{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T10:59:27Z","timestamp":1787828367779,"version":"build-2784847793"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T00:00:00Z","timestamp":1678665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31500037"],"award-info":[{"award-number":["31500037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["GDNRC [2021]054"],"award-info":[{"award-number":["GDNRC [2021]054"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2019A1515011829"],"award-info":[{"award-number":["2019A1515011829"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2019A1515011702"],"award-info":[{"award-number":["2019A1515011702"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong Provincial Special Fund for Marine Economic Development Project","award":["31500037"],"award-info":[{"award-number":["31500037"]}]},{"name":"Guangdong Provincial Special Fund for Marine Economic Development Project","award":["GDNRC [2021]054"],"award-info":[{"award-number":["GDNRC [2021]054"]}]},{"name":"Guangdong Provincial Special Fund for Marine Economic Development Project","award":["2019A1515011829"],"award-info":[{"award-number":["2019A1515011829"]}]},{"name":"Guangdong Provincial Special Fund for Marine Economic Development Project","award":["2019A1515011702"],"award-info":[{"award-number":["2019A1515011702"]}]},{"name":"Natural Science Foundation of Guangdong province","award":["31500037"],"award-info":[{"award-number":["31500037"]}]},{"name":"Natural Science Foundation of Guangdong province","award":["GDNRC [2021]054"],"award-info":[{"award-number":["GDNRC [2021]054"]}]},{"name":"Natural Science Foundation of Guangdong province","award":["2019A1515011829"],"award-info":[{"award-number":["2019A1515011829"]}]},{"name":"Natural Science Foundation of Guangdong province","award":["2019A1515011702"],"award-info":[{"award-number":["2019A1515011702"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Candida albicans is the main causal pathogen of fungal infections in human beings. Although diverse anti-C. albicans drugs have been explored, the drug resistance and side effects of these drugs are intensifying. Thus, it is urgent to explore new anti-C. albicans compounds from natural products. In this study, we identified trichoderma acid (TA), a compound from Trichoderma spirale with a strong inhibitory effect on C. albicans. Transcriptomic and iTRAQ-based proteomic analyses of TA-treated C. albicans in combination with scanning electronic microscopy and reactive oxygen species (ROS) detection were performed to investigate the potential targets of TA. The most significant differentially expressed genes and proteins after TA treatment were verified through Western blot analysis. Our results revealed that mitochondrial membrane potential, endoplasmic reticulum, ribosomes in the mitochondria, and cell walls were disrupted in TA-treated C. albicans, leading to the accumulation of ROS. The impaired enzymatic activities of superoxide dismutase further contributed to the increase in ROS concentration. The high concentration of ROS led to DNA damage and cell skeleton destruction. The expression levels of Rho-related GTP-binding protein RhoE (RND3), asparagine synthetase (ASNS), glutathione S-transferase, and heat shock protein 70 were significantly up-regulated in response to apoptosis and toxin stimulation. These findings suggest that RND3, ASNS, and supereoxide dismutase 5 are the potential targets of TA, as further demonstrated through Western blot analysis. The combination of transcriptomic, proteomic, and cellular analyses would provide clues for the anti-C. albicans mechanism of TA and the defensive response mechanism of C. albicans. TA is thus recognized as a promising new anti-C. albicans leading compound that alleviates the hazard of C. albicans infection in human beings.<\/jats:p>","DOI":"10.3390\/ijms24065445","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T05:36:21Z","timestamp":1678685781000},"page":"5445","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Potential Anti-Candida albicans Mechanism of Trichoderma Acid from Trichoderma spirale"],"prefix":"10.3390","volume":"24","author":[{"given":"Wei","family":"Ye","sequence":"first","affiliation":[{"name":"State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Institute of Microbiology, Guangdong Academy of Sciences, No. 100 Xianlie Middle Road, Yuexiu District, Guangzhou 510070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchan","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Institute of Microbiology, Guangdong Academy of Sciences, No. 100 Xianlie Middle Road, Yuexiu District, Guangzhou 