT-43\/09.3.3.-LMT-K71201-0058\/LSS-600000-58"],"award-info":[{"award-number":["09.33-LMT-K-712","DOTSUT-43\/09.3.3.-LMT-K71201-0058\/LSS-600000-58"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>3-Amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) and other heteroaromatic N-oxides (ArN\u2192O) exhibit tumoricidal, antibacterial, and antiprotozoal activities. Their action is attributed to the enzymatic single-electron reduction to free radicals that initiate the prooxidant processes. In order to clarify the mechanisms of aerobic mammalian cytotoxicity of ArN\u2192O, we derived a TPZ-resistant subline of murine hepatoma MH22a cells (resistance index, 5.64). The quantitative proteomic of wild-type and TPZ-resistant cells revealed 5818 proteins, of which 237 were up- and 184 down-regulated. The expression of the antioxidant enzymes aldehyde- and alcohol dehydrogenases, carbonyl reductases, catalase, and glutathione reductase was increased 1.6\u20135.2 times, whereas the changes in the expression of glutathione peroxidase, superoxide dismutase, thioredoxin reductase, and peroxiredoxins were less pronounced. The expression of xenobiotics conjugating glutathione-S-transferases was increased by 1.6\u20132.6 times. On the other hand, the expression of NADPH:cytochrome P450 reductase was responsible for the single-electron reduction in TPZ and for the 2.1-fold decrease. These data support the fact that the main mechanism of action of TPZ under aerobic conditions is oxidative stress. The unchanged expression of intranuclear antioxidant proteins peroxiredoxin, glutaredoxin, and glutathione peroxidase, and a modest increase in the expression of DNA damage repair proteins, tend to support non-site-specific but not intranuclear oxidative stress as a main factor of TPZ aerobic cytotoxicity.<\/jats:p>","DOI":"10.3390\/ijms24076863","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T09:26:01Z","timestamp":1680773161000},"page":"6863","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Redox Proteomic Profile of Tirapazamine-Resistant Murine Hepatoma Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Au\u0161ra","family":"Nemeikait\u0117-\u010c\u0117nien\u0117","sequence":"first","affiliation":[{"name":"State Research Institute Center for Innovative Medicine, Santari\u0161ki\u0173 St. 5, LT-08406 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5608-9062","authenticated-orcid":false,"given":"Per","family":"Haberkant","sequence":"additional","affiliation":[{"name":"Proteomics Core Facility EMBL Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dalius","family":"Ku\u010diauskas","sequence":"additional","affiliation":[{"name":"Department of Xenobiotics Biochemistry, Institute of Biochemistry of Vilnius University, Saul\u0117tekio 7, LT-10257 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9695-1692","authenticated-orcid":false,"given":"Frank","family":"Stein","sequence":"additional","affiliation":[{"name":"Proteomics Core Facility EMBL Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Narimantas","family":"\u010c\u0117nas","sequence":"additional","affiliation":[{"name":"Department of Xenobiotics Biochemistry, Institute of Biochemistry of Vilnius University, Saul\u0117tekio 7, LT-10257 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1042\/bss0610171","article-title":"Radicals from one-electron reduction of nitro compounds, aromatic N-oxides and quinones: The kinetic basis for hypoxia-selective, bioreductive drugs","volume":"61","author":"Wardman","year":"1995","journal-title":"Biochem. Soc. Symp."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6047","DOI":"10.1021\/jm300123s","article-title":"Discovery and optimization of benzotriazine di-N-oxides targeting replicating and nonreplicating Mycobacterium tuberculosis","volume":"55","author":"Chopra","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/1574-6968.12223","article-title":"The anticancer drug tirapazamine has antimicrobial activity against Escherichia coli, Staphylococcus aureus and Clostridium difficile","volume":"347","author":"Shah","year":"2013","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s12936-019-2825-8","article-title":"Primaquine-quinoxaline 1,4-di-N-oxide hybrids with action of exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species","volume":"18","author":"Galiano","year":"2019","journal-title":"Malaria J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1111\/cbdd.13921","article-title":"Current status of quinoxaline and quinoxaline 1,4-di-N-oxides derivatives as potential antiparasitic drugs","volume":"98","year":"2021","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1021\/acs.chemrestox.9b00036","article-title":"Enzyme-activated generation of reactive oxygen species from heterocyclic N-oxides under aerobic and anaerobic conditions and its relevance to hypoxia-selective prodrugs","volume":"32","author":"Shen","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Nemeikait\u0117-\u010c\u0117nien\u0117, A., \u0160arlauskas, J., Jonu\u0161ien\u0117, V., Marozien\u0117, A., Misevi\u010dien\u0117, L., Yantsevich, A.V., and \u010c\u0117nas, N. (2019). Kinetics of flavoenzyme-catalyzed reduction of tirapazamine derivatives: Implications for their prooxidant cytotoxicity. