Browsing by Author "Menezes, Ana Paula de Jesus"

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    Atividade tripanocida e anti-inflamatória de compostos derivados de 1,8-dioxo-octa-hidroxantenos.
    (2019) Menezes, Ana Paula de Jesus; Silva, André Talvani Pedrosa da; Costa, Guilherme de Paula; Costa, Daniela Caldeira; Sousa, Lirlândia Pires de; Andrade Neto, Valter Ferreira de; Veloso, Vanja Maria
    A infecção pelo Trypanosoma cruzi acomete milhares de pessoas pelo mundo e a eficácia dos fármacos disponíveis para eliminar este parasito é limitada à fase aguda da doença. A busca por moléculas mais efetivas contra o T. cruzi e de menor toxicidade para o hospedeiro é, portanto, uma prioridade para a saúde pública mundial. Neste contexto surgem as 1,8-dioxo-octahidroxanthenos ou xanthenodionas, compostos sintéticos derivados das xantonas que possuem inúmeras aplicações terapêuticas descritas, dentre elas atividades anti-inflamatória, tripanocida e cardioprotetora. Assim, o objetivo deste trabalho foi avaliar a ação tripanocida, in vitro, de compostos derivados das 1,8-dioxo-octahydroxantenos e sua influência, in vivo, na parasitemia e na alteração dos parâmetros inflamatórios durante a infecção murina. Para avaliar a toxicidade dos compostos in vitro utilizou-se testes colorimétricos (MTT) em formas tripomastigotas (cepa Y) e em macrófagos J774A.1, além de ensaios fluorimétricos (AlamarBlue) em células Vero com parasitos da cepa CL expressando uma proteína vermelho fluorescente (CLtdTomato) para determinação da CC50, IC50 e IS. Nesta etapa, doze compostos foram avaliados (MI17, MI18, MI24, MI25, MI39, MI45, MI68, MI73, MI78, MI79, MI80 e MI81) foram avaliados nesta etapa. O compostos MI80 (IC50=30.65) destacou-se por apresentar atividade anti-T. cruzi, com o melhor IS (170). Para avaliar in vivo o desempenho tripanocida e imunológico do composto MI80, camundongos Swiss foram infectados com as cepas Y (n = 10) e CL (n = 10) de T. cruzi utilizando um protocolo de tratamento por 10 dias com 50mg / kg de MI80. O MI80 reduziu 40% do pico de parasitemia em animais infectados com a cepa Y, enquanto reduziu, em ambas as cepas, o infiltrado inflamatório cardíaco. RankL, CCL2 e IFN-g foram mensurados no tecido cardíaco, mas o MI80 não foi capaz de modificar seu padrão em animais infectados com a cepa Y. No entanto, o MI80 aumentou o RankL e IL-10 em camundongos infectados com CL. Não foi observada toxicidade hepática e renal nos animais advindas do tratamento com o composto MI80. . Nossos achados mostraram que o 1,8-dioxo-octa-hidroxanteno tem um efeito anti-parasitário limitado e foi capaz de melhorar os parâmetros inflamatórios cardíacos relacionados à infecção por T. cruzi.
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    Combination therapy with benznidazole and doxycycline shows no additive effect to monotherapy with benznidazole in mice infected with the VL-10 strain of the Trypanosoma cruzi.
    (2020) Carneiro, Ana Cláudia Alvarenga; Costa, Guilherme de Paula; Ferreira, Cyntia Silva; Ramos, Isalira Peroba Rezende; Sarandy, Mariáurea Matias; Leite, Ana Luísa Junqueira; Menezes, Ana Paula de Jesus; Silva, Breno de Mello; Nogueira, Katiane de Oliveira Pinto Coelho
    Background: Chagas heart disease is the most important clinical manifestation of Trypanosoma cruzi infection. Pharmacological therapies have been proposed aiming to reduce inflammatory response and cardiac damage in infected hosts. In this study, we investigated the use of doxycycline (Dox), in a sub-antimicrobial dose, in monotherapy and in combination with benznidazole (Bz) during the acute phase of infection with the VL-10 strain of T. cruzi, evaluating the therapeutic effect during the acute and chronic phases of the infection. Methods and results: C57BL/6 mice were treated for 20 days with Dox (30 mg/kg), Bz (100 mg/kg), or both drugs in combination starting 9 days after infection. Parasitemia was measured during the acute phase and the animals were monitored for 12 months, after which echocardiography analysis was performed. Blood samples were obtained from euthanized mice for CCL2, CCL5, IL-10 analysis, and cardiac fragments were collected for histopathological evaluation. Dox treatment did not ameliorate parasitological/inflammatory parameters but reduced the cardiac collagen neoformation (CN) in 35%. In contrast, Bz administration reduced parasitemia, plasma levels of CCL2 and CCL5, and cardiac infiltration during acute infection, and reduced the level of IL-10 and CN (95%) at 12 months. Dox was unable to improve ejection fraction, while Bz treatment ameliorated the ejection fraction. No additive effect was observed in combination therapy. Conclusion: Dox monotherapy is not effective in the acute or chronic phases of experimental cardiomyopathy induced by the VL-10 strain of T. cruzi. Furthermore, combination therapy with Dox does not potentiate the effects of Bz monotherapy.
