{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T18:34:39Z","timestamp":1787423679710,"version":"build-2736575974"},"reference-count":122,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>For many years, staphylococci have been detected mainly in infections of the skin and soft tissues, organs, bone inflammations, and generalized infections. Thromboembolic diseases have also become a serious plague of our times, which, as it turns out, are closely related to the toxic effects of staphylococci. Staphylococcus aureus, because of the presence of many different kinds of virulence factors, is capable of manipulating the host\u2019s innate and adaptive immune responses. These include toxins and cofactors that activate host zymogens and exoenzymes, as well as superantigens, which are highly inflammatory and cause leukocyte death. Coagulases and staphylokinases can control the host\u2019s coagulation system. Nucleases and proteases inactivate various immune defense and surveillance proteins, including complement components, peptides and antibacterial proteins, and surface receptors that are important for leukocyte chemotaxis. On the other hand, secreted toxins and exoenzymes are proteins that disrupt the endothelial and epithelial barrier as a result of cell lysis and disintegration of linking proteins, which ultimately increases the risk of thromboembolism. In this review, we discuss various virulence factors and substances that may inhibit their activity.<\/jats:p>","DOI":"10.3390\/toxins17070340","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T11:20:11Z","timestamp":1751628011000},"page":"340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Potential Compounds as Inhibitors of Staphylococcal Virulence Factors Involved in the Development of Thrombosis"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5399-3144","authenticated-orcid":false,"given":"Anna","family":"Lichota","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Microbiology and Microbiological Diagnostics, Medical University of Lodz, 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2590-7496","authenticated-orcid":false,"given":"Krzysztof","family":"Gwozdzinski","sequence":"additional","affiliation":[{"name":"Department of Oncobiology and Epigenetics, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9823-4176","authenticated-orcid":false,"given":"Monika","family":"Sienkiewicz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Microbiology and Microbiological Diagnostics, Medical University of Lodz, 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.imj.2023.11.006","article-title":"Metal nanoparticles as inhibitors of enzymes and toxins of multidrug-resistant Staphylococcus aureus","volume":"2","author":"Joshi","year":"2023","journal-title":"Infect. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Olchowik-Grabarek, E., Sekowski, S., Bitiucki, M., Dobrzynska, I., Shlyonsky, V., Ionov, M., Burzynski, P., Roszkowska, A., Swiecicka, I., and Abdulladjanova, N. (2020). Inhibition of interaction between Staphylococcus aureus \u03b1-hemolysin and erythrocytes membrane by hydrolysable tannins: Structure-related activity study. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-68030-1"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105204","DOI":"10.1016\/j.chemphyslip.2022.105204","article-title":"Liposome evaluation in inhibiting pump efflux of NorA of Staphylococcus aureus","volume":"245","author":"Coutinho","year":"2022","journal-title":"Chem. Phys. Lipids"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"W\u00f3jcik-Bojek, U., R\u00f3\u017calska, B., and Sadowska, B. (2022). Staphylococcus aureus\u2014A Known Opponent against Host Defense Mechanisms and Vaccine Development\u2014Do We Still Have a Chance to Win?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020948"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ford, C.A., Hurford, I.M., and Cassat, J.E. (2021). Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.632706"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sabino, Y.N.V., Cotter, P.D., and Mantovani, H.C. (2023). Anti-virulence compounds against Staphylococcus aureus associated with bovine mastitis: A new therapeutic option?. Microbiol. Res., 271.","DOI":"10.1016\/j.micres.2023.127345"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"xtae006","DOI":"10.1093\/femsmc\/xtae006","article-title":"The role of proteinaceous toxins secreted by Staphylococcus aureus in interbacterial competition","volume":"5","author":"Garrett","year":"2024","journal-title":"FEMS Microbes"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1111\/jth.15703","article-title":"\u03b1-hemolysin of Staphylococcus aureus impairs thrombus formation","volume":"20","author":"Jahn","year":"2022","journal-title":"J. Thromb. Haemost."