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Type 2 diabetes (T2D) is a multifaceted and heterogeneous syndrome associated with complications such as hypertension, coronary artery disease, and notably, breast cancer (BC). The connection between T2D and BC is established through processes that involve insulin resistance, inflammation and other factors. Despite this comprehension the specific cellular and molecular mechanisms linking T2D to BC, especially through microRNAs (miRNAs), remain elusive. miRNAs are regulators of gene expression at the post-transcriptional level and have the function of regulating target genes by modulating various signaling pathways and biological processes. However, the signaling pathways and biological processes regulated by miRNAs that are associated with T2D and BC have not yet been elucidated. This review aims to identify dysregulated miRNAs in both T2D and BC, exploring potential signaling pathways and biological processes that collectively contribute to the development of BC.

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Natural compounds that have the potential to act as antimicrobials and antitumors are a constant search in the field of pharmacotherapy. Eragrostis plana NEES (Poaceae) is a grass with high allelopathic potential. Allelopathy is associated with compounds generated in the primary and secondary metabolism of the plant, which act to protect it from phytopathogens. Tabernaemontana catharinensis A DC (Apocynaceae), a tree in which its leaves and bark are used for the preparation of extracts and infusions that have anti-inflammatory and antinociceptive effects, is attributed to its phytochemical constitution. The objective of this study was to elucidate the phytochemical constitution, the antibacterial potential, the toxicity against immune system cells, hemolytic potential, and antitumor effect of methanolic extracts of E. plana and T. catharinensis. The phytochemical investigation was carried out using the UHPLC-QTOF MS equipment. The antibacterial activity was tested using the broth microdilution plate assay, against Gram-negative and Gram-positive strains, and cytotoxicity assays were performed on human peripheral blood mononuclear cells (PBMC) and in vitro hemolysis. Antitumor activity was performed against the colon cancer cell line (CT26). Results were expressed as mean and standard deviation and analyzed by ANOVA. p < 0.05 was considered significant. More than 19 possible phytochemical constituents were identified for each plant, with emphasis on phenolic compounds (acids: vanillic, caffeic, and quinic) and alkaloids (alstovenine, rhyncophylline, amezepine, voacangine, and coronaridine). Both extracts showed antibacterial activity at concentrations below 500 µg/mL and were able to decrease the viability of CT26 at concentrations below 2000 µg/mL, without showing cytotoxic effect on PBMCs and in vitro hemolysis at the highest concentration tested. This is the first report of the activity of E. plana and T. catharinensis extracts against colon cancer cell line (CT26). Studies should be carried out to verify possible molecular targets involved in the antitumor effect in vivo.

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Overweight and obesity (OBT) is a serious health condition worldwide, and one of the major risk factors for cardiovascular disease (CVD), the main reason for morbidity and mortality worldwide. OBT is the proportional increase of Adipose Tissue (AT) compared with other tissue and fluids, associated with pathological changes in metabolism, hemodynamic overload, cytokine secretion, systemic inflammatory profile, and cardiac metabolism. In turn, AT is heterogeneous in location, and displays secretory capacity, lipolytic activation, insulin sensitivity, and metabolic status, performing anatomic, metabolic, and endocrine functions. Evidence has emerged on the bidirectional crosstalk exerted by miRNAs as regulators between the heart and AT on metabolism and health conditions. Here, we discuss the bidirectional endocrine role of miRNAs between heart and AT, rescuing extracellular vesicles' (EVs) role in cell-to-cell communication, and the most recent results that show the potential of common therapeutic targets through the elucidation of parallel and /or common epigenetic mechanisms.

