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

Oral Ang-(1-7) treatment improves white adipose tissue remodeling and hypertension in rats with metabolic syndrome.

Objective: Angiotensin (Ang)-(1-7) has preventive effects on metabolic syndrome (MetS). The aim of this study was to evaluate the therapeutic effect of oral Ang-(1-7) on mean arterial pressure (MAP), insulin resistance (IR), inflammatory process, and remodeling of white adipose tissue (WAT) in rats with establishedMetS. Methods: Rats were subjected to control (CT; AIN-93M) or high-fat (HF) diets for 13 wk to induce MetS and treated with Ang-(1-7) or vehicle (V) for the last 6 wk. At the end of 13 wk, MAP, biochemical and histological parameters, and uncoupling protein (UCP) and inflammatory gene expression were determined by quantitative reverse transcription polymerase chain reaction. Results: HF-V rats showed increased visceral fat deposition, inflammatory cytokine expression, hyperplasia, and hypertrophy in retroperitoneal (WAT) and brown adipose tissue (BAT). Additionally, the gastrocnemius muscle reduced UCP-3 and increased the UCP-1 expression in BAT. HF-V also elevated levels of plasma insulin, glucose, homeostatic model assessment (HOMA) of IR and HOMA-b, and increased body mass, adiposity, and MAP. Ang-(1-7) treatment in rats with MetS [HF-Ang-(1-7)] reduced WAT area, number of adipocytes, and expression of proinflammatory adipokines in WAT and BAT and increased UCP-3 in gastrocnemius muscle and UCP-1 expression in BAT compared with the HF-V group. These events prevented body mass gain, reduced adiposity, and normalized fasting plasma glucose, insulin levels, HOMA-IR, HOMA-b, and MAP. Conclusion: Data from the present study demonstrated that oral Ang-(1-7) treatment is effective in restoring biochemical parameters and hypertension in established MetS by improving hypertrophy and hyperplasia in WAT and inflammation in adipose tissue, and regulating metabolic processes in the gastrocnemius muscle and BAT

Antioxidant effects of oral Ang-(1-7) restore insulin pathway and RAS components ameliorating cardiometabolic disturbances in rats.

In prevention studies of metabolic syndrome (MetS), Ang-(1-7) has shown to improve the insulin signaling. We evaluated the HP?CD/Ang-(1-7) treatment on lipid metabolism, renin-angiotensin system (RAS) components, oxidative stress, and insulin pathway in the liver and gastrocnemius muscle and hepatic steatosis in rats with established MetS. After 7 weeks of high-fat (FAT) or control (CT) diets, rats were treated with cyclodextrin (HP?CD) or HP?CD/Ang-(1-7) in the last 6 weeks. FATHP?CD/ empty rats showed increased adiposity index and body mass, gene expression of ACE/ANG II/AT1R axis, and oxidative stress. These results were accompanied by imbalances in the insulin pathway, worsening of liver function, hyperglycemia, and dyslipidemia. Oral HP?CD/Ang-(1-7) treatment decreased ACE and AT1R, increased ACE2 gene expression. in the liver, and restored thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), insulin receptor substrate (Irs-1), glucose transporter type 4 (GLUT4), and serine/threonine kinase 2 (AKT-2) gene expression in the liver and gastrocnemius muscle improving hepatic function, cholesterol levels, and hyperglycemia in MetS rats. Overall, HP?CD/Ang-(1-7) treatment restored the RAS components, oxidative stress, and insulin signaling in the liver and gastrocnemius muscle contributing to the establishment of blood glucose and lipid homeostasis in MetS rats

Renovascular hypertension increases serum TNF and CX3CL1 in experimental Trypanosoma cruzi infection.

