Experimental Model Exposed to Bisphenol and Submitted to a High-Fat Diet and Related Morphologic Testicular Parameters Alterations Analysis.

PURPOSE: To evaluate the morphological and stereological parameters of the testicles in mice exposed to bisphenol S and/or high-fat diet-induced obesity. MATERIAL AND METHODS: Forty adult male C57BL/6 mice were fed a standard diet (SC) or high-fat diet (HF) for a total of 12 weeks. The sample was randomly divided into 4 experimental groups with 10 mices as follows: a) SC - animals fed a standard diet; b) SC-B - animals fed a standard diet and administration of BPS (25 µg/kg of body mass/day) in drinking water; c) HF: animals fed a high-fat diet; d) HF-B - animals fed a high-fat diet and administration of BPS (25 µg/Kg of body mass/day) in drinking water. BPS administration lasted 12 weeks, following exposure to the SC and HF diets. BPS was diluted in absolute ethanol (0.1%) and added to drinking water (concentration of 25 µg/kg body weight/day). The animals were euthanized, and the testes were processed and stained with hematoxylin and eosin (H&E) for morphometric and stereological parameters, including density of seminiferous tubules per area, length density and total length of seminiferous tubules, height of the tunica albuginea and the diameter of the seminiferous tubules. The images were captured with an Olympus BX51 microscope and Olympus DP70 camera. The stereological analysis was done with the Image Pro and Image J programs. Means were statistically compared using ANOVA and the Holm-Sidak post-test (p<0.05). RESULTS: The seminiferous tubule density per area reduced in all groups when compared with SC samples (p<0.001): HF (40%), SC-B 3(2%), and HF-B (36%). Length density was reduced significantly (p<0.001) in all groups when compared with SC group: HF (40%), SC-B (32%), and HF-B (36%). The seminiferous tubule total length was reduced (p<0.001) when compared to f HF (28%) and SC-B (26%) groups. The tubule diameter increased significantly (p<0.001) only when we compared the SC group with SC (54%) an SC-B (25%) groups and the tunica thickness increased significantly only in HF group (117%) when compared with SC-B (20%) and HF-B 31%. CONCLUSION: Animals exposed to bisphenol S and/or high-fat diet-induced obesity presented important structural alterations in testicular morphology.

Adipose tissue plasticity mediated by the counterregulatory axis of the renin-angiotensin system: Role of Mas and MrgD receptors.

The renin-angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked to obesity-associated metabolic effects. On the other hand, the counterregulatory axis appears to exert antiobesity effects through the activation of two receptors, the G protein-coupled receptor (MasR) and Mas-related receptor type D (MrgD). The local RAS in adipose organ has prompted extensive research into white adipose tissue and brown adipose tissue (BAT), with a key role in regulating the cellular and metabolic plasticity of these tissues. The MasR activation favors the brown plasticity signature in the adipose organ by improve the thermogenesis, adipogenesis, and lipolysis, decrease the inflammatory state, and overall energy homeostasis. The MrgD metabolic effects are related to the maintenance of BAT functionality, but the signaling remains unexplored. This review provides a summary of RAS counterregulatory actions triggered by Mas and MrgD receptors on adipose tissue plasticity. Focus on the effects related to the morphology and function of adipose tissue, especially from animal studies, will be given targeting new avenues for treatment of obesity-associated metabolic effects.

Obesity-induced skeletal muscle remodeling: A comparative analysis of exercise training and ACE-inhibitory drug in male mice.

Obesity over-activates the classical arm of the renin-angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin-converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high-fat (HF) diet for 16 weeks. At the eighth week, the HF-fed animals were divided into four subgroups-sedentary (HF), treated with enalapril (HF-E), exercise training protocol (HF-T), and combined interventions (HF-ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF-T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity-induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training.

ER stress improvement by aerobic training or enalapril differently ameliorates pathological cardiac remodeling in obese mice.