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184602"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1021\/ja908689f","article-title":"Characterization of radicals formed following enzymatic reduction of 3-substituted analogues of the hypoxia-selective cytotoxin 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine)","volume":"132","author":"Shinde","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1021\/acs.chemrestox.6b00133","article-title":"Radical chemistry and cytotoxicity of bioreductive 3-substituted quinoxaline di-N-oxides","volume":"29","author":"Anderson","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1021\/tx2004213","article-title":"DNA strand cleavage by the phenazine di-N-oxide natural product myxin under both aerobic and anaerobic conditions","volume":"12","author":"Chowdhury","year":"2012","journal-title":"Chem. Res. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1021\/jo001232j","article-title":"3-Amino-1,2,4-benzotriazine 4-oxide: Characterization of a new metabolite arising from bioreductive processing of the antitumour agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine)","volume":"66","author":"Fuchs","year":"2001","journal-title":"J. Org. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3711","DOI":"10.1016\/j.bmc.2004.04.013","article-title":"Synthesis and anticancer activity evaluation of new 2-alkylcarbonyl and 2-benzoyl-1-trifluoromethyl-quinoxaline-1,4-di-N-oxide derivatives","volume":"12","author":"Zarranz","year":"2004","journal-title":"Bioorg. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9683","DOI":"10.3390\/molecules17089683","article-title":"Synthesis and biological evaluation of 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives as hypoxic selective anti-tumour agents","volume":"17","author":"Hu","year":"2012","journal-title":"Molecules"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"531","DOI":"10.3389\/fphar.2017.00531","article-title":"Reductive metabolism influences the toxicity and pharmacokinetics of the hypoxia-targeted benzotriazine di-oxide anticancer agent SN30000 in mice","volume":"8","author":"Gu","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.tox.2010.12.001","article-title":"Metabolites and JAK\/DTAT pathway were involved in the liver and spleen damage in male Wistar rats fed with mequindox","volume":"280","author":"Wang","year":"2011","journal-title":"Toxicology"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cheng, G., Li, B., Wang, X., Zhang, H., Liang, G., Weng, Z., Hao, H., Wang, X., Liu, Z., and Dai, M. (2015). Systematic and molecular basis of the antibacterial action of quinoxaline 1,4-di-N-oxides against Escherichia coli. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136450"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"887647","DOI":"10.3389\/fcimb.2022.887647","article-title":"Proteomic and functional analysis of the effects of quinoxaline derivatives on Entamoeba histolytica","volume":"12","author":"Marchat","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1038\/bjc.1997.558","article-title":"Overexpression of human NADPH:cytochrome c (P450) reductase confers enhanced sensitivity to both tirapazamine (SR 4233) and RSU 1069","volume":"76","author":"Patterson","year":"1997","journal-title":"Br. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4211","DOI":"10.1158\/0008-5472.CAN-15-1107","article-title":"Identification of P450 reductase as a major determinant of sensitivity to hypoxia-activated prodrugs","volume":"75","author":"Hunter","year":"2015","journal-title":"Cancer Res."},{"key":"ref_20","first-page":"2098","article-title":"Tirapazamine is metabolized to its DNA-damaging radical by intranuclear enzymes","volume":"58","author":"Evans","year":"1998","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/S0006-2952(01)00784-5","article-title":"Metabolism of tirapazamine by multiple reductases in the nucleus","volume":"62","author":"Delahoussaye","year":"2001","journal-title":"Biochem. