Antileishmanial activity, cytotoxicity and cellular response of amphotericin B in combination with crotamine derived from Crotalus durissus terrificus venom using in vitro and in silico approaches.

Autor: Valentim-Silva JR; Post-Doctoral Fellow in Health Sciences, Federal University of Acre (UFAC), Rio Branco, AC, Brazil; Physical Education Department of Federal University of Rondônia (UNIR), Porto Velho, RO, Brazil; Oswaldo Cruz Foundation (Fiocruz Rondônia), Porto Velho, RO, Brazil., de Barros NB; Oswaldo Cruz Foundation (Fiocruz Rondônia), Porto Velho, RO, Brazil., Macedo SRA; Oswaldo Cruz Foundation (Fiocruz Rondônia), Porto Velho, RO, Brazil., Ferreira ADS; Oswaldo Cruz Foundation (Fiocruz Rondônia), Porto Velho, RO, Brazil., Silva RS; Center of Study of Biomolecules Applied in Medicine (CEBio), Oswaldo Cruz Foundation (Fiocruz Rondônia) and Federal University of Rondônia (UNIR), Porto Velho, RO, Brazil., Dill LSM; Center of Study of Biomolecules Applied in Medicine (CEBio), Oswaldo Cruz Foundation (Fiocruz Rondônia) and Federal University of Rondônia (UNIR), Porto Velho, RO, Brazil., Zanchi FB; Center of Study of Biomolecules Applied in Medicine (CEBio), Oswaldo Cruz Foundation (Fiocruz Rondônia) and Federal University of Rondônia (UNIR), Porto Velho, RO, Brazil., do Nascimento JR; Immunophysiology Laboratory, Department of Pathology, Center for Biological and Health Sciences, Federal University of Maranhão (UFMA), São Luís, MA, Brazil., do Nascimento FRF; Immunophysiology Laboratory, Department of Pathology, Center for Biological and Health Sciences, Federal University of Maranhão (UFMA), São Luís, MA, Brazil., Lourenzoni MR; Oswaldo Cruz Foundation (Fiocruz Ceará), Eusébio, CE, Brazil., Soares AM; Center of Study of Biomolecules Applied in Medicine (CEBio), Oswaldo Cruz Foundation (Fiocruz Rondônia) and Federal University of Rondônia (UNIR), Porto Velho, RO, Brazil; eCentro Universitário São Lucas (UniSL), Porto Velho, RO, Brazil., Calderon LA; Center of Study of Biomolecules Applied in Medicine (CEBio), Oswaldo Cruz Foundation (Fiocruz Rondônia) and Federal University of Rondônia (UNIR), Porto Velho, RO, Brazil., Nicolete R; Oswaldo Cruz Foundation (Fiocruz Rondônia), Porto Velho, RO, Brazil; Oswaldo Cruz Foundation (Fiocruz Ceará), Eusébio, CE, Brazil. Electronic address: roberto.nicolete@fiocruz.br.
Jazyk: angličtina
Zdroj: Toxicon : official journal of the International Society on Toxinology [Toxicon] 2022 Oct 15; Vol. 217, pp. 96-106. Date of Electronic Publication: 2022 Aug 14.
DOI: 10.1016/j.toxicon.2022.08.009
Abstrakt: Objective: To investigate the in vitro activity, synergism, cytotoxicity and cellular immunological response, as well as the molecular affinity between amphotericin B (AmB) and crotamine (CTA), derived from Crotalus durissus terrificus venom against Leishmania amazonensis.
Methods: This study performed the inhibition of promastigotes and amastigotes' growth under different concentrations of the drug and pharmacological combinations (AmB + CTA) based on the Berimbaum method (synergism study). The lactate dehydrogenase (LDH) quantification method was used to determine the cytotoxicity of the drug and combinations employing four cell lines (J774, HepG2, VERO, and C2C12). Following, the levels of Tumour Necrose Factor-alpha (TNF-α) and Interleukin-12 (IL-12) cytokines, using enzyme-linked immunosorbent assay (ELISA) and nitrites, as an indirect measure of Nitric Oxide (NO), using the Griess reaction were assessed in the supernatants of infected macrophages. In silico approach (molecular docking and dynamics) and binding affinity (surface plasmon resonance) between the drug and toxin were also investigated.
Results: CTA enhanced AmB effect against promastigote and amastigote forms of L. amazonensis, decreased the drug toxicity in different cell lines and induced the production of important Th1-like cytokines and NO by infected macrophages. The pharmacological combination also displayed consistent molecular interactions with low energy of coupling and a concentration-dependent profile.
Conclusion: Our data suggest that this pharmacological approach is a promising alternative treatment against L. amazonensis infection due to the improved activity (synergistic effect) achieved against the parasites' forms and to the decreased cytotoxic effect.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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