{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T09:13:41Z","timestamp":1763975621474,"version":"3.45.0"},"reference-count":56,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T00:00:00Z","timestamp":1763856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ETEP Research Group"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study aimed to characterize the transcriptional response of Porphyromonas gingivalis biofilms to treatment with xanthohumol and curcumin. A validated dynamic in vitro biofilm model, based on microbial growth under flow and shear conditions resembling the oral cavity, was used to develop mature biofilms of P. gingivalis on sterile ceramic calcium hydroxyapatite discs. Transcriptional profiles of biofilms, treated and untreated with both extracts, were obtained through RNA-Sequencing (RNA-Seq). The biofilm development and the lack of phenotypic effects from sublethal concentrations of xanthohumol and curcumin were confirmed via Scanning Electron Microscopy (SEM) and Confocal Laser Scanning Microscopy (CLSM). Reverse transcription quantitative PCR (RT-qPCR) was employed to verify differentially expressed genes identified by RNA-Seq. Xanthohumol and curcumin caused extensive reprogramming of P. gingivalis biofilm gene expression. Out of 1,973 genes, xanthohumol activated 173 and repressed 286, whereas curcumin activated 170 and repressed 163. These changes affected genes involved in membrane integrity, oxidative stress, transmembrane transport, and virulence, suggesting a mechanism of action that involves membrane disruption.<\/jats:p>","DOI":"10.3390\/ijms262311315","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T09:02:07Z","timestamp":1763974927000},"page":"11315","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential Gene Expression of Porphyromonas gingivalis in the Presence or Absence of Xanthohumol and Curcumin in a Dynamic In Vitro Biofilm Model"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4050-5842","authenticated-orcid":false,"given":"Enrique","family":"Bravo","sequence":"first","affiliation":[{"name":"ETEP (Etiology and Therapy of Periodontal and Peri-Implant Diseases) Research Group, Faculty of Dentistry, Complutense University, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8556-0733","authenticated-orcid":false,"given":"Cristina","family":"Chamorro","sequence":"additional","affiliation":[{"name":"ETEP (Etiology and Therapy of Periodontal and Peri-Implant Diseases) Research Group, Faculty of Dentistry, Complutense University, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5554-2777","authenticated-orcid":false,"given":"David","family":"Herrera","sequence":"additional","affiliation":[{"name":"ETEP (Etiology and Therapy of Periodontal and Peri-Implant Diseases) Research Group, Faculty of Dentistry, Complutense University, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6293-5755","authenticated-orcid":false,"given":"Mariano","family":"Sanz","sequence":"additional","affiliation":[{"name":"ETEP (Etiology and Therapy of Periodontal and Peri-Implant Diseases) Research Group, Faculty of Dentistry, Complutense University, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/prd.12361","article-title":"The dental plaque biofilm matrix","volume":"86","author":"Jakubovics","year":"2021","journal-title":"Periodontology 2000"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"395","DOI":"10.5114\/bta.2024.145259","article-title":"Biofilm architecture and dynamics of the oral ecosystem","volume":"105","author":"Ray","year":"2024","journal-title":"BioTechnologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1177\/0022034509351812","article-title":"Oral biofilms: Emerging concepts in microbial ecology","volume":"89","author":"Filoche","year":"2010","journal-title":"J. Dent. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bloch, S., Hager-Mair, F.F., Andrukhov, O., and Schaffer, C. (2024). Oral streptococci: Modulators of health and disease. Front. Cell. Infect. Microbiol., 14.","DOI":"10.3389\/fcimb.2024.1357631"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S173","DOI":"10.1002\/JPER.17-0721","article-title":"Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions","volume":"89","author":"Papapanou","year":"2018","journal-title":"J. Periodontol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S313","DOI":"10.1002\/JPER.17-0739","article-title":"Peri-implant diseases and conditions: Consensus report of workgroup 4 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions","volume":"89","author":"Berglundh","year":"2018","journal-title":"J. Periodontol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1034\/j.1600-0757.2002.280102.x","article-title":"Dental biofilms: Difficult therapeutic targets","volume":"28","author":"Socransky","year":"2002","journal-title":"Periodontol. 