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These compounds are endowed with several biological activities and exert protective effects in various physiopathological contexts, including cancer. We herein investigated novel potential mechanisms of action of polyphenols, focusing on the proteasome, which has emerged as an attractive therapeutic target in cancers such as multiple myeloma. We carried out a structure-based virtual screening study using the DrugBank database as a repository of FDA-approved polyphenolic molecules. Starting from 86 polyphenolic compounds, based on the theoretical binding affinity and the interactions established with key residues of the chymotrypsin binding site, we selected 2 promising candidates, namely Hesperidin and Diosmin. The further assessment of the biologic activity highlighted, for the first time, the capability of these two molecules to inhibit the \u03b25-proteasome activity and to exert anti-tumor activity against proteasome inhibitor-sensitive or resistant multiple myeloma cell lines.<\/jats:p>","DOI":"10.3390\/ph16121712","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T03:25:31Z","timestamp":1702265131000},"page":"1712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["New Insights for Polyphenolic Compounds as Naturally Inspired Proteasome Inhibitors"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5701-0873","authenticated-orcid":false,"given":"Emanuela","family":"Marchese","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Eugenia","family":"Gallo Cantafio","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4874-2946","authenticated-orcid":false,"given":"Francesca Alessandra","family":"Ambrosio","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Torcasio","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilenia","family":"Valentino","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Trapasso","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Viglietto","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0437-358X","authenticated-orcid":false,"given":"Stefano","family":"Alcaro","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, 88100 Catanzaro, Italy"},{"name":"Net4Science Academic Spin-Off, Universit\u00e0 \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, 88100 Catanzaro, Italy"},{"name":"Associazione CRISEA\u2014Centro di Ricerca e Servizi Avanzati per l\u2019Innovazione Rurale, Loc. Condoleo, 88055 Belcastro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0947-9479","authenticated-orcid":false,"given":"Giosu\u00e8","family":"Costa","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, 88100 Catanzaro, Italy"},{"name":"Net4Science Academic Spin-Off, Universit\u00e0 \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Amodio","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. 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Longev."},{"key":"ref_4","unstructured":"Andr\u00e9s-Lacueva, C., Medina-Remon, A., Llorach, R., Urpi-Sarda, M., Khan, N., Chiva-Blanch, G., Zamora-Ros, R., Rotches-Ribalta, M., and Lamuela-Raventos, R.M. (2010). Fruit and Vegetable Phytochemicals: Chemistry, Nutritional Value and Stability, Wiley-Blackwell."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1080\/10942912.2016.1220393","article-title":"Natural polyphenols: An overview","volume":"20","author":"Abbas","year":"2017","journal-title":"Int. J. Food Prop."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/1471-0307.12515","article-title":"A review on polyphenols: Classification, beneficial effects and their application in dairy products","volume":"71","author":"Cutrim","year":"2018","journal-title":"Int. J. Dairy Technol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.foodchem.2010.08.012","article-title":"The Molecular Basis of Working Mechanism of Natural Polyphenolic Antioxidants","volume":"125","author":"Leopoldini","year":"2011","journal-title":"Food Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ejmech.2017.03.061","article-title":"Free Radicals and Polyphenols: The Redox Chemistry of Neurodegenerative Diseases","volume":"133","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102294","DOI":"10.1016\/j.ctim.2019.102294","article-title":"Oxidative stress in alzheimer\u2019s disease: A review on emergent natural polyphenolic therapeutics","volume":"49","author":"Cassidy","year":"2020","journal-title":"Complement. Ther. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s12013-009-9043-x","article-title":"A Review of the antioxidant mechanisms of polyphenol compounds related to iron binding","volume":"53","author":"Perron","year":"2009","journal-title":"Cell Biochem. Biophys."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2986796","DOI":"10.1155\/2016\/2986796","article-title":"Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More","volume":"2016","author":"Costa","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Marchese, E., Orlandi, V., Turrini, F., Romeo, I., Boggia, R., Alcaro, S., and Costa, G. (2023). In Silico and In Vitro Study of Antioxidant Potential of Urolithins. Antioxidants, 12.","DOI":"10.3390\/antiox12030697"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2174\/1381612824666180130112652","article-title":"Polyphenols: Potential Use in the Prevention and Treatment of Cardiovascular Diseases","volume":"24","author":"Giglio","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fernandes, I., Oliveira, J., Pinho, A., and Carvalho, E. (2022). The Role of Nutraceutical Containing Polyphenols in Diabetes Prevention. Metabolites, 12.","DOI":"10.3390\/metabo12020184"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"913883","DOI":"10.3389\/fnut.2022.913883","article-title":"The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity","volume":"9","author":"Li","year":"2022","journal-title":"Front. