1. Methyl gallate: Selective antileishmanial activity correlates with host-cell directed effects.
- Author
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Noleto Dias C, Nunes TAL, Sousa JMS, Costa LH, Rodrigues RRL, Araújo AJ, Marinho Filho JDB, da Silva MV, Oliveira MR, Carvalho FAA, and Rodrigues KADF
- Subjects
- Amphotericin B pharmacology, Antiprotozoal Agents chemistry, Gallic Acid adverse effects, Gallic Acid chemistry, Gallic Acid pharmacology, Gene Expression Regulation drug effects, Macrophages drug effects, Meglumine Antimoniate pharmacology, Molecular Structure, Reactive Oxygen Species, Antiprotozoal Agents pharmacology, Gallic Acid analogs & derivatives, Leishmania drug effects
- Abstract
Leishmaniasis is a widespread tropical infection caused by different species of Leishmania protozoa. Many of the available drugs against the disease are toxic and in certain cases parasite drug resistance is developed. The discovery of drugs for the treatment of leishmaniasis is a pressing concern. In the present work, we describe in vitro studies of the phenolic compound methyl gallate (MG) against Leishmania (Leishmania) amazonensis and its possible mechanisms of action. The in vitro activity of MG was assayed against L. amazonensis (promastigotes, axenic amastigotes, and intramacrophagic amastigotes). Cytotoxicity tests were performed with J774A.1 macrophages and THP-1 cell derived macrophages. To evaluate mechanisms of action, we analyzed cellular TNF-α, IL-12, IFN-γ, IL-10, IL-6, NO, ROS levels, arginase activity, and structural mechanisms (phagocytic and lysosomal activities) involving macrophage activation. Meglumine antimoniate and amphotericin B were used as reference drugs. It was observed that MG effectively inhibited the growth of both promastigote (IC
50 5.71 μM) and amastigote-like forms (EC50 5.39 μM), with much higher selectivity indexes than the reference drugs, being more benign towards J774A.1 macrophages than meglumine antimoniate and amphotericin B, at 1631- and 70.92-fold respectively, with respect to the promastigote form. Additionally, MG proved to be even more active against intracellular amastigotes of the parasite (EC50 4.24 μM). Our results showed that antileishmania activity was associated with increased TNF-α, IL-12, NO and ROS levels, as well as decreased IL-6 and decreased arginase activity. In addition, MG induced increased phagocytic capability, and lysosomal volume in macrophages; structural parameters of microbicidal activity. Taken together, our results suggest that MG may be a promising candidate for new drug development against leishmaniasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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