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Guise, C.P., Abbattista, M.R., Anderson, R.F., Li, D., Taghipouran, R., Tsai, A., Lee, S.J., Smaill, J.B., Deny, W.A., and Hay, M.P. (2020). Subcellular location of tirapazamine reduction dramatically affects aerobic but not anoxic cytotoxicity. Molecules, 25.","DOI":"10.3390\/molecules25214888"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/0006-2952(93)90067-7","article-title":"Metabolism of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) by purified DT-diaphorase under aerobic and anaerobic conditions","volume":"45","author":"Cahill","year":"1993","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Nemeikait\u0117-\u010c\u0117nien\u0117, A., \u0160arlauskas, J., Misevi\u010dien\u0117, L., Marozien\u0117, A., Jonu\u0161ien\u0117, V., Lesanavi\u010dius, M., and \u010c\u0117nas, N. (2020). Aerobic cytotoxicity of aromatic N-oxides: The role of NAD(P)H:quinone oxidoreductase (NQO1). Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228754"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/0006-2952(93)90251-Q","article-title":"Initial characterization of the major mouse cytochrome P450 enzymes involved in the reductive metabolism of the hypoxic cytotoxin 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide (tirapazamine, SR 4233, WIN 59075)","volume":"45","author":"Riley","year":"1993","journal-title":"Biochem. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/bjc.1995.151","article-title":"Molecular mechanisms of tirapazamine (SR 4233, WIN 59075)-induced hepatocyte toxicity under low oxygen concentrations","volume":"71","author":"Khan","year":"1995","journal-title":"Br. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0006-2952(97)00171-8","article-title":"Adaptation of human tumor cells to tirapazamine under aerobic conditions. Implications of increased antioxidant enzyme activity to mechanism of aerobic cytotoxicity","volume":"54","author":"Elwell","year":"1997","journal-title":"Biochem. Pharmacol."},{"key":"ref_28","first-page":"145","article-title":"Mitochondrial dysfunction after aerobic exposure to the hypoxic cytotoxin tirapazamine","volume":"61","author":"Wouters","year":"2001","journal-title":"Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1124\/mol.105.012963","article-title":"Large-scale analysis of genes that alter sensitivity to the anticancer drug tirapazamine in Saccharomyces cerevisiae","volume":"68","author":"Hellauer","year":"2005","journal-title":"Mol. Pharm."},{"key":"ref_30","first-page":"1","article-title":"Genomic and proteomic analysis of the inhibition of synthesis and secretion of aldosterone hormone induced by quinacetone in NCI-H295R cells","volume":"350\u2013352","author":"Wang","year":"2016","journal-title":"Toxicology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1016\/j.bcp.2004.07.045","article-title":"Induction of alkaline phosphatase in the inflamed intestine: A novel pharmacological target for inflammatory bowel disease","volume":"68","author":"Gonzalez","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/S0167-4838(01)00193-5","article-title":"Mammalian intestinal alkaline phosphatase acts as highly active exopolyphosphatase","volume":"1547","author":"Lorenz","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.molcel.2017.12.021","article-title":"Maintaining a healthy proteome during oxidative stress","volume":"69","author":"Reichmann","year":"2018","journal-title":"Mol. Cell."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"On the origin of cancer cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.bbapap.2015.11.005","article-title":"Quantitative proteomic analysis of anticancer drug RH1 resistance in liver carcinoma","volume":"1864","author":"Ger","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1016\/j.freeradbiomed.2010.08.004","article-title":"Molecular characterization, expression analysis, and role of ALDH3B1 in the cellular protection against oxidative stress","volume":"49","author":"Marchitti","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.cbi.2011.01.013","article-title":"Murine hepatic aldehyde dehydrogenase 1a1 is a major contributor to oxidation of aldehydes formed by lipid peroxidation","volume":"191","author":"Makia","year":"2011","journal-title":"Chem. Biol. Interact."