Overactivation of the classic arm of the renin-angiotensin system (RAS) is one of the main mechanisms involved in obesity-related cardiac remodeling, and a possible relationship between RAS and ER stress in the cardiovascular system have been described. Thus, the aim of this study is to evaluate if activating the protective arm of the RAS by ACE inhibition or aerobic exercise training could overturn diet-induced pathological cardiac hypertrophy by attenuating ER stress. Male C57BL/6 mice were fed a control (SC) or a high-fat diet (HF) for 16 weeks. In the 8th week, HF-fed animals were randomly divided into HF, enalapril treatment (HF-En), and aerobic exercise training (HF-Ex) groups. Body mass (BM), food and energy intake, plasma analyzes, systolic blood pressure (SBP), physical conditioning, and plasma ACE and ACE2 activity were evaluated. Cardiac morphology, and protein expression of hypertrophy, cardiac metabolism, RAS, and ER stress markers were assessed. Data presented as mean ± standard deviation and analyzed by one-way ANOVA with Holm-Sidak post-hoc. HF group had increased BM and SBP, and developed pathological concentric cardiac hypertrophy, with overactivation of the classic arm of the RAS, and higher ER stress. Both interventions reverted the increase in BM, and SBP, and favored the protective arm of the RAS. Enalapril treatment improved pathological cardiac hypertrophy with partial reversal of the concentric pattern, and slightly attenuated cardiac ER stress. In contrast, aerobic exercise training induced physiological eccentric cardiac hypertrophy, and fully diminished ER stress.

Gender Disparity in First and Senior Authorship in Brazilian Cardiology Journals. / Disparidade de Gênero na Autoria Principal e Sênior em Periódicos Brasileiros de Cardiologia.

BACKGROUND: Despite the importance of women in clinical research, no assessment has been made of the fraction of women in a leadership positions in the Cardiology journals of the SBC. OBJECTIVES: To assess the fraction of female authors in the International Journal of Cardiovascular Sciences (IJCS) and the Arquivos Brasileiros de Cardiologia (ABC Cardiol) over the last decades. METHODS: We searched the original articles of the ABC Cardiol, from 2000 to 2019, and of the IJCS, from 2010 to 2019. We surveyed the number of first and senior female authors and the total number of original articles from 2010 to 2019. We calculated the total proportion of female authorship and compared the first quinquennium with the second. Only data from the ABC Cardiol were analyzed to assess the temporal evolution of the two decades. We used the chi-square test to assess the differences within each journal and between them. The IBM® SPSS® software was used in the analyses. The level of significance adopted was 5%. RESULTS: From 2010 to 2019, 1,157 original articles were published in the ABC Cardiol and 398 in the IJCS. We observed that women are more prevalent as first authors in the IJCS compared to the ABC Cardiol, but men prevail as senior authors in both journals. From 2010 to 2019, there was no significant change in the proportion of female authorship. Throughout the decades analyzed for the ABC Cardiol, there was a projection of linear growth of female authorship, with the slope of the line being greater in the first authorship than in senior authorship. CONCLUSIONS: There is gender disparity, with lower female representativeness in authorship in the articles from the Brazilian Cardiology journals analyzed: Arquivos Brasileiros de Cardiologia and International Journal of Cardiovascular Sciences. We believe that based on these results, more efforts should be implemented in the search for gender equity in the cardiology scientific production published by these journals.

FUNDAMENTO: Apesar da importância das mulheres na pesquisa clínica, não existe uma avaliação da fração de mulheres em posições de autoria nos periódicos de cardiologia da SBC. OBJETIVOS: Avaliar a fração de mulheres autoras na International Journal of Cardiovascular Sciences (IJCS) e nos Arquivos Brasileiros de Cardiologia (ABC Cardiol) nas últimas décadas. MÉTODOS: Realizamos busca dos artigos originais dos ABC Cardiol, entre 2000 e 2019, e da IJCS, entre 2010 e 2019. Foi feito levantamento do número de primeiras e últimas autoras e do total de artigos originais de 2010 a 2019. Calculamos as proporções totais de autorias femininas e comparamos o primeiro quinquênio com o segundo. Para avaliar a evolução temporal das duas décadas, analisamos apenas dados dos ABC Cardiol. Utilizamos o teste Qui-quadrado para analisar as diferenças dentro de cada revista e entre ambas. O software IBM® SPSS® foi utilizado nas análises. O nível de significância adotado foi de 5%. RESULTADOS: De 2010 a 2019, foram publicados 1157 artigos originais nos ABC Cardiol e 398 na IJCS. Observamos que as mulheres têm maior predominância como primeiras autoras na IJCS em relação aos ABC Cardiol, mas os homens predominam como últimos autores em ambos. De 2010 a 2019, não houve modificação significativa na proporção de autorias femininas. Ao longo das décadas analisadas para os ABC Cardiol, houve projeção de crescimento linear de autorias femininas, sendo que a inclinação da reta é maior na projeção da primeira autoria que na autoria sênior. CONCLUSÕES: Há disparidade de gênero com menor representatividade feminina nas autorias dos artigos dos periódicos cardiológicos brasileiros analisados: Arquivos Brasileiros de Cardiologia e International Journal of Cardiovascular Sciences. Acreditamos que a partir destes resultados mais esforços devam ser implementados em busca de equidade de gênero na produção científica cardiológica veiculada por estes periódicos.

