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Abstract:

Trypanosoma cruzi is the causative agent of Chagas' disease, which is a major endemic disease in Latin America and is recognized by the WHO as one of the 17 neglected tropical diseases in the world. Psilostachyin and psilostachyin C, two sesquiterpene lactones isolated from Ambrosia spp., have been demonstrated to have trypanocidal activity. Considering both the potential therapeutic targets present in the parasite, and the several mechanisms of action proposed for sesquiterpene lactones, the aim of this work was to characterize the mode of action of psilostachyin and psilostachyin C on Trypanosoma cruzi and to identify the possible targets for these molecules. Psilostachyin and psilostachyin C were isolated from Ambrosia tenuifolia and Ambrosia scabra, respectively. Interaction of sesquiterpene lactones with hemin, the induction of oxidative stress, the inhibition of cruzi-pain and trypanothione reductase and their ability to inhibit sterol biosynthesis were evaluated. The induction of cell death by apoptosis was also evaluated by analyzing phosphatidylserine exposure detected using annexin-V/propidium iodide, decreased mitochondrial membrane potential, assessed with Rhodamine 123 and nuclear DNA fragmentation evaluated by the TUNEL assay. Both STLs were capable of interacting with hemin. Psilostachyin increased about 5 times the generation of reactive oxygen species in Trypanosoma cruzi after a 4h treatment, unlike psilostachyin C which induced an increase in reactive oxygen species levels of only 1.5 times. Only psilostachyin C was able to inhibit the biosynthesis of ergosterol, causing an accumulation of squalene. Both sesquiterpene lactones induced parasite death by apoptosis. Upon evaluating the combination of both compounds, and additive trypanocidal effect was observed. Despite their structural similarity, both sesquiterpene lactones exerted their anti-T. cruzi activity through interaction with different targets. Psilostachyin accomplished its antiparasitic effect by interacting with hemin, while psilostachyin C interfered with sterol synthesis. © 2016 Sülsen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Registro:

Documento: Artículo
Título:Mode of action of the sesquiterpene lactones psilostachyin and psilostachyin C on trypanosoma cruzi
Autor:Sülsen, V.P.; Puente, V.; Papademetrio, D.; Batlle, A.; Martino, V.S.; Frank, F.M.; Lombardo, M.E.
Filiación:Cátedra de Farmacognosia, Instituto de Químicay Metabolismo Del Fármaco, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Farmaciay Bioquímica, Buenos Aires, Argentina
Centrode Investigaciones Sobre Porfirinasy Porfirias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Hospital de Clínicas José de San Martín, Buenos Aires, Argentina
Cátedra de Inmunología, Facultad de Farmaciay Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
Institutode Microbiologíay Parasitología Médica, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Medicina, Buenos Aires, Argentina
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:cruzipain; hemin; lipocortin 5; phosphatidylserine; propidium iodide; psilostachyin; psilostachyin C; reactive oxygen metabolite; sesquiterpene lactone derivative; squalene; sterol; trypanothione reductase; unclassified drug; fused heterocyclic rings; hemin; lactone; plant extract; psilostachyin A; psilostachyin C; pyrone derivative; reactive oxygen metabolite; sesquiterpene; Ambrosia scabra; Ambrosia tenuifolia; apoptosis; Article; bacterium isolation; biosynthesis; cell death; controlled study; drug activity; drug isolation; drug protein binding; mitochondrial membrane potential; nonhuman; oxidative stress; ragweed; structure analysis; Trypanosoma cruzi; TUNEL assay; Chagas disease; chemistry; drug effects; human; metabolism; parasitology; pathogenicity; Trypanosoma cruzi; Ambrosia; Apoptosis; Chagas Disease; Hemin; Heterocyclic Compounds, 3-Ring; Humans; Lactones; Plant Extracts; Pyrones; Reactive Oxygen Species; Sesquiterpenes; Trypanosoma cruzi
Año:2016
Volumen:11
Número:3
DOI: http://dx.doi.org/10.1371/journal.pone.0150526
Título revista:PLoS ONE
Título revista abreviado:PLoS ONE
ISSN:19326203
CODEN:POLNC
CAS:cruzipain; hemin, 16009-13-5; lipocortin 5, 111237-10-6; propidium iodide, 25535-16-4; squalene, 111-02-4, 7683-64-9; trypanothione reductase, 102210-35-5; lactone, 1338-03-0; Hemin; Heterocyclic Compounds, 3-Ring; Lactones; Plant Extracts; psilostachyin A; psilostachyin C; Pyrones; Reactive Oxygen Species; Sesquiterpenes
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v11_n3_p_Sulsen

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Citas:

---------- APA ----------
Sülsen, V.P., Puente, V., Papademetrio, D., Batlle, A., Martino, V.S., Frank, F.M. & Lombardo, M.E. (2016) . Mode of action of the sesquiterpene lactones psilostachyin and psilostachyin C on trypanosoma cruzi. PLoS ONE, 11(3).
http://dx.doi.org/10.1371/journal.pone.0150526
---------- CHICAGO ----------
Sülsen, V.P., Puente, V., Papademetrio, D., Batlle, A., Martino, V.S., Frank, F.M., et al. "Mode of action of the sesquiterpene lactones psilostachyin and psilostachyin C on trypanosoma cruzi" . PLoS ONE 11, no. 3 (2016).
http://dx.doi.org/10.1371/journal.pone.0150526
---------- MLA ----------
Sülsen, V.P., Puente, V., Papademetrio, D., Batlle, A., Martino, V.S., Frank, F.M., et al. "Mode of action of the sesquiterpene lactones psilostachyin and psilostachyin C on trypanosoma cruzi" . PLoS ONE, vol. 11, no. 3, 2016.
http://dx.doi.org/10.1371/journal.pone.0150526
---------- VANCOUVER ----------
Sülsen, V.P., Puente, V., Papademetrio, D., Batlle, A., Martino, V.S., Frank, F.M., et al. Mode of action of the sesquiterpene lactones psilostachyin and psilostachyin C on trypanosoma cruzi. PLoS ONE. 2016;11(3).
http://dx.doi.org/10.1371/journal.pone.0150526