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.freeradbiomed.2011.11.033","article-title":"Aldehyde dehydrogenases and cell proliferation","volume":"52","author":"Muzio","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.bbrc.2012.03.002","article-title":"Expression of human carbonyl reductase 3 (CBR3; SDR21C2) is inducible by pro-inflammatori stimuli","volume":"420","author":"Malatkova","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.freeradbiomed.2020.01.183","article-title":"Aldehyde dehydrogenase 3A1 confers oxidative stress resistance accompanied by altered DNA damage response in human corneal epithelial cells","volume":"150","author":"Voulgaridou","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1089\/ars.2012.4599","article-title":"Thioredoxins, glutaredoxins and peroxiredoxins-molecular mechanisms and health significance: From cofactors to antioxidants to redox signaling","volume":"19","author":"Hanschmann","year":"2013","journal-title":"Antiox. Redox Signal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1093\/carcin\/bgq028","article-title":"The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth","volume":"31","author":"Dietrich","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s12964-023-01058-8","article-title":"When AHR signaling pathways meet viral infections","volume":"21","author":"Hu","year":"2023","journal-title":"Cell Commun. Signal."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5993","DOI":"10.1074\/jbc.M109.075770","article-title":"Interaction between oxidative stress sensor Nrf2 and xenobiotic-activated aryl hydrocarbon receptor in the regulation of the human phase II detoxifying UDP-glucuronosyltransferase 1A10","volume":"285","author":"Kalthoff","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13291","DOI":"10.1074\/jbc.R900010200","article-title":"The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress","volume":"284","author":"Nguyen","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1016\/j.febslet.2005.04.058","article-title":"Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: Protection against reactive oxygen and nitrogen species-induced cell injury","volume":"579","author":"Zhu","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/S0003-9861(03)00281-9","article-title":"Cytotoxicity of RH1 and related aziridinylbenzoquinones: Involvement of activation by NAD(P)H: Quinone oxidoreductase (NQO1) and oxidative stress","volume":"416","author":"Nivinskas","year":"2003","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"757","DOI":"10.15252\/msb.20145625","article-title":"Ultrasensitive proteome analysis using paramagnetic bead technology","volume":"10","author":"Hughes","year":"2014","journal-title":"Mol. Syst. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.1021\/acs.jproteome.7b00913","article-title":"Extending the compatibility of the SP36 paramagnetic bead processing approach for proteomics","volume":"17","author":"Moggridge","year":"2018","journal-title":"J. Proteome Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3594","DOI":"10.1021\/ac500140s","article-title":"Ion coalescence of neutron encoded TMT10-plex reporter ions","volume":"86","author":"Werner","year":"2014","journal-title":"Anal. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1038\/nprot.2015.101","article-title":"Thermal proteome profiling for unbiased identification of direct and indirect drug targets using multiplexed quantitative mass spectrometry","volume":"10","author":"Franken","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1074\/mcp.M114.046995","article-title":"A scalable approach for protein false discovery rate estimation in large proteomic data sets","volume":"14","author":"Savitski","year":"2015","journal-title":"Mol. Cell. Proteom."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"S96","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96","article-title":"Variance stabilization applied to microarray data calibration and to the quantitation of differential expression","volume":"18","author":"Huber","year":"2002","journal-title":"Bioinformatics"},{"key":"ref_56","first-page":"46","article-title":"Cytotoxicity of anticancer aziridinyl-benzoquinones in murine hepatoma MH22a cells: The properties of RH1-resistant subline","volume":"26","author":"Nivinskas","year":"2015","journal-title":"Chemija"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/7\/6863\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:11:25Z","timestamp":1760123485000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/7\/6863"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,6]]},"references-count":56,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24076863"],"URL":"https:\/\/doi.org\/10.3390\/ijms24076863","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,4,6]]}}}