The acute phase of Chagas disease (CD) is characterized by high parasitic proliferation and intense inflammation, exacerbating the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive molecules are also increased by the metabolism of the nitroheterocyclic compounds benznidazole (BZ) and nifurtimox, the only drugs available for the treatment of CD. This oxidative environment, associated with the intracellular multiplication of , leads to tissue destruction, triggering the pathogenic process. Both drugs have limited efficacy and serious side effects, which demonstrates the need to seek alternative therapies. Due to the difficulty in developing new drugs, reviewing therapeutic regimens appears advantageous, and the use of BZ in low doses associated with antioxidants, such as ascorbic acid (AA), would be a valid alternative to attenuate oxidative stress. In our studies, mice receiving the combination of 7.14 mg/kg of body weight/day AA and 10 mg/kg/day BZ10 (AA+BZ10) showed a reduction in parasitemia that was more effective than that with those receiving BZ or AA alone. The combined treatment was effective in decreasing intracellular ROS and lipid peroxidation in cardiac tissue. Histological and PCR analyzes showed that AA also reduced the cardiac parasitism. However, the greatest benefit was seen in AA+BZ10 group, since cardiac inflammation was significantly reduced. In addition, the combined therapy prevented the hepatic damage induced by the infection. Our findings suggest that AA combined with a low dose of BZ may improve the trypanocidal activity and attenuate the toxic effects of BZ. The decrease in oxidative damage and inflammation observed in mice treated with AA+BZ10 could result in increased cardioprotection.
Chagas disease is a tropical illness caused by the protozoan Trypanosoma cruzi. The disease affects populations of the Americas and has been spread to other continents due to the migration process. The disease is partially controlled by two drugs, Benznidazole and Nifurtimox. These molecules are active in the acute phase of the infection but are usually ineffective during the symptomatic chronic phase. Several research groups have developed novel candidates to control Chagas disease; however, no novel commercial formulation is available. In this article, we described the anti-T. cruzi effects of phenothiazinium dyes in amastigote and trypomastigote forms of the parasite. Methylene Blue, New Methylene Blue, Toluidine Blue O, and 1,9-Dimethyl Methylene Blue inhibited the parasite proliferation at nanomolar concentrations and also demonstrated low toxicity in host cells. Moreover, combinations of phenothiazinium dyes indicated a synergic pattern against amastigotes compared to the Benznidazole counterparts. Phenothiazinium dyes levels of reactive oxygen species (ROS) and decreased the mitochondrial potential in trypomastigotes, indicating the mechanism of action of the dyes in T. cruzi. Our article offers a basis for future strategies for the control of Chagas disease using low-cost formulations, an important point for endemic underdeveloped regions.
PROVIDELLO, M. V. Determination of the therapeutic potential of natural antioxidants in experimental Chagas' disease. 2017. 82f. Dissertation (Master).
Cardiac damage during the acute phase of Chagas disease (CD) is associated with an increase in pro-inflammatory markers and oxidative stress. Melatonin has emerged as a promising therapy for CD due to its antioxidant and immunomodulatory properties. However, the protective action of melatonin in the cardiac tissue as well as its direct action on the parasite cycle is not fully understood. We investigated the effects of melatonin on heart parasitism in mice infected with Trypanosoma cruzi (T. cruzi) and also its effects on the parasitic proliferation in vitro. Our in vivo study showed that melatonin reduced circulating parasitemia load, but did not control tissue (heart, liver and spleen) parasitism in mice. Melatonin did not prevent the redox imbalance in the left ventricle of infected mice. Our in vitro findings showed that melatonin did not inhibit parasites replication within cells, but rather increased their release from cells. Melatonin did not control parasitism load in the heart or prevented the cardiac redox imbalance induced by acute T. cruzi infection. The hormone controlled the circulating parasitic load, but in cells melatonin accelerated parasitic release, a response that can be harmful.
O uso de substâncias ergogênicas, aquelas com a propriedade de alterar o rendimento físico de um indivíduo, já é antiga, visto que o homem sempre teve dificuldades em aceitar suas limitações físicas e mentais. Nas competições esportivas, novas técnicas e produtos químicos vêm sendo utilizados por atletas, o que coloca à prova as técnicas analíticas empregadas na detecção da dopagem. Com isso, a busca pelo aprimoramento no controle do doping torna-se essencial para a comunidade esportiva, visando tornar as competições mais igualitárias. Essa revisão bibliográfica objetivou analisar as amostras atualmente empregadas na detecção do doping e compará-las com matrizes alternativas que vêm sendo estudadas, apontando as vantagens e desvantagens de cada uma delas. Os resultados obtidos demonstram que as amostras “alternativas” (cabelo/pêlos, saliva e ar exalado) podem aprimorar as análises realizadas em amostras de sangue e urina, consideradas o “padrão-ouro” na atualidade. Apresentando algumas vantagens frente a essas amostras, as matrizes alternativas poderiam sanar algumas deficiências analíticas apresentadas. A constante ascensão dos métodos ergogênicos, exige que o controle do doping também esteja em constante aprimoramento. Afim de cumprir a legislação esportiva, as técnicas analíticas podem encontrar avanço ao se utilizar novas amostras biológicas.
A doença de Chagas afeta hoje, aproximadamente, sete milhões de pessoas em todo o mundo. Causada pelo protozoário Trypanosoma cruzi (T. cruzi), a patologia compreende os estágios agudo e crônico. As manifestações em órgãos-alvo, como coração e trato digestivo, são consequência da persistência parasitária nos tecidos deflagrando uma intensa resposta inflamatória com consequente aumento do estresse oxidativo. Atualmente, o tratamento se baseia no uso de dois compostos nitroheterocíclicos, benznidazol (BZ) e nifurtimox, estando apenas o primeiro disponível no Brasil. Estudos recentes demonstraram que o BZ reduz a carga parasitária, mas falha em, de fato, curar a infecção ou combater danos teciduais previamente instaurados. Com isso, a demanda por novas opções terapêuticas torna-se essencial e considerando as décadas em que o desenvolvimento de novas moléculas vêm falhando, a pesquisa com BZ em novos protocolos terapêuticos (regimes drug-sparing), associados ou não a outras substâncias, parece promissora. Nesse estudo, foi avaliado o papel tripanocida e antioxidante bem como os possíveis efeitos tóxicos de uma baixa dose de BZ (25mg/kg/dia) associada a duas doses de ácido ascórbico (aa =7,14 mg/kg/dia e AA=88,1 mg/kg/dia). Camundongos Swiss fêmeas e a cepa Y de T. cruzi foram usadas em modelos agudo e crônico de infecção. Os resultados demonstraram que, de modo geral, usar uma baixa dose de BZ pode reduzir alguns efeitos tóxicos da terapia e o tratamento combinado com o antioxidante trouxe melhorias em ambas as fases da doença, seja aumentando a atividade tripanocida ou melhorando o controle redox. Em especial durante a fase crônica, as terapias associadas promoveram também a redução nos títulos de anticorpos, o que pode indicar benefícios em longo prazo. Juntos, esses achados reforçam a necessidade de se explorar variações nos protocolos terapêuticos empregando BZ e que o ácido ascórbico poderia atuar como um adjuvante no tratamento da infecção chagásica, provendo melhorias nas fases aguda e crônica da doença.
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