{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:30:52Z","timestamp":1793831452283,"version":"4.6.1"},"reference-count":39,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scientific Research Project Unit of Mersin University","award":["2023-1-AP3-4843"],"award-info":[{"award-number":["2023-1-AP3-4843"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Increasing antifungal resistance and side effects of existing drugs demand alternative approaches for treating Candida (C.) infections. This study aimed to comprehensively evaluate the antifungal efficacy of myricetin (MYR), a natural flavonoid, against both fluconazole (FLC)-resistant and susceptible clinical Candida strains, with a particular focus on its inhibitory effects on C. albicans biofilms. Antifungal susceptibility was evaluated on Candida spp. by the broth microdilution method, and the impact of myricetin on C. albicans biofilms was determined using the Cell Counting Kit-8 (CCK-8) assay. To understand the molecular mechanisms underlying the antibiofilm properties of myricetin, expression analysis of genes in the RAS1\/cAMP\/EFG1 pathway (ALS3, HWP1, ECE1, UME6, HGC1) and cAMP-dependent protein kinase regulation (RAS1, CYR1, EFG1) involved in the transition from yeast to hyphae was performed. Field emission scanning electron microscopy (FESEM) was used to study the ultrastructural changes and morphological dynamics of Candida biofilms after exposure to MYR and FLC. The in vivo toxicity of myricetin was evaluated by survival analysis using the Galleria mellonella model. Myricetin significantly suppressed key genes related to hyphae development (RAS1, CYR1, EFG1, UME6, and HGC1) and adhesion (ALS3 and HWP1) in both clinical and reference Candida strains at a concentration of 640 \u00b5g\/mL. FESEM analysis revealed that myricetin inhibited hyphae growth and elongation in C. albicans. This study highlights the promising antibiofilm potential of myricetin through a significant inhibition of biofilm formation and hyphal morphogenesis.<\/jats:p>","DOI":"10.3390\/jof11050398","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T06:31:27Z","timestamp":1747809087000},"page":"398","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Myricetin Exerts Antibiofilm Effects on Candida albicans by Targeting the RAS1\/cAMP\/EFG1 Pathway and Disruption of the Hyphal Network"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5628-6154","authenticated-orcid":false,"given":"Melda","family":"Meral Ocal","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Faculty of Science, Mersin University, Mersin 33343, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1522-6083","authenticated-orcid":false,"given":"Merve","family":"Aydin","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan 24100, Turkey"},{"name":"Department of Medical Microbiology, Faculty of Medicine, KTO Karatay University, Konya 42020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5004-5958","authenticated-orcid":false,"given":"Esra","family":"Sumlu","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology, Faculty of Medicine, KTO Karatay University, Konya 42020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7034-4130","authenticated-orcid":false,"given":"Emine Nedime","family":"Korucu","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Science, Necmettin Erbakan University, Konya 42090, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2428-1831","authenticated-orcid":false,"given":"Ali","family":"Ozturk","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine, Nigde Omer Halisdemir University, Nigde 51240, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kim, D.J., Lee, M.W., Choi, J.S., Lee, S.G., Park, J.Y., and Kim, S.W. (2017). Inhibitory activity of hinokitiol against biofilm formation in fluconazole-resistant Candida species. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171244"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"ftw018","DOI":"10.1093\/femspd\/ftw018","article-title":"Pathogenesis of Candida albicans biofilm","volume":"74","author":"Tsui","year":"2016","journal-title":"Pathog. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Q-Malinovsk\u00e1, Z., \u010conkov\u00e1, E., and V\u00e1czi, P. (2023). Biofilm formation in medically important Candida species. J. Fungi, 9.","DOI":"10.3390\/jof9100955"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.idc.2015.10.013","article-title":"Invasive Candidiasis","volume":"30","author":"McCarty","year":"2016","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"de Almeida, R.F.M., Santos, F.C., Marycz, K., Alicka, M., Krasowska, A., Suchodolski, J., Panek, J.J., Jezierska, A., and Starosta, R. (2019). New diphenylphosphane derivatives of ketoconazole are promising antifungal agents. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-52525-7"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1111\/tmi.12577","article-title":"Candida species epidemiology 2000\u20132013: A laboratory-based report","volume":"20","author":"Ng","year":"2015","journal-title":"Trop. Med. Int. Health"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Cerdeira, C., Mart\u00ednez-Herrera, E., Carnero-Gregorio, M., L\u00f3pez-Barcenas, A., Fabbrocini, G., Fida, M., El-Samahy, M., and Gonz\u00e1lez-Cesp\u00f3n, J.L. (2020). Pathogenesis and clinical relevance of Candida biofilms in vulvovaginal candidiasis. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.544480"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.tim.2016.09.004","article-title":"Portrait of Candida species biofilm regulatory network genes","volume":"25","author":"Henriques","year":"2017","journal-title":"Trends Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1007\/s12033-023-00796-x","article-title":"Molecular Determinants Involved in Candida albicans Biofilm Formation and Regulation","volume":"66","author":"Kumar","year":"2024","journal-title":"Mol. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.micinf.2016.01.002","article-title":"Candida albicans biofilms: Development, regulation, and molecular mechanisms","volume":"18","author":"Gulati","year":"2016","journal-title":"Microbes Infect."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Glazier, V.E. (2022). EFG1, everyone\u2019s favorite gene in Candida albicans: A comprehensive literature review. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.855229"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/j.1567-1364.2008.00459.x","article-title":"UME6 is a crucial downstream target of other transcriptional regulators of true hyphal development in Candida albicans","volume":"9","author":"Zeidler","year":"2009","journal-title":"FEMS Yeast Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sumlu, E., Aydin, M., Korucu, E.N., Alyar, S., and Nsangou, A.M. (2024). Artemisinin May Disrupt Hyphae Formation by Suppressing Biofilm-Related Genes of Candida albicans: In Vitro and In Silico Approaches. Antibiotics, 13.","DOI":"10.3390\/antibiotics13040310"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ajetunmobi, O.H., Badali, H., Romo, J.A., Ramage, G., and Lopez-Ribot, J.L. (2023). Antifungal therapy of Candida biofilms: Past, present and future. Biofilm, 5.","DOI":"10.1016\/j.bioflm.2023.100126"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.coph.2013.08.008","article-title":"Antifungal therapy with an emphasis on biofilms","volume":"13","author":"Pierce","year":"2013","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Roscetto, E., Contursi, P., Vollaro, A., Fusco, S., Notomista, E., and Catania, M.R. (2018). Antifungal and anti-biofilm activity of the first cryptic antimicrobial peptide from an archaeal protein against Candida spp. clinical isolates. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-35530-0"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s11101-018-9591-z","article-title":"Comprehensive review of antimicrobial activities of plant flavonoids","volume":"18","author":"Bartoszewski","year":"2019","journal-title":"Phytochem. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"37","DOI":"10.4014\/jmb.2110.10014","article-title":"Myricetin Disturbs the Cell Wall Integrity and Increases the Membrane Permeability of Candida albicans","volume":"32","author":"Lee","year":"2022","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"17903","DOI":"10.3390\/molecules201017903","article-title":"Activity of Polyphenolic Compounds against Candida glabrata","volume":"20","year":"2015","journal-title":"Molecules"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rocha, G.R., Florez Salamanca, E.J., de Barros, A.L., Lobo, C.I.V., and Klein, M.I. (2018). Effect of tt-farnesol and myricetin on in vitro biofilm formation by Streptococcus mutans and Candida albicans. BMC Complement. Altern. Med., 18.","DOI":"10.1186\/s12906-018-2132-x"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"153223","DOI":"10.1016\/j.phymed.2020.153223","article-title":"In vitro and in vivo effects of the combination of myricetin and miconazole nitrate incorporated into thermosensitive hydrogels on C. albicans biofilms","volume":"71","author":"Mo","year":"2020","journal-title":"Phytomedicine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1055\/a-1224-3625","article-title":"Current Pharmacological Trends on Myricetin","volume":"70","author":"Gupta","year":"2020","journal-title":"Drug Res."},{"key":"ref_23","unstructured":"Clinical and Laboratory Standards Institute (2012). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, CLSI. Fourth Informational Supplement."