Potential role of Carvedilol in the cardiac immune response induced by experimental infection with Trypanosoma cruzi.

Trypanosoma cruzi causes a cardiac infection characterized by an inflammatory imbalance that could become the inciting factor of the illness. To this end, we evaluated the role of carvedilol, a beta-blocker with potential immunomodulatory properties, on the immune response in C57BL/6 mice infected with VL-10 strain of T. cruzi in the acute phase. Animals (? = 40) were grouped: (i) not infected, (ii) infected, (iii) infected + carvedilol, and (iv) not infected + carvedilol.We analyzed parameters related to parasitemia, plasma levels of TNF, IL-10, and CCL2, and cardiac histopathology after the administration of carvedilol for 30 days. We did not observe differences in the maximum peaks of parasitemia in the day of their detection among the groups. The plasma TNF was elevated at 60 days of infection in mice treated or not with carvedilol. However, we observed a decreased CCL2 level and increased IL-10 levels in those infected animals treated with carvedilol, which impacted the reduction of the inflammatory infiltration in cardiac tissue. For this experimentalmodel, carvedilol therapy was not able to alter the levels of circulating parasites butmodulates the pattern of CCL2 and IL-10 mediators when the VL10 strain of T. cruzi was used in C57BL6 mice

Interferência da terapia com o betabloqueador Carvedilol na resposta inflamatória cardíaca aguda em camundongos C57BL/6 infectados pela cepa colombiana do Trypanosoma cruzi.

Programa de Pós-Graduação em Ciências Biológicas. Núcleo de Pesquisas em Ciências Biológicas, Pró-Reitoria de Pesquisa de Pós Graduação, Universidade Federal de Ouro Preto.A resposta inflamatória gerada pela infecção pelo Trypanosoma cruzi promove alterações morfofisiológicas nas células cardíacas de hospedeiros mamíferos. Esta inflamação progressiva contribui para a geração de um quadro patológico de caráter fibrogênico culminando em possíveis alterações estruturais/ funcionais ao coração. Fármacos com propriedades cardiovasculares e prescritos no manejo clínico de indivíduos chagásicos têm sido investigados por suas ações imunomodulatórias. Nesta proposta, foram avaliadas as ações do betabloqueador Carvedilol (CV) e do benznidazol (BZ), em camundongos machos da linhagem C57BL/6, infectados com 50 formas tripomastigotas da cepa Colombiana do Trypanosoma cruzi, e agrupados de acordo com as seguintes intervenções: (I) 15 animais infectados que não receberam tratamento (II) 15 animais tratados com 100mg/Kg/dia de BZ (III) 15 animais tratados com o CV 25mg/kg/dia (IV) 15 animais tratados com a combinação dos fármacos BZ 100mg/kg/dia e CV 25mg/kg/dia. Além disso, foram utilizados 10 animais como controle não infectado. A ação do betabloqueador (CV) 25 mg/kg e/ ou BZ 100 mg/kg, foi avaliada após 28 dias de infecção, e 23 dias de tratamento, período análogo à fase aguda. A eutanásia ocorreu no 280 dia, sendo o coração conservado para análise histopatológica, e avaliação de Estresse oxidativo (SOD, catalase, TBARs, proteínas carboniladas), e o sangue/plasma destinado aos ensaios imunoenzimáticos (CCL2, CCL5, TNF-alfa, IL-10), além de avaliar a parasitemia e sobrevida ao longo da infecção. Desta maneira, observou-se, que a terapia com o CV elevou a mortalidade dos animais, a parasitemia, assim como o nível das quimiocinas CCL2 e CCL5 no tecido muscular cardíaco, mas por outro lado reduziu os níveis de TNF. Em contrapartida, o CV não alterou o perfil da citocina regulatória IL-10. O tratamento em monoterapia com o CV promoveu, ainda, o aumento do infiltrado inflamatório no tecido muscular cardíaco mediante infecção pelo T. cruzi, em relação aos animais infectados não tratados. Conclui-se que o CV não foi capaz de oferecer proteção cardíaca ao hospedeiro mamífero durante a fase aguda da infecção pelo T. cruzi por elevar os mediadores inflamatórios e, consequentemente, o infiltrado inflamatório cardíaco. Outros estudos em diferentes modelos experimentais tornam-se necessários para compreender as ações pleiotrópica do CV em roedores, uma vez que em seres humanos este fármaco apresenta propriedade protetora cardíaca em indivíduos cardiopatas crônicos.The inflammatory response generated by Trypanosoma cruzi infection promotes morphophysiological changes in the cardiac cells of mammalian hosts. This progressive inflammation contributes to the generation of a pathological picture of fibrogenic character culminating in possible structural / functional changes to the heart. Drugs with cardiovascular properties and prescribed in the clinical management of chagasic individuals have been investigated for their immunomodulatory actions. In this proposal, the actions of the beta blocker Carvedilol (CV) and benznidazole (BZ) were evaluated in infected male C57BL / 6 mice with 50 trypomastigote forms of the Trypanosoma cruzi Colombian strain, and grouped according to the following interventions: (I) 15 infected animals not receiving treatment (II) 15 animals treated with 100 mg / kg / day BZ (III) 15 treated animals With CV 25mg / kg / day (IV) 15 animals treated with the combination of drugs BZ 100mg / kg / day and CV 25mg / kg / day. In addition, 10 animals were used as uninfected control. The action of beta-blocker (CV) 25 mg / kg and / or Benznidazole (BZ) 100 mg/ kg, was evaluated after 28 days of infection, and 23 days of treatment, a period analogous to the acute phase. Euthanasia occurred at 28th day, and the heart was preserved for histopathological analysis and oxidative Estresse evaluation (SOD, catalase, TBARs, carbonylated proteins), and blood / plasma for immunoenzymatic assays (CCL2, CCL5, TNF-alpha, IL -10), in addition to evaluating parasitemia and survival throughout the infection. In this way, we observed that CV therapy increased the mortality of the animals, parasitemia, as well as the level of chemokines CCL2 and CCL5 in cardiac muscle tissue, but on the other hand it reduced TNF levels. In contrast, CV did not alter the IL-10 regulatory cytokine profile. The monotherapy treatment with CV also promoted the increase of inflammatory infiltrate in cardiac muscle tissue. T. cruzi infection in relation to untreated infected animals. It is concluded that CV was unable to provide cardiac protection to the mammalian host during the acute phase of T. cruzi infection by elevating inflammatory mediators and, consequently, cardiac inflammatory infiltrate. Other studies in different experimental models become necessary to understand the pleiotropic actions of CV in rodents, since in humans this drug presents cardiac protective property in chronic cardiopathy individuals