2000"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1128\/microbiolspec.MB-0011-2014","article-title":"Bacterial Extracellular Polysaccharides in Biofilm Formation and Function","volume":"3","author":"Limoli","year":"2015","journal-title":"Microbiol. Spectr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1111\/jcpe.12682","article-title":"Role of microbial biofilms in the maintenance of oral health and in the development of dental caries and periodontal diseases. Consensus report of group 1 of the Joint EFP\/ORCA workshop on the boundaries between caries and periodontal disease","volume":"44","author":"Sanz","year":"2017","journal-title":"J. Clin. Periodontol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/bs.apcsb.2019.12.001","article-title":"Roles of Porphyromonas gingivalis and its virulence factors in periodontitis","volume":"120","author":"Xu","year":"2020","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lamont, R.J., and Kuboniwa, M. (2024). The polymicrobial pathogenicity of Porphyromonas gingivalis. Front. Oral Health, 5.","DOI":"10.3389\/froh.2024.1404917"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Cui, Z., Wang, P., and Gao, W. (2025). Microbial dysbiosis in periodontitis and peri-implantitis: Pathogenesis, immune responses, and therapeutic. Front. Cell. Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1517154"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sanchez, M.C., Romero-Lastra, P., Ribeiro-Vidal, H., Llama-Palacios, A., Figuero, E., Herrera, D., and Sanz, M. (2019). Comparative gene expression analysis of planktonic Porphyromonas gingivalis ATCC 33277 in the presence of a growing biofilm versus planktonic cells. BMC Microbiol., 19.","DOI":"10.1186\/s12866-019-1423-9"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Romero-Lastra, P., Sanchez, M.C., Llama-Palacios, A., Figuero, E., Herrera, D., and Sanz, M. (2019). Gene expression of Porphyromonas gingivalis ATCC 33277 when growing in an in vitro multispecies biofilm. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0221234"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Romero-Lastra, P., Sanchez, M.C., Ribeiro-Vidal, H., Llama-Palacios, A., Figuero, E., Herrera, D., and Sanz, M. (2017). Comparative gene expression analysis of Porphyromonas gingivalis ATCC 33277 in planktonic and biofilms states. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174669"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/idh.12393","article-title":"Efficacy of aloe vera mouthwash versus chlorhexidine on plaque and gingivitis: A systematic review","volume":"18","author":"Nassani","year":"2020","journal-title":"Int. J. Dent. Hyg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2829854","DOI":"10.1155\/2020\/2829854","article-title":"Effects of Herbal Mouthwashes on Plaque and Inflammation Control for Patients with Gingivitis: A Systematic Review and Meta-Analysis of Randomised Controlled Trials","volume":"2020","author":"Cai","year":"2020","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Halboub, E., Al-Maweri, S.A., Al-Wesabi, M., Al-Kamel, A., Shamala, A., Al-Sharani, A., and Koppolu, P. (2020). Efficacy of propolis-based mouthwashes on dental plaque and gingival inflammation: A systematic review. BMC Oral Health, 20.","DOI":"10.1186\/s12903-020-01185-5"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rozalski, M., Micota, B., Sadowska, B., Stochmal, A., Jedrejek, D., Wieckowska-Szakiel, M., and Rozalska, B. (2013). Antiadherent and antibiofilm activity of Humulus lupulus L. derived products: New pharmacological properties. Biomed Res. Int., 2013.","DOI":"10.1155\/2013\/101089"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1177\/154405910708600908","article-title":"Hop bract polyphenols reduced three-day dental plaque regrowth","volume":"86","author":"Shinada","year":"2007","journal-title":"J. Dent. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1111\/apm.12747","article-title":"Strong antimicrobial activity of xanthohumol and other derivatives from hops (Humulus lupulus L.) on gut anaerobic bacteria","volume":"125","author":"Cermak","year":"2017","journal-title":"APMIS"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sleha, R., Radochova, V., Mikyska, A., Houska, M., Bolehovska, R., Janovska, S., Pejchal, J., Muckova, L., Cermak, P., and Bostik, P. (2021). Strong Antimicrobial Effects of Xanthohumol and Beta-Acids from Hops against Clostridioides difficile Infection In Vivo. Antibiotics, 10.","DOI":"10.3390\/antibiotics10040392"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1016\/j.ijbiomac.2018.09.003","article-title":"Antibacterial hop extracts encapsulated in nanochitosan matrices","volume":"120","author":"Leonida","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1007\/s00018-008-7452-4","article-title":"Curcumin: From ancient medicine to current clinical trials","volume":"65","author":"Hatcher","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"204","DOI":"10.2174\/092986732102131206115810","article-title":"Curcumin and curcumin-like molecules: From spice to drugs","volume":"21","author":"Marchiani","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.nutres.2020.03.002","article-title":"A systemic review on the antioxidant and anti-inflammatory effects of resveratrol, curcumin, and dietary nitric oxide supplementation on human cardiovascular health","volume":"78","author":"Banez","year":"2020","journal-title":"Nutr. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Praditya, D., Kirchhoff, L., Bruning, J., Rachmawati, H., Steinmann, J., and Steinmann, E. (2019). Anti-infective Properties of the Golden Spice Curcumin. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.00912"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1080\/14787210.2020.1730815","article-title":"Curcumin and curcumin-loaded nanoparticles: Antipathogenic and antiparasitic activities","volume":"18","author":"Rai","year":"2020","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Alonso-Espanol, A., Bravo, E., Ribeiro-Vidal, H., Virto, L., Herrera, D., Alonso, B., and Sanz, M. (2023). The Antimicrobial Activity of Curcumin and Xanthohumol on Bacterial Biofilms Developed over Dental Implant Surfaces. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032335"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1111\/clr.14410","article-title":"Antimicrobial Effect and Cytocompatibility After Using Different Decontamination Methods on Titanium Implant Surfaces: An In Vitro Study","volume":"36","author":"Bravo","year":"2025","journal-title":"Clin. Oral Implant. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Murai, H., Kuboniwa, M., Kakiuchi, M., Matsumura, R., Hirata, Y., and Amano, A. (2024). Curcumin inhibits growth of Porphyromonas gingivalis by arrest of bacterial dipeptidyl peptidase activity. J. Oral Microbiol., 16.","DOI":"10.1080\/20002297.2024.2373040"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s10266-020-00514-y","article-title":"Effect of curcumin on growth, biofilm formation and virulence factor gene expression of Porphyromonas gingivalis","volume":"109","author":"Kumbar","year":"2021","journal-title":"Odontology"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Izui, S., Sekine, S., Murai, H., Takeuchi, H., and Amano, A. (2021). Inhibitory effects of curcumin against cytotoxicity of Porphyromonas gingivalis outer membrane vesicles. Arch. Oral Biol., 124.","DOI":"10.1016\/j.archoralbio.2021.105058"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1093\/dnares\/dsn013","article-title":"Determination of the genome sequence of Porphyromonas gingivalis strain ATCC 33277 and genomic comparison with strain W83 revealed extensive genome rearrangements in P. gingivalis","volume":"15","author":"Naito","year":"2008","journal-title":"DNA Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1021\/acs.jmedchem.2c01793","article-title":"Discovery of Amphiphilic Xanthohumol Derivatives as Membrane-Targeting Antimicrobials against Methicillin-Resistant Staphylococcus aureus","volume":"66","author":"Cheng","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"499","DOI":"10.4067\/S0718-58392023000400499","article-title":"Antimicrobial activity of compounds from hop (Humulus lupulus L.) following supercritical fluid extraction: An overview","volume":"83","author":"Betancur","year":"2023","journal-title":"Chil. J. Agric. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kolodziejczak, A., Dziedzic, M., Algiert-Zielinska, B., Mucha, P., and Rotsztejn, H. (2024). A Novel Look at Mechanisms and Applications of Xanthohumol (XN) in Dermatology and Cosmetology. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252211938"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Reveron, I., Plaza-Vinuesa, L., Santamaria, L., Oliveros, J.C., Rivas, B.L., Munoz, R., and Lopez de Felipe, F. (2020). Transcriptomic Evidence of Molecular Mechanisms Underlying the Response of Lactobacillus Plantarum WCFS1 to Hydroxytyrosol. Antioxidants, 9.","DOI":"10.3390\/antiox9050442"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1089\/mdr.2012.0244","article-title":"Antibacterial activity and mode of action of ferulic and gallic acids against pathogenic bacteria","volume":"19","author":"Borges","year":"2013","journal-title":"Microb. Drug Resist."