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"149719","DOI":"10.1016\/j.scitotenv.2021.149719","article-title":"Polyphenols and their potential role to fight viral diseases: An overview","volume":"801","author":"Vecino","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Shakoor, H., Feehan, J., Apostolopoulos, V., Platat, C., Al Dhaheri, A.S., Ali, H.I., Ismail, L.C., Bosevski, M., and Stojanovska, L. (2021). Immunomodulatory Effects of Dietary Polyphenols. Nutrients, 13.","DOI":"10.3390\/nu13030728"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"891748","DOI":"10.1155\/2013\/891748","article-title":"Polyphenols: Multipotent therapeutic agents in neurodegenerative diseases","volume":"2013","author":"Bhullar","year":"2013","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2174\/1574892817666220512220036","article-title":"Exploring the Anticancer Potentials of Polyphenols: A Comprehensive Review of Patents in the Last Five Years","volume":"18","author":"Gupta","year":"2023","journal-title":"Recent Pat. Anticancer Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Juli, G., Oliverio, M., Bellizzi, D., Gallo Cantafio, M.E., Grillone, K., Passarino, G., Colica, C., Nardi, M., Rossi, M., and Procopio, A. (2019). Anti-tumor Activity and Epigenetic Impact of the Polyphenol Oleacein in Multiple Myeloma. Cancers, 11.","DOI":"10.3390\/cancers11070990"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Todoerti, K., Gallo Cantafio, M.E., Oliverio, M., Juli, G., Rocca, C., Citraro, R., Tassone, P., Procopio, A., De Sarro, G., and Neri, A. (2021). Oleil Hydroxytyrosol (HTOL) Exerts Anti-Myeloma Activity by Antagonizing Key Survival Pathways in Malignant Plasma Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111639"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Niedzwiecki, A., Roomi, M.W., Kalinovsky, T., and Rath, M. (2016). Anticancer Efficacy of Polyphenols and Their Combinations. Nutrients, 8.","DOI":"10.3390\/nu8090552"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sharma, E., Attri, D.C., Sati, P., Dhyani, P., Szopa, A., Sharifi-Rad, J., Hano, C., Calina, D., and Cho, W.C. (2022). Recent updates on anticancer mechanisms of polyphenols. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1005910"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/s41580-018-0040-z","article-title":"Regulation of proteasome assembly and activity in health and disease","volume":"19","author":"Rousseau","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1073\/pnas.1621129114","article-title":"Structural insights into the functional cycle of the ATPase module of the 26S proteasome","volume":"114","author":"Wehmer","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ito, S. (2020). Proteasome Inhibitors for the Treatment of Multiple Myeloma. Cancers, 12.","DOI":"10.3390\/cancers12020265"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S0140-6736(21)00135-5","article-title":"Multiple myeloma","volume":"397","author":"Pawlyn","year":"2021","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2174\/156800911794519752","article-title":"Bortezomib as the First Proteasome Inhibitor Anticancer Drug: Current Status and Future Perspectives","volume":"11","author":"Chen","year":"2011","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4559","DOI":"10.1158\/1078-0432.CCR-13-0755","article-title":"U.S. Food and Drug Administration approval: Carfilzomib for the treatment of multiple myeloma","volume":"19","author":"Herndon","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s40265-016-0548-5","article-title":"Ixazomib: First Global Approval","volume":"76","author":"Shirley","year":"2016","journal-title":"Drugs"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.drup.2008.08.002","article-title":"Mechanisms of proteasome inhibitor action and resistance in cancer","volume":"11","author":"McConkey","year":"2008","journal-title":"Drug Res. Updates"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Paradzik, T., Bandini, C., Mereu, E., Labrador, M., Taiana, E., Amodio, N., Neri, A., and Piva, R. (2021). The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma. Cancers, 13.","DOI":"10.3390\/cancers13061235"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Taiana, E., Gallo Cantafio, M.E., Favasuli, V.K., Bandini, C., Viglietto, G., Piva, R., Neri, A., and Amodio, N. (2021). Genomic Instability in Multiple Myeloma: A \u201cNon-Coding RNA\u201d Perspective. Cancers, 13.","DOI":"10.3390\/cancers13092127"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"358","DOI":"10.2174\/1389203718666170111121856","article-title":"Discovery of Natural Proteasome Inhibitors as Novel Anticancer Therapeutics: Current Status and Perspectives","volume":"19","author":"Wang","year":"2018","journal-title":"Curr. Protein. Pept. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ambrosio, F.A., Costa, G., Gallo Cantafio, M.E., Torcasio, R., Trapasso, F., Alcaro, S., Viglietto, G., and Amodio, N. (2023). Natural Agents as Novel Potential Source of Proteasome Inhibitors with Anti-Tumor Activity: Focus on Multiple Myeloma. Molecules, 28.","DOI":"10.3390\/molecules28031438"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3389\/fchem.2020.00343","article-title":"Structure-Based Virtual Screening: From Classical to Artificial Intelligence","volume":"8","author":"Maia","year":"2020","journal-title":"Front. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D668","DOI":"10.1093\/nar\/gkj067","article-title":"DrugBank: A comprehensive resource for in silico drug discovery and exploration","volume":"34","author":"Wishart","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_38","first-page":"1934578X1300800435","article-title":"Diosmin\u2014Isolation techniques, determination in plant material and pharmaceutical formulations, and clinical use","volume":"8","author":"Feldo","year":"2013","journal-title":"Nat. Prod. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"100122","DOI":"10.1016\/j.crphar.2022.100122","article-title":"Plant metabolite diosmin as the therapeutic agent in human diseases","volume":"3","author":"Mustafa","year":"2022","journal-title":"Curr. Res. Pharmacol. Drug Discov."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1126\/science.aaf8993","article-title":"The Inhibition Mechanism of Human 20S Proteasomes Enables Next-Generation Inhibitor Design","volume":"353","author":"Schrader","year":"2016","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Malacrida, A., Cavalloro, V., Martino, E., Costa, G., Ambrosio, F.A., Alcaro, S., Rigolio, R., Cassetti, A., Miloso, M., and Collina, S. (2021). Anti-multiple myeloma potential of secondary metabolites from Hibiscus sabdariffa\u2014Part 2. Molecules, 26.","DOI":"10.3390\/molecules26216596"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Listro, R., Malacrida, A., Ambrosio, F.A., Rossino, G., Di Giacomo, M., Cavalloro, V., Garbagnoli, M., Linciano, P., Rossi, D., and Cavaletti, G. (2022). From Nature to Synthetic Compounds: Novel 1(N),2,3 Trisubstituted-5-oxopyrrolidines Targeting Multiple Myeloma Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113061"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Guedes, R.A., Grilo, J.H., Carvalho, A.N., Fernandes, P.M.P., Ressurrei\u00e7\u00e3o, A.S., Brito, V., Santos, A.O., Silvestre, S., Gallerani, E., and Gama, M.J. (2023). New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies. Pharmaceuticals, 16.","DOI":"10.3390\/ph16081096"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"524","DOI":"10.36290\/vnl.2019.091","article-title":"Diosmin\u2014Still an important modality in the treatment of venous insufficiency","volume":"65","author":"Sliva","year":"2019","journal-title":"Vnitr. Lek."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Feldo, M., W\u00f3jciak-Kosior, M., Sowa, I., Kocki, J., Bogucki, J., Zubilewicz, T., K\u0119sik, J., and Bogucka-Kocka, A. (2019). Effect of Diosmin Administration in Patients with Chronic Venous Disorders on Selected Factors Affecting Angiogenesis. Molecules, 24.","DOI":"10.3390\/molecules24183316"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1177\/0003319794045006021","article-title":"Flavonoids: A Review of the Pharmacology and Therapeutic Efficacy of Daflon 500 mg in Patients with Chronic Venous Insufficiency and Related Disorders","volume":"45","author":"Struckmann","year":"1994","journal-title":"Angiology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ejmech.2019.04.075","article-title":"Therapeutic potential of natural compounds in inflammation and chronic venous insufficiency","volume":"176","author":"Lichota","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"296","DOI":"10.2174\/156800911794519743","article-title":"Green tea polyphenols as proteasome inhibitors: Implication in chemoprevention","volume":"11","author":"Yang","year":"2011","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"891","DOI":"10.2174\/187152012802649978","article-title":"Targeting tumor ubiquitin-proteasome pathway with polyphenols for chemosensitization","volume":"12","author":"Shen","year":"2012","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_50","first-page":"197","article-title":"Black Tea Polyphenols Inhibit Tumor Proteasome Activity","volume":"26","author":"Mujtaba","year":"2012","journal-title":"In Vivo"},{"key":"ref_51","unstructured":"(2018). Schr\u00f6dinger Release 2018-1: Protein Preparation Wizard, Schr\u00f6dinger LLC."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"11225","DOI":"10.1021\/ja9621760","article-title":"Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids","volume":"118","author":"Jorgensen","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_53","unstructured":"(2018). Schr\u00f6dinger Release 2018-1: Prime, Schr\u00f6dinger LLC."},{"key":"ref_54","unstructured":"(2018). Schr\u00f6dinger Release 2018-1: Glide, Schr\u00f6dinger LLC."},{"key":"ref_55","unstructured":"(2018). Schr\u00f6dinger Release 2018-1: LigPrep, Schr\u00f6dinger LLC."},{"key":"ref_56","unstructured":"(2018). Schr\u00f6dinger Release 2018-1: MacroModel, Schr\u00f6dinger LLC."},{"key":"ref_57","unstructured":"(2018). Schr\u00f6dinger Release 2018-1: Desmond Molecular Dynamics System, D.E. Shaw Research."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ci100275a","article-title":"Assessing the performance of the MM\/PBSA and MM\/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations","volume":"51","author":"Hou","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s40164-022-00305-x","article-title":"Therapeutic activation of G protein-coupled estrogen receptor 1 in Waldenstr\u00f6m Macroglobulinemia","volume":"11","author":"Morelli","year":"2022","journal-title":"Exp. Hematol. Oncol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/12\/1712\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:36:31Z","timestamp":1760132191000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/12\/1712"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,11]]},"references-count":59,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ph16121712"],"URL":"https:\/\/doi.org\/10.3390\/ph16121712","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,11]]}}}