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Aerobic exercise training (ET) produces beneficial adaptations in skeletal muscles, including angiogenesis. The renin-angiotensin system (RAS) is highly involved in angiogenesis stimuli. However, the molecular mechanisms underlying capillary growth in skeletal muscle induced by aerobic ET are not completely understood. This study aimed to investigate the effects of volume-dependent aerobic ET on skeletal muscle angiogenesis involving the expression of miRNAs-27a and 27b on RAS and oxidant-antioxidant balance. Eight-week-old female Wistar rats were divided into three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 min/day of swimming, 5×/week, for 10 weeks. P2 consisted of the same protocol as P1 until the 8th week, but in the 9th week, rats trained 2×/day, and in the 10th week, trained 3×/day. Angiogenesis and molecular analyses were performed in soleus muscle samples. Furthermore, to establish ET-induced angiogenesis through RAS, animals were treated with an AT1 receptor blocker (losartan). Aerobic ET promoted higher VO2 peak and exercise tolerance values. In contrast, miRNA-27a and -27b levels were reduced in both trained groups, compared with the SC group. This was in parallel with an increase in the ACE1/Ang II/VEGF axis, which led to a higher capillary-to-fiber ratio. Moreover, aerobic ET induced an antioxidant profile increasing skeletal muscle SOD2 and catalase gene expression, which was accompanied by high nitrite levels and reduced nitrotyrosine concentrations in the circulation. Additionally, losartan treatment partially re-established the miRNAs expression and the capillary-to-fiber ratio in the trained groups. In summary, aerobic ET promoted angiogenesis through the miRNA-27a/b-ACE1/Ang II/VEGF axis and improved the redox balance. Losartan treatment demonstrates the participation of RAS in ET-induced vascular growth. miRNAs and RAS components are promising potential targets to modulate angiogenesis for combating vascular diseases, as well as potential biomarkers to monitor training interventions and physical performance.

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Physical exercise training (PET) has been considered an excellent non-pharmacological strategy to prevent and treat several diseases. There are various benefits offered by PET, especially on the immune system, promoting changes in the morphology and function of cells, inducing changes in the expression pattern of pro and anti-inflammatory cytokines. However, these changes depend on the type, volume and intensity of PET and whether it is being evaluated acutely or chronically. In this context, PET can be a tool to improve the immune system and fight various infections. However, the current COVID-19 pandemic, caused by SARS-CoV-2, which produces cytokine storm, inducing inflammation in several organs, with high infection rates in both sedentary and physically active individuals, the role of PET on immune cells has not yet been elucidated. Thus, this review focused on the role of PET on immune system cells and the possible effects of PET-induced adaptive responses on SARS-CoV-2 infection and COVID-19.

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The current pandemic was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The quarantine period during corona virus disease 19 (COVID-19) outbreak might affect the quality of life leading thousands of individuals to diminish the daily caloric expenditure and mobility, leading to a sedentary behavior and increase the number of health disorders. Exercising is used as a non-pharmacological treatment in many chronic diseases. Here, we review the molecular mechanisms of physical exercise in COVID-19 pandemic on mental health. We also point links between exercise, mental, and cardiovascular health. The infection caused by SARS-CoV-2 affects host cells binding to angiotensin-converting enzyme-2 (ACE2), which is the receptor for SARS-CoV-2. If there is not enough oxygen supply the lungs and other tissues, such as the heart or brain, are affected. SARS-CoV-2 enhances ACE2 leading to inflammation and neuronal death with possible development of mood disorders, such as depression and anxiety. Physical exercise also enhances the ACE2 expression. Conversely, the activation of ACE2/Ang 1-7/Mas axis by physical exercise induces an antiinflammatory and antifibrotic effect. Physical exercise has beneficial effects on mental health enhancing IGF-1, PI3K, BDNF, ERK, and reducing GSK3ß levels. In addition, physical exercise enhances the activity of PGC-1α/ FNDC5/Irisin pathway leading to neuronal survival and the maintenance of a good mental health. Thus, SARS-CoV-2 infection leads to elevation of ACE2 levels through pathological mechanisms that lead to neurological and cardiovascular complications, while the physiological response of ACE2 to physical exercise improves cardiovascular and mental health.

