Milena B P Soares

CEP America, Emeryville, California, United States

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Publications (97)312 Total impact

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    ABSTRACT: Here, we describe the trypanocidal and antimalarial activities from essential oils extracted from Annona vepretorum (AVOE) and Annona squamosa (ASOE) (Annonaceae) leaves. The essential oils were obtained by hydrodistillation and analyzed by gas chromatography–mass spectrometry (GC–MS) and GC–flame ionization detection (GC–FID). A total of twenty-one compounds were identified in AVOE and twenty-three in ASOE. The sesquiterpenes are more abundant in the both essential oils. ASOE contained significant quantities of (E)-caryophyllene (27.4%), germacrene D (17.1%) and bicyclogermacrene (10.8%). The major compounds in AVOE were bicyclogermacrene (39.0%), spathulenol (14.0%) and α-phellandrene (11.5%). The essential oils demonstrated potent trypanocidal and antimalarial activities with values of IC50 lower than 20 μg/mL, and a strong inhibition of the proliferation of amastigotes, the clinically relevant forms of Trypanosoma cruzi. In addition, through ultrastructural studies and flow cytometry analysis with trypomastigotes of T. cruzi, we identified significant ultrastructural alterations induced by the essential oils, especially in the cell membrane and mitochondria, which ultimately results in necrotic parasite death.
    Journal of Essential Oil Research 01/2015; · 0.82 Impact Factor
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    ABSTRACT: Abstract 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.
    Journal of Enzyme Inhibition and Medicinal Chemistry 11/2014; · 1.50 Impact Factor
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    ABSTRACT: The cis-[RuCl(NO2)(dppb)(5,5' -mebipy)] ( 1: ), cis-[Ru(NO2)2(dppb)(5,5' -mebipy)] ( 2: ), ct-[RuCl(NO)(dppb)(5,5' -mebipy)](PF6)2 ( 3: ) and cc-[RuCl(NO)(dppb)(5,5' -mebipy)]PF6 ( 4: ) complexes, where 5,5' -mebipy = 5,5' -dimethyl-2,2' -bipyridine and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized. The structure of the cis-[Ru(NO2)2(dppb)(5,5' -mebipy)] ( 2: ) complex was determined by X-ray crystallography. These complexes exhibited a higher anti-T. cruzi activity than benznidazole, the current antiparasitic drug. Complex ( 3: ) was the most potent, displaying EC50 = 2.1±0.6 μM against trypomastigotes and IC50 = 1.3±0.2 μM against amastigotes, while it displayed a 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: ) (5 x 75 μmol/kg) 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.
    Antimicrobial Agents and Chemotherapy 08/2014; · 4.45 Impact Factor
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    Bioorganic & Medicinal Chemistry Letters. 08/2014; 24(15):3315–3320.
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    ABSTRACT: This work describes a novel ent-kaurane diterpene, ent-3β-hydroxy-kaur-16-en-19-al along with five known ent-kaurane diterpenes, ent-3β,19-dihydroxy-kaur-16-eno, ent-3β-hydroxy-kaur-16-eno, ent-3β-acetoxy-kaur-16-eno, ent-3β-hydroxy-kaurenoic acid and kaurenoic acid, as well as caryophyllene oxide, humulene epoxide II, β-sitosterol, stigmasterol and campesterol from the stem bark of Annona vepretorum Mart. (Annonaceae). Cytotoxic activities towards tumor B16-F10, HepG2, K562 and HL60 and non-tumor PBMC cell lines were evaluated for ent-kaurane diterpenes. Among them, ent-3β-hydroxy-kaur-16-en-19-al was the most active compound with higher cytotoxic effect over K562 cell line (IC50 of 2.49μg/mL) and lower over B16-F10 cell line (IC50 of 21.02μg/mL).
    Bioorganic & medicinal chemistry letters. 06/2014;
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    ABSTRACT: 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.