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    Correlação entre a carga parasitária do Trypanosoma cruzi no tecido cardíaco e detecção de autoanticorpos no soro de cães infectados com a patologia da doença de chagas experimental.
    (2015) Menezes, Ana Paula de Jesus; Caldas, Ivo Santana; Caldas, Sérgio; Bahia, Maria Terezinha; Roatt, Bruno Mendes; Marques, Marcos José
    Na cardiomiopatia Chagásica Crônica a presença do parasito parece ser essencial para a perpetuação da inflamação, entretanto devido à intensidade das lesões com escassos parasitos, o fenômeno de autoimunidade é apontado como importante na indução da miocardite. Dessa forma, o uso de drogas tripanocidas pode alterar a patogênese ao diminuir o parasitismo. No Brasil a droga indicada, o Benznidazol (Bz), gera cura parasitológica somente no tratamento realizado na fase aguda da infecção.O objetivo deste estudo foi quantificar o parasitismo no tecido cardíaco e avaliar a presença de autoanticorpos no soro de cães inoculados com diferentes cepas do T. cruzi e correlacionar a carga parasitária e a autoimunidade com a intensidade das lesões cardíacas. Sessenta cães sem raça definida, nascidos e mantidos no canil da UFOP foram infectados com 2,0x103 tripomastigotas metacíclicos/Kg das cepas Berenice-78, AAS e VL-10 do T.cruzi, e após a confirmação da infecção, metade dos cães foi tratada com Bz e a outra metade mantida sem tratamento. Noventa dias após a infecção, 30 animais foram eutanasiados na fase aguda, sendo os outros 30 na fase crônica da infecção. O átrio direito foi seccionado para análise da intensidade do infiltrado inflamatório por H&E, e utilizado para a quantificação do T.cruzi por qPCR. Além da detecção de autoanticorpos por immunoblotting no soro. Todos os grupos experimentais apresentaram miocardite intensa tanto na fase aguda, quanto na fase crônica. A quantificação do DNA do parasito nos animais infectados e não tratados variou de 5,0x102 a 2,6x106cópias/μL na fase aguda e na fase crônica o pico de quantificação foi de 4,9x105 cópias/μL. O tratamento com Bz reduziu significativamente o parasitismo cardíaco entre os animais infectados com a cepa VL-10 e Berenice-78(p<0.05) durante a fase aguda da infecção. Entretanto,na fase crônica não foi houve redução da carga parasitária entre os cães infectados pela cepa VL-10, não sendo possível avaliar a redução entre as outras duas cepas. A análise entre inflamação cardíaca e o parasitismo revelou uma correlação positiva entre o aumento da quantidade de DNA do parasito com o aumento da inflamação. Em relação à autoimunidade, foi observada maior produção de autoanticorpos durante a fase aguda em relação à fase crônica sem correlação com a miocardite.
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    Diet rich in lard promotes a metabolic environment favorable to Trypanosoma cruzi growth.