Disparidade de Gênero na Autoria Principal e Sênior em Periódicos Brasileiros de Cardiologia / Gender Disparity in First and Senior Authorship in Brazilian Cardiology Journals

Resumo Fundamento: Apesar da importância das mulheres na pesquisa clínica, não existe uma avaliação da fração de mulheres em posições de autoria nos periódicos de cardiologia da SBC. Objetivos: Avaliar a fração de mulheres autoras na International Journal of Cardiovascular Sciences (IJCS) e nos Arquivos Brasileiros de Cardiologia (ABC Cardiol) nas últimas décadas. Métodos: Realizamos busca dos artigos originais dos ABC Cardiol, entre 2000 e 2019, e da IJCS, entre 2010 e 2019. Foi feito levantamento do número de primeiras e últimas autoras e do total de artigos originais de 2010 a 2019. Calculamos as proporções totais de autorias femininas e comparamos o primeiro quinquênio com o segundo. Para avaliar a evolução temporal das duas décadas, analisamos apenas dados dos ABC Cardiol. Utilizamos o teste Qui-quadrado para analisar as diferenças dentro de cada revista e entre ambas. O software IBM® SPSS® foi utilizado nas análises. O nível de significância adotado foi de 5%. Resultados: De 2010 a 2019, foram publicados 1157 artigos originais nos ABC Cardiol e 398 na IJCS. Observamos que as mulheres têm maior predominância como primeiras autoras na IJCS em relação aos ABC Cardiol, mas os homens predominam como últimos autores em ambos. De 2010 a 2019, não houve modificação significativa na proporção de autorias femininas. Ao longo das décadas analisadas para os ABC Cardiol, houve projeção de crescimento linear de autorias femininas, sendo que a inclinação da reta é maior na projeção da primeira autoria que na autoria sênior. Conclusões: Há disparidade de gênero com menor representatividade feminina nas autorias dos artigos dos periódicos cardiológicos brasileiros analisados: Arquivos Brasileiros de Cardiologia e International Journal of Cardiovascular Sciences. Acreditamos que a partir destes resultados mais esforços devam ser implementados em busca de equidade de gênero na produção científica cardiológica veiculada por estes periódicos.

Abstract Background: Despite the importance of women in clinical research, no assessment has been made of the fraction of women in a leadership positions in the Cardiology journals of the SBC. Objectives: To assess the fraction of female authors in the International Journal of Cardiovascular Sciences (IJCS) and the Arquivos Brasileiros de Cardiologia (ABC Cardiol) over the last decades. Methods: We searched the original articles of the ABC Cardiol, from 2000 to 2019, and of the IJCS, from 2010 to 2019. We surveyed the number of first and senior female authors and the total number of original articles from 2010 to 2019. We calculated the total proportion of female authorship and compared the first quinquennium with the second. Only data from the ABC Cardiol were analyzed to assess the temporal evolution of the two decades. We used the chi-square test to assess the differences within each journal and between them. The IBM® SPSS® software was used in the analyses. The level of significance adopted was 5%. Results: From 2010 to 2019, 1,157 original articles were published in the ABC Cardiol and 398 in the IJCS. We observed that women are more prevalent as first authors in the IJCS compared to the ABC Cardiol, but men prevail as senior authors in both journals. From 2010 to 2019, there was no significant change in the proportion of female authorship. Throughout the decades analyzed for the ABC Cardiol, there was a projection of linear growth of female authorship, with the slope of the line being greater in the first authorship than in senior authorship. Conclusions: There is gender disparity, with lower female representativeness in authorship in the articles from the Brazilian Cardiology journals analyzed: Arquivos Brasileiros de Cardiologia and International Journal of Cardiovascular Sciences. We believe that based on these results, more efforts should be implemented in the search for gender equity in the cardiology scientific production published by these journals.

Comparison between aerobic exercise training and enalapril treatment as tools to improve diet-induced metabolic-associated fatty liver disease: Effects on endoplasmic reticulum stress markers.

AIMS: Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. MAIN METHODS: C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. KEY FINDINGS: Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. SIGNIFICANCE: This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model.

Cilostazol attenuates cardiac oxidative stress and inflammation in hypercholesterolemic rats.