510070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8945-9448","authenticated-orcid":false,"given":"Weimin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Institute of Microbiology, Guangdong Academy of Sciences, No. 100 Xianlie Middle Road, Yuexiu District, Guangzhou 510070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taomei","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Institute of Microbiology, Guangdong Academy of Sciences, No. 100 Xianlie Middle Road, Yuexiu District, Guangzhou 510070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuping","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Institute of Microbiology, Guangdong Academy of Sciences, No. 100 Xianlie Middle Road, Yuexiu District, Guangzhou 510070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengran","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Institute of Microbiology, Guangdong Academy of Sciences, No. 100 Xianlie Middle Road, Yuexiu District, Guangzhou 510070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saini","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Institute of Microbiology, Guangdong Academy of Sciences, No. 100 Xianlie Middle Road, Yuexiu District, Guangzhou 510070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqiong","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Institute of Microbiology, Guangdong Academy of Sciences, No. 100 Xianlie Middle Road, Yuexiu District, Guangzhou 510070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxin","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Institute of Microbiology, Guangdong Academy of Sciences, No. 100 Xianlie Middle Road, Yuexiu District, Guangzhou 510070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s12275-011-1064-7","article-title":"Candida albicans, a major human fungal pathogen","volume":"49","author":"Kim","year":"2011","journal-title":"J. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/S0966-842X(01)02094-7","article-title":"Virulence factors of Candida albicans","volume":"9","author":"Calderone","year":"2001","journal-title":"Trends Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1080\/21505594.2016.1163458","article-title":"The Cek1-mediated MAP kinase pathway regulates exposure of \u03b1-1,2 and \u03b2-1,2-mannosides in the cell wall of Candida albicans modulating immune recognition","volume":"7","author":"Roman","year":"2016","journal-title":"Virulence"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7070","DOI":"10.1074\/jbc.M116.714873","article-title":"Prostaglandins from cytosolic phospholipase A2\u03b1\/cyclooxygenase-1 pathway and mitogen-activated protein kinases regulate gene expression in Candida albicans-infected macrophages","volume":"291","author":"Yun","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jprot.2018.06.018","article-title":"Serum responsive proteome reveals correlation between oxidative phosphorylation and morphogenesis in Candida albicans ATCC10231","volume":"185","author":"Radfan","year":"2018","journal-title":"J. Proteom."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1517\/14656566.2010.493875","article-title":"Antifungals to treat Candida albicans","volume":"11","author":"Moudgal","year":"2018","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1517\/17460441.2013.807245","article-title":"Candidasis drug discovery and development: New approaches targeting virulence for discovery and identifying new drugs","volume":"8","author":"Pierce","year":"2013","journal-title":"Expert Opin. Drug Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.bjm.2016.06.009","article-title":"Extracellular phospholipase production of oral Candida albicans isolates from smokers, diabetics, asthmatics, denture wearers and healthy individuals following brief exposure to polyene, echinocandin and azole antimycotics","volume":"47","author":"Ellepola","year":"2016","journal-title":"Braz. J. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2174\/187152106774755554","article-title":"Azoles: Mode of antifungal action and resistance development. Effect of miconazole on endogenous reactive oxygen species production in Candida albicans","volume":"5","author":"Francois","year":"2006","journal-title":"Anti-Infect. Agents Med. Chem."},{"key":"ref_10","first-page":"158","article-title":"Anidulafungin: A potent antifungal that targets Candida and Aspergillus","volume":"13","author":"Mahmoud","year":"2005","journal-title":"Infect. Dis. Clin. Pract."},{"key":"ref_11","unstructured":"Serrano-Wu, M., Du, X., Balasubramanian, N., and Laurent-St, D.R. (2002). Novel Thio-Derivatives of Sordarin as Antifungal Agents. PCT International Application, WO2002022567."