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Exercise training elicits acute and adaptive long term changes in human physiology that mediate the improvement of performance and health state. The responses are integrative and orchestrated by several mechanisms, as gene expression. Gene expression is essential to construct the adaptation of the biological system to exercise training, since there are molecular processes mediating oxidative and non-oxidative metabolism, angiogenesis, cardiac and skeletal myofiber hypertrophy, and other processes that leads to a greater physiological status. Epigenetic is the field that studies about gene expression changes heritable by meiosis and mitosis, by changes in chromatin and DNA conformation, but not in DNA sequence, that studies the regulation on gene expression that is independent of genotype. The field approaches mechanisms of DNA and chromatin conformational changes that inhibit or increase gene expression and determine tissue specific pattern. The three major studied epigenetic mechanisms are DNA methylation, Histone modification, and regulation of noncoding RNA-associated genes. This review elucidates these mechanisms, focusing on the relationship between them and their relationship with exercise training, physical performance and the enhancement of health status. On this chapter, we clarified the relationship of epigenetic modulations and their intimal relationship with acute and chronic effect of exercise training, concentrating our effort on skeletal muscle, heart and vascular responses, that are the most responsive systems against to exercise training and play crucial role on physical performance and improvement of health state.

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Background. We investigated the effects of exercise training (ET) on miR-126 levels and skeletal muscle angiogenesis in obese Zucker rats. Results. Zucker rats were randomly assigned to sedentary and swimming-trained groups: lean sedentary (LS) and trained (LTR); obese sedentary (OB) and trained (OBTR). The OB group displayed capillary rarefaction compared with the LS group. In contrast, ET increased the capillary/fiber ratio by 38% in the LTR group and normalized capillary rarefaction in the OBTR group. VEGF, PI3K, and eNOS levels were reduced in the skeletal muscle of the OB group. ET normalized VEGF, PI3K, and eNOS levels in OBTR, contributing to vascular network homeostasis. PI3KR2 inhibits PI3K, a key mediator of the VEGF signaling pathway. Obesity decreased miR-126 and increased PI3KR2 levels compared with the LS group. However, ET normalized miR-126 levels in the OBTR group versus the LS group and decreased expression of PI3KR2. Conclusion. Our findings show that obesity leads to skeletal muscle capillary rarefaction, which is regulated by decreased miR-126 levels and increased PI3KR2. Inversely, ET normalizes miR-126 levels and VEGF signaling and should be considered an important therapeutic strategy for vascular disorders.

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Aerobic exercise-induced cardiac hypertrophy (CH) is a physiological response involving accurate orchestration of gene and protein expression of contractile and metabolic components. The microRNAs: miR-208a, miR-208b and miR-499 are each encoded by a myosin gene and thus are also known as 'MyomiRs', regulating several mRNA targets that in turn regulate CH and metabolic pathways. To understand the role of myomiRs in the fine-tuning of cardiac myosin heavy chain (MHC) isoform expression by exercise training-induced physiological hypertrophy, Wistar rats were subjected to two different swim training protocols. We observed that high-volume swim training (T2), improved cardiac diastolic function, induced CH and decreased the expression of miR-208a and miR-208b Consequently, the increased expression of their targets, sex determining region y-related transcription factor 6 (Sox6), Med13, Purß, specificity proteins (Sp)/Krüppel-like transcription factor 3 (SP3) and HP1ß (heterochromatin protein 1ß) was more prominent in T2, thus converging to modulate cardiac metabolic and contractile adaptation by exercise training, with an improvement in the α-MHC/ß-MHC ratio, bypassing the increase in PPARß and histone deacetylase (HDAC) class I and II regulation. Altogether, we conclude that high-volume swim training finely assures physiological cardiac remodelling by epigenetic regulation of myomiRs, because inhibition of miR-208a and miR-208b increases the expression of their target proteins and stimulates the interaction among metabolic, contractile and epigenetic genes.