    International Journal of Experimental Pathology 06/2014; · 2.05 Impact Factor
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    ABSTRACT: The present study describes the synthesis, characterization, antileishmanial and antiplasmodial activities of novel diimine/(2,2'-bipyridine (bipy), 1,10-phenanthroline (phen), 4,4'-methylbipyridine (Me-bipy) and 4,4'-methoxybipyridine (MeO-bipy)/phosphine/ruthenium(II) complexes containing lapachol (Lap, 2-hydroxy-3-(3-33 methyl-2-buthenyl)-1,4-naphthoquinone) as bidentate ligand. The [Ru(Lap)(PPh3)2(bipy)]PF6 (1), [Ru(Lap)(PPh3)2(Me-bipy)]PF6 (2), [Ru(Lap)(PPh3)2(MeO-bipy)]PF6(3) and[Ru(Lap)(PPh3)2(phen)]PF6 (4) complexes, PPh3=triphenylphospine, were synthesized from the reactions of cis-[RuCl2(PPh3)2(X-bipy)] or cis-[RuCl2(PPh3)2(phen)], with lapachol. The [RuCl2(Lap)(dppb)] (5) [dppb=1,4-bis(diphenylphosphine)butane] was synthesized from the mer-[RuCl3(dppb)(H2O)] complex. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-vis spectroscopy, (31)P{(1)H} and (1)H NMR, and cyclic voltammetry. The Ru(III) complex, [RuCl2(Lap)(dppb)], was also characterized by the EPR technique. The structure of the complexes [Ru(Lap)(PPh3)2(bipy)]PF6 and [RuCl2(Lap)(dppb)] was elucidated by X-ray diffraction. The evaluation of the antiparasitic activities of the complexes against Leishmania amazonensis and Plasmodium falciparum demonstrated that lapachol-ruthenium complexes are more potent than the free lapachol. The [RuCl2(Lap)(dppb)] complex is the most potent and selective antiparasitic compound among the five new ruthenium complexes studied in this work, exhibiting an activity comparable to the reference drugs.
    Journal of inorganic biochemistry 03/2014; 136C:33-39. · 3.25 Impact Factor
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    ABSTRACT: Guatteria blepharophylla Mart. (synonym Guatteriopsis blepharophylla Mart.) and Guatteria hispida (R.E. Fr.) Erkens & Maas (synonym Guatteriopsis hispida R.E. Fr.) belong to the Annonaceae family and are found in the Brazilian and Colombian Amazon basin. Both species are popularly known as ‘envira’ or ‘envireira’. In the present study, the leaf essential oils of G. blepharophylla (EOGB) and G. hispida (EOGH) were selected to investigate their cytotoxic effects. Tumour cell lines were treated with increasing concentrations of both essential oils for 72 h and analysed by a methyl-[3H]thymidine incorporation assay. The pro-apoptotic effect of these essential oils was assessed in HepG2 cells by morphological analysis (using haematoxylin/eosin staining and acridine orange/ethidium bromide staining), flow cytometry (cell membrane integrity and internucleosomal DNA fragmentation analysis) and a caspase-3 activation assay after 24 h incubation. Both essential oils displayed potent cytotoxicity in different tumour cell lines. EOGB showed IC50 values from 6.03 to 16.46 µg/ml for HepG2 and K562 cell lines, and EOGH showed IC50 values from 5.45 to 24.89 µg/ml for HepG2 and K562 cell lines, respectively. Cell morphologies consistent with apoptosis and a remarkable activation of caspase-3 were observed in the HepG2 cells treated with essential oils for 24 h. Significant increases in internucleosomal DNA fragmentation without altered membrane integrity were also found. In conclusion, both essential oils investigated were able to inhibit tumour cell proliferation and induce cell death by apoptosis pathways. Copyright © 2014 John Wiley & Sons, Ltd.
    Flavour and Fragrance Journal 03/2014; · 1.82 Impact Factor
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    ABSTRACT: Five ruthenium–lapachol complexes were synthesized and evaluated against Leishmania amazonensis and Plasmodium falciparum. The metal complexes are promising antiparasite metallodrug candidates, in which they are more potent than lapachol free and the reference drugs.
    Journal of Inorganic Biochemistry. 01/2014; 136:33–39.
