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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Carajurin is the main constituent of Arrabidaea chica species with reported anti-Leishmania activity. However, its mechanism of action has not been described. This study investigated the mechanisms of action of carajurin against promastigote forms of Leishmania amazonensis. Carajurin was effective against promastigotes with IC50 of 7.96 ± 1.23 μg.mL−1 (26.4 µM), and the cytotoxic concentration for peritoneal macrophages was 258.2 ± 1.20 μg.mL−1 (856.9 µM) after 24 h of treatment. Ultrastructural evaluation highlighted pronounced swelling of the kinetoplast with loss of electron-density in L. amazonensis promastigotes induced by carajurin treatment. It was observed that carajurin leads to a decrease in the mitochondrial membrane potential (p = 0.0286), an increase in reactive oxygen species production (p = 0.0286), and cell death by late apoptosis (p = 0.0095) in parasites. Pretreatment with the antioxidant NAC prevented ROS production and significantly reduced carajurin-induced cell death. The electrochemical and density functional theory (DFT) data contributed to support the molecular mechanism of action of carajurin associated with the ROS generation, for which it is possible to observe a correlation between the LUMO energy and the electroactivity of carajurin in the presence of molecular oxygen. All these results suggest that carajurin targets the mitochondria in L. amazonensis. In addition, when assessed for its drug-likeness, carajurin follows Lipinski’’s rule of five, and the Ghose, Veber, Egan, and Muegge criteria.

Details

Title
Carajurin Induces Apoptosis in Leishmania amazonensis Promastigotes through Reactive Oxygen Species Production and Mitochondrial Dysfunction
Author
Silva-Silva, João Victor 1   VIAFID ORCID Logo  ; Moragas-Tellis, Carla J 2   VIAFID ORCID Logo  ; Chagas, Maria S S 2 ; Souza, Paulo Victor R 3 ; Moreira, Davyson L 2 ; Hardoim, Daiana J 1 ; Taniwaki, Noemi N 4 ; Costa, Vanessa F A 5 ; Bertho, Alvaro L 6 ; Brondani, Daniela 7   VIAFID ORCID Logo  ; Zapp, Eduardo 7   VIAFID ORCID Logo  ; Aldo Sena de Oliveira 7   VIAFID ORCID Logo  ; Calabrese, Kátia S 1   VIAFID ORCID Logo  ; Behrens, Maria D 2 ; Almeida-Souza, Fernando 8   VIAFID ORCID Logo 

 Laboratory of Immunomodulation and Protozoology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil; [email protected] (J.V.S.-S.); [email protected] (D.J.H.); [email protected] (F.A.-S.) 
 Laboratory of Natural Products for Public Health, Pharmaceutical Technology Institute, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil; [email protected] (C.J.M.-T.); [email protected] (M.S.S.C.); [email protected] (P.V.R.S.); [email protected] (D.L.M.); [email protected] (M.D.B.) 
 Laboratory of Natural Products for Public Health, Pharmaceutical Technology Institute, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil; [email protected] (C.J.M.-T.); [email protected] (M.S.S.C.); [email protected] (P.V.R.S.); [email protected] (D.L.M.); [email protected] (M.D.B.); Postgraduate Program in Translational Research in Drugs and Medicines, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil 
 Electron Microscopy Nucleus, Adolfo Lutz Institute, Sao Paulo 01246-000, Brazil; [email protected] 
 Laboratory of Immunoparasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil; [email protected] (V.F.A.C.); [email protected] (A.L.B.) 
 Laboratory of Immunoparasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil; [email protected] (V.F.A.C.); [email protected] (A.L.B.); Flow Cytometry Technological Platform, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil 
 Research Group on Medicinal and Biological Chemistry (GPQMedBio), Department of Exact Sciences and Education, Federal University of Santa Catarina, Blumenau 89036-002, Brazil; [email protected] (D.B.); [email protected] (E.Z.); [email protected] (A.S.d.O.) 
 Laboratory of Immunomodulation and Protozoology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil; [email protected] (J.V.S.-S.); [email protected] (D.J.H.); [email protected] (F.A.-S.); Postgraduate Program in Animal Science, State University of Maranhão, Sao Luis 65055-310, Brazil 
First page
331
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
14248247
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2642630765
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.