Atherosclerosis is a multifactorial chronic disease associated with pro-inflammatory and pro-oxidative cardiovascular states. Cilostazol, a selective phosphodiesterase 3 inhibitor (PDE3), is clinically used in the treatment of intermittent claudication and secondary prevention of cerebral infarction. The aim of this study was to evaluate the cardioprotective effects of cilostazol and the molecular mechanisms involved in hypercholesterolemic rats. Male Wistar rats were divided into four groups: control group (C) and control + cilostazol group (C+CILO), that were fed a standard chow diet, and hypercholesterolemic diet group (HCD) and HCD + cilostazol (HCD+CILO) that were fed a hypercholesterolemic diet. Cilostazol treatment started after 30 days for C+CILO and HCD+CILO groups. Animals were administered cilostazol once a day for 15 days. Subsequently, serum and left ventricles were extracted for evaluation of lipid profile, inflammatory, and oxidative biomarkers. The HCD group displayed increased serum lipid levels, inflammatory cytokines production, and cardiac NF-kB protein expression and decreased cardiac Nrf2-mediated antioxidant activity. Conversely, the cilostazol treatment improved all these cardiac deleterious effects, inhibiting NF-kB activation and subsequently decreasing inflammatory mediators, reestablishing the antioxidant properties through Nrf2-mediated pathway, including increased SOD, GPx, and catalase expression. Taken together, our results indicated that cilostazol protects hypercholesterolemia-induced cardiac damage by molecular mechanisms targeting the crosstalk between Nrf2 induction and NF-kB inhibition in the heart.

Renin-angiotensin system modulation through enalapril and/or exercise training improves visceral adiposity in obese mice.

INTRODUCTION: Obesity-related metabolic diseases occur as a result of disruptions in white adipose tissue (WAT) plasticity, especially through visceral fat accumulation and adipocyte hypertrophy. This study aimed to evaluate the impact of renin-angiotensin system (RAS) and bradykinin receptors modulation by enalapril treatment and/or exercise training on WAT morphology and related deleterious outcomes. METHODS: Male C57BL/6 mice were fed either a standard chow or a high-fat (HF) diet for 16 weeks. At the 8th week, HF-fed animals were divided into sedentary (HF), enalapril treatment (HF-E), exercise training (HF-T), and enalapril treatment plus exercise training (HF-ET) groups. Following the experimental protocol, body mass gain, adiposity index, insulin resistance, visceral WAT morphometry, renin-angiotensin system, and bradykinin receptors were evaluated. RESULTS: The HF group displayed increased adiposity, larger visceral fat mass, and adipocyte hypertrophy, which was accompanied by insulin resistance, overactivation of Ang II/AT1R arm, and favoring of B1R in bradykinin receptors profile. All interventions ameliorated visceral adiposity and related outcomes by favoring the Ang 1-7/MasR arm and the B2R expression in B1R/B2R ratio. However, combined therapy additively reduced Ang II/Ang 1-7 ratio. CONCLUSION: Our results suggest that Ang 1-7/MasR arm and B2R activation might be relevant targets in the treatment of visceral obesity.

Crosstalk between the renin-angiotensin system and the endoplasmic reticulum stress in the cardiovascular system: Lessons learned so far.

The renin-angiotensin (Ang) system (RAS) is a complex hormonal system present locally in several tissues such as cardiovascular organs. RAS deregulation through overactivation of the classical arm [Ang-converting enzyme (ACE)/Ang-II/Ang type 1 receptor (AT1R)] has been linked to the development of cardiovascular diseases and activation of endoplasmic reticulum (ER) stress pathways. The ER stress is a condition that, if unresolved, might lead to heart failure, atherosclerosis, hypertension, and endothelial dysfunction. Accumulated evidence has shown that the RAS modulates the UPR activation. Several studies reported increased ER stress markers in response to Ang-II treatment, in both in vivo and in vitro models. Evidence has also pointed that targeting the RAS classical arm through RAS blockers, gene silencing or genetic models leads to lower levels of ER stress markers. Few studies demonstrated protective effects of the counter-regulatory arm (ACE-2/Ang-(1-7)/Mas receptor) over ER stress. However, the crosstalk mechanisms between the arms of the RAS and ER stress remain unclear. In this review, we sought to explore the classical arm of the RAS as a key mechanism in UPR activation and to suggest a possible protective role of the counter-regulatory arm in mitigating ER stress.

Modulation of cardiac renin-angiotensin system, redox status and inflammatory profile by different volumes of aerobic exercise training in obese rats.