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O treinamento físico aeróbio (TF) e a hipertensão arterial (HA) induzem hipertrofia cardíaca (HC) com características diferentes, e entre as diferenças moleculares podem estar a elucidação de abordagens terapêuticas como os microRNAs (miRNAs). Selecionamos de dados de miRNAarray, 15 miRNAs cardíacos induzidos por dois protocolos de treinamento físico de natação (TF) e comparamos com o miRNAarray em modelo de hipertensão arterial (animais espontaneamente hipertensos, SHR). Foram selecionados 4 miRNAs de interesse (miRNA-27a, 27b, 126 e 29c) que seguiram para a confirmação de sua expressão por qRT-PCR. Destes, selecionamos o miRNA-29c para que fosse realizada a modulação in vivo em SHR jovens. Foi realizada injeção cardíaca intramuscular de partículas de vetor lentiviral para a superexpressão do miRNA-29c. Foram testadas duas doses: baixa (B), 0,6x109 pv/animal e alta (A), 3x109 pv/animal; e por dois períodos de tratamento: 7 e 14 dias. Foi avaliada a expressão de GFP em fígado e coração por western blott para observar a eficiência da transdução viral in vivo. Os efeitos do tratamento na pressão arterial (PA) foram analisados por pletismografia de cauda; na HC pela razão VE/PC (peso do ventrículo esquerdo/peso corporal), peso do coração/PC e (cor/PC), e pelo diâmetro de cardiomiócitos (dCMO) por histologia. qRT-PCR foi utilizado para investigar a expressão do miRNA-29c e seus alvos, colágeno do tipo I e do tipo III (COLIAI e COLIIIAI). O conteúdo de colágeno também foi medido por análise histológica (picrossírius), pela fração volumétrica de colágeno (% col), e pela concentração de OHprolina no VE. Os grupos que receberam baixa dose das partículas lentivirais foram positivos para GFP em coração e fígado, tendo sido assumida a dose baixa como eficiente para futuras transduções. Todos os grupos tratados apresentaram aumento da expressão do miRNA-29c. A expressão gênica do COLIAI diminuiu para os grupos tratados o que não ocorreu para o COLIIIAI. A fração...

Both aerobic exercise training (ET) and Hypertension (HY) induce different cardiac hypertrophy (CH) phenotypes which molecular differences and may lead to new targets for therapies in cardiovascular disease, as microRNAs (miRNAs). We selected 15 miRNAS that were changed by ET from miRNAarray data and compared them with other from HY miRNAarray data. Four miRNAs were selected for qRT-PCR confirmation: miRNA-27a, 27b, 126 e 29c. Among then, miRNA 29c was choosen to be modulated by lentiviral vector due its role in fibrosis regulation. Intramuscular cardiac injection of the lentiviral vector particles was performed following two doses; low-dose , 0,6x109 vp/rat and high 3x109 vp/rat; and for two different times (7 and 14 days). The transduction efficiency was assessed by GFP expression by western blot. Blood pressure (BP) was measured by caudal pletysmography, CH was analysed by ratio LVw/BW (left ventricle weight/body weight), heartw/BW (heart weight/body weight) and by cardiomyocyte diameter (dCMO). qRT-PCR was used to assess miRNA-29c expression and its targets COLIAI and COLIIIAI gene expression. The LV collagen content was assessed by histology (Picrossirius red), by collagen volume fraction, and by Hydroxiproline concentration. Both groups that received the lowe doses were GFP positive in the heart and liver tissue,We assumed that low doses were better for future in vivo transduction. BP did not increase to SHR14A and SHR14B, what did not occurred to the 7 days groups. The miRNA-29c expression increased in all treated groups versus their control (CSI). COLIAI expression decreased in treated groups, while COLIIIAI did not change. Collagen volume fraction decreased in all treated groups, which shows that the treatment was efficient to decrease the cardiac collagen. Heart/BW decreased 7-11% in SHR14B and SHR14A and there were an increase in dCMO in all treated groups, that shows that cardiac remodeling of treated SHR included an increase in size...

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OBJECTIVES: Aerobic exercise training prevents cardiovascular risks. Regular exercise promotes functional and structural adaptations that are associated with several cardiovascular benefits. The aim of this study is to investigate the effects of swimming training on coronary blood flow, adenosine production and cardiac capillaries in normotensive rats. METHODS: Wistar rats were randomly divided into two groups: control (C) and trained (T). An exercise protocol was performed for 10 weeks and 60 min/day with a tail overload of 5% bodyweight. Coronary blood flow was quantified with a color microsphere technique, and cardiac capillaries were quantified using light microscopy. Adenine nucleotide hydrolysis was evaluated by enzymatic activity, and protein expression was evaluated by western blot. The results are presented as the means ± SEMs (p<0.05). RESULTS: Exercise training increased the coronary blood flow and the myocardial capillary-to-fiber ratio. Moreover, the circulating and cardiac extracellular adenine nucleotide hydrolysis was higher in the trained rats than in the sedentary rats due to the increased activity and protein expression of enzymes, such as E-NTPDase and 59'-nucleotidase. CONCLUSIONS: Swimming training increases coronary blood flow, number of cardiac capillaries, and adenine nucleotide hydrolysis. Increased adenosine production may be an important contributor to the enhanced coronary blood flow and angiogenesis that were observed in the exercise-trained rats; collectively, these results suggest improved myocardial perfusion.

