Publications by authors named "Elisalva T Guimaraes"

7 Publications

  • Page 1 of 1

Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent.

J Enzyme Inhib Med Chem 2015 28;30(4):615-21. Epub 2014 Nov 28.

Fundação Oswaldo Cruz, Centro de Pesquisas Gonçalo Moniz , Salvador, BA , Brazil .

This study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally-occurring lapachol and lapachone. Of the compounds tested, 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against Plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. Compound 1 was able to reduce the in vitro parasite burden, in vitro parasite cell cycle, as well as the blood parasitemia in Plasmodium berghei-infected mice. More importantly, infection reduction under compound 1-treatment was achieved without exhibiting mouse genotoxicity. Regarding the molecular mechanism of action, this compound inhibited the hemozoin crystal formation in P. falciparum treated cells, and this was further confirmed by observing that it inhibits the β-hematin polymerization process similarly to chloroquine. Interestingly, this compound did not affect either mitochondria structure or cause DNA fragmentation in parasite treated cells. In conclusion, we identified a semi-synthetic antimalarial naphthoquinone closely related to isolapachol, which had stronger antimalarial activity than lapachol.
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http://dx.doi.org/10.3109/14756366.2014.958083DOI Listing
April 2016

Nitro/nitrosyl-ruthenium complexes are potent and selective anti-Trypanosoma cruzi agents causing autophagy and necrotic parasite death.

Antimicrob Agents Chemother 2014 Oct 4;58(10):6044-55. Epub 2014 Aug 4.

FIOCRUZ, Centro de Pesquisas Gonçalo Moniz, Salvador, Bahia, Brazil Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Salvador, Bahia, Brazil

cis-[RuCl(NO2)(dppb)(5,5'-mebipy)] (complex 1), cis-[Ru(NO2)2(dppb)(5,5'-mebipy)] (complex 2), ct-[RuCl(NO)(dppb)(5,5'-mebipy)](PF6)2 (complex 3), and cc-[RuCl(NO)(dppb)(5,5'-mebipy)](PF6)2 (complex 4), where 5,5'-mebipy is 5,5'-dimethyl-2,2'-bipyridine and dppb is 1,4-bis(diphenylphosphino)butane, were synthesized and characterized. The structure of complex 2 was determined by X-ray crystallography. These complexes exhibited a higher anti-Trypanosoma cruzi activity than benznidazole, the current antiparasitic drug. Complex 3 was the most potent, displaying a 50% effective concentration (EC50) of 2.1 ± 0.6 μM against trypomastigotes and a 50% inhibitory concentration (IC50) of 1.3 ± 0.2 μM against amastigotes, while it displayed a 50% cytotoxic concentration (CC50) of 51.4 ± 0.2 μM in macrophages. It was observed that the nitrosyl complex 3, but not its analog lacking the nitrosyl group, releases nitric oxide into parasite cells. This release has a diminished effect on the trypanosomal protease cruzain but induces substantial parasite autophagy, which is followed by a series of irreversible morphological impairments to the parasites and finally results in cell death by necrosis. In infected mice, orally administered complex 3 (five times at a dose of 75 μmol/kg of body weight) reduced blood parasitemia and increased the survival rate of the mice. Combination index analysis of complex 3 indicated that its in vitro activity against trypomastigotes is synergic with benznidazole. In addition, drug combination enhanced efficacy in infected mice, suggesting that ruthenium-nitrosyl complexes are potential constituents for drug combinations.
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http://dx.doi.org/10.1128/AAC.02765-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187982PMC
October 2014

Bone marrow cells migrate to the heart and skeletal muscle and participate in tissue repair after Trypanosoma cruzi infection in mice.

Int J Exp Pathol 2014 Oct 30;95(5):321-9. Epub 2014 Jun 30.

Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil; Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Salvador, Brazil.