Overactivation of the classical arm of the renin-angiotensin (Ang) system (RAS) occurs during inflammation, oxidative stress and obesity-induced cardiomyopathy. The activation of the protective arm of RAS may act to counterbalance the deleterious effects of the classical RAS. Although aerobic exercise training (AET) shifts the balance of the RAS towards the protective arm, little is known about the molecular adaptations to different volumes of AET. The aim of this study was to evaluate the impact of AET volume on the modulation of RAS, as well as on cardiac biomarkers of oxidative stress and inflammation, in a diet-induced obesity model. Male Wistar rats were fed either control (CON) or high fat (HF) diet for 32 weeks. At week 20, HF group was subdivided into sedentary, low (LEV, 150 min/week) or high (HEV, 300 min/week) exercise volume. After 12 weeks of exercise, body mass gain, systolic blood pressure and heart rate were evaluated, as well as RAS, oxidative stress and inflammation in the heart. Body mass gain, systolic blood pressure and heart rate were higher in HF group when compared with SC group. Both trained groups restored systolic blood pressure and heart rate, but only HEV reduced body mass gain. Regarding the cardiac RAS, the HF group exhibited favoring of the classical arm and both trained groups shifted the balance towards the counterregulatory protective arm. The HF group had higher B1R expression and lower B2R expression than the control group, and B2R expression was reverted in both trained groups. The HF group also presented oxidative stress. The LEV and HEV groups improved the cardiac redox status by reducing Nox 2 and nitrotyrosine expression, but only the LEV group was able to increase the antioxidant defense by increasing Nrf2 signaling. While the HF group presented higher TNF-α, IL-6 and NFκB expression, and lower IL-10 expression, than the SC group, both training protocols improved the inflammatory profile. Although both trained groups improved the deleterious changes related to obesity cardiomyopathy, it is clear that the molecular mechanisms differ between them. Our results suggest that different exercise volumes might reach different molecular targets, and this could be a relevant factor when using exercise to manage obesity.

Effects of short-term high-intensity interval and continuous exercise training on body composition and cardiac function in obese sarcopenic rats.

AIM: We investigated the effects of high-intensity interval and continuous short-term exercise on body composition and cardiac function after myocardial ischemia-reperfusion injury (IRI) in obese rats. METHODS: Rats fed with a standard chow diet (SC) or high-fat diet (HFD) for 20 weeks underwent systolic blood pressure (SBP), glycemia and dual-energy X-ray absorptiometry analyses. Then, animals fed with HFD were subdivided into three groups: sedentary (HFD-SED); moderate-intensity continuous training (HFD-MICT); and high-intensity interval training (HFD-HIIT). Exercised groups underwent four isocaloric aerobic exercise sessions, in which HFD-MICT maintained the intensity continuously and HFD-HIIT alternated it. After exercise sessions, all groups underwent global IRI and myocardial infarct size (IS) was determined histologically. Fat and muscle mass were weighted, and protein levels involved in muscle metabolism were assessed in skeletal muscle. RESULTS: HFD-fed versus SC-fed rats reduced lean body mass by 31% (P < 0.001), while SBP, glycemia and body fat percentage were increased by 10% (P = 0.04), 30% (P = 0.006) and 54% (P < 0.001); respectively. HFD-induced muscle atrophy was restored in exercised groups, as only HFD-SED presented lower gastrocnemius (32%; P = 0.001) and quadriceps mass (62%; P < 0.001) than SC. PGC1-α expression was 2.7-fold higher in HFD-HIIT versus HFD-SED (P = 0.04), whereas HFD-HIIT and HFD-MICT exhibited 1.7-fold increase in p-mTORSer2481 levels compared to HFD-SED (P = 0.04). Although no difference was detected among groups for IS (P = 0.30), only HFD-HIIT preserved left-ventricle developed pressure after IRI (+0.7 mmHg; P = 0.9). SIGNIFICANCE: Short-term exercise, continuous or HIIT, restored HFD-induced muscle atrophy and increased mTOR expression, but only HIIT maintained myocardial contractility following IRI in obese animals.

Aerobic exercise modulates cardiac NAD(P)H oxidase and the NRF2/KEAP1 pathway in a mouse model of chronic fructose consumption.