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1055\/s-0038-1637735","article-title":"Secreted Immunomodulatory Proteins of Staphylococcus aureus Activate Platelets and Induce Platelet Aggregation","volume":"47","author":"Binsker","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/nrmicro.2017.27","article-title":"Leukocidins: Staphylococcal bi-component pore-forming toxins find their receptors","volume":"15","author":"Spaan","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.thromres.2012.06.013","article-title":"The role of hypervirulent Staphylococcus aureus infections in the development of deep vein thrombosis","volume":"130","author":"Martin","year":"2012","journal-title":"Thromb. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Escajadillo, T., and Nizet, V. (2018). Pharmacological Targeting of Pore-Forming Toxins as Adjunctive Therapy for Invasive Bacterial Infection. Toxins, 10.","DOI":"10.3390\/toxins10120542"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1007\/s12257-019-0059-9","article-title":"Staphylococcus aureus Toxins: From Their Pathogenic Roles to Anti-virulence Therapy Using Natural Products","volume":"24","author":"Kim","year":"2019","journal-title":"Biotechnol. Bioprocess Eng."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Donadio, G., Mensitieri, F., Santoro, V., Parisi, V., Bellone, M.L., De Tommasi, N., Izzo, V., and Dal Piaz, F. (2021). Interactions with Microbial Proteins Driving the Antibacterial Activity of Flavonoids. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13050660"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3892\/mi.2024.191","article-title":"Recent advances in the use of resveratrol against Staphylococcus aureus infections (Review)","volume":"4","author":"Cui","year":"2024","journal-title":"Med. Int."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Duda-Madej, A., Stecko, J., Sobieraj, J., Szyma\u0144ska, N., and Koz\u0142owska, J. (2022). Naringenin and Its Derivatives\u2014Health-Promoting Phytobiotic against Resistant Bacteria and Fungi in Humans. Antibiotics, 11.","DOI":"10.3390\/antibiotics11111628"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1128\/AEM.02581-15","article-title":"Combination Therapy of LysGH15 and Apigenin as a New Strategy for Treating Pneumonia Caused by Staphylococcus aureus","volume":"82","author":"Xia","year":"2016","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3923\/tb.2013.91.100","article-title":"In silico Molecular Interaction Studies of Gamma-hemolysin of Staphylococcus aureus with Flavonoid Compounds","volume":"6","author":"Mohan","year":"2013","journal-title":"Trends Bioinforma."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3329\/bjp.v9i1.17368","article-title":"Virtual screening of compounds derived from Garcinia pedunculata as an inhibitor of gamma hemolysin component A of Staphylococcus aureus","volume":"9","author":"Chowdhury","year":"2014","journal-title":"Bangladesh J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8185","DOI":"10.1021\/jf402222v","article-title":"Structure\u2013Activity Relationship of Flavonoids on Their Anti-Escherichia coli Activity and Inhibition of DNA Gyrase","volume":"61","author":"Wu","year":"2013","journal-title":"J. Agric. Food Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1248\/bpb.32.489","article-title":"Synergistic Effect of Kaempferol Glycosides Purified from Laurus nobilis and Fluoroquinolones on Methicillin-Resistant Staphylococcus aureus","volume":"32","author":"Liu","year":"2009","journal-title":"Biol. Pharm. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s10930-015-9609-y","article-title":"Inhibition of Staphylococcus aureus PriA Helicase by Flavonol Kaempferol","volume":"34","author":"Huang","year":"2015","journal-title":"Protein J."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ming, D., Wang, D., Cao, F., Xiang, H., Mu, D., Cao, J., Li, B., Zhong, L., Dong, X., and Zhong, X. (2017). Kaempferol Inhibits the Primary Attachment Phase of Biofilm Formation in Staphylococcus aureus. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.02263"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.phytochem.2014.07.028","article-title":"Galloylated flavonol rhamnosides from the leaves of Calliandra tergemina with antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)","volume":"107","author":"Chan","year":"2014","journal-title":"Phytochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1128\/AAC.04564-14","article-title":"\u03c9-Hydroxyemodin Limits Staphylococcus aureus Quorum Sensing-Mediated Pathogenesis and Inflammation","volume":"59","author":"Daly","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Jiang, L., Yi, T., Shen, Z., Teng, Z., and Wang, J. (2019). Aloe-emodin Attenuates Staphylococcus aureus Pathogenicity by Interfering with the Oligomerization of \u03b1-Toxin. Front. Cell. Infect. Microbiol., 9.","DOI":"10.3389\/fcimb.2019.00157"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gong, G., Guan, Y.