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Fundamentos: O treinamento físico aeróbio (TF) acarreta adaptações cardiovasculares, dentre as quais se destaca a hipertrofia cardíaca (HC). Marcadores moleculares sãoapontados na distinção da HC fisiológica da patológica. Objetivo: Investigar a magnitude de HC induzida pordiferentes volumes de TF, verificando se estas respostas adaptativas estão associadas a marcadores molecularesde HC patológica. Métodos: Vinte e uma ratas Wistar foram separadas emtrês grupos: sedentárias-controle (SC), treinadas protocolo 1 (P1), treinadas protocolo 2 (P2). P1:treinamento de natação durante 60min, 1x/dia, 5dias/semana/10 semanas, com 5% de sobrecarga. P2: o mesmo de P1 até a 8ª semana; na 9ª semana os animais treinaram 2x/dia, e na 10ª semana 3x/dia. Resultados: O TF promoveu bradicardia de repouso, HC, aumento da tolerância ao esforço e consumo de oxigênio de pico no grupo P1, sendo estas adaptações exacerbadaspara P2. A expressão gênica de α-miosina de cadeia pesada (MHC), β-MHC, α/β-MHC, fator natriuréticoatrial (ANF) e α-actina esquelética não mudou no P1. Em P2 houve melhora neste perfil genético com aumento naexpressão gênica da α-MHC, redução de β-MHC, aumento da α/β- MHC e redução da α-actina esquelética. O aumento de atividade da proteína quinase-B (Akt)ocorreu de forma dependente ao volume de TF. Conclusões: A magnitude da HC foi dependente do aumento do volume de TF e os mecanismos molecularespor ele ativados são diferentes dos encontrados na HC patológica, conferindo-lhes o caráter de HC fisiológica.

Background: Aerobic exercise training (ET) induces cardiovascular adaptations, including cardiac hypertrophy (CH). Molecular markers differentiatebetween physiological and pathological CH. Objective: To investigate the amount of CH induced by different amounts of ET, ascertaining whether these adaptive responses are associated with pathological CH molecular markers.Methods: Twenty-one female Wistar rats were divided into 3 groups: sedentary control (SC), trained protocol 1 (T1) and trained protocol 2 (T2). T1: swimming for60 min, 1xdayx10 weeks, with 5% workload. T2 was the same as T1 until the 8th week, with training 2xday in the 9th week and 3xday in the 10th week.Results: ET promoted resting bradycardia, CH, increased effort tolerance and peak oxygen uptake inthe T1 group, with these responses increased in the P2 group. In T1 the cardiac gene levels of α- myosin heavy chain (MHC), β- MHC, α/β- MHC, atrialnatriuretic factor (ANF) and skeletal α-actin did not change, with an improvement in this genetic profile noted in T2 with increased α- MHC, lower β-MHC, higher α/β- MHC and lower skeletal α-actin. Protein kinase B (Akt) activity increased in parallel to theamount of ET. Conclusions: The magnitude of the CH was dependent on the increase in the amount of ET and the molecular markers that it activates differ from those found in pathological CH, thus indicating physiological CH.