The present study investigated the effects of exercise on the cardiac nuclear factor (erythroid-derived 2) factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) pathway in an experimental model of chronic fructose consumption. Male C57BL/6 mice were assigned to Control, Fructose (20% fructose in drinking water), Exercise (treadmill exercise at moderate intensity), and Fructose + Exercise groups (n = 10). After 12 wk, the energy intake and body weight in the groups were similar. Maximum exercise testing, resting energy expenditure, resting oxygen consumption, and carbon dioxide production increased in the exercise groups (Exercise and Fructose + Exercise vs. Control and Fructose groups, P < 0.05). Chronic fructose intake induced circulating hypercholesterolemia, hypertriglyceridemia, and hyperleptinemia and increased white adipose tissue depots, with no changes in blood pressure. This metabolic environment increased circulating IL-6, IL-1ß, IL-10, cardiac hypertrophy, and cardiac NF-κB-p65 and TNF-α expression, which were reduced by exercise (P < 0.05). Cardiac ANG II type 1 receptor and NAD(P)H oxidase 2 (NOX2) were increased by fructose intake and exercise decreased this response (P < 0.05). Exercise increased the cardiac expression of the NRF2-to-KEAP1 ratio and phase II antioxidants in fructose-fed mice (P < 0.05). NOX4, glutathione reductase, and catalase protein expression were similar between the groups. These findings suggest that exercise confers modulatory cardiac effects, improving antioxidant defenses through the NRF2/KEAP1 pathway and decreasing oxidative stress, representing a potential nonpharmacological approach to protect against fructose-induced cardiometabolic diseases.NEW & NOTEWORTHY This is the first study to evaluate the cardiac modulation of NAD(P)H oxidase (NOX), the NRF2/Kelch-like ECH-associated protein 1 pathway (KEAP), and the thioredoxin (TRX1) system through exercise in the presence of moderate fructose intake. We demonstrated a novel mechanism by which exercise improves cardiac antioxidant defenses in an experimental model of chronic fructose intake, which involves NRF2-to-KEAP1 ratio modulation, enhancing the local phase II antioxidants hemoxygenase-1, thioredoxin reductase (TXNRD1), and peroxiredoxin1B (PDRX1), and inhibiting cardiac NOX2 overexpression.

Exercise-induced cardiac opioid system activation attenuates apoptosis pathway in obese rats.

AIM: To compare the effect of 150 min vs. 300 min of weekly moderate intensity exercise training on the activation of the opioid system and apoptosis in the hearts of a diet-induced obesity model. METHODS: Male Wistar rats were fed with either control (CON) or high fat (HF) diet for 32 weeks. At the 20th week, HF group was subdivided into sedentary, low (LEV, 150 min·week-1) or high (HEV, 300 min·week-1) exercise volume. After 12 weeks of exercise, body mass gain, adiposity index, systolic blood pressure, cardiac morphometry, apoptosis biomarkers and opioid system expression were evaluated. RESULTS: Sedentary animals fed with HF presented pathological cardiac hypertrophy and higher body mass gain, systolic blood pressure and adiposity index than control group. Both exercise volumes induced physiological cardiac hypertrophy, restored systolic blood pressure and improved adiposity index, but only 300 min·week-1 reduced body mass gain. HF group exhibited lower proenkephalin, PI3K, ERK and GSK-3ß expression, and greater activated caspase-3 expression than control group. Compared to HF, no changes in the cardiac opioid system were observed in the 150 min·week-1 of exercise training, while 300 min·week-1 showed greater proenkephalin, DOR, KOR, MOR, Akt, ERK and GSK-3ß expression, and lower activated caspase-3 expression. CONCLUSION: 300 min·week-1 of exercise training triggered opioid system activation and provided greater cardioprotection against obesity than 150 min·week-1. Our findings provide translational aspect with clinical relevance about the critical dose of exercise training necessary to reduce cardiovascular risk factors caused by obesity.

Effects of a high energy density diet in the "corpus cavernosum" of mice.

Erectile dysfunction is a common condition that affects men over age 40. It is highly related to obesity. The corpus cavernosum is the most important structure involved in erection. The aim of this study was to evaluate the structure of the corpus cavernosum of mice fed with a high energy density diet (HED). At 3 months of age, male C57BL/6 mice were fed with a HED diet (50% lipids) or standard chow (SC) diet (10% lipids) for 14 weeks. Afterwards, the animals were euthanized and the corpus cavernosum was analyzed through stereology. Statistical significance was calculated by the student's t-test (p < 0.05). The group fed with HED diet showed higher values of body weight, blood pressure and higher rates of cholesterol, triglycerides, and glucose from the second week to the end of the experiment. The HED group showed a significant increase in the connective tissue (15%) and a decrease in smooth muscle fibers (41%). The testosterone concentration in the HED group was 63% lower than in SC animals. Animals fed with a HED presented reduced testosterone serum levels and morphological changes on the corpus cavernosum, which may be related to erectile dysfunction.