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    ABSTRACT: Hecogenin is a steroidal sapogenin largely drawn from the plants of the genus Agave, commonly known as 'sisal', and is one of the important precursors used by the pharmaceutical industry for the synthesis of steroid hormones. Hecogenin acetate (HA) is a steroidal sapogenin-acetylated that produces antinociceptive activity. Thus, we evaluate the antihyperalgesic profile of HA in mice in inflammatory models, as well as its possible involvement with c-fos expression on spinal cord area and cytokines to produces analgesic profile. Acute pretreatment with HA (5, 10, or 20 mg/kg; i.p.) inhibited the development of mechanical hyperalgesia induced by carrageenan, TNF-α, dopamine and PGE2. Additionally, the immunofluorescence data demonstrated that acute pretreatment with HA, at all doses tested, significantly inhibited Fos-like expression in the spinal cord dorsal horn normally observed after carrageenan-inflammation. Moreover, HA did not affect the motor performance of the mice as tested in the Rota rod test. This antinociceptive profile seems to be related, at least in part, to a reduction of pro-inflammatory cytokines, as IL-1β. The present results suggest that HA attenuates mechanical hyperalgesia by blocking the neural transmission of pain at the spinal cord levels and by cytokines-inhibitory mechanisms.
    Molecules (Basel, Switzerland). 01/2014; 19(6):8303-8316.
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    ABSTRACT: SUMMARY 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.
    Parasitology 09/2013; · 2.36 Impact Factor
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    ABSTRACT: Chagas disease, caused by Trypanosoma cruzi infection, is a leading cause of heart failure in Latin American countries. In a previous study, we showed beneficial effects of granulocyte colony-stimulating factor (G-CSF) administration in the heart function of mice with chronic T. cruzi infection. Presently, we investigated the mechanisms by which this cytokine exerts its beneficial effects. Mice chronically infected with T. cruzi were treated with human recombinant G-CSF (3 courses of 200 μg/kg/d for 5 d). Inflammation and fibrosis were reduced in the hearts of G-CSF-treated mice, compared with the hearts of vehicle-treated mice, which correlated with decreased syndecan-4, intercellular adhesion molecule-1, and galectin-3 expressions. Marked reductions in interferon-γ and tumor necrosis factor-α and increased interleukin-10 and transforming growth factor-β were found after G-CSF administration. Because the therapy did not induce a Th1 to Th2 immune response deviation, we investigated the role of regulatory T (Treg) cells. A significant increase in CD3(+)Foxp3(+) cells was observed in the hearts of G-CSF-treated mice. In addition, a reduction of parasitism was observed after G-CSF treatment. Our results indicate a role of Treg cells in the immunosuppression induced by G-CSF treatment and reinforces its potential therapeutic use for patients with Chagas disease.-Vasconcelos, J. F., Souza, B. S. F., Lins, T. F. S., Garcia, L. M. S., Kaneto, C. M., Smapaio, G. P., de Alcântara, A. C., Meira, C. S., Macambira, S. G., Ribeiro-dos-Santos, R., Soares, M. B. P. Administration of granulocyte colony-stimulating factor induces immunomodulation, recruitment of T regulatory cells, reduction of myocarditis and decrease of parasite load in a mouse model of chronic Chagas disease cardiomyopathy.
    The FASEB Journal 08/2013; · 5.48 Impact Factor
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    ABSTRACT: The literature has shown that low-level laser therapy accelerates the repair of cutaneous wounds. However, there is a scarcity of scientific studies that characterise the possible systemic interference of laser photobiomodulation. The aim of this research was to quantitatively evaluate blood corticosterone levels and tissue cytokine expression in cutaneous wounds of rats treated with low-level laser therapy (semiconductor diode AsGaAl, continuous emission, 9 mW, 670 nm, 0.031 W/cm(2), beam with an output area of 0.28 cm(2)) and normal controls. A total of 36 male Wistar rats were used and randomly divided into two groups of 18 rats each. A standardised circular 6-mm-diameter wound was made in the dorsal skin region of each rat, and they were euthanised at 1, 6 and 12 h after cutaneous surgery. The blood was collected, and portions of cutaneous tissue and subcutaneous muscle were removed and cryopreserved. Corticosterone levels in the blood were measured by a radioimmunoassay technique; histological sections were submitted to the ELISA technique for analysis of tissue cytokine expression levels. At 6 h after surgery, a significant increase in corticosterone and a significant reduction in the levels of IL-1β and IL-6 in tissues of irradiated wounds were observed when compared to controls (p < 0.05). The levels of TNF-α and IL-10 expression were not significantly different between the groups at different time intervals. Thus, this study strongly suggests a systemic and local biomodulation of low-level laser therapy as indicated by the blood levels of corticosterone and the tissue expression of IL-1β and IL-6, respectively.