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OBJECTIVES: Aerobic exercise training prevents cardiovascular risks. Regular exercise promotes functional and structural adaptations that are associated with several cardiovascular benefits. The aim of this study is to investigate the effects of swimming training on coronary blood flow, adenosine production and cardiac capillaries in normotensive rats. METHODS: Wistar rats were randomly divided into two groups: control (C) and trained (T). An exercise protocol was performed for 10 weeks and 60 min/day with a tail overload of 5 percent bodyweight. Coronary blood flow was quantified with a color microsphere technique, and cardiac capillaries were quantified using light microscopy. Adenine nucleotide hydrolysis was evaluated by enzymatic activity, and protein expression was evaluated by western blot. The results are presented as the means ± SEMs (p<0.05). RESULTS: Exercise training increased the coronary blood flow and the myocardial capillary-to-fiber ratio. Moreover, the circulating and cardiac extracellular adenine nucleotide hydrolysis was higher in the trained rats than in the sedentary rats due to the increased activity and protein expression of enzymes, such as E-NTPDase and 59- nucleotidase. CONCLUSIONS: Swimming training increases coronary blood flow, number of cardiac capillaries, and adenine nucleotide hydrolysis. Increased adenosine production may be an important contributor to the enhanced coronary blood flow and angiogenesis that were observed in the exercise-trained rats; collectively, these results suggest improved myocardial perfusion.

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Os esteróides anabolizantes androgênicos (EAA) são sintéticos de testosterona desenvolvidos para fins terapêuticos. São também utilizados por populações fisicamente ativas, que normalmente excedem nas doses, o que potencializa danos à saúde. Para estudar alguns dos efeitos de EAA sobre o sistema cardiovascular, ratos "Wistar" foram divididos em quatro grupos: sedentário controle (SC), sedentário anabolizado (SA), treinado controle (TC) e treinado anabolizado (TA). Foram avaliados os efeitos da associação do uso de EAA (Decanoato de nandrolona - 5 mg/kg sc, 2x/sem) e do treinamento físico de natação (TFN - 60 min/dia, 5x/sem, durante 10 sem) sobre o débito cardíaco (DC) e fluxo sanguíneo basal (DCbasal, Qbasal) e após infusão do vasodilatador acetilcolina (DC Ach, Q Ach) para observar a vasodilatação endotélio dependente (QAch), razão capilar/fibra (rc/f) e expressão do fator de crescimento endotelial vascular (VEGF) em músculo sóleo (predominância de fibras oxidativas). A testosterona plasmática aumentou nos grupos com uso de EAA e foi observada bradicardia de repouso como efeito do TFN. O DC foi menor para o Grupo TA, tanto na condição basal quanto sob infusão de Ach. O Qbasal não foi diferente entre os grupos no músculo estudado. O QAch foi maior no grupo TC, entretanto, no grupo TA este efeito benéfico do TFN foi prejudicado pela associação com o EAA. Aumento da rc/f e VEGF foi observado somente no grupo TC. Estes resultados sugerem que a associação do EAA ao TFN atenua a angiogênese e arteriogênese observadas como efeito do treinamento físico aeróbio e causa prejuízo ao fluxo sanguíneo muscular, o que poderia predispor o praticante de esportes e atividades físicas e usuário destas substâncias a problemas vasculares.

Androgenic anabolic steroids (EAA) are synthetic derivatives of testosterone, used in therapeutic dosages in medical practice and in high doses by physically active people that could be health damaging. To study the effects of EAA on the cardiovascular system, Wistar rats were randomized into Sedentary Control (SC), Sedentary Steroid (SA), Trained Control (TC) and Trained Steroid (TA) groups. We evaluated the effects of swimming training (60min/day, 5x/week during 10 week) and AAS (nandrolone decanoate - 5 mg/kg sc, 2x/week) on cardiac output, basal blood flow (Qb, DC basal) and after injection of a vasodilator to observe the endothelium dependent vasodilatation (acetylcholine - Q Ach)(Q Ach, DC Ach), capillary to fiber ratio (r c/f) and vascular-endothelial growth factor expression (VEGF) in soleus muscle (oxidative fibers). Serum testosterone increased in SA and TA. Exercise training significantly decreased resting heart rate. Qb was not different among groups, and QAch was higher in TC group, however in TA group this beneficial effect of swimming exercise training was lost by association with EAA. Rc/f and VEGF were higher only in TC group. These results suggest that swimming training associated with EAA inhibit angiogenesis and arteriogenesis observed as effects of aerobic training, and impairs the red skeletal muscle blood flow which predispose physically active AAS users to vascular diseases.

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