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1093\/jac\/dki268","article-title":"Activity of aminocandin (IP960) compared with amphotericin B and fluconazole in a neutropenic murine model of disseminated infection caused by afluconazole-resistant strain of Candida tropicalis","volume":"56","author":"Warn","year":"2005","journal-title":"J. Antimicrob. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.bbagen.2011.02.001","article-title":"Retigeric acid B exerts antifungal effect through enhanced reactive oxygen species and decreased cAMP","volume":"1810","author":"Chang","year":"2011","journal-title":"Biochim. Biophys. Acta (BBA)-Gen. Subj."},{"key":"ref_14","first-page":"654","article-title":"In vitro antifungal activity of dictamnine against Candida albicans","volume":"27","author":"Shi","year":"2011","journal-title":"J. Clin. Stomatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/nature17625","article-title":"Candidalysin is a fungal peptide toxin critical for mucosal infection","volume":"532","author":"Moyes","year":"2016","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.biocel.2017.02.006","article-title":"Nerol triggers mitochondrial dysfunction and disruption via elevation of Ca2+ and ROS in Candida albicans","volume":"85","author":"Tian","year":"2017","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"a019752","DOI":"10.1101\/cshperspect.a019752","article-title":"Mechanisms of antifungal drug resistance","volume":"5","author":"Cowen","year":"2014","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12275-009-0163-1","article-title":"Isolation and identification of anti-tumor constituents from an endophytic fungus of Baimuxiang (Aquilaria sinensis)","volume":"30","author":"Li","year":"2010","journal-title":"J. Microbiol."},{"key":"ref_19","unstructured":"Yamada, N. (2004). Octahydronaphthalene Derivative and Medicine. PCT International Application, WO200507-856 A1."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1046\/j.1365-2567.1996.d01-742.x","article-title":"The involvement of nitric oxide in the anti-Candida albicans activity of rat neutrophils","volume":"89","author":"Fierro","year":"1996","journal-title":"Immunology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1128\/iai.64.8.3127-3133.1996","article-title":"Peroxynitrite contributes to the candidacidal activity of nitric oxide-producing macrophages","volume":"64","author":"Balish","year":"1996","journal-title":"Infect. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Madariaga-Venegas, F., Fern\u00e1ndez-Soto, R., Duarte, L.F., Suarez, N., Delgadillo, D., Jara, J.A., Fern\u00e1ndez-Ramires, R., Urzua, B., and Molina-Berrios, B. (2018). A characterization of a novel antibiofilm effect of nitric oxide-releasing aspirin (NCX-4040) on Candida albicans isolates from denture stomatitis patients. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176755"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.cbi.2011.01.010","article-title":"ROS-Ca2+ is associated with mitochondria permeability transition pore involved in surfactin-induced MCF-7 cells apoptosis","volume":"190","author":"Cao","year":"2011","journal-title":"Chem.-Biol. Interact."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.phymed.2017.12.001","article-title":"Genistein induced anticancer effects on pancreatic cancer cell lines involves mitochondrial apoptosis, G0\/G1cell cycle arrest and regulation of stat3 signalling pathway","volume":"15","author":"Bi","year":"2018","journal-title":"Phytomedicine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1111\/febs.14186","article-title":"Bax, bak and beyond-mitochondrial performance in apoptosis","volume":"285","year":"2018","journal-title":"FEBS J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/1567-1364.12113","article-title":"Aging and cell death in the other yeasts, Schizosaccharomyces pombe and Candida albicans","volume":"14","author":"Li","year":"2014","journal-title":"FEMS Yeast Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.freeradbiomed.2016.09.014","article-title":"Endoplasmic reticulum-derived reactive oxygen species (ROS) is involved in toxicity of cell wall stress to Candida albicans","volume":"99","author":"Yu","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"586","DOI":"10.4162\/nrp.2015.9.6.586","article-title":"Cytoprotective effect of rhamnetin on miconazole-induced H9c2 cell damage","volume":"9","author":"Lee","year":"2015","journal-title":"Nutr. Res. Pract."