Exercise training reduces cardiac fibrosis, promoting improvement in arrhythmias and cardiac dysfunction in an experimental model of chronic chagasic cardiomyopathy Alex Cleber Improta-Caria, Carolina Kymie Vasques Nonaka, Pâmela Santana Daltro, Carine Machado Azevedo, Breno Cardim Barreto, et al. Frontiers in Physiology, 2025 BackgroundChagas disease, caused by the parasite Trypanosoma cruzi, is associated with inflammation and fibrosis, which characterizes chronic Chagasic cardiomyopathy (CCC). CCC manifests as arrhythmias, hypertrophy or dilation of the left ventricle, and it may progress to heart failure. Therefore, interventions are needed to slow the progression of CCC. Aims: We investigated the effects of exercise training in an animal model of CCC.MethodsC57BL/6 mice infected with Trypanosoma cruzi were submitted to a progressively treadmill exercise training protocol. The cardiac function was evaluated by echocardiogram and electrocardiogram. RT-qPCR and morphometric analyses were performed on samples of cardiac tissue to quantify inflammation and fibrosis.ResultsEKG analysis confirmed that all infected mice developed arrhythmias, with different degrees of severity. Exercise improved arrhythmias in 43.75% of chagasic trained mice, and the remaining mice did not show any alteration in EKG. The untrained chagasic group had no improvement in arrhythmias. The ventricular compliance in chagasic trained mice increased, as revealed by the reduction in isovolumetric relaxation time when compared to untrained mice. Exercise induced the reduction of gene expression of TGF-β, TNF-α, IL-1β, IL-6 and MMP-9 and reduced fibrosis in the heart tissue of chagasic mice.ConclusionExercise reduced fibrosis in the heart and skeletal muscle, favoring the improvement of arrhythmias, and augment of cardiac complacency in mice with CCC, in addition to decreasing the expression of profibrotic and proinflammatory genes in the heart.
The effects of inflammation on connexin 43 in chronic Chagas disease cardiomyopathy Breno Cardim Barreto, Maria Vitória Gomes das Neves, Carine Machado Azevedo Cardoso, Cássio Santana Meira, Pâmela Santana Daltro, et al. Frontiers in Immunology, 2024 BackgroundCardiac arrhythmias are the main cause of sudden death due to Chronic Chagasic Cardiomyopathy (CCC). Here we investigated alterations in connexin 43 (Cx43) expression and phosphorylation in cardiomyocytes as well as associations with cardiac arrhythmias in CCC.MethodsC57Bl/6 mice infected with Trypanosoma cruzi underwent cardiac evaluations at 6 and 12 months after infection via treadmill testing and EKG. Histopathology, cytokine gene expression, and distribution of total Cx43 and its phosphorylated forms Cx43S368 and Cx43S325/328/330 were investigated. Human heart samples obtained from subjects with CCC were submitted to immunofluorescence analysis. In vitro simulation of a pro-inflammatory microenvironment (IL-1β, TNF, and IFN-γ) was performed in H9c2 cells and iPSC-derived cardiomyocytes to evaluate Cx43 distribution, action potential duration, and Lucifer Yellow dye transfer.ResultsMice chronically infected with T. cruzi exhibited impaired cardiac function associated with increased inflammation, fibrosis and upregulated IL-1β, TNF, and IFN-γ gene expression. Confocal microscopy revealed altered total Cx43, Cx43S368 and Cx43S325/328/330 localization and phosphorylation patterns in CCC, with dispersed staining outside the intercalated disc areas, i.e., in lateral membranes and the cytoplasm. Reduced co-localization of total Cx43 and N-cadherin was observed in the intercalated discs of CCC mouse hearts compared to controls. Similar results were obtained in human CCC heart samples, which showed Cx43 distribution outside the intercalated discs. Stimulation of human iPSC-derived cardiomyocytes or H9c2 cells with IL-1β, TNF, and IFN-γ induced alterations in Cx43 localization, reduced action potential duration and dye transfer between adjacent cells.ConclusionHeart inflammation in CCC affects the distribution and phosphorylation pattern of Cx43, which may contribute to the generation of conduction disturbances in Chagas disease.
Green Tea Induces the Browning of Adipose Tissue—Systematic Review Ana Paula Azevêdo Macêdo, Mariane dos Santos Gonçalves, Jairza Maria Barreto-Medeiros, Oscar Caetano da Silva Neto, Jorge Mauricio David, et al. Obesities, 2023 Several foods and nutrients are being studied extensively because they have a positive effect on thermogenesis and the browning of white adipose tissue. Therefore, this study aims to evaluate, through a systematic review, the effect of green tea for inducing browning of adipose tissue. The systematic review was built following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyze. We searched the following electronic databases: PubMed (Medline), Science Direct, Scopus, and Web of Science. We included ten experimental articles that used green tea to treat induced obesity in rodents. Green tea reduced the weight of white and brown adipose tissue, positively regulated gene expression and microRNA that regulate the metabolism of adipose tissue, and morphological changes were identified as beige tissue. According to the results found, the factors involved in this induction to browning are PPARγ, PGC-1α, UCP1, CPT, and PRDM16. Therefore, green tea promotes the browning of adipose tissue in rodents. It is important to emphasize the need for studies in obese humans to identify whether the same metabolic response occurs.
