Browsing by Author "Santos, Fabiane Matos dos"

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    Avaliação da susceptibilidade/resistência ao benznidazol em populações de Trypanosoma cruzi submetidas a diferentes formas de manutenção no laboratório.
    (Programa de Pós-Graduação em Ciências Biológicas. Núcleo de Pesquisas em Ciências Biológicas, Pró-Reitoria de Pesquisa e Pós Graduação, Universidade Federal de Ouro Preto., 2006) Santos, Fabiane Matos dos; Bahia, Maria Terezinha
    O objetivo deste estudo foi avaliar a possibilidade de indução de resistência ao benznidazol de populações do Trypanosoma cruzi consideradas 100% sensíveis ao fármaco. Para isto, foram utilizados camundongos Swiss infectados com cinco (Be-62A, Be-62B, Be-78C, Be-78D e Be-78E) populações do T. cruzi, obtidas de diferentes cães chagásicos crônicos infectados com as cepas do T. cruzi Be-62 e Be-78, ambas 100% sensíveis ao benznidazol. Quatro diferentes populações resistentes do T. cruzi foram selecionadas após dois a 11 ciclos sucessivos de tratamento com benznidazol. Para avaliar a estabilidade do fenótipo de resistência ao benznidazol as populações do T. cruzi foram mantidas durante seis a 12 meses sem a pressão do fármaco: (1) através de passagens sangüíneas sucessivas em camundongos não tratados, e (2) em meio de cultura acelular, meio LIT. Novas alterações do nível de resistência ao benznidazol foram detectadas após a manutenção do parasito sem a pressão do fármaco. Todas as populações do T. cruzi benznidazol-resistentes mantidas através de passagens sangüíneas sucessivas em camundongos continuaram a apresentar 100% de resistência ao fármaco. Entretanto, a maior dificuldade encontrada na detecção da falha terapêutica indica o aumento de subpopulações do T. cruzi sensíveis ao benznidazol dentro de cada isolado. Por outro lado, os isolados Be-78C e E (100% resistentes), passaram a apresentar 50% e 20% de susceptibilidade ao benznidazol após serem mantidos por um ano e seis meses em meio de fenótipo de resistência , respectivamente. Estes resultados colaboram com a hipótese de que a forma de manipulação do T. cruzi pode influenciar o fenótipo de resistência ao benznidazol
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    Cardiomyopathy prognosis after benznidazole treatment in chronic canine Chagas' disease.
    (2012) Santos, Fabiane Matos dos; Lima, Wanderson Geraldo de; Gravel, André da Silva; Martins, Tassiane Assíria Fontes; Silva, André Talvani Pedrosa da; Torres, Rosália Morais; Bahia, Maria Terezinha
    Objectives: To evaluate the effects of benznidazole on Chagas’ disease cardiac prognosis using an experimental dog model of infection. Methods: A total of 28 dogs were divided into three groups: 10 were infected with Trypanosoma cruzi and treated benznidazole during the chronic phase, 10 were infected but untreated, and 8 were non-infected/ healthy. The trypanocidal efficacy was measured by parasite kDNA detection in blood and cardiac tissue samples. The effects of benznidazole in ameliorating the cardiac systolic function were evaluated by echodopplercardiogram. Results: The benznidazole initially induced a potent suppression of parasitaemia in treated animals. However, 12 months post-treatment, the parasite kDNA detections were similar between infected groups. In the baseline echocardiographic parameters there was no variation among all animals. Similarly, 1 month post-treatment there was no significant difference among healthy and infected animals with regard to systolic function. At 12 months post-treatment, an increase in cardiac chamber size related to cardiomegaly was detected among treated and untreated animals, but not in the healthy controls. Interestingly, in spite of both groups of infected animals developing a decrease in their systolic cardiac function, this decline was slightly less in the treated animals. We also evaluated levels of tumour necrosis factor-a and interleukin-10 in peripheral blood mononuclear cell culture supernatant. Cytokine profiles were similar between infected animal groups and correlated with alterations in cardiac function. Conclusions: The temporary suppression of the T. cruzi infection induced by benznidazole treatment was efficient in reducing systolic cardiac function alterations, but not in preventing the development of cardiomyopathy.
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    Chagas cardiomyopathy : the potential effect of benznidazole treatment on diastolic dysfunction and cardiac damage in dogs chronically infected with Trypanosoma cruzi.
