Browsing by Author "Huang, Huan"

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    Efeito da Resolvina D1 na infecção experimental aguda e crônica pela Cepa Brazil do Trypanosoma cruzi.
    (2020) Horta, Aline Luciano; Silva, André Talvani Pedrosa da; Huang, Huan; Weiss, Louis M.; Silva, Vanessa Pinho da; Rachid, Milene Alvarenga; Magalhães, Cíntia Lopes de Brito; Costa, Daniela Caldeira
    A doença de Chagas é ainda hoje um grande problema médico- social que atinge cerca de 10 milhões de pessoas no mundo todo. Transmitida pelo protozoário Trypanosoma cruzi (T. cruzi), esta infecção desencadeia processos inflamatórios agudos e crônicos que, em última instância, culminam em disfunções neurológicas, digestórias e cardíacas em graus distintos. A ineficácia e alta toxicidade das terapias disponíveis para o tratamento da doença Chagas reforçam a necessidade de novas estratégias farmacológicas efetivas e seguras contra este parasito. A resolvina D1 (RvD1) é um mediador lipídico de pró-resolução com ações mitigadoras sobre a resposta inflamatória. Por esta ação imunoduladora, o presente estudo avaliou se o tratamento com a RvD1 atuaria sobre a imunopatogênese induzida pelo T. cruzi em modelo experimental murino. Assim, camundongos do modelo CD-1 foram infectados pela cepa Brazil do T. cruzi e tratados com 3 µg/kg de RvD1, por via intraperitoneal, nos dias 5, 10, e 15 pósinfecção e eutanasiados 45º dia pós-infecção (dpi) (fase aguda). Na fase crônica, os animais foram tratados com a mesma dosagem nos dias 60, 65, e 70 pós-infecção, e submetidos ao exame ecocardiográfico aos 90 dpi, e sacrificados com 120 dias de infecção. Após a eutanásia, o sangue e o coração foram coletados para ensaios imunoenzimáticos (IFN-γ, TGF-ß, IL-10), análise do infiltrado inflamatório, formação de tecido fibroso e quantificação relativa do RNA em tempo real - qPCR (TGF-ß). A terapia com RvD1 aumentou a sobrevida e reduziu o número de parasitos observados em animais em fase aguda de infecção, além de reduzir os níveis de IFN-γ e TGF-ß em fase crônica. Também observamos um aumento nos níveis de IL-10 em animais tratados com RvD1 tanto na infecção aguda quanto na crônica, e redução dos níveis de TGF- ß (mRNA) e do conteúdo de colágeno no tecido cardíaco. Juntos, estes dados indicam que a terapia com RvD1 minimiza a resposta inflamatória induzida por este parasito e previne a formação de fibrose cardíaca, contribuíndo para o quadro resolutivo da infecção experimental pela cepa Brazil do T. cruzi.
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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 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.