Infection by Trypanosoma cruzi, the aetiological agent of Chagas disease, causes an intense inflammatory reaction in several tissues, including the myocardium. We have previously shown that transplantation of bone marrow cells (BMC) ameliorates the myocarditis in a mouse model of chronic Chagas disease. We investigated the participation of BMC in lesion repair in the heart and skeletal muscle, caused by T. cruzi infection in mice. Infection with a myotropic T. cruzi strain induced an increase in the percentage of stem cells and monocytes in the peripheral blood, as well as in gene expression of chemokines SDF-1, MCP1, 2, and 3 in the heart and skeletal muscle. To investigate the fate of BMC within the damaged tissue, chimeric mice were generated by syngeneic transplantation of green fluorescent protein (GFP(+) ) BMC into lethally irradiated mice and infected with Trypanosoma cruzi. Migration of GFP(+) BMC to the heart and skeletal muscle was observed during and after the acute phase of infection. GFP(+) cardiomyocytes and endothelial cells were present in heart sections of chimeric chagasic mice. GFP(+) myofibres were observed in the skeletal muscle of chimeric mice at different time points following infection. In conclusion, BMC migrate and contribute to the formation of new resident cells in the heart and skeletal muscle, which can be detected both during the acute and the chronic phase of infection. These findings reinforce the role of BMC in tissue regeneration.
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http://dx.doi.org/10.1111/iep.12089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209924PMC
October 2014

Physalins B and F, seco-steroids isolated from Physalis angulata L., strongly inhibit proliferation, ultrastructure and infectivity of Trypanosoma cruzi.

Parasitology 2013 Dec 4;140(14):1811-21. Epub 2013 Sep 4.

Fundação Oswaldo Cruz, Centro de Pesquisas Gonçalo Moniz, Rua Waldemar Falcão, 121, Candeal, Salvador, Bahia, CEP: 40296-710, Brazil.

We previously observed that physalins have immunomodulatory properties, as well as antileishmanial and antiplasmodial activities. Here, we investigated the anti-Trypanosoma cruzi activity of physalins B, D, F and G. We found that physalins B and F were the most potent compounds against trypomastigote and epimastigote forms of T. cruzi. Electron microscopy of trypomastigotes incubated with physalin B showed disruption of kinetoplast, alterations in Golgi apparatus and endoplasmic reticulum, followed by the formation of myelin-like figures, which were stained with MDC to confirm their autophagic vacuole identity. Physalin B-mediated alteration in Golgi apparatus was likely due to T. cruzi protease perturbation; however physalins did not inhibit activity of the trypanosomal protease cruzain. Flow cytometry examination showed that cell death is mainly caused by necrosis. Treatment with physalins reduced the invasion process, as well as intracellular parasite development in macrophage cell culture, with a potency similar to benznidazole. We observed that a combination of physalins and benznidazole has a greater anti-T. cruzi activity than when compounds were used alone. These results indicate that physalins, specifically B and F, are potent and selective trypanocidal agents. They cause structural alterations and induce autophagy, which ultimately lead to parasite cell death by a necrotic process.
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http://dx.doi.org/10.1017/S0031182013001297DOI Listing
December 2013

Anti-Trypanosoma cruzi activity of nicotinamide.

Acta Trop 2012 May 18;122(2):224-9. Epub 2012 Jan 18.

Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Rua Waldemar Falcão, Salvador, BA, Brazil.