    (2016) Santos, Fabiane Matos dos; Mazzeti, Ana Lia; Caldas, Sérgio; Gonçalves, Karolina Ribeiro; Lima, Wanderson Geraldo de; Torres, Rosália Morais; Bahia, Maria Terezinha
    Cardiac involvement represents the main cause of mortality among patients with Chagas disease, and therelevance of trypanocidal treatment to improving diastolic dysfunction is still doubtful. In the presentstudy, we used a canine model infected with the benznidazole-sensitive Berenice-78 Trypanosoma cruzistrain to verify the efficacy of an etiologic treatment in reducing the parasite load and ameliorating cardiacmuscle tissue damage and left ventricular diastolic dysfunction in the chronic phase of the infection. Theeffect of the treatment on reducing the parasite load was monitored by blood PCR and blood cultureassays, and the effect of the treatment on the outcome of heart tissue damage and on diastolic function wasevaluated by histopathology and echo Doppler cardiogram. The benefit of the benznidazole-treatmentin reducing the parasite burden was demonstrated by a marked decrease in positive blood culture andPCR assay results until 30 days post-treatment. At this time, the PCR and blood culture assays yieldednegative results for 82% of the treated animals, compared with only 36% of the untreated dogs. However,a progressive increase in the parasite load could be detected in the peripheral blood for one year post-treatment, as evidenced by a progressive increase in positive results for both the PCR and the bloodculture assays at follow-up. The parasite load reduction induced by treatment was compatible with thelower degree of tissue damage among animals euthanized in the first month after treatment and withthe increased cardiac damage after this period, reaching levels similar to those in untreated animals atthe one-year follow-up. The two infected groups also presented similar, significantly smaller values forearly tissue septal velocity (E’ SIV) than the non-infected dogs did at this later time. Moreover, in thetreated animals, an increase in the E/E’ septal tissue filling pressure ratio was observed when comparedwith basal values as well as with values in non-infected dogs. These findings strongly suggest that thetemporary reduction in the parasite load that was induced by benznidazole treatment was not able toprevent myocardial lesions and diastolic dysfunction for long after treatment.
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    Chagas cardiomyopathy : the potential effect of benznidazole treatment on diastolic dysfunction and cardiac damage in dogschronically infected with Trypanosoma cruzi.
    (2016) Santos, Fabiane Matos dos; Mazzeti, Ana Lia; Caldas, Sérgio; Gonçalves, Karolina Ribeiro; Lima, Wanderson Geraldo de; Torres, Rosália Morais; Bahia, Maria Terezinha
    Cardiac involvement represents the main cause of mortality among patients with Chagas disease, and therelevance of trypanocidal treatment to improving diastolic dysfunction is still doubtful. In the presentstudy, we used a canine model infected with the benznidazole-sensitive Berenice-78 Trypanosoma cruzistrain to verify the efficacy of an etiologic treatment in reducing the parasite load and ameliorating cardiacmuscle tissue damage and left ventricular diastolic dysfunction in the chronic phase of the infection. Theeffect of the treatment on reducing the parasite load was monitored by blood PCR and blood cultureassays, and the effect of the treatment on the outcome of heart tissue damage and on diastolic function wasevaluated by histopathology and echo Doppler cardiogram. The benefit of the benznidazole-treatmentin reducing the parasite burden was demonstrated by a marked decrease in positive blood culture andPCR assay results until 30 days post-treatment. At this time, the PCR and blood culture assays yieldednegative results for 82% of the treated animals, compared with only 36% of the untreated dogs. However,a progressive increase in the parasite load could be detected in the peripheral blood for one year post-treatment, as evidenced by a progressive increase in positive results for both the PCR and the bloodculture assays at follow-up. The parasite load reduction induced by treatment was compatible with thelower degree of tissue damage among animals euthanized in the first month after treatment and withthe increased cardiac damage after this period, reaching levels similar to those in untreated animals atthe one-year follow-up. The two infected groups also presented similar, significantly smaller values forearly tissue septal velocity (E’ SIV) than the non-infected dogs did at this later time. Moreover, in thetreated animals, an increase in the E/E’ septal tissue filling pressure ratio was observed when comparedwith basal values as well as with values in non-infected dogs. These findings strongly suggest that thetemporary reduction in the parasite load that was induced by benznidazole treatment was not able toprevent myocardial lesions and diastolic dysfunction for long after treatment.
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    Evolução da cardiopatia chagásica em cães tratados com Benznidazol na fase crônica da infecção experimental pelo Trypanosoma cruzi.