Potential therapeutic effects of green tea on obese lipid profile – a systematic review Ana Paula Azevêdo Macêdo, Mariane dos Santos Gonçalves, Jairza Maria Barreto Medeiros, Jorge Mauricio David, Cristiane Flora Villarreal, et al. Nutrition and Health, 2022 Background: Green tea, obtained from the plant Camellis sinensis, is one of the oldest drinks in the world and contains numerous bioactive compounds. Studies have demonstrated the efficacy of green tea in preventing obesity and cardiovascular diseases that may be related to the reduction of lipid levels. Aim: This study aimed to evidence, through a systematic review, the therapeutic potential of green tea on the lipid profile in preclinical studies in obese animals and clinical studies in obese individuals. Methods: This systematic review follows the recommendations of the preferred report items for systematic reviews and meta-analyses. The electronic databases, PubMed (Medline), Science Direct, Scopus, and Web of Science were consulted. Articles from January 2009 to December 2019 were selected. Results: This search resulted in twenty-nine articles were included cirtically reviewed. In experimental studies, green tea administration has been shown to reduce total cholesterol, triglycerides and low-density lipoprotein cholesterol in animals exposed to obesity-inducing diet. In humans’ studies green tea was not shown to be effective for obese lipid control. Because supplementation with green tea extract reduced total cholesterol, triglycerides, low-density lipoprotein for three months at a specific dose. Conclusion: Therefore, green tea appears to act as a protective agent for dyslipidemia in obesity-induced animals. In human studies, green tea has not been shown to be effective in controlling obese lipids.
Exercise training-induced changes in microRNAs: Beneficial regulatory effects in hypertension, type 2 diabetes, and obesity Alex Cleber Improta Caria, Carolina Kymie Vasques Nonaka, Ciro Silveira Pereira, Milena Botelho Pereira Soares, Simone Garcia Macambira, et al. International Journal of Molecular Sciences, 2018 MicroRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally. They are involved in the regulation of physiological processes, such as adaptation to physical exercise, and also in disease settings, such as systemic arterial hypertension (SAH), type 2 diabetes mellitus (T2D), and obesity. In SAH, microRNAs play a significant role in the regulation of key signaling pathways that lead to the hyperactivation of the renin-angiotensin-aldosterone system, endothelial dysfunction, inflammation, proliferation, and phenotypic change in smooth muscle cells, and the hyperactivation of the sympathetic nervous system. MicroRNAs are also involved in the regulation of insulin signaling and blood glucose levels in T2D, and participate in lipid metabolism, adipogenesis, and adipocyte differentiation in obesity, with specific microRNA signatures involved in the pathogenesis of each disease. Many studies report the benefits promoted by exercise training in cardiovascular diseases by reducing blood pressure, glucose levels, and improving insulin signaling and lipid metabolism. The molecular mechanisms involved, however, remain poorly understood, especially regarding the participation of microRNAs in these processes. This review aimed to highlight microRNAs already known to be associated with SAH, T2D, and obesity, as well as their possible regulation by exercise training.
Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy Juliana Fraga Vasconcelos, Cássio Santana Meira, Daniela Nascimento Silva, Carolina Kymie Vasques Nonaka, Pâmela Santana Daltro, et al. Scientific Reports, 2017 Chagas disease cardiomyopathy is a parasite-driven inflammatory disease to which there are no effective treatments. Here we evaluated the therapeutic potential of N,N-dimethylsphingosine(DMS), which blocks the production of sphingosine-1-phosphate(S1P), a mediator of cellular events during inflammatory responses, in a model of chronic Chagas disease cardiomyopathy. DMS-treated, Trypanosoma cruzi-infected mice had a marked reduction of cardiac inflammation, fibrosis and galectin-3 expression when compared to controls. Serum concentrations of galectin-3, IFNγ and TNFα, as well as cardiac gene expression of inflammatory mediators were reduced after DMS treatment. The gene expression of M1 marker, iNOS, was decreased, while the M2 marker, arginase1, was increased. DMS-treated mice showed an improvement in exercise capacity. Moreover, DMS caused a reduction in parasite load in vivo. DMS inhibited the activation of lymphocytes, and reduced cytokines and NO production in activated macrophage cultures in vitro, while increasing IL-1β production. Analysis by qRT-PCR array showed that DMS treatment modulated inflammasome activation induced by T. cruzi on macrophages. Altogether, our results demonstrate that DMS, through anti-parasitic and immunomodulatory actions, can be beneficial in the treatment of chronic phase of T. cruzi infection and suggest that S1P-activated processes as possible therapeutic targets for the treatment of Chagas disease cardiomyopathy.