Efeito da Resolvina D1 na infec??o experimental aguda e cr?nica pela Cepa Brazil do Trypanosoma cruzi.

Programa de P?s-Gradua??o em Ci?ncias Biol?gicas. N?cleo de Pesquisas em Ci?ncias Biol?gicas, Pr?-Reitoria de Pesquisa de P?s Gradua??o, Universidade Federal de Ouro Preto.A doen?a de Chagas ? ainda hoje um grande problema m?dico- social que atinge cerca de 10 milh?es de pessoas no mundo todo. Transmitida pelo protozo?rio Trypanosoma cruzi (T. cruzi), esta infec??o desencadeia processos inflamat?rios agudos e cr?nicos que, em ?ltima inst?ncia, culminam em disfun??es neurol?gicas, digest?rias e card?acas em graus distintos. A inefic?cia e alta toxicidade das terapias dispon?veis para o tratamento da doen?a Chagas refor?am a necessidade de novas estrat?gias farmacol?gicas efetivas e seguras contra este parasito. A resolvina D1 (RvD1) ? um mediador lip?dico de pr?-resolu??o com a??es mitigadoras sobre a resposta inflamat?ria. Por esta a??o imunoduladora, o presente estudo avaliou se o tratamento com a RvD1 atuaria sobre a imunopatog?nese 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 ?g/kg de RvD1, por via intraperitoneal, nos dias 5, 10, e 15 p?sinfec??o e eutanasiados 45? dia p?s-infec??o (dpi) (fase aguda). Na fase cr?nica, os animais foram tratados com a mesma dosagem nos dias 60, 65, e 70 p?s-infec??o, e submetidos ao exame ecocardiogr?fico aos 90 dpi, e sacrificados com 120 dias de infec??o. Ap?s a eutan?sia, o sangue e o cora??o foram coletados para ensaios imunoenzim?ticos (IFN-?, TGF-?, IL-10), an?lise do infiltrado inflamat?rio, forma??o de tecido fibroso e quantifica??o relativa do RNA em tempo real - qPCR (TGF-?). A terapia com RvD1 aumentou a sobrevida e reduziu o n?mero de parasitos observados em animais em fase aguda de infec??o, al?m de reduzir os n?veis de IFN-? e TGF-? em fase cr?nica. Tamb?m observamos um aumento nos n?veis de IL-10 em animais tratados com RvD1 tanto na infec??o aguda quanto na cr?nica, e redu??o dos n?veis de TGF- ? (mRNA) e do conte?do de col?geno no tecido card?aco. Juntos, estes dados indicam que a terapia com RvD1 minimiza a resposta inflamat?ria induzida por este parasito e previne a forma??o de fibrose card?aca, contribu?ndo para o quadro resolutivo da infec??o experimental pela cepa Brazil do T. cruzi.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 to be 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 ? 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 TGFlevels 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