    (Programa de Pós-Graduação em Ciências Biológicas. Núcleo de Pesquisas em Ciências Biológicas, Pró-Reitoria de Pesquisa e Pós Graduação, Universidade Federal de Ouro Preto., 2010) Santos, Fabiane Matos dos; Bahia, Maria Terezinha
    A eficácia do tratamento com Benznidazol (Bz) na fase crônica da infecção e conseqüente prognóstico da cardiopatia chagásica permanece controversa. Neste estudo foram avaliados os efeitos do tratamento com Bz na evolução da cardiopatia chagásica crônica, utilizando cães infectados com a cepa Berenice-78 como modelo experimental. Os animais infectados foram divididos em dois grupos experimentais: (i) 12 cães tratados na fase crônica com 7,0 mg de Bz/kg, divididos em duas doses diárias, durante 60 dias; (ii) 12 cães mantidos como controles não tratados. Outros 8 animais constituíram o grupo controle não-infectado. A parasitemia foi monitorada pela PCR realizada em amostras de sangue e tecido muscular cardíaco coletados no 1o e 12o mês após o tratamento (MAT). A potente supressão da parasitemia, induzida pelo tratamento com Bz, foi observada pelos resultados negativos em 81,9% (9 de 11) dos animais tratados em relação a 36,3% (4 de 11) nos animais não tratados quando realizada a PCR no sangue coletado no 1o MAT. Resultados semelhantes foram observados na PCR do tecido muscular cardíaco, realizada no mesmo período, quando o kDNA do parasito foi detectado somente em 33%,3 (2 de 6) dos animais tratados e em 100% dos animais não tratados. Um aumento dos resultados positivos na PCR do sangue e tecido foi detectado 12 MAT. Este resultado foi verificado em 60% (3 de 5) no sangue e 80% (4 de 5) no tecido muscular cardíaco dos animais tratados. Para avaliação da cardiomegalia e função sistólica ou diastólica os animais foram examinados por ecocardiograma no 1o e 12o MAT. Foram mensurados os parâmetros fração de encurtamento, volume do Átrio Esquerdo (AE), fração de ejeção, volume diastólico e diâmetro sistólico do Ventrículo Esquerdo (VE). Após essa avaliação, metade dos animais foi eutanaziada para realização das análises histopatológicas no coração. O tratamento induziu uma redução de 20% a 36% de células inflamatórias e deposição intrafascicular de colágeno no 1o MAT. Nesta fase da infecção, não houve diferença significativa nos parâmetros ecocardiográficos mensurados entre os grupos de animais infectados (tratados ou não) e não infectados. Diferentemente, 12 MAT, as lesões cardíacas foram semelhantes entre os animais infectados (tratados ou não) e significativamente maiores que naqueles não infectados. Variáveis ecocardiográficas relacionadas com cardiomegalia e disfunção diastólica também foram semelhantes entre os animais infectados (tratados ou não) e significativamente maiores que nos animais não infectados. De modo interessante, o tratamento preveniu alterações na função sistólica, uma vez que não ocorreram diferenças na fração de ejeção e fração de encurtamento entre os animais tratados e não infectados. Esses resultados demonstram que o tratamento com Bz na fase crônica da infecção de cães é eficiente em prevenir as lesões cardíacas imediatamente após o tratamento e a função sistólica um longo tempo após o término do tratamento.
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    L-arginine supplementation increases cardiac collagenogenesis in mice chronically infected with Berenice-78 Trypanosoma cruzi strain.
    (2021) Narde, Maiara Bianchini; Domingues, Elisa Liz Belli Cassa; Gonçalves, Karolina Ribeiro; Vian, Mirelle Lomar; Zanini, Marcos Santos; Lima, Wanderson Geraldo de; Bahia, Maria Terezinha; Santos, Fabiane Matos dos
    Chagas disease, caused by Trypanosoma cruzi, is a major neglected tropical disease that occurs mainly as chronic infection and systemic infection. Currently, there is no suitable and effective drug to treat this parasitic disease. Administration of nutrients with immunomodulatory properties, such as arginine and nitric oxide radicals, may be helpful as antiparasitic therapy. In this study, we evaluated the effects of arginine supplementation during the acute phase of infection under the development of chronic Chagas’ heart disease in Swiss mice inoculated with the Berenice-78 strain of T. cruzi. The effectiveness of arginine was determined by daily detection of the parasite in the blood and long-term serum levels of nitric oxide and tumor necrosis factor-alpha, in addition to evaluation of heart tissue damage. Arginine could flatten parasitemia and prevent elevation of tumor necrosis factor-alpha in T. cruzi-infected mice. Regarding chronic inflammatory myocardial derangements, similar findings were verified among T. cruzi-infected groups. Arginine promoted collagenogenesis in the heart muscle tissue of T. cruzi-infected arginine-supplemented group. These data show the paradoxical benefits of arginine in improving the outcome of Chagas chronic cardiomyopathy.