Trypanosoma cruzi triggers a progressive inflammatory response affecting cardiovascular functions in humans and experimental models. Angiotensin II, a key effector of the renin-angiotensin system, plays roles in mediating hypertension, heart failure, and inflammatory responses. T. cruzi and AngII can induce inflammatory responses by releasing inflammatory mediators. The aim of this study was to evaluate systemic AngII, tumor necrosis factor (TNF), and CX3CL1 mediators in a two-kidney one-clip (2K1C) renovascular hypertension model using Wistar rats infected with T. cruzi. Our data showed an increase in serum AngII in uninfected and T. cruzi-infected rats 1 week after 2K1C surgery compared to non-2K1C (Sham) animals. The baseline systolic blood pressure was higher in both uninfected and infected 2K1C rats. Despite no difference in circulating parasites in the acute phase of infection, elevated serum TNF and CX3CL1 were observed at 8 weeks post-infection in 2K1C rats in association with higher cardiac inflammatory infiltration. In summary, AngII-induced hypertension associated with T. cruzi infection may act synergistically to increase TNF and CX3CL1 in the 2K1C rat model, thereby intensifying cardiac inflammatory infiltration and worsening the underlying inflammation triggered by this protozoan

CXCL-16, IL-17, and bone morphogenetic protein 2 (BMP-2) are associated with overweight and obesity conditions in middle-aged and elderly women.

The current concept of overweight/obesity is most likely related to a combination of increased caloric intake and decreased energy expenditure. Widespread inflammation, associated with both conditions, appears to contribute to the development of some obesity-related comorbidities. Interventions that directly or indirectly target individuals at high risk of developing obesity have been largely proposed because of the increasing number of overweight/obese cases worldwide. The aim of the present study was to assess CXCL16, IL-17, and BMP-2 plasma factors in middle-aged and elderly women and relate them to an overweight or obese status. In total, 117 women were selected and grouped as eutrophic, overweight, and obese, according to anthropometric parameters. Analyses of anthropometric and circulating biochemical parameters were followed by plasma immunoassays for CXCL-16, IL- 17, and BMP-2

A infecção experimental pelo Trypanosoma cruzi agrava o desenvolvimento de lesões ateroscleróticas em camundongos apoE-/-.

