{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T09:45:34Z","timestamp":1781775934935,"version":"3.54.5"},"reference-count":97,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>Leishmaniasis is a serious multifactorial parasitic disease with limited treatment options. Current chemotherapy is mainly consisted of drugs with serious drawbacks such as toxicity, variable efficacy and resistance. Alternative bioactive phytocompounds may provide a promising source for discovering new anti-leishmanial drugs. Extra Virgin Olive Oil (EVOO), a key-product in the Mediterranean diet, is rich in phenols which are associated with anti-inflammatory, anti-cancer and anti-microbial effects. In this study, we investigate the anti-leishmanial effect of Total Phenolic Fraction (TPF) derived from EVOO in both<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>systems by investigating the contributing mechanism of action.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methodology\/Principal findings<\/jats:title><jats:p>We tested the ability of TPF to cause apoptotic-like programmed cell death in<jats:italic>L<\/jats:italic>.<jats:italic>infantum<\/jats:italic>and<jats:italic>L<\/jats:italic>.<jats:italic>major<\/jats:italic>exponential-phase promastigotes by evaluating several apoptotic indices, such as reduction of proliferation rate, sub-G0\/G1 phase cell cycle arrest, phosphatidylserine externalization, mitochondrial transmembrane potential disruption and increased ROS production, by using flow cytometry and microscopy techniques. Moreover, we assessed the therapeutic effect of TPF in<jats:italic>L<\/jats:italic>.<jats:italic>major<\/jats:italic>-infected BALB\/c mice by determining skin lesions, parasite burden in popliteal lymph nodes,<jats:italic>Leishmania<\/jats:italic>-specific antibodies and biomarkers of tissue site cellular immune response, five weeks post-treatment termination. Our results show that TPF triggers cell-cycle arrest and apoptotic-like changes in<jats:italic>Leishmania<\/jats:italic>spp. promastigotes. Moreover, TPF treatment induces significant reduction of parasite burden in draining lymph nodes together with an antibody profile indicative of the polarization of Th1\/Th2 immune balance towards the protective Th1-type response, characterized by the presence of IFN-\u03b3-producing CD4+ T-cells and increased Tbx21\/GATA-3 gene expression ratio in splenocytes.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Conclusions\/Significance<\/jats:title><jats:p>TPF exhibits chemotherapeutic anti-leishmanial activity by inducing programmed cell death on cell-free promastigotes and immunomodulatory properties that induce<jats:italic>in vivo<\/jats:italic>T cell-mediated responses towards the protective Th1 response in experimental cutaneous leishmaniasis. These findings enable deeper understanding of TPF\u2019s dual mode of action that encourages further studies.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pntd.0008968","type":"journal-article","created":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T21:39:19Z","timestamp":1610401159000},"page":"e0008968","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Total Phenolic Fraction (TPF) from Extra Virgin Olive Oil: Induction of apoptotic-like cell death in Leishmania spp. promastigotes and in vivo potential of therapeutic immunomodulation"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2996-5845","authenticated-orcid":true,"given":"Kalliopi","family":"Karampetsou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga S.","family":"Koutsoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Gogou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5100-0321","authenticated-orcid":true,"given":"Apostolis","family":"Angelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandros-Alexios","family":"Skaltsounis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9264-6965","authenticated-orcid":true,"given":"Eleni","family":"Dotsika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"key":"pntd.0008968.ref001","article-title":"Leishmaniasis","author":"S 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