-Y., Zhang, Z.-L., Rahman, K., Wang, S.-J., Zhou, S., Luan, X., and Zhang, H. (2020). Isorhamnetin: A review of pharmacological effects. Biomed. Pharmacother., 128.","DOI":"10.1016\/j.biopha.2020.110301"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Liu, Z.-H., Wang, W.-M., Zhang, Z., Sun, L., and Wu, S.-C. (2022). Natural Antibacterial and Antivirulence Alkaloids From Macleaya cordata Against Methicillin-Resistant Staphylococcus aureus. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.813172"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.celrep.2019.03.018","article-title":"Apicidin Attenuates MRSA Virulence through Quorum-Sensing Inhibition and Enhanced Host Defense","volume":"27","author":"Parlet","year":"2019","journal-title":"Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e13004","DOI":"10.1111\/jfs.13004","article-title":"Effect of sub-lethal treatment of carvacrol and thymol on virulence potential and resistance to several bactericidal treatments of Staphylococcus aureus","volume":"42","author":"Kim","year":"2022","journal-title":"J. Food Saf."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"279","DOI":"10.5455\/jcmr.2020.11.01.31","article-title":"Evaluation of the effect of Carvacrol and Linalool on the growth of Staphylococcus aureus and E. coli enterotoxin and production of ent A and ent B toxins in Staphylococcus aureus and ST1 and ST2 toxins in E. coli enterotoxins","volume":"11","author":"Hayati","year":"2020","journal-title":"J. Complement. Med. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111498","DOI":"10.1016\/j.indcrop.2019.111498","article-title":"Antibacterial mechanism of oregano essential oil","volume":"139","author":"Cui","year":"2019","journal-title":"Ind. Crops Prod."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hao, Y., Li, J., and Shi, L. (2021). A Carvacrol-Rich Essential Oil Extracted From Oregano (Origanum vulgare \u201cHot & Spicy\u201d) Exerts Potent Antibacterial Effects Against Staphylococcus aureus. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.741861"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"28743","DOI":"10.1039\/D3RA02711B","article-title":"Carvacrol inhibits bacterial polysaccharide intracellular adhesin synthesis and biofilm formation of mucoid Staphylococcus aureus: An in vitro and in vivo study","volume":"13","author":"Peng","year":"2023","journal-title":"RSC Adv."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Mir, M., Ahmed, N., Permana, A.D., Rodgers, A.M., Donnelly, R.F., and Rehman, A. (2019). Enhancement in Site-Specific Delivery of Carvacrol against Methicillin Resistant Staphylococcus aureus Induced Skin Infections Using Enzyme Responsive Nanoparticles: A Proof of Concept Study. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11110606"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.sajb.2022.09.012","article-title":"Geraniol\u2014A review update","volume":"150","author":"Chen","year":"2022","journal-title":"S. Afr. J. Bot."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.2147\/IDR.S318989","article-title":"The Inhibitory Efficiencies of Geraniol as an Anti-Inflammatory, Antioxidant, and Antibacterial, Natural Agent Against Methicillin-Resistant Staphylococcus aureus Infection in vivo","volume":"14","author":"Lin","year":"2021","journal-title":"Infect. Drug Resist."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Gu, K., Ouyang, P., Hong, Y., Dai, Y., Tang, T., He, C., Shu, G., Liang, X., Tang, H., and Zhu, L. (2022). Geraniol inhibits biofilm formation of methicillin-resistant Staphylococcus aureus and increase the therapeutic effect of vancomycin in vivo. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.960728"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.chembiol.2014.12.016","article-title":"Converting a Staphylococcus aureus Toxin into Effective Cyclic Pseudopeptide Antibiotics","volume":"22","author":"Solecki","year":"2015","journal-title":"Chem. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ganesan, N., Mishra, B., Felix, L., and Mylonakis, E. (2023). Antimicrobial Peptides and Small Molecules Targeting the Cell Membrane of Staphylococcus aureus. Microbiol. Mol. Biol. Rev., 87.","DOI":"10.1128\/mmbr.00037-22"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1186\/s12967-025-06321-9","article-title":"Antimicrobial peptide biological activity, delivery systems and clinical translation status and challenges","volume":"23","author":"Zheng","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10039","DOI":"10.1007\/s11033-022-07572-1","article-title":"Antimicrobial peptides: Features, applications and the potential use against COVID-19","volume":"49","author":"Mabrouk","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Yang, Z., He, S., Wu, H., Yin, T., Wang, L., and Shan, A. (2021). Nanostructured Antimicrobial Peptides: Crucial Steps of Overcoming the Bottleneck for Clinics. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.710199"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ma, X., Wang, Q., Ren, K., Xu, T., Zhang, Z., Xu, M., Rao, Z., and Zhang, X. (2024). A Review of Antimicrobial Peptides: Structure, Mechanism of Action, and Molecular Optimization Strategies. Fermentation, 10.","DOI":"10.3390\/fermentation10110540"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Vieira, A.P.G.C., de Souza, A.N., Lima, W.G., Brito, J.C.M., Simi\u00e3o, D.C., Gon\u00e7alves, L.V.R., Cordeiro, L.P.B., de Oliveira Scoaris, D., Fernandes, S.O.A., and Resende, J.M. (2024). The Synthetic Peptide LyeTx I mn\u2206K, Derived from Lycosa erythrognatha Spider Toxin, Is Active against Methicillin-Resistant Staphylococcus aureus (MRSA) In Vitro and In Vivo. Antibiotics, 13.","DOI":"10.3390\/antibiotics13030248"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"100954","DOI":"10.1016\/j.drup.2023.100954","article-title":"Antimicrobial peptides for combating drug-resistant bacterial infections","volume":"68","author":"Xuan","year":"2023","journal-title":"Drug Resist. Updat."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Liu, L., Beck, C., N\u00f8hr-Meldgaard, K., Peschel, A., Kretschmer, D., Ingmer, H., and Vestergaard, M. (2020). Inhibition of the ATP synthase sensitizes Staphylococcus aureus towards human antimicrobial peptides. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-68146-4"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e00576-22","DOI":"10.1128\/msphere.00576-22","article-title":"Host Cationic Antimicrobial Molecules Inhibit S. aureus Exotoxin Production","volume":"8","author":"Schlievert","year":"2023","journal-title":"mSphere"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Vasilchenko, A.S., and Rogozhin, E.A. (2019). Sub-inhibitory Effects of Antimicrobial Peptides. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.01160"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Cogen, A.L., Yamasaki, K., Muto, J., Sanchez, K.M., Crotty Alexander, L., Tanios, J., Lai, Y., Kim, J.E., Nizet, V., and Gallo, R.L. (2010). Staphylococcus epidermidis Antimicrobial \u03b4-Toxin (Phenol-Soluble Modulin-\u03b3) Cooperates with Host Antimicrobial Peptides to Kill Group A Streptococcus. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008557"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1089\/mdr.2020.0196","article-title":"In Silico Evaluation of Human Cathelicidin LL-37 as a Novel Therapeutic Inhibitor of Panton-Valentine Leukocidin Toxin of Methicillin-Resistant Staphylococcus aureus","volume":"27","author":"Toor","year":"2021","journal-title":"Microb. Drug Resist."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Dlozi, P.N., Gladchuk, A., Crutchley, R.D., Keuler, N., Coetzee, R., and Dube, A. (2022). Cathelicidins and defensins antimicrobial host defense peptides in the treatment of TB and HIV: Pharmacogenomic and nanomedicine approaches towards improved therapeutic outcomes. Biomed. Pharmacother., 151.","DOI":"10.1016\/j.biopha.2022.113189"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Qiu, Y., Chu, A.J., Tsang, T.F., Zheng, Y., Lam, N.M., Li, K.S.L., Ip, M., Yang, X., and Ma, C. (2022). Synthesis and biological evaluation of nusbiarylin derivatives as bacterial rRNA synthesis inhibitor with potent antimicrobial activity against MRSA and VRSA. Bioorg. Chem., 124.","DOI":"10.1016\/j.bioorg.2022.105863"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Gherardi, G. (2023). Staphylococcus aureus Infection: Pathogenesis and Antimicrobial Resistance. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24098182"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Clegg, J., Soldaini, E., McLoughlin, R.M., Rittenhouse, S., Bagnoli, F., and Phogat, S. (2021). Staphylococcus aureus Vaccine Research and Development: The Past, Present and Future, Including Novel Therapeutic Strategies. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.705360"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Liu, F., Guan, Z., Liu, Y., Li, J., Liu, C., Gao, Y., Ma, Y., Feng, J., Shen, B., and Yang, G. (2021). Identification of a Human Anti-Alpha-Toxin Monoclonal Antibody Against Staphylococcus aureus Infection. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.692279"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4526","DOI":"10.1128\/AAC.00510-15","article-title":"MEDI4893* Promotes Survival and Extends the Antibiotic Treatment Window in a Staphylococcus aureus Immunocompromised Pneumonia Model","volume":"59","author":"Hua","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2083467","DOI":"10.1080\/19420862.2022.2083467","article-title":"Antigenic landscapes on Staphylococcus aureus pore-forming toxins reveal insights into specificity and cross-neutralization","volume":"14","author":"Kailasan","year":"2022","journal-title":"MAbs"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1080\/21505594.2017.1391447","article-title":"Disarming Staphylococcus aureus from destroying human cells by simultaneously neutralizing six cytotoxins with two human monoclonal antibodies","volume":"9","author":"Rouha","year":"2018","journal-title":"Virulence"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e00968-17","DOI":"10.1128\/AAC.00968-17","article-title":"Commercial Intravenous Immunoglobulin Preparations Contain Functional Neutralizing Antibodies against the Staphylococcus aureus Leukocidin LukAB (LukGH)","volume":"61","author":"Wood","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.jiac.2017.12.023","article-title":"Effective concentration of intravenous immunoglobulin for neutralizing Panton-Valentine leukocidin in human blood","volume":"24","author":"Tanaka","year":"2018","journal-title":"J. Infect. Chemother."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1080\/21645515.2020.1744362","article-title":"Determining the immunological characteristics of a novel human monoclonal antibody developed against staphylococcal enterotoxin B","volume":"16","author":"Liu","year":"2020","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1080\/21505594.2016.1231295","article-title":"Monoclonal antibodies protect from Staphylococcal Enterotoxin K (SEK) induced toxic shock and sepsis by USA300 Staphylococcus aureus","volume":"8","author":"Aguilar","year":"2017","journal-title":"Virulence"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/femsre\/fuz030","article-title":"Development of a vaccine against Staphylococcus aureus invasive infections: Evidence based on human immunity, genetics and bacterial evasion mechanisms","volume":"44","author":"Miller","year":"2020","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1084\/jem.20072208","article-title":"Vaccine protection against Staphylococcus aureus pneumonia","volume":"205","author":"Wardenburg","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3390\/microbiolres15010009","article-title":"Updates on Staphylococcal Vaccines","volume":"15","author":"Popa","year":"2023","journal-title":"Microbiol. Res. (Pavia)"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"8702","DOI":"10.1038\/s41467-024-52714-7","article-title":"Enhanced Staphylococcus aureus protection by uncoupling of the \u03b1-toxin-ADAM10 interaction during murine neonatal vaccination","volume":"15","author":"Tomaszewski","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Adhikari, R.P., Kort, T., Shulenin, S., Kanipakala, T., Ganjbaksh, N., Roghmann, M.-C., Holtsberg, F.W., and Aman, M.J. (2015). Antibodies to S. aureus LukS-PV Attenuated Subunit Vaccine Neutralize a Broad Spectrum of Canonical and Non-Canonical Bicomponent Leukotoxin Pairs. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0143493"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1080\/21645515.2016.1248326","article-title":"Safety and immunogenicity of a recombinant Staphylococcus aureus \u03b1 -toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults","volume":"13","author":"Landrum","year":"2017","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Venkatasubramaniam, A., Liao, G., Cho, E., Adhikari, R.P., Kort, T., Holtsberg, F.W., Elsass, K.E., Kobs, D.J., Rudge, T.L., and Kauffman, K.D. (2021). Safety and Immunogenicity of a 4-Component Toxoid-Based Staphylococcus aureus Vaccine in Rhesus Macaques. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.621754"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Wu, X., Wang, H., Xiong, J., Yang, G.-X., Hu, J.-F., Zhu, Q., and Chen, Z. (2024). Staphylococcus aureus biofilm: Formulation, regulatory, and emerging natural products-derived therapeutics. Biofilm, 7.","DOI":"10.1016\/j.bioflm.2023.100175"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Roetzer, A., Stich, N., Model, N., Schwameis, M., Firbas, C., Jilma, B., and Eibl, M.M. (2020). High Titer Persistent Neutralizing Antibodies Induced by TSST-1 Variant Vaccine Against Toxic Shock Cytokine Storm. Toxins, 12.","DOI":"10.3390\/toxins12100640"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"102404","DOI":"10.1016\/j.eclinm.2023.102404","article-title":"A randomized, double-blind study on the safety and immunogenicity of rTSST-1 variant vaccine: Phase 2 results","volume":"67","author":"Schoergenhofer","year":"2024","journal-title":"eClinicalMedicine"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1701366","DOI":"10.1002\/adhm.201701366","article-title":"Broad-Spectrum Neutralization of Pore-Forming Toxins with Human Erythrocyte Membrane-Coated Nanosponges","volume":"7","author":"Chen","year":"2018","journal-title":"Adv. Healthc. Mater."