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Aydin, M., Unusan, N., Sumlu, E., and Korucu, E.N. (2024). Rosmarinic Acid Exhibits Antifungal and Antibiofilm Activities Against Candida albicans: Insights into Gene Expression and Morphological Changes. J. Fungi, 10.","DOI":"10.3390\/jof10110751"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/j.1600-0463.2007.apm_630.x","article-title":"Quantification of biofilm in microtiter plates: Overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci","volume":"115","author":"Stepanovic","year":"2007","journal-title":"APMIS"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1099\/mic.0.037549-0","article-title":"Pseudomonas aeruginosa secreted factors impair biofilm development in Candida albicans","volume":"156","author":"Holcombe","year":"2010","journal-title":"Microbiology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e00527-18","DOI":"10.1128\/IAI.00527-18","article-title":"Comparative Analysis of the Capacity of the Candida Species to Elicit Vaginal Immunopathology","volume":"86","author":"Willems","year":"2018","journal-title":"Infect. Immun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"473","DOI":"10.3109\/13693786.2012.743051","article-title":"The inhibitory activity of linalool against the filamentous growth and biofilm formation in Candida albicans","volume":"51","author":"Hsu","year":"2013","journal-title":"Med. Mycol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4078","DOI":"10.1128\/JCM.01377-09","article-title":"Characteristics of Candida albicans biofilms grown in a synthetic urine medium","volume":"47","author":"Uppuluri","year":"2009","journal-title":"J. Clin. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1128\/EC.00042-10","article-title":"Differential filamentation of Candida albicans and Candida dubliniensis is governed by nutrient regulation of UME6 expression","volume":"9","author":"Caplice","year":"2010","journal-title":"Eukaryot. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Song, X., Tan, L., Wang, M., Ren, C., Guo, C., Yang, B., Ren, Y., Cao, Z., Li, Y., and Pei, J. (2021). Myricetin: A review of the most recent research. Biomed. Pharmacother., 134.","DOI":"10.1016\/j.biopha.2020.111017"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5854","DOI":"10.1002\/fsn3.2513","article-title":"Myricetin: A comprehensive review on its biological potentials","volume":"9","author":"Imran","year":"2021","journal-title":"Food Sci. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Aboody, M.S.A., and Mickymaray, S. (2020). Anti-Fungal Efficacy and Mechanisms of Flavonoids. Antibiotics, 9.","DOI":"10.3390\/antibiotics9020045"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.mib.2019.04.005","article-title":"Regulatory mechanisms controlling morphology and pathogenesis in Candida albicans","volume":"52","author":"Kadosh","year":"2019","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/mmi.14148","article-title":"Multiple roles and diverse regulation of the Ras\/cAMP\/protein kinase A pathway in Candida albicans","volume":"111","author":"Huang","year":"2019","journal-title":"Mol. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chow, E.W.L., Pang, L.M., and Wang, Y. (2021). From Jekyll to Hyde: The Yeast-Hyphal Transition of Candida albicans. Pathogens, 10.","DOI":"10.20944\/preprints202106.0386.v1"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.tim.2014.09.001","article-title":"Candida albicans hyphal initiation and elongation","volume":"22","author":"Lu","year":"2014","journal-title":"Trends Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Marena, G.D., Thomaz, L., Nosanchuk, J.D., and Taborda, C.P. (2025). Galleria mellonella as an Invertebrate Model for Studying Fungal Infections. J. Fungi, 11.","DOI":"10.3390\/jof11020157"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Silva, L.N., Da Hora, G.C.A., Soares, T.A., Bojer, M.S., Ingmer, H., Macedo, A.J., and Trentin, D.S. (2017). Myricetin protects Galleria mellonella against Staphylococcus aureus infection and inhibits multiple virulence factors. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-02712-1"}],"container-title":["Journal of Fungi"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2309-608X\/11\/5\/398\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:36:19Z","timestamp":1760031379000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2309-608X\/11\/5\/398"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,21]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["jof11050398"],"URL":"https:\/\/doi.org\/10.3390\/jof11050398","relation":{},"ISSN":["2309-608X"],"issn-type":[{"value":"2309-608X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,21]]}}}