    (2021) Souza, Débora Maria Soares de; Silva, Maria Cláudia; Farias, Sílvia Elvira Barros; Menezes, Ana Paula de Jesus; Milanezi, Cristiane Maria; Lúcio, Karine de Pádua; Paiva, Nívia Carolina Nogueira de; Vieira, Paula Melo de Abreu; Costa, Daniela Caldeira; Pinto, Kelerson Mauro de Castro; Costa, Guilherme de Paula; Silva, João Santana da; Silva, André Talvani Pedrosa da
    Background: Trypanosoma cruzi is a protozoan parasite that causes Chagas disease and affects 6–7 million people mainly in Latin America and worldwide. Here, we investigated the effects of hyperlipidic diets, mainly composed of olive oil or lard on experimental T. cruzi infection. C57BL/6 mice were fed two different dietary types in which the main sources of fatty acids were either monounsaturated (olive oil diet) or saturated (lard diet). Methods: After 60 days on the diet, mice were infected with 50 trypomastigote forms of T. cruzi Colombian strain. We evaluated the systemic and tissue parasitism, tissue inflammation, and the redox status of mice after 30 days of infection. Results: Lipid levels in the liver of mice fed with the lard diet increased compared with that of the mice fed with olive oil or normolipidic diets. The lard diet group presented with an increased parasitic load in the heart and adipose tissues following infection as well as an increased expression of Tlr2 and Tlr9 in the heart. However, no changes were seen in the survival rates across the dietary groups. Infected mice receiving all diets presented comparable levels of recruited inflammatory cells at 30 days post-infection but, at this time, we observed lard diet inducing an overproduction of CCL2 in the cardiac tissue and its inhibition in the adipose tissue. T. cruzi infection altered liver antioxidant levels in mice, with the lard diet group demonstrating decreased catalase (CAT) activity compared with that of other dietary groups. Conclusions: Our data demonstrated that T. cruzi growth is more favorable on tissue of mice subjected to the lard diet. Our findings supported our hypothesis of a relationship between the source of dietary lipids and parasite-induced immunopathology.
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    Expression and production of cardiac angiogenic mediators depend on the Trypanosoma cruzi-genetic population in experimental C57BL/6 mice infection.
    (2017) Bajracharya, Deena Shrestha; Bajracharya, Bijay; Costa, Guilherme de Paula; Salles, Beatriz Cristina Silveira; Leite, Ana Luísa Junqueira; Menezes, Ana Paula de Jesus; Souza, Débora Maria Soares de; Oliveira, Laser Antônio Machado de; Silva, André Talvani Pedrosa da
    Mammalian cardiac cells are important targets to the protozoan Trypanosoma cruzi. The inflammatory reaction in the host aims at eliminating this parasite, can lead to cell destruction, fibrosis and hypoxia. Local hypoxia iswelldefined stimulus to the production of angiogenesis mediators. Assuming that different genetic T. cruzi populations induce distinct inflammation and disease patterns, the current study aims to investigate whether the production of inflammatory and angiogenic mediators is a parasite strain-dependent condition. C57BL/6 mice were infectedwith the Y and Colombian strains of T. cruzi and euthanized at the 12th and 32nd days, respectively. The blood and heart tissue were processed in immune assays and/or qPCR (TNF, IL-17, IL-10, CCL2, CCL3, CCL5, CCR2, CCR5 and angiogenic factors VEGF, Ang-1, Ang-2) and in histological assays. The T. cruzi increased the inflammatory and angiogenicmediators in the infectedmicewhen theywere compared to non-infected animals.However, the Colombian strain has led to higher (i) leukocyte infiltration, (ii) cardiac TNF and CCL5 production/expression, (iii) cardiac tissue parasitism, and to higher (iv) ratio between heart/body weights. On the other hand, the Colombian strain has caused lower production and expression VEGF, Ang-1 and Ang-2, when it was compared to the Y strain of the parasite. The present study highlights that the T. cruzi-genetic population defines the pattern of angiogenic/inflammatory mediators in the heart tissue, and that itmay contribute to themagnitude of the cardiac pathogenesis. Besides, such assumption opens windows to the understanding of the angiogenic mediator's role in association with the experimental T. cruzi infection.
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    A high-fat diet exacerbates the course of experimental Trypanosoma cruzi infection that can be mitigated by treatment with Simvastatin.
