{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T06:09:50Z","timestamp":1790489390974,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2017,4,25]],"date-time":"2017-04-25T00:00:00Z","timestamp":1493078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2012\/18756-1"],"award-info":[{"award-number":["2012\/18756-1"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2013\/50228-8"],"award-info":[{"award-number":["2013\/50228-8"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Leishmaniases are neglected infectious diseases caused by parasites of the \u2018protozoan\u2019 genus Leishmania. Depending on the parasite species, different clinical forms are known as cutaneous, muco-cutaneous, and the visceral leishmaniasis (VL). VL is particularly fatal and the therapy presents limitations. In the search for new anti-leishmanial hit compounds, seven natural sesquiterpene lactones were evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum, a pathogen causing VL. The pseudoguaianolides mexicanin I and helenalin acetate demonstrated the highest selectivity and potency against intracellular amastigotes. In addition, promastigotes treated with helenalin acetate were subject to an ultrastructural and biochemical investigation. The lethal action of the compound was investigated by fluorescence-activated cell sorting and related techniques to detect alterations in reactive oxygen species (ROS) content, plasma membrane permeability, and mitochondrial membrane potential. Helenalin acetate significantly reduced the mitochondrial membrane potential and the mitochondrial structural damage was also confirmed by transmission electron microscopy, displaying an intense organelle swelling. No alteration of plasma membrane permeability or ROS content could be detected. Additionally, helenalin acetate significantly increased the production of nitric oxide in peritoneal macrophages, probably potentiating the activity against the intracellular amastigotes. Helenalin acetate could hence be a useful anti-leishmanial scaffold for further optimization studies.<\/jats:p>","DOI":"10.3390\/molecules22050685","type":"journal-article","created":{"date-parts":[[2017,4,25]],"date-time":"2017-04-25T13:21:12Z","timestamp":1493126472000},"page":"685","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Investigation of the Anti-Leishmania (Leishmania) infantum Activity of Some Natural Sesquiterpene Lactones"],"prefix":"10.3390","volume":"22","author":[{"given":"Imke","family":"Wulsten","sequence":"first","affiliation":[{"name":"Department of Biology, Chemistry, Pharmacy, Freie Universit\u00e4t Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thais","family":"Costa-Silva","sequence":"additional","affiliation":[{"name":"Centre for Parasitology and Mycology, Instituto Adolfo Lutz (IAL), Av. Dr. Arnaldo, 351, CEP 01246-900 S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Mesquita","sequence":"additional","affiliation":[{"name":"Centre for Parasitology and Mycology, Instituto Adolfo Lutz (IAL), Av. Dr. Arnaldo, 351, CEP 01246-900 S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Lima","sequence":"additional","affiliation":[{"name":"Centre for Parasitology and Mycology, Instituto Adolfo Lutz (IAL), Av. Dr. Arnaldo, 351, CEP 01246-900 S\u00e3o Paulo, SP, Brazil"},{"name":"Instituto de Medicina Tropical, Universidade de Sa\u0303o Paulo, Av. Dr. En\u00e9as de Carvalho Aguiar, 470, CEP 05403-000 S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Galuppo","sequence":"additional","affiliation":[{"name":"Centre for Parasitology and Mycology, Instituto Adolfo Lutz (IAL), Av. Dr. Arnaldo, 351, CEP 01246-900 S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi","family":"Taniwaki","sequence":"additional","affiliation":[{"name":"Centre for Parasitology and Mycology, Instituto Adolfo Lutz (IAL), Av. Dr. Arnaldo, 351, CEP 01246-900 S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samanta","family":"Borborema","sequence":"additional","affiliation":[{"name":"Centre for Parasitology and Mycology, Instituto Adolfo Lutz (IAL), Av. Dr. Arnaldo, 351, CEP 01246-900 S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2345-5804","authenticated-orcid":false,"given":"Fernando","family":"Da Costa","sequence":"additional","affiliation":[{"name":"AsterBioChem Research Team, Laboratory of Pharmacognosy, School of Pharmaceutical Sciences of Ribeir\u00e3o Preto, USP, Av. do Caf\u00e9 s\/n, 14040-903 Ribeir\u00e3o Preto, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-9705","authenticated-orcid":false,"given":"Thomas","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of M\u00fcnster, PharmaCampus, Corrensstra\u00dfe 48, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Tempone","sequence":"additional","affiliation":[{"name":"Centre for Parasitology and Mycology, Instituto Adolfo Lutz (IAL), Av. Dr. Arnaldo, 351, CEP 01246-900 S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,4,25]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2016, July 01). The 17 Neglected Tropical Diseases. Available online: http:\/\/www.who.int\/neglected_diseases\/diseases\/en\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1128\/CMR.6.3.230","article-title":"Leishmaniasis of the New World: Current concepts and implications for future research","volume":"6","author":"Grimaldi","year":"1993","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/273595a0","article-title":"Epidemiology and ecology of leishmaniasis in Latin-America","volume":"5664","author":"Lainson","year":"1978","journal-title":"Nature"},{"key":"ref_4","first-page":"153","article-title":"The Contribution of Immune Evasive Mechanisms to Parasite Persistence in Visceral Leishmaniasis","volume":"7","author":"Leoratti","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"151","DOI":"10.4103\/0974-777X.62883","article-title":"Treatment of visceral leishmaniasis","volume":"2","author":"Moore","year":"2010","journal-title":"J. Glob. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1111\/j.1469-0691.2011.03630.x","article-title":"Leishmaniasis chemotherapy-challenges and opportunities","volume":"10","author":"Croft","year":"2011","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1055\/s-0030-1250663","article-title":"Current approaches to discover marine antileishmanial natural products","volume":"6","author":"Tempone","year":"2011","journal-title":"Planta Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.phymed.2011.03.004","article-title":"Plant derived therapeutics for the treatment of Leishmaniasis","volume":"12","author":"Sen","year":"2011","journal-title":"Phytomedicine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.2174\/092986712800229023","article-title":"The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases\u2014Part I","volume":"14","author":"Schmidt","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.2174\/092986712800229087","article-title":"The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases\u2014Part II","volume":"14","author":"Schmidt","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1021\/np200906s","article-title":"Natural products as sources of new drugs over the 30 years from 1981 to 2010","volume":"3","author":"Newman","year":"2012","journal-title":"J. Nat. Prod."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/S0031-9422(00)97430-2","article-title":"Biological activities of sesquiterpene lactones","volume":"15","author":"Rodriguez","year":"1976","journal-title":"Phytochemistry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1021\/jm00294a001","article-title":"Tumor inhibitors. Structure-cytotoxicity relationships among the sesquiterpene lactones","volume":"12","author":"Kupchan","year":"1971","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1055\/s-2006-958055","article-title":"Recent studies on the zoopharmacognosy, pharmacology and neurotoxicology of sesquiterpene lactones","volume":"3","author":"Robles","year":"1995","journal-title":"Planta Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1021\/np50070a004","article-title":"The gastric cytoprotective effect of several sesquiterpene lactones","volume":"4","author":"Giordano","year":"1990","journal-title":"J. Nat. Prod."},{"key":"ref_16","first-page":"691","article-title":"Dehydroleucodine, a Sesquiterpene Lactone from Gynoxys verrucosa, Demonstrates Cytotoxic Activity against Human Leukemia Cells","volume":"4","author":"Sharma","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1645\/0022-3395(2000)086[0407:TSLDDA]2.0.CO;2","article-title":"The sesquiterpene lactone dehydroleucodine (DhL) affects the growth of cultured epimastigotes of Trypanosoma cruzi","volume":"2","author":"Brengio","year":"2000","journal-title":"J. Parasitol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1055\/s-2002-33799","article-title":"Anti-trypanosomal activity of helenalin and some structurally related sesquiterpene lactones","volume":"8","author":"Schmidt","year":"2002","journal-title":"Planta Med."},{"key":"ref_19","first-page":"170","article-title":"The trypanocidal effect of sesquiterpene lactones helenalin and mexicanin on cultured epimastigotes","volume":"1","author":"Brengio","year":"2005","journal-title":"J. Parasitol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1645\/GE-1501.1","article-title":"Natural sesquiterpene lactones are active against Leishmania mexicana","volume":"5","author":"Barrera","year":"2008","journal-title":"J. Parasitol."},{"key":"ref_21","first-page":"14","article-title":"Cell death in amastigote forms of Leishmania amazonensis induced by parthenolide","volume":"10","author":"Tiuman","year":"2014","journal-title":"BMC Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.3390\/molecules14062062","article-title":"Quantitative structure--antiprotozoal activity relationships of sesquiterpene lactones","volume":"6","author":"Schmidt","year":"2009","journal-title":"Molecules"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1128\/AAC.01263-13","article-title":"In Silico prediction and experimental evaluation of furanoheliangolide sesquiterpene lactones as potent agents against Trypanosoma brucei rhodesiense","volume":"1","author":"Schmidt","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1073\/pnas.82.6.1716","article-title":"Protonmotive force-driven active transport of d-glucose and l-proline in the protozoan parasite Leishmania donovani","volume":"6","author":"Zilberstein","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/978-1-60761-594-1_25","article-title":"Characterization of the leishmanicidal activity of antimicrobial peptides","volume":"Volume 