Modulation of the renin-angiotensin system in white adipose tissue and skeletal muscle: focus on exercise training.

Overactivation of the renin-angiotensin (Ang) system (RAS) increases the classical arm (Ang-converting enzyme (ACE)/Ang II/Ang type 1 receptor (AT1R)) to the detriment of the protective arm (ACE2/Ang 1-7/Mas receptor (MasR)). The components of the RAS are present locally in white adipose tissue (WAT) and skeletal muscle, which act co-operatively, through specific mediators, in response to pathophysiological changes. In WAT, up-regulation of the classical arm promotes lipogenesis and reduces lipolysis and adipogenesis, leading to adipocyte hypertrophy and lipid storage, which are related to insulin resistance and increased inflammation. In skeletal muscle, the classical arm promotes protein degradation and increases the inflammatory status and oxidative stress, leading to muscle wasting. Conversely, the protective arm plays a counter-regulatory role by opposing the effect of Ang II. The accumulation of adipose tissue and muscle mass loss is associated with a higher risk of morbidity and mortality, which could be related, in part, to overactivation of the RAS. On the other hand, exercise training (ExT) shifts the balance of the RAS towards the protective arm, promoting the inhibition of the classical arm in parallel with the stimulation of the protective arm. Thus, fat mobilization and maintenance of muscle mass and function are facilitated. However, the mechanisms underlying exercise-induced changes in the RAS remain unclear. In this review, we present the RAS as a key mechanism of WAT and skeletal muscle metabolic dysfunction. Furthermore, we discuss the interaction between the RAS and exercise and the possible underlying mechanisms of the health-related aspects of ExT.

High, but not low, exercise volume shifts the balance of renin-angiotensin system toward ACE2/Mas receptor axis in skeletal muscle in obese rats.

Metabolic syndrome is a cluster of metabolic risk factors that is linked to central obesity, elevated blood pressure, insulin resistance (IR), and dyslipidemia, where the renin-angiotensin system (RAS) may provide a link among them. This study aimed to evaluate volume exercise effects comparing low vs. high volume of chronic aerobic exercise on RAS axes in skeletal muscle in a diet-induced obesity (DIO) rat model. For this, male Wistar-Kyoto rats were fed a standard chow (SC) diet or a high-fat (HF) diet for 32 wk. Animals receiving the HF diet were randomly divided into low exercise volume (LEV, 150 min/wk) and high exercise volume (HEV, 300 min/wk) at the 20th week. After 12 wk of aerobic treadmill training, the body mass and composition, blood pressure, glucose and lipid metabolism, RAS axes, insulin signaling, and inflammatory pathway were performed. HEV slowed the body mass gain, reduced intra-abdominal fat pad and leptin levels, improved total and peripheral body composition and inflammatory cytokine, reduced angiotensin II type 1 receptor expression, and increased Mas receptor protein expression compared with the HF animals. Sedentary groups (SC and HF) presented lower time to exhaustion and maximal velocity compared with the LEV and HEV groups. Both exercise training groups showed reduced resting systolic blood pressure and heart rate, improved glucose tolerance, IR, insulin signaling, and lipid profile. We conclude that the HEV, but not LEV, shifted the balance of RAS toward the ACE2/Mas receptor axis in skeletal muscle, presenting protective effects against the DIO model.

Exercise training modulates the hepatic renin-angiotensin system in fructose-fed rats.

NEW FINDINGS: What is the central question of this study? What are the effects of exercise training on the hepatic renin-angiotensin system and their contribution to damage resulting from fructose overload in rats? What is the main finding and its importance? Exercise training attenuated the deleterious actions of the angiotensin-converting enzyme/angiotensin II/angiotensin II type 1 receptor axis and increased expression of the counter-regulatory (angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor) axis in the liver. Therefore, our study provides evidence that exercise training modulates the hepatic renin-angiotensin system, which contributes to reducing the progression of metabolic dysfunction and non-alcoholic fatty liver disease in fructose-fed rats. The renin-angiotensin system (RAS) has been implicated in the development of metabolic syndrome. We investigated whether the hepatic RAS is modulated by exercise training and whether this modulation improves the deleterious effects of fructose overload in rats. Male Wistar rats were divided into (n = 8 each) control (CT), exercise control (CT-Ex), high-fructose (HFr) and exercise high-fructose (HFr-Ex) groups. Fructose-drinking rats received d-fructose (100 g l-1 ). After 2 weeks, CT-Ex and HFr-Ex rats were assigned to a treadmill training protocol at moderate intensity for 8 weeks (60 min day-1 , 4 days per week). We assessed body mass, glucose and lipid metabolism, hepatic histopathology, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity, the angiotensin concentration and the expression profile of proteins affecting the hepatic RAS, gluconeogenesis and inflammation. Neither fructose overload nor exercise training influenced body mass gain and serum ACE and ACE2 activity. The HFr group showed hyperinsulinaemia, but exercise training normalized this parameter. Exercise training was effective in preventing hepatic steatosis and in preventing triacylglycerol and glycogen accumulation. Furthermore, exercise improved the response to the deleterious effects of HFr overload by normalizing the gluconeogenesis pathway and the protein levels of interleukin-6 and tumour necrosis factor-α. The HFr rats displayed increased hepatic ACE activity and protein expression and angiotensin II concentration, which were attenuated by exercise training. Exercise training restored the ACE2/angiotensin-(1-7)/Mas receptor axis. Exercise training may favour the counter-regulatory ACE2/angiotensin-(1-7)/Mas receptor axis over the classical RAS (ACE/angiotensin II/angiotensin II type 1 receptor axis), which could be responsible for the reduction of metabolic dysfunction and the prevention of non-alcoholic fatty liver disease.

