trans-Chalcone modulates Leishmania amazonensis infection in vitro by Nrf2 overexpression affecting iron availability.

Abstract

Leishmania parasites infect macrophages causing a wide spectrum of human diseases encompassing from cutaneous to visceral forms. The drugs currently used in leishmaniasis treatment are highly toxic and associated with acquired resistance. Seeking novel therapeutic targets, we conducted a comprehensive in vitro study to investigate the action of trans-chalcone (TC) against Leishmania amazonensis promastigote and amastigote forms. TC is a common precursor of flavonoids, however, no extensive research has been developed regarding its pharmacological properties. In silico predictions showed good drug-likeness potential for TC with high oral bioavailability and intestinal absorption. The TC-treatment had a direct action on promastigote forms leading to death by late apoptosis-like process resulting from an increased production of reactive oxygen species (ROS), loss of mitochondrial integrity, phosphatidylserine exposure, and damage on the membrane. Similar results were found for L. amazonensis-axenic amastigotes. The TC-treatment of L.amazonensis-infected macrophages proved to reduce the percentage of infected cells as well as the number of amastigotes per macrophage, consequently, the number of promastigotes recovered without cytotoxic effects on macrophages, having indicated a selectivity index (SI) of 53.8 for the parasite. Such leishmanicidal effect was followed by a decrease in the levels of TNF-α, TGF-β, IL-10, ROS and NO, in addition to upregulation mRNA expression of Nrf2, heme oxygenase 1, and ferritin, modulating iron metabolism, depleting available iron for parasite replication, and survival within macrophages. These results suggested trans-chalcone as a satisfactory support for further studies as well as a possible further lead molecule for the design of new prototypes of antileishmanial drugs.

• Authors: Milena Menegazzo Miranda-Sapla, Fernanda Tomiotto-Pellissier, João Paulo Assolini, Amanda Cristina Machado Carloto, Bruna Taciane da Silva Bortoleti, Manoela Daiele Gonçalves, Eliandro Reis Tavares, Jean Henrique da Silva Rodrigues, Andréa Name Colado Simão, Lucy Megumi Yamauchi, Celso Vataru Nakamura, Waldiceu A Verri Jr, Idessania Nazareth Costa, Ivete Conchon-Costa, Wander Rogerio Pavanelli
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 853 Pg. 275-288 (Jun 15 2019) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 30965057 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Chalcones
• NF-E2-Related Factor 2
• Reactive Oxygen Species
• Nitric Oxide
• Iron

Topics

• Animals
• Cell Survival (drug effects)
• Chalcones (chemistry, pharmacology)
• Gene Expression Regulation (drug effects)
• Hemolysis (drug effects)
• Iron (metabolism)
• Leishmania (drug effects, physiology)
• Macrophages, Peritoneal (cytology, drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• NF-E2-Related Factor 2 (metabolism)
• Nitric Oxide (metabolism)
• Reactive Oxygen Species (metabolism)
• Stereoisomerism