Solidagenone acts on promastigotes of L. amazonensis by inducing apoptosis-like processes on intracellular amastigotes by IL-12p70/ROS/NO pathway activation.

Autor: Bortoleti BTDS; Biosciences and Biotechnology Postgraduate Program, Carlos Chagas Institute (ICC/Fiocruz-PR), Curitiba, Paraná, Brazil; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., Gonçalves MD; State University of Londrina (UEL/PR), Laboratory of Biotransformation and Phytochemistry, Londrina, Paraná, Brazil., Tomiotto-Pellissier F; Biosciences and Biotechnology Postgraduate Program, Carlos Chagas Institute (ICC/Fiocruz-PR), Curitiba, Paraná, Brazil; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., Contato VM; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., Silva TF; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., de Matos RLN; State University of Londrina (UEL/PR), Laboratory of Biotransformation and Phytochemistry, Londrina, Paraná, Brazil., Detoni MB; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., Rodrigues ACJ; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., Carloto AC; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., Lazarin DB; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., Arakawa NS; State University of Londrina (UEL/PR), Laboratory of Biotransformation and Phytochemistry, Londrina, Paraná, Brazil., Costa IN; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., Conchon-Costa I; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., Miranda-Sapla MM; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil., Wowk PF; Carlos Chagas Institute (ICC/Fiocruz-PR), Laboratory of Molecular Virology, Curitiba, Paraná, Brazil. Electronic address: pryscilla.wowk@fiocruz.br., Pavanelli WR; State University of Londrina (UEL/PR), Laboratory of Immunoparasitology, Londrina, Paraná, Brazil. Electronic address: wanderpavanelli@yahoo.com.br.
Jazyk: angličtina
Zdroj: Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2021 May; Vol. 85, pp. 153536. Date of Electronic Publication: 2021 Mar 03.
DOI: 10.1016/j.phymed.2021.153536
Abstrakt: Background: Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the Leishmania genus. Currently, the treatment has limited effectiveness and high toxicity, is expensive, requires long-term treatment, induces significant side effects, and promotes drug resistance. Thus, new therapeutic strategies must be developed to find alternative compounds with high efficiency and low cost. Solidagenone (SOL), one of the main constituents of Solidago chilensis, has shown gastroprotective, anti-inflammatory and immunomodulatory effects.
Purpose: This study assessed the in vitro effect of SOL on promastigotes and Leishmania amazonensis-infected macrophages, as well its microbicide and immunomodulatory mechanisms.
Methods: SOL was isolated from the roots of S. chilensis, 98% purity, and identified by chromatographic methods, and the effect of SOL on leishmanicidal activity against promastigotes in vitro, SOL-induced cytotoxicity in THP-1, J774 cells, sheep erythrocytes, and L. amazonensis-infected J774 macrophages, and the mechanisms of death involved in this action were evaluated.
Results: In silico predictions showed good drug-likeness potential for SOL with high oral bioavailability and intestinal absorption. SOL treatment (10-160 μM) inhibited promastigote proliferation 24, 48, and 72 h after treatment. After 24 h of treatment, SOL at the IC 50 (34.5 μM) and 2 × the IC 50 (69 μM) induced several morphological and ultrastructural changes in promastigotes, altered the cell cycle and cellular volume, increased phosphatidylserine exposure on the cell surface, induced the loss of plasma membrane integrity, increased the reactive oxygen species (ROS) level, induced loss of mitochondrial integrity (characterized by an apoptosis-like process), and increased the number of lipid droplets and autophagic vacuoles. Additionally, SOL induced low cytotoxicity in J774 murine macrophages (CC 50 of 1587 μM), THP-1 human monocytes (CC 50 of 1321 μM), and sheep erythrocytes. SOL treatment reduced the percentage of L. amazonensis-infected macrophages and the number of amastigotes per macrophage (IC 50 9.5 μM), reduced TNF-α production and increased IL-12p70, ROS and nitric oxide (NO) levels.
Conclusion: SOL showed in vitro leishmanicidal effects against the promastigotes by apoptosis-like mechanism and amastigotes by reducing TNF-α and increasing IL-12p70, ROS, and NO levels, suggesting their potential as a candidate for use in further studies on the design of antileishmanial drugs.
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Databáze: MEDLINE
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