Potential Role of Carvedilol in the Cardiac Immune Response Induced by Experimental Infection with Trypanosoma cruzi

Trypanosoma cruzi causes a cardiac infection characterized by an inflammatory imbalance that could become the inciting factor of the illness. To this end, we evaluated the role of carvedilol, a beta-blocker with potential immunomodulatory properties, on the immune response in C57BL/6 mice infected with VL-10 strain of T. cruzi in the acute phase. Animals (n=40) were grouped: (i) not infected, (ii) infected, (iii) infected + carvedilol, and (iv) not infected + carvedilol. We analyzed parameters related to parasitemia, plasma levels of TNF, IL-10, and CCL2, and cardiac histopathology after the administration of carvedilol for 30 days. We did not observe differences in the maximum peaks of parasitemia in the day of their detection among the groups. The plasma TNF was elevated at 60 days of infection in mice treated or not with carvedilol. However, we observed a decreased CCL2 level and increased IL-10 levels in those infected animals treated with carvedilol, which impacted the reduction of the inflammatory infiltration in cardiac tissue. For this experimental model, carvedilol therapy was not able to alter the levels of circulating parasites but modulates the pattern of CCL2 and IL-10 mediators when the VL10 strain of T. cruzi was used in C57BL6 mice

Enalapril in combination with benznidazole reduces cardiac inflammation and creatine kinases in mice chronically infected with Trypanosoma cruzi

The protozoan Trypanosoma cruzi triggers an inflammatory process in mammalian heart causing events such as fibrosis, changes in the architecture and functionality in this organ. Enalapril, an angiotensin II-converting enzyme inhibitor, is a drug prescribed to ameliorate this heart dysfunction, and appears to exert a potential role in immune system regulation. Our aim was to evaluate the chronic cardiac inflammatory parameters after therapeutic treatment with enalapril and benznidazole in C57BL/6 mice infected with the VL-10 strain of T. cruzi. After infection, animals were treated with oral doses of enalapril (25 mg/kg), benznidazole (100 mg/kg), or both during 30 days. Morphometric parameters and levels of chemokines (CCL2, CCL5), IL-10, creatine kinases (CKs), and C-reactive protein were evaluated in the heart and serum at the 120th day of infection. Enalapril alone or in combination with benznidazole did not change the number of circulating parasites, but reduced cardiac leukocyte recruitment and total collagen in the cardiac tissue. Interestingly, the combination therapy (enalapril/benznidazole) also reduced the levels of chemokines, CK and CK-MB, and C-reactive proteins in chronic phase. In conclusion, during the chronic experimental T. cruzi infection, the combination therapy using enalapril plus benznidazole potentiated their immunomodulatory effects, resulting in a low production of biomarkers of cardiac lesions

The β-blocker carvedilol and the benznidazole modulate the cardiac immune response in the acute infection induced by Colombian strain of the Trypanosoma cruzi