    Lasers in Medical Science 07/2013; · 2.42 Impact Factor
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    ABSTRACT: Eudesmols are naturally occurring sesquiterpenoid alcohols that present cytotoxic effect to cancer cells. All eudesmol isomers displayed cytotoxicity to different tumor cell lines. α-Eudesmol showed IC50 values ranging from 5.38 ± 1.10 to 10.60 ± 1.33 μg/mL for B16-F10 and K562 cell lines, β-eudesmol showed IC50 values ranging from 16.51 ± 1.21 to 24.57 ± 2.75 μg/mL for B16-F10 and HepG2 cell lines and γ-eudesmol showed IC50 values ranging from 8.86 ± 1.27 to 15.15 ± 1.06 μg/mL for B16-F10 and K562 cell lines, respectively. In this work, we studied the mechanisms of cytotoxic action of eudesmol isomers (α-, β- and γ-eudesmol) in human hepatocellular carcinoma HepG2 cells. After 24 h incubation, HepG2 cells treated with eudesmol isomers presented typical hallmarks of apoptosis, as observed by morphological analysis in cells stained with hematoxylin-eosin and acridine orange/ethidium bromide. None of eudesmol isomers caused membrane disruption at any concentration tested. In addition, eudesmol isomers induced loss of mitochondrial membrane potential and an increase of caspase-3 activation in HepG2 cells, suggesting the induction of caspase-mediated apoptotic cell death. In conclusion, the eudesmol isomers herein investigated are able to reduce cell proliferation and to induce tumor cell death by caspase-mediated apoptosis pathways. This article is protected by copyright. All rights reserved.
    Basic & Clinical Pharmacology & Toxicology 06/2013; 113:300-306. · 2.18 Impact Factor
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    ABSTRACT: Emphysema is a chronic obstructive pulmonary disease characterized abnormal dilatation of alveolar spaces, which impairs alveolar gas exchange, compromising the physical capacity of a patient due to airflow limitations. Here we tested the effects of G-CSF administration in pulmonary tissue and exercise capacity in emphysematous mice. C57Bl/6 female mice were treated with elastase intratracheally to induce emphysema. Their exercise capacities were evaluated in a treadmill. Lung histological sections were prepared to evaluate mean linear intercept measurement. Emphysematous mice were treated with G-CSF (3 cycles of 200 μg/kg/day for 5 consecutive days, with 7-day intervals) or saline and submitted to a third evaluation 8 weeks after treatment. Values of run distance and linear intercept measurement were expressed as mean ± SD and compared applying a paired t-test. Effects of treatment on these parameters were analyzed applying a Repeated Measures ANOVA, followed by Tukey's post hoc analysis. p<0.05 was considered statistically significant. Twenty eight days later, animals ran significantly less in a treadmill compared to normal mice (549.7±181.2 m and 821.7±131.3 m, respectively; p<0.01). Treatment with G-CSF significantly increased the exercise capacity of emphysematous mice (719.6±200.5 m), whereas saline treatment had no effect on distance run (595.8±178.5 m). The PCR cytokines genes analysis did not detect difference between experimental groups. Morphometric analyses in the lung showed that saline-treated mice had a mean linear intersept significantly higher (p<0.01) when compared to mice treated with G-CSF, which did not significantly differ from that of normal mice. Treatment with G-CSF promoted the recovery of exercise capacity and regeneration of alveolar structural alterations in emphysematous mice.