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    Myocardial scars correlate with eletrocardiographic changes in chronic Trypanosoma cruzi infection for dogs treated with Benznidazole.
    (2013) Caldas, Ivo Santana; Guedes, Paulo Marcos da Matta; Santos, Fabiane Matos dos; Diniz, Lívia de Figueiredo; Martins, Tassiane Assíria Fontes; Nascimento, Alvaro Fernando da Silva do; Azevedo, Maíra Araújo; Lima, Wanderson Geraldo de; Nascimento Neto, Raimundo Marques do; Torres, Rosália Morais; Silva, André Talvani Pedrosa da; Bahia, Maria Terezinha
    objectives The cardiac form of Chagas disease is evidenced by a progressive cardiac inflammation that leads to myocarditis, fibrosis and electrocardiographic (ECG) conduction abnormalities. Considering these characteristics, the aim of this study was to prospectively evaluate the early ECG changes in dogs that were experimentally inoculated with Benznidazole (Bz)-susceptibly (Berenice-78) and Bz-resistant (VL-10, and AAS) Trypanosoma cruzi strains and, later, evaluate the efficacy of Bz treatment for preventing these ECG alterations. methods Electrocardiographic changes of treated and untreated animals were prospectively evaluated for up to 270 days after infection, at which point collagen (right atrium) quantification was performed. results All infected dogs had a high intensity of heart fibrosis (4616.00 ± 1715.82 collagen ⁄ 74931 lm2 in dogs infected with Berenice-78 strain, 5839.2 ± 1423.49 collagen ⁄ 74931 lm2 in infected by AAS and 6294.40 ± 896.04 collagen ⁄ 74931 lm2 in animals infected with VL-10 strain), while 78.57% of all infected dogs showed ECG alterations. Bz Therapy reduced or prevented fibrosis in Bz-susceptible Berenice-78 (2813.00 ± 607.13 collagen ⁄ 74931 lm2) and Bz-resistant AAS strains (4024 ± 1272.44 collagen ⁄ 74931 lm2), coincident with only 10% de ECG alterations at 270 days. However, in those animals infected with a Bz-resistant VL-10 strain, specific treatment did not alter collagen deposition (6749.5 ± 1596.35 collagen ⁄ 74931 lm2) and there was first atrioventricular block and chamber overload at 120 and 270 days after infection, with 75% abnormal ECG exams. conclusions These findings indicate that an effective antiparasitic treatment in the early stage of Chagas disease can lead to a significant reduction in the frequency and severity of the parasite-induced cardiac disease, even if parasites are not completely eliminated.
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    Protein deficiency alters CX3CL1 and endothelin-1 in experimental Trypanosoma cruzi-induced cardiomyopathy.
    (2013) Martins, Régia Ferreira; Martinelli, Patrícia Massara; Guedes, Paulo Marcos da Matta; Pádua, Bruno da Cruz; Santos, Fabiane Matos dos; Silva, Marcelo Eustáquio; Bahia, Maria Terezinha; Silva, André Talvani Pedrosa da
    objective Chagas heart disease is developed as a result of the infection with Trypanosoma cruzi. Protein malnutrition contributes to secondary immunodeficiency. The aim of this study was to investigate the role of a low protein diet on the production of endothelin-1 and CX3CL1 in blood and cardiac tissue samples in an experimental model with T. cruzi infection. methods Fisher rats were submitted to low protein (6%) and normal protein (15%) diets and then infected with the Y strain of T. cruzi. At days 15 and 120, parasites and immune cells were evaluated. results The low protein diet reduced body weight and circulating serum proteins, but promoted elevation of CX3CL1 and endothelin-1 levels in infected animals, which were unable to control blood parasitemia replication. In heart tissue, the low protein diet reduced cardiac CX3CL1, endothelin-1 and leucocyte infiltration in the acute phase, in particular CD68 and CD163 macrophage phenotypes. conclusion Together, these results highlight the participation of endothelin-1 and CX3CL1 in the inflammatory process of Chagas diesease, both being mediators partially controlled by the host nutritional status.
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    The role of fat on cardiomyopathy outcome in mouse models of chronic Trypanosoma cruzi infection.