618","author":"Rivas","year":"2010","journal-title":"Antimicrobial Peptides"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5344","DOI":"10.1128\/AAC.00790-10","article-title":"Tafenoquine, an antiplasmodial 8-aminoquinoline, targets leishmania respiratory complex III and induces apoptosis","volume":"12","author":"Carvalho","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1017\/S0031182096008591","article-title":"Leishmania infantum promastigotes have a poor capacity for anaerobic functioning and depend mainly on respiration for their energy generation","volume":"114","author":"Tielens","year":"1997","journal-title":"Parasitology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"98","DOI":"10.2144\/000113610","article-title":"Mitochondrial membrane potential probes and the proton gradient: A practical usage guide","volume":"2","author":"Perry","year":"2011","journal-title":"Biotechniques"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S0891-5849(98)00216-0","article-title":"Mitochondrial damage induced by conditions of oxidative stress","volume":"3\u20134","author":"Kowaltowski","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11798","DOI":"10.1074\/jbc.M309341200","article-title":"Apoptotic death in Leishmania donovani promastigotes in response to respiratory chain inhibition: Complex II inhibition results in increased pentamidine cytotoxicity","volume":"12","author":"Mehta","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1016\/j.tiv.2015.06.011","article-title":"Sesquiterpene lactones from Ambrosia spp. are active against a murine lymphoma cell line by inducing apoptosis and cell cycle arrest","volume":"7","author":"Martino","year":"2015","journal-title":"Toxicol. In Vitro"},{"key":"ref_32","first-page":"1191","article-title":"Britannin, a sesquiterpene lactone, inhibits proliferation and induces apoptosis through the mitochondrial signaling pathway in human breast cancer cells","volume":"2","author":"Aghaei","year":"2015","journal-title":"Tumour Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6790","DOI":"10.18632\/oncotarget.6828","article-title":"EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells","volume":"6","author":"Shao","year":"2016","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"163404","DOI":"10.1155\/2013\/163404","article-title":"Natural Sesquiterpene Lactones Induce Oxidative Stress in Leishmania mexicana","volume":"2013","author":"Barrera","year":"2013","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.ceb.2004.09.011","article-title":"Death by design: Apoptosis, necrosis and autophagy","volume":"6","author":"Edinger","year":"2004","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6085","DOI":"10.1128\/IAI.73.9.6085-6090.2005","article-title":"Arginase I Induction during Leishmania major Infection Mediates the Development of Disease","volume":"9","author":"Iniesta","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1046\/j.1365-3024.2002.00444.x","article-title":"Arginase I induction in macrophages, triggered by Th2-type cytokines, supports the growth of intracellular Leishmania parasites","volume":"3","author":"Iniesta","year":"2002","journal-title":"Parasite Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6166","DOI":"10.4049\/jimmunol.164.12.6166","article-title":"M-1\/M-2 macrophages and the Th1\/Th2 paradigm","volume":"12","author":"Mills","year":"2000","journal-title":"J. Immunol."},{"key":"ref_39","first-page":"539","article-title":"Role of phosphatidylinositol-3-kinase-\u03b3 (PI3K\u03b3)-mediated pathway in 17\u03b2-estradiol-induced killing of L. mexicana in macrophages from C57BL\/6 mice","volume":"6","author":"Barbi","year":"2008","journal-title":"Immunol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0022-1759(86)90183-3","article-title":"An improved colorimetric assay for interleukin 2","volume":"2","author":"Tada","year":"1986","journal-title":"J. Immunol. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"475","DOI":"10.3109\/01913129209057832","article-title":"A fast method for processing biologic material for electron microscopic diagnosis in infectious disease","volume":"4","author":"Duarte","year":"1992","journal-title":"Ultrastruct. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.exppara.2013.09.016","article-title":"Antimicrobial peptides isolated from Phyllomedusa nordestina (Amphibia) alter the permeability of plasma membrane of Leishmania and Trypanosoma cruzi","volume":"135","author":"Pinto","year":"2013","journal-title":"Exp. Parasitol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/s11010-013-1954-6","article-title":"Activity of imidazole compounds on Leishmania (L.) infantum chagasi: Reactive oxygen species induced by econazole","volume":"1\u20132","author":"Mesquita","year":"2014","journal-title":"Mol. Cell. Biochem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/5\/685\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:33:44Z","timestamp":1760207624000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/5\/685"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,25]]},"references-count":43,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2017,5]]}},"alternative-id":["molecules22050685"],"URL":"https:\/\/doi.org\/10.3390\/molecules22050685","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,25]]}}}