Inhibition of Trypanosoma brucei and Leishmania spp. sirtuins has shown promising antiparasitic activity, indicating that these enzymes may be used as targets for drug discovery against trypanosomatid infections. In the present work we carried out a virtual screening focused on the C pocket of Sir2 from Trypanosoma cruzi. Using this approach, the best ligand found was nicotinamide. In vitro tests confirmed the anti-T. cruzi activity of nicotinamide on epimastigote and trypomastigote forms. Moreover, treatment of T. cruzi-infected macrophages with nicotinamide caused a significant reduction in the number of amastigotes. In addition, alterations in the mitochondria and an increase in the vacuolization in the cytoplasm were observed in epimastigotes treated with nicotinamide. Analysis of the complex of Sir2 and nicotinamide revealed the details of the possible ligand-target interaction. Our data reveal a potential use of TcSir2 as a target for anti-T. cruzi drug discovery.
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http://dx.doi.org/10.1016/j.actatropica.2012.01.001DOI Listing
May 2012

Activity of physalins purified from Physalis angulata in in vitro and in vivo models of cutaneous leishmaniasis.

J Antimicrob Chemother 2009 Jul 19;64(1):84-7. Epub 2009 May 19.

Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brazil.

Objectives: We have previously demonstrated the immunomodulatory effects of physalins, secosteroids purified from Physalis angulata. Here we investigate the antileishmanial activity of physalins in vitro and in vivo in a model of cutaneous leishmaniasis.

Methods: The antileishmanial activity of physalins B, D and F was tested in Leishmania-infected macrophage cultures. For the in vivo studies, BALB/c mice were infected with Leishmania amazonensis subcutaneously in the ear pinna and treated with physalin F by topical administration.

Results: Physalins B and F were able to reduce the percentage of Leishmania-infected macrophages and the intracellular parasite number in vitro at concentrations non-cytotoxic to macrophages. More importantly, topical treatment with physalin F significantly reduced the lesion size, the parasite load and histopathological alterations in BALB/c mice infected with L. amazonensis.

Conclusions: Our results demonstrate the potent antileishmanial activity of physalins, especially physalin F, and suggest these molecules as the basis for the development of new therapeutic options for cutaneous leishmaniasis.
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http://dx.doi.org/10.1093/jac/dkp170DOI Listing
July 2009

Role of interleukin-4 and prostaglandin E2 in Leishmania amazonensis infection of BALB/c mice.

Microbes Infect 2006 Apr 19;8(5):1219-26. Epub 2006 Jan 19.

Centro de Pesquisas Gonçalo Moniz, FIOCRUZ, Rua Waldemar Falcão 121, 40296-710 Salvador, Bahia, Brazil.

The role of cytokines in Leishmania amazonensis experimental infection has not been as well studied as in Leishmania major infection model. Here we investigated the role of interleukin (IL)-4 and PGE(2) in L. amazonensis infection of susceptible BALB/c mice. IL-4 deficient (-/-) or wild-type (+/+) BALB/c mice were infected with different inocula of L. amazonensis. Two weeks after infection with 5x10(6) promastigotes/footpad, the production of interferon (IFN)-gamma upon L. amazonensis antigen stimulation was significantly higher in lymph node cell cultures of IL-4-/- mice than in IL-4+/+ mice. The levels of anti-leishmania IgG2a antibodies were also significantly higher in serum from IL-4-/- mice. In contrast, the levels of IgG1 antibodies were increased in IL-4+/+ mice and almost undetectable in IL-4-/- mice. Despite the increased Th1 response, lesions of IL-4-/- BALB/c mice progressed similarly to those of IL-4+/+ mice upon infection with the 5x10(6) inoculum. However, IL-4-/- mice developed smaller lesions upon infection with 10(5), 10(4) or 10(3) parasites than IL-4+/+ mice. The resistance of IL-4-/- correlated with higher Th1 response, compared to IL-4+/+ upon infection with 10(4)L. amazonensis. IL-4+/+ mice treated with indomethacin, an inhibitor of PGE(2) synthesis, during the first 3weeks of infection developed smaller lesions and lower parasitic load when compared to the control group. The lesions of indomethacin-treated groups contained mostly macrophages without vacuoles and small or absent necrotic areas. These results indicate that IL-4 and PGE(2) are susceptibility factors to L. amazonensis infection.
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http://dx.doi.org/10.1016/j.micinf.2005.11.011DOI Listing
April 2006