    (2020) Zaki, Paul; Domingues, Elisa Liz Belli Cassa; Amjad, Farhad Mohammad; Narde, Maiara Bianchini; Gonçalves, Karolina Ribeiro; Viana, Mirelle Lomar; Paula, Heberth de; Lima, Wanderson Geraldo de; Huang, Huan; Bahia, Maria Terezinha; Sherer, Philipp E.; Santos, Fabiane Matos dos; Weiss, Louis M.; Tanowitz, Herbert Bernard
    The underlying pathogenic mechanisms of cardiomyopathy in Chagas disease are still unsolved. In order to better clarify the role of fat on the evolution of cardiomyopathy, the presentstudy employed three murine models of chronic Trypanosoma cruzi infection: (1) aP2- RIDα/β transgenic mice (RID mice; an adipose tissue model which express a gain-of-function potent anti-inflammatory activity), (2) allograft inflammatory factor-1 knockout mice (Aif1−/− ), and (3) a Swiss outbred mice. RID mice and non-transgenic mice (wild type, WT) were infected with blood trypomastigotes of Brazil strain. During the acute stage of infection, RID mice had lower parasitemia, lower heart inflammation, and a decrease in the relative distribution of parasite load from cardiac muscle tissue toward epididymal fat. Nevertheless, comparable profiles of myocardial inflammatory infiltrates and relative distribution of parasite load were observed among RID and WT at the chronic stage of infection. Aif1−/− and Aif1+/+ mice were infected with bloodstream trypomastigotes of Tulahuen strain and fed with high-fat diet (HFD) or regular diet (RD). Interestingly, Aif1+/+ HFD infected mice showed the highest mortality. Swiss mice infected with blood trypomastigotes of Berenice-78 strain on a HFD had higher levels of TNFα and more inflammation in their heart tissue than infected mice fed a RD. These various murine models implicate adipocytes in the pathogenesis of chronic Chagas disease and suggest that HFD can lead to a significant increase in the severity of parasite-induced chronic cardiac damage. Furthermore, these data implicate adipocyte TLR4-, TNFα-, and IL-1β-mediated signaling in pro-inflammatory pathways and Aif-1 gene expression in the development of chronic Chagas disease.
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    Trypanosoma cruzi : acute and long-term infection in the vertebrate host can modify the response to benznidazole.
    (2008) Caldas, Sérgio; Santos, Fabiane Matos dos; Lana, Marta de; Diniz, Lívia de Figueiredo; Coelho, George Luiz Lins Machado; Veloso, Vanja Maria; Bahia, Maria Terezinha
    We analyzed the influence of Trypanosoma cruzi maintenance in different hosts (dog and mouse) on its susceptibility to benznidazole treatment. Five T. cruzi stocks were isolated from dogs inoculated with Be-62 or Be-78 strain (both sensitive to benznidazole) 2–10 years ago, and the benznidazole sensitivity was then determined using the mouse as experimental model. The different T. cruzi stocks obtained from long-term infected dogs showed 50–90% drug resistance right after isolation. However, maintenance of these T. cruzi stocks in mice, by successive blood passages (2.5 years), led to either a decrease or stability of the drug resistance pattern and an increase in parasite virulence. We also demonstrated the effectiveness of the induction of parasitemia reactivation by cyclophosphamide immunosuppression in the evaluation of the response to the specific drug treatment.
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    Trypanosoma cruzi : induction of benznidazole resistance in vivo and its modulation by in vitro culturing and mice infection.
    (2008) Santos, Fabiane Matos dos; Caldas, Sérgio; Cáu, Stêfany Bruno de Assis; Crepalde, Geovam Pereira; Lana, Marta de; Coelho, George Luiz Lins Machado; Veloso, Vanja Maria; Bahia, Maria Terezinha
    Through a continuous in vivo drug pressure protocol, using mice as experimental model, we induced benznidazole resistance in Trypanosoma cruzi stocks. Full resistance was obtained for four out of five T. cruzi stocks analyzed. However, the number of benznidazole doses (40–180), as well as the time (4–18 months) necessary to induce resistance varied among the different T. cruzi stocks. The resistance phenotype remained stable after T. cruzi stocks has been maintained by 12 passages in mice (six months) and in acellular culture for the same time. However, the maintenance of resistant parasite for 12 months in acellular culture induces a reduction in its level of benznidazole resistance, while no alteration was detected in parasite maintained for the same time in mice. The data showed the stability of the resistance acquired by drug pressure, but suggest the possibility of reversible changes in the resistance levels after maintenance for long time in acellular culture.