A resposta inflamatória sistêmica desencadeada por alguns agentes infecciosos exercem efeitos pró-aterogênicos via produção e ação de mediadores inflamatórios sobre a parede vascular. Nesse contexto, a infecção desencadeada pelo protozoário Trypanosoma cruzi apresenta um caráter inflamatório responsável pelo desenvolvimento de inúmeras manifestações cardiovasculares enquanto a aterosclerose, doença crônico-degenerativa, também é capaz de ocasionar obstrução de artérias pelo acúmulo de lipídeos em suas paredes através de um evento inflamatório local. A saber, a apolipoproteína E (apoE) é a principal glicoproteína responsável pelo transporte e metabolismo de colesterol e triglicerideos, sendo uma constituinte das lipoproteínas VLDL, HDL e quilomícrons. Neste estudo avaliamos a interferência da apoE no desenvolvimento das lesões cardiovasculares em camundongos C57BL/6 (n=28) e apoE knockout/ -/- (n=28) com 10 semanas, infectados pelas cepas Berenice 78 (Be 78) e Colombiana do T. cruzi. Avaliou-se diariamente a parasitemia e semanalmente o peso dos animais. Antes e após 30 dias de infecção, coletou-se sangue para dosagens bioquímicas (colesterol total, colesterol HDL e triglicérideos) e imunológicas (CCL2/MCP-1 e CCL5/RANTES). Após a eutanásia, o fígado e as fezes foram utilizados para extração e quantificação dos lipídeos totais e o arco aórtico, juntamente com o tecido muscular cardíaco, para avaliações morfométricas. Observou-se um menor período pré-patente nos animais selvagens (dia 9) em relação aos apoE-/- (dia 12), sendo que nestes últimos a parasitemia foi menor para ambas as cepas estudadas. Não houve diferença no peso dos animais entre os grupos, mas o colesterol total e os triglicerídeos plasmáticos mostraram-se elevados no grupo apoE-/-. Em relação à genética do parasito, a cepa Be 78 nos animais apoE-/- mostrou-se associada ao aumento dos lipídeos fecais, enquanto a cepa Colombiana neste mesmo grupo apresentou-se associada a níveis elevados de triglicérideos plasmáticos. Na análise plasmática de quimiocinas, verificou-se elevada produção de CCL2 e CCL5 em todos os animais infectados, porém apenas com a cepa Be 78, avaliada em animais apoE-/-, houve uma redução dos níveis séricos de CCL5. Observou-se aumento de células inflamatórias no tecido cardíaco, bem como de parasitos teciduais, no grupo infectado com a cepa Colombiana. Em relação à aterogênese, o grupo apoE-/- infectado por esta cepa, apresentou maiores áreas de lesão e alterações no conteúdo de colágeno. Estes dados sugerem que a infecção experimental pelo T. cruzi interfere no desenvolvimento de lesões ateroscleróticas em camundongos apoE-/-, assim como na produção de mediadores inflamatórios plasmáticos e de alguns tipos lipídicos. A análise e compreensão da interferência da apoE na patogênese cardíaca da doença de Chagas associado à variabilidade genética do parasito constituirão importantes elementos para estudos futuros envolvendo a resposta inflamatória cardiovascular.Inflammatory effects induced by photogenic organisms may exert pro-atherogenic effects thought inflammatory mediators in the vascular walls. In this context, the protozoan Trypanosoma cruzi is responsible for the development of inflammatory cardiovascular events while atherosclerosis, a chronic degenerative disease, leads to clogged arteries, by the accumulation of lipids in their walls, also induced by inflammatory events. Apolipoprotein E (apoE) is a major glycoprotein responsible for the transport and metabolism of cholesterol and triglycerides, being a constituent of VLDL, HDL, and chylomicrons. This study evaluated the interference of apoE in the development of cardiovascular lesions in C57BL/6 (n = 28) and C57BL/6 Apo E-knockout/-/- (n = 28) at 10 weeks, infected with the Berenice-78 strains (Be 78) and Colombian of T. cruzi. Daily parasitemia and weekly weight of animals were performed and, before and after 30 days of infection, blood was collected by biochemical (total cholesterol, HDL cholesterol and triglycerides) and immune (CCL2/MCP-1 and CCL5/RANTES) assays. After euthanasia, liver and feces were used for extraction and quantification of total lipids and aortic arch and cardiac muscles collected to morphometric analysis. There was a lower pre-patent period in the wild group (9 days) compared to the apoE-/-(12 days). There was no difference in weight between the groups of animals and total cholesterol and triglycerides were elevated in the group apoE-/-. Regarding the genetics of parasite strain Be-78 animals in apoE-/-, it was associated with increased fecal lipids, while the Colombian strain in this same group showed elevated levels of plasma triglycerides. In the analysis of plasma chemokines, there was high production of CCL2 and CCL5 in all infected animals, but only with the Be 78 strain, evaluated in apoE-/- animals, it was detected a reduction in plasma levels of CCL5. The inflammatory infiltration and parasites in the infected cardiac tissues was observed mainly in the group infected with Colombian strain. In relation to atherogenesis, apoE-/- group infected with Colombian strain had larger lesions and changes in the collagen content. These data suggest that the experimental infection with T. cruzi interferes with the development of atherosclerotic lesions in apoE-/- mice as well as in plasma production of inflammatory mediators and some types of lipid. The analysis and understanding of the interference of apoE in the pathogenesis of Chagas heart disease, as well as possible links with the genetic variability of the parasite, constitute important elements for future studies involving cardiovascular inflammatory response

Avalia??o de par?metros inflamat?rios na infec??o aguda e cr?nica de camundongos infectados pelo Trypanosoma cruzi e submetidos ? dieta hiperlip?dica.

