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In this study, piperine isolated from the fruits of Piper nigrum showed anti-Candida activity. Furthermore, the mechanisms of action of piperine and its impact on virulence factors in Candida albicans, which have not been comprehensively understood, were also assessed. Initially, piperine suppressed the hyphal transition in both liquid and solid media, hindered biofilm formation, and resulted in observable cell distortions in scanning electron microscope (SEM) samples, for both fluconazole-sensitive and fluconazole-resistant C. albicans strains. Additionally, the morphogenetic switches triggered by piperine were found to rely on the activity of mutant C. albicans strains. Secondly, piperine treatment increased cell membrane permeability and disrupted mitochondrial membrane potential, as evidenced by propidium iodine and Rhodamine 123 staining, respectively. Moreover, it induced the accumulation of intracellular reactive oxygen species in C. albicans. Synergy was obtained between the piperine and the fluconazole against the fluconazole-sensitive strain. Interestingly, there were no hemolytic effects of piperine, and it resulted in reduced cytotoxicity on fibroblast cells at low concentrations. The results suggest that piperine could have a dual mode of action inhibiting virulence factors and modulating cellular processes, leading to cell death in C. albicans.<\/jats:p>","DOI":"10.3390\/biom13121729","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T09:39:12Z","timestamp":1701337152000},"page":"1729","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Exploring the Potential Mechanism of Action of Piperine against Candida albicans and Targeting Its Virulence Factors"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6855-0770","authenticated-orcid":false,"given":"Claudia Patricia","family":"Bravo-Chaucan\u00e9s","sequence":"first","affiliation":[{"name":"Unidad de Prote\u00f3mica y Micosis Humanas, Grupo de Enfermedades Infecciosas, Departamento de Microbiolog\u00eda, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogot\u00e1 110231, DC, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1422-5545","authenticated-orcid":false,"given":"Luis Carlos","family":"Chitiva","sequence":"additional","affiliation":[{"name":"Grupo de Investigaci\u00f3n Fitoqu\u00edmica Universidad Javeriana (GIFUJ), Departamento de Qu\u00edmica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogot\u00e1 110231, DC, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4788-8150","authenticated-orcid":false,"given":"Yerly","family":"Vargas-Casanova","sequence":"additional","affiliation":[{"name":"Unidad de Prote\u00f3mica y Micosis Humanas, Grupo de Enfermedades Infecciosas, Departamento de Microbiolog\u00eda, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogot\u00e1 110231, DC, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9804-2254","authenticated-orcid":false,"given":"Valentina","family":"Diaz-Santoyo","sequence":"additional","affiliation":[{"name":"Unidad de Prote\u00f3mica y Micosis Humanas, Grupo de Enfermedades Infecciosas, Departamento de Microbiolog\u00eda, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogot\u00e1 110231, DC, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0856-2643","authenticated-orcid":false,"given":"Andrea Ximena","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Grupo de Investigaci\u00f3n Fitoqu\u00edmica Universidad Javeriana (GIFUJ), Departamento de Qu\u00edmica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogot\u00e1 110231, DC, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2449-1986","authenticated-orcid":false,"given":"Geison M.","family":"Costa","sequence":"additional","affiliation":[{"name":"Grupo de Investigaci\u00f3n Fitoqu\u00edmica Universidad Javeriana (GIFUJ), Departamento de Qu\u00edmica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogot\u00e1 110231, DC, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1302-5429","authenticated-orcid":false,"given":"Claudia Marcela","family":"Parra-Giraldo","sequence":"additional","affiliation":[{"name":"Unidad de Prote\u00f3mica y Micosis Humanas, Grupo de Enfermedades Infecciosas, Departamento de Microbiolog\u00eda, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogot\u00e1 110231, DC, Colombia"},{"name":"Departamento de Microbiolog\u00eda y Parasitolog\u00eda, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1146\/annurev-micro-091014-104330","article-title":"Candida albicans Biofilms and Human Disease","volume":"69","author":"Nobile","year":"2015","journal-title":"Annu. 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