    (2020) Souza, Débora Maria Soares de; Costa, Guilherme de Paula; Leite, Ana Luísa Junqueira; Oliveira, Daniela Silva de; Pinto, Kelerson Mauro de Castro; Farias, Sílvia Elvira Barros; Simões, Natália Figueira; Paiva, Nívia Carolina Nogueira de; Vieira, Paula Melo de Abreu; Silva, Camilo Adalton Mariano da; Figueiredo, Vivian Paulino; Menezes, Ana Paula de Jesus; Silva, André Talvani Pedrosa da
    The protozoan Trypanosoma cruzi is responsible for triggering a damage immune response in the host cardiovascular system. This parasite has a high affinity for host lipoproteins and uses the low-density lipoprotein (LDL) receptor for its invasion. Assuming that the presence of LDL cholesterol in tissues could facilitate T. cruzi proliferation, dietary composition may affect the parasite-host relationship. Therefore, the aim of this study was to evaluate myocarditis in T. cruzi-infected C57BL/6 mice—acute phase—fed a high-fat diet and treated with simvastatin, a lipid-lowering medication. Animals (n = 10) were infected with 5 × 103 cells of the VL-10 strain of T. cruzi and treated or untreated daily with 20 mg/kg simvastatin, starting 24 h after infection and fed with a normolipidic or high-fat diet. Also, uninfected mice, treated or not with simvastatin and fed with normolipidic or high-fat diet, were evaluated as control groups. Analyses to measure the production of chemokine (C-C motif) ligand 2 (CCL2), interferon- (IFN-) γ, interleukin- (IL-) 10, and tumor necrosis factor (TNF); total hepatic lipid dosage; cholesterol; and fractions, as well as histopathological analysis, were performed on day 30 using cardiac and fat tissues. Our results showed that the high-fat diet increased (i) parasite replication, (ii) fat accumulation in the liver, (iii) total cholesterol and LDL levels, and (iv) the host inflammatory state through the production of the cytokine TNF. However, simvastatin only reduced the production of CCL2 but not that of other inflammatory mediators or biochemical parameters. Together, our data suggest that the high-fat diet may have worsened the biochemical parameters of the uninfected and T. cruzi-infected animals, as well as favored the survival of circulating parasites.
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    In vitro tripanocidal effect of 1,8-dioxooctahydroxanthenes (xanthenodiones) and tetraketones and improvement of cardiac parameters in vivo.
    (2020) Menezes, Ana Paula de Jesus; Silva, Milene Lopes da; Pereira, Wagner Luiz; Costa, Guilherme de Paula; Horta, Aline Luciano; Mendonça, Andréa Aparecida dos Santos; Carneiro, Ana Cláudia Alvarenga; Souza, Débora Maria Soares de; Novaes, Rômulo Dias; Teixeira, Róbson Ricardo; Silva, André Talvani Pedrosa da
    Objective: Trypanosoma cruzi infection affects millions of people worldwide, and the drugs available for its treatment have limited efficacy. 1,8-Dioxooctahydroxanthenes and tetraketones are compounds with important biological applications. The aim of this study was to assess the trypanocidal and inflammatory activities of nine 1,8-dioxooctahydroxanthenes (1–9) and three tetraketones (10–12). Methods and results: By in vitro killing assay, three compounds were able to eliminate CL TdTomato expressing strain of T. cruzi, 9 (IC50 = 30.65mM), 10 (IC50 = 14.11mM), and 11 (IC50 = 26.43mM). However, only 9 was not toxic to Vero cells. Next, to evaluate the in vivo antitrypanosomal and immunological efficacy of 9, Swiss mice were infected with the Y and CL strains of T. cruzi and treated for 10 days with 50 mg/kg of 9. This compound reduced the cardiac inflammatory infiltration in animals infected with both strains. Rank's ligand (RankL), CCL2, and interferon (IFN)-g were measured in the cardiac tissue homogenate of the Y-strain-infected animals, and no interference of 9 was observed. However, compound 9 increased the RankL and interleukin (IL)-10 levels in CL-infected mice. No hepatic and renal toxicity was observed. Conclusion: Our findings showed that 1,8-dioxooctahydroxanthene has antiparasitic effect and ameliorates the cardiac inflammatory parameters related to T. cruzi infection.
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    Parasitaemia and parasitic load are limited targets of the aetiological treatment to control the progression of cardiac fibrosis and chronic cardiomyopathy in Trypanosoma cruzi-infected dogs.
    (2019) Caldas, Ivo Santana; Menezes, Ana Paula de Jesus; Diniz, Lívia de Figueiredo; Nascimento, Alvaro Fernando da Silva do; Novaes, Rômulo Dias; Caldas, Sérgio; Bahia, Maria Terezinha
    It is still unclear whether the progression of acute to chronic Chagas cardiomyopathy is predominantly associated with the limited efficacy of aetiological chemotherapy, or with the pharmacological resistance profiles and pathogenicity of specific Trypanosoma cruzi strains. Thus, we tested the hypothesis that parasitic load could be a limited target of aetiological chemotherapy to prevent chronic cardiomyopathy in dogs infected by different T. cruzi strains. Animals were infected with benznidazole-susceptible (Berenice-78) and -resistant (VL-10 and AAS) strains of T. cruzi. A quantitative real-time PCR strategy was developed to comparatively quantify the parasite load of the three different strains using a single standard curve. For dogs infected with the VL-10 strain, benznidazole treatment reduced cardiac parasitism during the acute phase of infection. However, similar parasite load and collagen deposition were detected in the myocardium of treated and untreated animals in the chronic phase of the infection. In animals infected with the AAS strain, benznidazole reduced parasite load, myocarditis and type III collagen deposition in the acute phase. However, increased type III collagen deposition was verified in the chronic phase. Dogs infected with the Berenice-78 strain showed a parasitological cure and no evidence of myocardial fibrosis. Parasitic load and cardiac fibrosis presented no correlation in acute or chronic phases of T. cruzi infection. Our findings in a canine model of Chagas disease suggest that parasite burden is a limited predictor for disease progression after treatment and show that benznidazole, although not inducing parasitological cure, is able to prevent total fibrosis in the early stages of infection, as well as complete prevention of cardiac damage when it eliminates parasites at the onset of infection.