Beneficial effects of Renin-Angiotensin system blockers on testicular steroidogenesis.

PURPOSE: We evaluated whether antihypertensive drugs that act through the renin-angiotensin system would affect testis function. MATERIALS AND METHODS: Ten mice were fed standard chow and 40 received a high energy density diet. At 8 weeks the high energy density diet mice were divided into 4 groups of 10 each. The untreated group received the high energy density diet alone. The 3 treated groups received that diet plus aliskiren (50 mg/kg daily), enalapril (30 mg/kg daily) and losartan (10 mg/kg daily), respectively, for the next 6 weeks. Blood pressure was measured twice monthly. At the end of the treatment period all mice were sacrificed. One-way ANOVA and the Holm-Sidak post hoc test were used to analyze results. RESULTS: The high energy density diet led to a significant increase in blood pressure (p <0.05). All treatments resulted in normalized blood pressure. In regard to reproductive function, and serum testosterone and estradiol the gene and protein expression of StAR, aromatase and luteinizing hormone receptor, and the protein expression of angiotensin-converting enzyme, renin and angiotensin type 1 receptor blocker were significantly decreased by the high energy density diet. Of the treatments only enalapril reverted the changes. Also, angiotensin-converting enzyme, angiotensin type 1 receptor blocker and renin protein expression were lower in all high energy density diet groups except the group that received enalapril. CONCLUSIONS: Only angiotensin-converting enzyme inhibitor reverted the hormonal and testis alterations caused by the high energy density diet. This suggests that enalapril should be the drug of choice for a patient who presents with previous reproductive dysfunction.

Comparative effects of the renin-angiotensin system blockers on nonalcoholic fatty liver disease and insulin resistance in C57BL/6 mice.

BACKGROUND: The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. The current study evaluated the effects of RAS blockers in a model of diet-induced insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). METHODS: Male C57BL/6 mice were fed a standard chow (SC; 10% lipids, n=15) diet or a high-fat (HF; 50% lipids, n=60) diet for 8 weeks and then treated with aliskiren (HF-A; 50 mg/kg per day, n=15), enalapril (HF-E; 30 mg/kg per day, n=15), or losartan (HF-L; 10 mg/kg per day, n=15) for an additional 6 weeks. We assessed glucose and lipid metabolism, hepatic histopathology, the expression profile of genes and proteins affecting hepatic gluconeogenesis, RAS and insulin signaling, and lipid beta-oxidation and accumulation. The differences between the groups were tested via analysis of variance (ANOVA) and the post hoc Holm-Sidak test. RESULTS: All treatments restored the up-regulation of hepatic RAS. The enalapril treatment, but not aliskiren or losartan, was effective in improving leptin, glucose intolerance, IR, hepatic steatosis, and triglycerides and in preventing increased hepatic protein levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and glucose transporter-2 (GLUT-2). Furthermore, enalapril improved the response to the deleterious effects of the HF diet by upregulating signal transduction through the insulin receptor substrate (IRS) 1/protein kinase B (Akt) pathway, as well as downregulating the protein levels and mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1c (SREBP-1c), and fatty acid synthase (FAS). CONCLUSIONS: Enalapril was the most successful treatment in protecting against hepatic IR and NAFLD by enhancing hepatic insulin action, leptin, and gluconeogenesis and by reducing the lipogenic pathway and lipid accumulation in the liver.