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

Doxycycline and Benznidazole Reduce the Profile of Th1, Th2, and Th17 Chemokines and Chemokine Receptors in Cardiac Tissue from Chronic Trypanosoma cruzi-Infected Dogs

Chemokines (CKs) and chemokine receptors (CKR) promote leukocyte recruitment into cardiac tissue infected by the Trypanosoma cruzi. This study investigated the long-term treatment with subantimicrobial doses of doxycycline (Dox) in association, or not, with benznidazole (Bz) on the expression of CK and CKR in cardiac tissue. Thirty mongrel dogs were infected, or not, with the Berenice-78 strain of T. cruzi and grouped according their treatments: (i) two months after infection, Dox (50 mg/kg) 2x/day for 12 months; (ii) nine months after infection, Bz (3,5 mg/kg) 2x/day for 60 days; (iii) Dox + Bz; and (iv) vehicle. After 14 months of infection, hearts were excised and processed for qPCR analysis of Th1 (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL11), Th2 (CCL1, CCL17, CCL24, and CCL26), Th17 (CCL20) CKs, Th1 (CCR5, CCR6, and CXCR3), and Th2/Th17 (CCR3, CCR4, and CCR8) CKR, as well as IL-17. T. cruzi infection increases CCL1, CCL2, CCL4, CCL5, CCL17, CXCL10, and CCR5 expression in the heart. Dox, Bz, or Dox + Bz treatments cause a reversal of CK and CKR and reduce the expression of CCL20, IL-17, CCR6, and CXCR3. Our data reveal an immune modulatory effect of Dox with Bz, during the chronic phase of infection suggesting a promising therapy for cardiac protection

A neurociência e a educação : como nosso cérebro aprende?

III Curso de atualização de professores da educação infantil, ensino fundamental e médio, realizado na UFOP, pelo Programa de Pós-Graduação em Ciências Biológicas e Mestrado Profissional em Ensino de Ciências. 2016.Qual é o objetivo do ensino? O que é aprendizagem? Como se aprende algo novo? Onde se localizam nossas memórias? Segundo o neurocientista Ivan Izquierdo, a memória é a aquisição, formação, conservação e evocação de informações. Esta aquisição de novos conhecimentos é também chamada de aprendizagem, pois só se retém na memória o conteúdo que foi aprendido. Aprendizagem, portanto, é um processo complexo que envolve a formação de novas memórias. A educação, por meio do processo ensino e aprendizagem, tem como objetivo o grande desenvolvimento pessoal, adequando o aprendiz ao meio no qual ele está inserido. Educar é proporcionar oportunidades e orientação para aprendizagem, para aquisição de novos comportamentos. Segundo Hipócrates, grande filósofo grego, pai da Medicina, no século IX A.C., o homem deveria saber que de nenhum outro lugar, mas do encéfalo vem a alegria, o pesar, adquirimos sabedoria e conhecimento, enxergamos, ouvimos e sabemos. Neste relato, Hipócrates evidencia que a aprendizagem depende do encéfalo. Muito tempo depois das afirmações de Hipócrates, o conceito de que o comportamento humano estaria diretamente ligado ao encéfalo foi intensamente investigado e publicado na década de 90, a chamada “Década do Cérebro”, quando diversas pesquisas científicas se destinaram intensamente ao estudo deste órgão. Estudar o encéfalo, portanto, é se dedicar ao estudo da parte do corpo humano responsável pela aprendizagem. É neste substrato biológico, o encéfalo, que se faz a aprendizagem. De acordo com a grande professora Leonor Guerra, desde o nascimento, o ser humano aprende algo novo todos os dias. É por meio da interação entre as pessoas, e com o meio ambiente, que se dá a aquisição de novos conhecimentos e a partir disso, podemos modificar os comportamentos que adquirimos ao longo de nossas vidas. Quando se aprende, novas habilidades e conhecimentos são demonstradas, ganha-se competências para realizar novos feitos que serão relevantes para a sobrevivência, seja essa sobrevivência a busca da saúde e bem estar ou a realização profissional e pessoal. Aprender é uma característica intrínseca do ser humano