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    Resolvin D1 administration is beneficial in Trypanosoma cruzi infection.
    (2020) Horta, Aline Luciano; Williams, Tere; Han, Bing; Ma, Yanfen; Menezes, Ana Paula de Jesus; Tu, Vincent; Silva, André Talvani Pedrosa da; Weiss, Louis M.; Huang, Huan
    Chagas disease is a major public health issue, affecting 10 million people worldwide. Transmitted by a protozoan named Trypanosoma cruzi, this infection triggers a chronic inflammatory process that can lead to cardiomyopathy (Chagas disease). Resolvin D1 (RvD1) is a novel proresolution lipid mediator whose effects on inflammatory diseases dampens pathological inflammatory responses and can restore tissue homeostasis. Current therapies are not effective in altering the outcome of T. cruzi infection, and as RvD1 has been evaluated as a therapeutic agent in various inflammatory diseases, we examined if exogenous RvD1 could modulate the pathogenesis of Chagas disease in a murine model. CD-1 mice infected with the T. cruzi Brazil strain were treated with RvD1. Mice were administered 3 g/kg of body weight RvD1 intraperitoneally on days 5, 10, and 15 to examine the effect of RvD1 on acute disease or administered the same dose on days 60, 65, and 70 to examine its effects on chronic infection. RvD1 therapy increased the survival rate and controlled parasite replication in mice with acute infection and reduced the levels of interferon gamma and transforming growth factor (TGF-) in mice with chronic infection. In addition, there was an increase in interleukin-10 levels with RvD1 therapy in both mice with acute infection and mice with chronic infection and a decrease in TGF- levels and collagen content in cardiac tissue. Together, these data indicate that RvD1 therapy can dampen the inflammatory response, promote the resolution of T. cruzi infection, and prevent cardiac fibrosis.
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    The β-blocker carvedilol and the benznidazole modulate the cardiac immune response in the acute infection induced by Colombian strain of the Trypanosoma cruzi.
    (2018) Horta, Aline Luciano; Figueiredo, Vivian Paulino; Leite, Ana Luísa Junqueira; Costa, Guilherme de Paula; Menezes, Ana Paula de Jesus; Ramos, Camila de Oliveira; Pedrosa, Tamiles Caroline Fernandes; Bezerra, Frank Silva; Vieira, Paula Melo de Abreu; Silva, André Talvani Pedrosa da
    BACKGROUND The infection led by Trypanosoma cruzi persists in mammalian tissues causing an inflammatory imbalance. Carvedilol (Cv), a non-selective beta blocker drug indicated to treat heart failure and antihypertensive has shown to promote antioxidant and immunomodulatory properties which might improve the inflammation induced by T. cruzi. OBJECTIVES Evaluate the role of Cv on the inflammatory response of C57BL/6 mice acutely infected with the Colombian strain of T. cruzi. METHODS Animals were infected with the Colombian strain of T. cruzi and treated with Cv (25 mg/kg/day), benznidazole (Bz) (100 mg/kg/day) or their combination. On the 28th day of infection and 23 days of treatment, the euthanasia occurred, and the heart preserved for histopathological, oxidative stress (SOD, catalase, TBARs, carbonylated proteins) and plasma (CCL2, CCL5, TNF, IL-10) analyses. Parasitaemia and survival were assessed along the infection. FINDINGS Cv decreased TBARs, but increased the mortality rate, the parasitaemia and the levels of CCL2, CCL5, catalase and the inflammatory infiltrate in the cardiac tissue. Bz led the reduction of the inflammatory infiltrate and circulating levels of oxidative stress and inflammatory mediators in the infected mice. MAIN CONCLUSIONS Our data suggest that Cv, in this experimental model using the Colombian strain of T. cruzi, caused damage to the host.