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1021\/acsnano.0c01665","article-title":"Cell-Membrane-Mimicking Nanodecoys against Infectious Diseases","volume":"14","author":"Rao","year":"2020","journal-title":"ACS Nano"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/nnano.2013.54","article-title":"A biomimetic nanosponge that absorbs pore-forming toxins","volume":"8","author":"Hu","year":"2013","journal-title":"Nat. Nanotechnol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"10980","DOI":"10.1073\/pnas.1106634108","article-title":"Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform","volume":"108","author":"Hu","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"4235","DOI":"10.1016\/j.apsb.2022.03.015","article-title":"Broad-spectrum and powerful neutralization of bacterial toxins by erythroliposomes with the help of macrophage uptake and degradation","volume":"12","author":"Liu","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Wolfmeier, H., Wardell, S.J.T., Liu, L.T., Falsafi, R., Draeger, A., Babiychuk, E.B., Pletzer, D., and Hancock, R.E.W. (2022). Targeting the Pseudomonas aeruginosa Virulence Factor Phospholipase C With Engineered Liposomes. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.867449"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1039\/D0TB02036B","article-title":"Combinatorial liposomes of berberine and curcumin inhibit biofilm formation and intracellular methicillin resistant Staphylococcus aureus infections and associated inflammation","volume":"9","author":"Bhatia","year":"2021","journal-title":"J. Mater. Chem. B"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Jabir, M.S., Rashid, T.M., Nayef, U.M., Albukhaty, S., AlMalki, F.A., Albaqami, J., AlYamani, A.A., Taqi, Z.J., and Sulaiman, G.M. (2022). Inhibition of Staphylococcus aureus \u03b1-Hemolysin Production Using Nanocurcumin Capped Au@ZnO Nanocomposite. Bioinorg. Chem. Appl., 2022.","DOI":"10.1155\/2022\/2663812"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.foodcont.2019.01.030","article-title":"Effect of AgWPA nanoparticles on the inhibition of Staphylococcus aureus growth in biofilms","volume":"100","author":"Liang","year":"2019","journal-title":"Food Control"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Yau, J.W., Teoh, H., and Verma, S. (2015). Endothelial cell control of thrombosis. BMC Cardiovasc. Disord., 15.","DOI":"10.1186\/s12872-015-0124-z"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s00441-021-03471-2","article-title":"Endothelial cells and coagulation","volume":"387","author":"Neubauer","year":"2022","journal-title":"Cell Tissue Res."},{"key":"ref_85","first-page":"319","article-title":"Mechanism Action of Platelets and Crucial Blood Coagulation Pathways in Hemostasis","volume":"11","author":"Periayah","year":"2017","journal-title":"Int J Hematol Oncol Stem Cell Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1161\/CIRCRESAHA.117.310795","article-title":"Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis","volume":"122","author":"Koupenova","year":"2018","journal-title":"Circ. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1172\/JCI60229","article-title":"New insights into the mechanisms of venous thrombosis","volume":"122","author":"Mackman","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Tsantes, A.G., Parastatidou, S., Tsantes, E.A., Bonova, E., Tsante, K.A., Mantzios, P.G., Vaiopoulos, A.G., Tsalas, S., Konstantinidi, A., and Houhoula, D. (2023). Sepsis-Induced Coagulopathy: An Update on Pathophysiology, Biomarkers, and Current Guidelines. Life, 13.","DOI":"10.3390\/life13020350"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e843","DOI":"10.1002\/ams2.843","article-title":"Sepsis-induced disseminated intravascular coagulation: An international estrangement of disease concept","volume":"10","author":"Ushio","year":"2023","journal-title":"Acute Med. Surg."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Cieza, M.Y.R., Bonsaglia, E.C.R., Rall, V.L.M., Santos, M.V.d., and Silva, N.C.C. (2024). Staphylococcal Enterotoxins: Description and Importance in Food. Pathogens, 13.","DOI":"10.3390\/pathogens13080676"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.3390\/toxins2082117","article-title":"Multiple Roles of Staphylococcus aureus Enterotoxins: Pathogenicity, Superantigenic Activity, and Correlation to Antibiotic Resistance","volume":"2","author":"Ortega","year":"2010","journal-title":"Toxins"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1365-3083.2011.02638.x","article-title":"Increased T Cell Chemotaxis Response to Staphylococcus Enterotoxin B Mediated Human Endothelial Cell Damage In Vitro","volume":"75","author":"Xiao","year":"2012","journal-title":"Scand. J. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"759","DOI":"10.4161\/viru.23905","article-title":"The staphylococcal enterotoxin (SE) family","volume":"4","author":"Krakauer","year":"2013","journal-title":"Virulence"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4865","DOI":"10.1128\/IAI.68.9.4865-4871.2000","article-title":"Adherence of Staphylococcus aureus to Endothelial Cells: Influence of Capsular Polysaccharide, Global Regulator agr, and Bacterial Growth Phase","volume":"68","author":"Ulrich","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Kwiecinski, J.M., Crosby, H.A., Valotteau, C., Hippensteel, J.A., Nayak, M.K., Chauhan, A.K., Schmidt, E.P., Dufr\u00eane, Y.F., and Horswill, A.R. (2019). Staphylococcus aureus adhesion in endovascular infections is controlled by the ArlRS\u2013MgrA signaling cascade. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007800"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.ijmm.2013.09.006","article-title":"Early Staphylococcus aureus-induced changes in endothelial barrier function are strain-specific and unrelated to bacterial translocation","volume":"303","author":"Kramko","year":"2013","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Alfeo, M.J., Pagotto, A., Barbieri, G., Foster, T.J., Vanhoorelbeke, K., De Filippis, V., Speziale, P., and Pietrocola, G. (2021). Staphylococcus aureus iron-regulated surface determinant B (IsdB) protein interacts with von Willebrand factor and promotes adherence to endothelial cells. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-02065-w"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1093\/infdis\/jis192","article-title":"ADAM10 Mediates Vascular Injury Induced by Staphylococcus aureus \u03b1-Hemolysin","volume":"206","author":"Powers","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Tran, P.M., Tang, S.S., and Salgado-Pab\u00f3n, W. (2022). Staphylococcus aureus \u03b2-Toxin Exerts Anti-angiogenic Effects by Inhibiting Re-endothelialization and Neovessel Formation. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.840236"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.chom.2019.01.015","article-title":"Staphylococcus aureus Leukocidins Target Endothelial DARC to Cause Lethality in Mice","volume":"25","author":"Lubkin","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Li, L., Pian, Y., Chen, S., Hao, H., Zheng, Y., Zhu, L., Xu, B., Liu, K., Li, M., and Jiang, H. (2016). Phenol-soluble modulin \u03b14 mediates Staphylococcus aureus-associated vascular leakage by stimulating heparin-binding protein release from neutrophils. Sci. Rep., 6.","DOI":"10.1038\/srep29373"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"10.1128","DOI":"10.1128\/microbiolspec.GPP3-0039-2018","article-title":"Staphylococcus aureus Secreted Toxins and Extracellular Enzymes","volume":"7","author":"Tam","year":"2019","journal-title":"Microbiol. Spectr."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1159\/000333447","article-title":"Staphylococcus aureus Secretes Coagulase and von Willebrand Factor Binding Protein to Modify the Coagulation Cascade and Establish Host Infections","volume":"4","author":"McAdow","year":"2012","journal-title":"J. Innate Immun."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Niemann, S., Bertling, A., Brodde, M.F., Fender, A.C., Van de Vyver, H., Hussain, M., Holzinger, D., Reinhardt, D., Peters, G., and Heilmann, C. (2018). Panton-Valentine Leukocidin associated with S. aureus osteomyelitis activates platelets via neutrophil secretion products. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-20582-z"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Cical\u0103u, G., Babes, P., Calniceanu, H., Popa, A., Ciavoi, G., Iova, G., Ganea, M., and Scrobot\u0103, I. (2021). Anti-Inflammatory and Antioxidant Properties of Carvacrol and Magnolol, in Periodontal Disease and Diabetes Mellitus. Molecules, 26.","DOI":"10.3390\/molecules26226899"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1007\/s10787-022-01039-2","article-title":"New insights into geraniol\u2019s antihemolytic, anti-inflammatory, antioxidant, and anticoagulant potentials using a combined biological and in silico screening strategy","volume":"30","author":"Saleh","year":"2022","journal-title":"Inflammopharmacology"},{"key":"ref_107","first-page":"785","article-title":"Thrombosis and platelets: An update","volume":"38","author":"Koupenova","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1111\/j.1538-7836.2005.01488.x","article-title":"Platelets in atherothrombosis: Lessons from mouse models","volume":"3","author":"Nieswandt","year":"2005","journal-title":"J. Thromb. Haemost."