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Nakao, R., Takatsuka, A., Mandokoro, K., Narisawa, N., Ikeda, T., Takai, H., and Ogata, Y. (2024). Multimodal inhibitory effect of matcha on Porphyromonas gingivalis. Microbiol. Spectr., 12.","DOI":"10.1128\/spectrum.03426-23"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Ding, J., Tan, L., Wu, L., Li, J., Zhang, Y., Shen, Z., Zhang, C., Zhao, C., and Gao, L. (2025). Regulation of tryptophan-indole metabolic pathway in Porphyromonas gingivalis virulence and microbiota dysbiosis in periodontitis. NPJ Biofilms Microbiomes, 11.","DOI":"10.1038\/s41522-025-00669-y"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Confessor, M.V.A., Agreles, M.A.A., Campos, L.A.D., Neto, A.F.S., Borges, J.C., Martins, R.M., Scavuzzi, A.M.L., Lopes, A.C.S., Kretzschmar, E.A.D., and Cavalcanti, I.M.F. (2024). Olive oil nanoemulsion containing curcumin: Antimicrobial agent against multidrug-resistant bacteria. Appl. Microbiol. Biotechnol., 108.","DOI":"10.1007\/s00253-024-13057-x"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Janesomboon, S., Sawaengwong, T., Muangsombut, V., Vanaporn, M., Santanirand, P., Kritsiriwuthinan, K., Gundogdu, O., Chantratita, N., Nale, J.Y., and Korbsrisate, S. (2025). Synergistic antibacterial activity of curcumin and phage against multidrug-resistant acinetobacter baumannii. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-94040-y"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Beganovic, S., and Wittmann, C. (2024). Medical properties, market potential, and microbial production of golden polyketide curcumin for food, biomedical, and cosmetic applications. Curr. Opin. Biotechnol., 87.","DOI":"10.1016\/j.copbio.2024.103112"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1039\/C8RA90104J","article-title":"Correction: Quantum curcumin mediated inhibition of gingipains and mixed-biofilm of Porphyromonas gingivalis causing chronic periodontitis","volume":"9","author":"Singh","year":"2018","journal-title":"RSC Adv."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ribeiro-Vidal, H., Sanchez, M.C., Alonso-Espanol, A., Figuero, E., Ciudad, M.J., Collado, L., Herrera, D., and Sanz, M. (2020). Antimicrobial Activity of EPA and DHA against Oral Pathogenic Bacteria Using an In Vitro Multi-Species Subgingival Biofilm Model. Nutrients, 12.","DOI":"10.3390\/nu12092812"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/jre.12110","article-title":"Characterization and application of a flow system for in vitro multispecies oral biofilm formation","volume":"49","author":"Blanc","year":"2014","journal-title":"J. Periodontal Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Bravo, E., Arce, M., Ribeiro-Vidal, H., Herrera, D., and Sanz, M. (2024). The Impact of Candida albicans in the Development, Kinetics, Structure, and Cell Viability of Biofilms on Implant Surfaces-An In Vitro Study with a Validated Multispecies Biofilm Model. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202402.1137.v1"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Chen, S., Huang, T., Zhou, Y., Han, Y., Xu, M., and Gu, J. (2017). AfterQC: Automatic filtering, trimming, error removing and quality control for fastq data. BMC Bioinform., 18.","DOI":"10.1186\/s12859-017-1469-3"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"giab008","DOI":"10.1093\/gigascience\/giab008","article-title":"Twelve years of SAMtools and BCFtools","volume":"10","author":"Danecek","year":"2021","journal-title":"Gigascience"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Robinson, J.T., Thorvaldsdottir, H., Turner, D., and Mesirov, J.P. (2023). igv.js: An embeddable JavaScript implementation of the Integrative Genomics Viewer (IGV). Bioinformatics, 39.","DOI":"10.1093\/bioinformatics\/btac830"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3211","DOI":"10.1093\/bioinformatics\/bts611","article-title":"SortMeRNA: Fast and accurate filtering of ribosomal RNAs in metatranscriptomic data","volume":"28","author":"Kopylova","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11315\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T09:09:03Z","timestamp":1763975343000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11315"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,23]]},"references-count":56,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311315"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311315","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,23]]}}}