    Pulmonary Pharmacology &amp Therapeutics 04/2013; · 2.54 Impact Factor
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    ABSTRACT: Medicinal plants are one of the most important sources of drugs used in the pharmaceutical industry. Among traditional medicinal plants, Lippia gracilis Schauer (Verbenaceae) had been used for several medicinal purposes in Brazilian northeastern. In this study, leaf essential oil (EO) of L. gracilis was prepared using hydrodistillation. Followed by GC-MS analysis, its composition was characterized by the presence of thymol (55.50%), as major constituent. The effects of EO on cell proliferation and apoptosis induction were investigated in HepG2 cells. Furthermore, mice bearing Sarcoma 180 tumor cells were used to confirm its in vivo effectiveness. EO and its constituents (thymol, p-cymene, γ-terpinene and myrcene) displayed cytotoxicity to different tumor cell lines. EO treatment caused G1 arrest in HepG2 cells accompanied by the induction of DNA fragmentation without affecting cell membrane integrity. Cell morphology consistent with apoptosis and a remarkable activation of caspase-3 were also observed, suggesting induction of caspase-dependent apoptotic cell death. In vivo antitumor study showed tumor growth inhibition rates of 38.5-41.9%. In conclusion, the tested essential oil of L. gracilis leaves, which has thymol as its major constituent, possesses significant in vitro and in vivo antitumor activity. These data suggest that leaf essential oil of L. gracilis is a potential medicinal resource.
    Phytomedicine: international journal of phytotherapy and phytopharmacology 02/2013; 20:615-621. · 2.97 Impact Factor
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    ABSTRACT: Stem cell-based therapy has been investigated in a number of degenerative and traumatic diseases, including spinal cord injury. In the present study, we investigated the use of autologous mesenchymal stem cells in the functional rehabilitation of a domestic cat presenting a compressive L1-L5 fracture. Bone marrow cells collected by puncture of the iliac crest were cultured to obtain mesenchymal stem cells three weeks before surgery. Hemilaminectomy was performed, followed by injection of the mesenchymal stem cells in the injured area. Clinical evaluation of the animal prior to surgery showed absence of pain, muscular tonus, and panniculi reflexes. Seven days after surgery and cell transplantation the examination revealed a progressive recovery of the panniculus reflexes and of the responses to superficial and deep pain stimuli despite the low proprioceptive and hyperreflexic ataxic hind limbs. Physiotherapy protocols were applied for clinical rehabilitation after surgery. The cat's first steps, three-minute weight-bearing, and intestine and urinary bladder partial reestablishment were observed 75 days post-surgery. Our results indicate the therapeutic potential of mesenchymal stem cells in chronic spinal cord injuries.
    International journal of stem cells. 11/2012; 5(2):146-150.
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    ABSTRACT: 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.
    Acta tropica 05/2012; 122(2):224-9. · 2.79 Impact Factor

Publication Stats

1k Citations
312.00 Total Impact Points

Institutions

  • 2013–2014
    • CEP America
      Emeryville, California, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Universidade Federal de Sergipe
      • Department of Chemistry
      São Cristóvão, Estado de Sergipe, Brazil
  • 2001–2014
    • Fundação Oswaldo Cruz
      • Aggeu Magalhães Research Center (CPqAM)
      Rio de Janeiro, Rio de Janeiro, Brazil
  • 2012
    • Universidade Federal da Bahia
      Bahia, Estado de Bahía, Brazil
  • 2011
    • Irmandade da Santa Casa da Misericórdia de Santos
      Santos, São Paulo, Brazil
  • 2004–2011
    • Santa Izabel Hospital
      Bahia, Estado de Bahía, Brazil
  • 2010
    • Hospital São Rafael
      Bahia, Estado de Bahía, Brazil
  • 2006–2009
    • Federal University of Pernambuco
      • Departamento de CIências Farmacêuticas
      Recife, Estado de Pernambuco, Brazil
  • 2002–2003
    • Federal University of Rio de Janeiro
      • Instituto de Biofísica Carlos Chagas Filho (IBCCF)
      Rio de Janeiro, Rio de Janeiro, Brazil
  • 1998
    • Harvard University
      • Department of Immunology and Infectious Diseases
      Boston, MA, United States
  • 1997
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States