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.O estado nutricional vem se destacando nas intera??es entre agentes infecciosos e a resposta imunofisiol?gica de seus hospedeiros apresentando-se diretamente ligado ? qualidade da dieta na qual o indiv?duo ? submetido. Como exemplo, uma dieta rica em lip?deos pode desencadear altera??es metab?licas e cardiovasculares. Na linha das altera??es cardiovasculares, a infec??o pelo protozo?rio Trypanosoma cruzi aparece como uma condi??o predisponente, ao lado da resposta imune do hospedeiro infectado. Assim, este estudo objetiva avaliar a interfer?ncia da dieta hiperlip?dica (DH) no processo inflamat?rio agudo e cr?nico da infec??o experimental pelo T. cruzi. Para tanto, foram utilizados camundongos machos da linhagem C57BL/6 divididos em 4 grupos: (i) dieta convencional, (ii) dieta convencional infectado com a cepa VL-10 do T. cruzi, (iii) DH e (iv) DH infectado com o T. cruzi. Os animais foram eutanasiados ao final de 12 semanas de dieta e ap?s um m?s de infec??o (fase aguda) e ao final de 22 semanas de dieta e 100 dias de infec??o (fase cr?nica). Os resultados indicam que a DH foi capaz de elevar a massa corporal, a quantidade de tecido adiposo nos animais, a parasitemia e os n?veis circulantes de colesterol total e HDL. Relativo ao contexto inflamat?rio, houve eleva??o de IL-10 e TNF plasm?tica nos animais infectados, independentemente da dieta, em contrapartida aos valores reduzidos de leptina. O infiltrado inflamat?rio card?aco tamb?m apresentou-se elevado nos animais submetidos ? DH em concord?ncia com a eleva??o nos lip?deos totais e presen?a de esteatose hep?tica, sendo a maior inflama??o associada ? infec??o. Ao contr?rio da MMP9, a atividade da MMP2 mostrou-se elevada no tecido card?aco dos animais infectados e submetidos ? DH na fase aguda. Nossos dados sugerem que a DH interfere na imunopatog?nese tanto card?aca quanto hep?tica e eleva a atividade de MMP2 e o remodelamento card?aco em animais infectados pelo T. cruzi.The quality of the diet defines the nutritional and immunophysiological status in the human population. The dissemination of a high fat (HF) diet enhances the metabolic and cardiovascular disturbances. Infectious disease, such as the Trypanosoma cruzi infection, is another predisposed condition to development of cardiovascular disturbances, in particular, conducted by the host immune response. In this present study the interference of a (HF) diet on the immune response and the metalloproteinase (MMP) activities was investigated during the acute and chronic infection with the VL-10 strain of T. cruzi. Thereby, C57BL/6 male mice were grouped (n=10) in (i) under regular diet (RD); (ii) under RD + T. cruzi; (iii) under HF and (iv) under HF + T. cruzi. The animals were euthanized after 12 weeks of diet and after one month of infection (acute phase) and the end of 22 weeks of diet and 100 days of infection (chronic phase). Biological samples were processed to histology, zymography and western blotting to MMP 2 and 9 and immunoassays to inflammatory mediators. Animals under HF diet presented higher parasitemia, HDL and total cholesterol. Regardless of diet, IL-10, TNF, CCL2 and CCL5 levels were elevated in infected animals while the leptin was lower. Meanwhile, the cardiac leukocyte infiltration and liver steatosis were elevated in the HF diet-infected animals. Together, these data suggest that a HF diet potentiates the load of blood parasites, the HDL and cholesterol as well as cardiac MMP2 activity and immunopathogenesis in both, heart and liver, in the C57BL/6 mice infected with the VL-10 strain of T. cruzi

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

Maternal high-fat diet triggers metabolic syndrome disorders that are transferred to first and second offspring generations.

A high-fat (H) diet increases metabolic disorders in offspring. However, there is great variability in the literature regarding the time of exposure, composition of the H diets offered to the genitors and/or offspring and parameters evaluated. Here, we investigated the effect of a H diet subjected to the genitors on different cardio-metabolic parameters on first (F1)- and second (F2)-generation offspring. Female Fischer rats, during mating, gestation and breast-feeding, were subjected to the H diet (G0HF) or control (G0CF) diets. Part of F1 offspring becomes G1 genitors for generating the F2 offspring. After weaning, F1 and F2 rats consumed only the C diet. Nutritional, biometric, biochemical and haemodynamic parameters were evaluated. G0HF genitors had a reduction in food intake but energy intake was similar to the control group. Compared with the control group, the F1H and F2H offspring presented increased plasma leptin, insulin and fasting glucose levels, dietary intake, energy intake, adiposity index, mean arterial pressure, sympathetic drive evidenced by the hexamethonium and insulin resistance. Our data showed that only during mating, gestation and breast-feeding, maternal H diet induced cardio-metabolic disorders characteristic of human metabolic syndrome that were transferred to both females and males of F1 and F2 offspring, even if they were fed control diet after weaning. This process probably occurs due to the disturbance in mechanisms related to leptin that increases energy intake in F1H and F2H offspring. The present data reinforce the importance of balanced diet during pregnancy and breast-feeding for the health of the F1 and F2 offspring