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s12199-020-00905-1","article-title":"Resveratrol inhibits Ca2+ signals and aggregation of platelets","volume":"25","author":"Marumo","year":"2020","journal-title":"Environ. Health Prev. Med."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Wici\u0144ski, M., Socha, M., Walczak, M., W\u00f3dkiewicz, E., Malinowski, B., Rewerski, S., G\u00f3rski, K., and Pawlak-Osi\u0144ska, K. (2018). Beneficial Effects of Resveratrol Administration\u2014Focus on Potential Biochemical Mechanisms in Cardiovascular Conditions. Nutrients, 10.","DOI":"10.3390\/nu10111813"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Huang, M., Deng, M., Nie, W., Zou, D., Wu, H., and Xu, D. (2021). Naringenin Inhibits Platelet Activation and Arterial Thrombosis Through Inhibition of Phosphoinositide 3-Kinase and Cyclic Nucleotide Signaling. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.722257"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2970","DOI":"10.1021\/jf0723209","article-title":"Apigenin Inhibits Platelet Adhesion and Thrombus Formation and Synergizes with Aspirin in the Suppression of the Arachidonic Acid Pathway","volume":"56","author":"Lozano","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_113","first-page":"ZC19","article-title":"Antimicrobial Effects of Garcinia Mangostana on Cariogenic Microorganisms","volume":"11","author":"Janardhanan","year":"2017","journal-title":"J. Clin. Diagn Res."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Espirito Santo, B.L.S.d., Santana, L.F., Kato Junior, W.H., de Ara\u00fajo, F.d.O., Bogo, D., Freitas, K.d.C., Guimar\u00e3es, R.d.C.A., Hiane, P.A., Pott, A., and Fili\u00fa, W.F.d.O. (2020). Medicinal Potential of Garcinia Species and Their Compounds. Molecules, 25.","DOI":"10.3390\/molecules25194513"},{"key":"ref_115","first-page":"2699","article-title":"Inhibitory effects of the extracts of Garcinia species on human low-density lipoprotein peroxidation and platelet aggregation in relation to their total phenolic contents","volume":"5","author":"Jantan","year":"2011","journal-title":"J. Med. Plants Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1017\/S0007114508061539","article-title":"Virgin olive oil polyphenol hydroxytyrosol acetate inhibits in vitro platelet aggregation in human whole blood: Comparison with hydroxytyrosol and acetylsalicylic acid","volume":"101","author":"Asensi","year":"2008","journal-title":"Br. J. Nutr."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Vijakumaran, U., Yazid, M.D., Hj Idrus, R.B., Abdul Rahman, M.R., and Sulaiman, N. (2021). Molecular Action of Hydroxytyrosol in Attenuation of Intimal Hyperplasia: A Scoping Review. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.663266"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1248\/bpb.25.1328","article-title":"Antithrombotic and Antiallergic Activities of Daidzein, a Metabolite of Puerarin and Daidzin Produced by Human Intestinal Microflora","volume":"25","author":"Choo","year":"2002","journal-title":"Biol. Pharm. Bull."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.fitote.2014.07.006","article-title":"Antithrombotic activities of wogonin and wogonoside via inhibiting platelet aggregation","volume":"98","author":"Ku","year":"2014","journal-title":"Fitoterapia"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1007\/s12551-020-00769-3","article-title":"Interaction of the putative anticancer alkaloid chelerythrine with nucleic acids: Biophysical perspectives","volume":"12","author":"Basu","year":"2020","journal-title":"Biophys. Rev."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.atherosclerosis.2014.12.048","article-title":"Histone deacetylases and atherosclerosis","volume":"240","author":"Zheng","year":"2015","journal-title":"Atherosclerosis"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s11239-012-0831-6","article-title":"Histone deacetylase inhibitors stimulate tissue-type plasminogen activator production in vascular endothelial cells","volume":"35","author":"Larsson","year":"2013","journal-title":"J. Thromb. Thrombolysis"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/17\/7\/340\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:04:39Z","timestamp":1760033079000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/17\/7\/340"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,4]]},"references-count":122,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["toxins17070340"],"URL":"https:\/\/doi.org\/10.3390\/toxins17070340","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,4]]}}}