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"235895","DOI":"10.1242\/jcs.235895","article-title":"Rnd3 interacts with TAO kinases and contributes to mitotic cell rounding and spindle positioning","volume":"133","author":"Garg","year":"2020","journal-title":"J. Cell Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1093\/jac\/dki105","article-title":"Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans","volume":"55","author":"Lee","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1007\/s00018-004-4464-6","article-title":"Hsp70 chaperones: Cellular functions and molecular mechanism","volume":"62","author":"Mayer","year":"2005","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jplph.2004.07.006","article-title":"Asparagine synthetase gene TaASN1 from wheat is up-regulated by salt stress, osmotic stress and ABA","volume":"162","author":"Wang","year":"2005","journal-title":"J. Plant Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.bbrc.2017.11.064","article-title":"Monoterpenoid perillyl a lcohol impairs metabolic flexibility of Candida albicans by inhibiting glyoxylate cycle","volume":"495","author":"Ansari","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.jfda.2016.12.014","article-title":"Evaluation of synergistic anticandidal and apoptotic effects of ferulic acid and caspofungin against Candida albicans","volume":"26","author":"Canturk","year":"2018","journal-title":"J. Food Drug Anal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1016\/S0968-0896(02)00038-X","article-title":"Anti-Candida albicans properties of novel benzoxazine analogues","volume":"10","author":"Fringuelli","year":"2002","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1007\/s10103-013-1473-4","article-title":"Photodynamic antimicrobial chemotherapy (pact) inhibits biofilm formation by Candida albicans, increasing both ROS production and membrane permeability","volume":"29","author":"Rosseti","year":"2014","journal-title":"Lasers Med. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.archoralbio.2016.08.030","article-title":"Review of flavonoids: A diverse group of natural compounds with anti-Candida albicans activity In Vitro","volume":"76","author":"Seleem","year":"2017","journal-title":"Arch. Oral Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mycmed.2016.10.002","article-title":"Anti-Candida albicans natural products, sources of new antifungal drugs: A review","volume":"27","author":"Zida","year":"2017","journal-title":"J. Mycol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Pistoia, E.S., Cosio, T., Campione, E., Pica, F., Volpe, A., Marino, D., Di Francesco, P., Monari, C., Fontana, C., and Favaro, M. (2022). All-Trans Retinoic Acid Effect on Candida albicans Growth and Biofilm Formation. J. Fungi, 8.","DOI":"10.3390\/jof8101049"},{"key":"ref_40","first-page":"519","article-title":"Macrolide antibiotics-Science Direct","volume":"7","author":"Kaneko","year":"2007","journal-title":"Compr. Med. Chem. II"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nrmicro3155","article-title":"Ribosome-targeting antibiotics and mechanisms of bacterial resistance","volume":"12","author":"Wilson","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.chembiol.2015.06.019","article-title":"Thiopeptide antibiotics exhibit a dual mode of action against intracellular pathogens by affecting both host and microbe","volume":"22","author":"Zheng","year":"2015","journal-title":"Chem. Biol."},{"key":"ref_43","first-page":"135","article-title":"Antimicrobial susceptibility testing by the Kirby-Bauer disc diffusion method","volume":"3","author":"Biemer","year":"1973","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1093\/jnci\/82.13.1107","article-title":"New colorimetric cytotoxicity assay for anticancerdrug screening","volume":"82","author":"Skenhan","year":"1990","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1016\/j.bbamcr.2016.05.016","article-title":"Effects of G6PD activity inhibition on the viability, ROS generation and mechanical properties of cervical cancer cells","volume":"1863","author":"Fang","year":"2016","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/nbt.3172","article-title":"Ballgown bridges the gap between transcriptome assembly and expression analysis","volume":"33","author":"Frazee","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"39007","DOI":"10.1038\/srep39007","article-title":"Bursaphelenchus xylophilus and B. mucronatus secretomes: A comparative proteomic analysis","volume":"6","author":"Cardoso","year":"2016","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5445\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:53:27Z","timestamp":1760122407000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5445"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,13]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065445"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065445","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,13]]}}}