A 2-week treatment with 5-azacytidine improved the hypercontractility state in prostate from obese mice: Role of the nitric oxide-cyclic guanosine monophosphate signalling pathway.

Benign prostatic hyperplasia (BPH) is characterised by increases in prostate volume and contraction. Downregulation of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling pathway contributes to prostate dysfunctions. Previous studies in cancer cells or vessels have shown that the epigenetic mechanisms control the gene and protein expression of the enzymes involved in the production of NO and cGMP. This study is aimed to evaluate the effect of a 2-week treatment of 5-azacytidine (5-AZA), a DNA-methyltransferase inhibitor, in the prostate function of mice fed with a high-fat diet. Functional, histological, biochemical and molecular assays were carried out. Obese mice presented greater prostate weight, α-actin expression and contractile response induced by the α-1adrenoceptors agonist. The relaxation induced by the NO-donor and the protein expression of endothelial nitric oxide synthase (eNOS) and soluble guanylate cyclase (sGC) were significantly decreased in the prostate of obese mice. The treatment with 5-AZA reverted the higher expression of α-actin, reduced the hypercontractility state of the prostate and increased the expression of eNOS and sGC and intraprostatic levels of cGMP. When prostates from obese mice treated with 5-AZA were incubated in vitro with inhibitors of the NOS or sGC, the inhibitory effect of 5-AZA was reverted, therefore, showing the involvement of NO and cGMP. In conclusion, our study paves the way to develop or repurpose therapies that recover the expression of eNOS and sGC and, hence, to improve prostate function in BPH.

Evidence that methylglyoxal and receptor for advanced glycation end products are implicated in bladder dysfunction of obese diabetic ob/ob mice.

Glycolytic overload in diabetes causes large accumulation of the highly reactive dicarbonyl compound methylglyoxal (MGO) and overproduction of advanced glycation end products (AGEs), which interact with their receptors (RAGE), leading to diabetes-associated macrovascular complications. The bladder is an organ that stays most in contact with dicarbonyl species, but little is known about the importance of the MGO-AGEs-RAGE pathway to diabetes-associated bladder dysfunction. Here, we aimed to investigate the role of the MGO-AGEs-RAGE pathway in bladder dysfunction of diabetic male and female ob/ob mice compared with wild-type (WT) lean mice. Diabetic ob/ob mice were treated with the AGE breaker alagebrium (ALT-711, 1 mg/kg) for 8 wk in drinking water. Compared with WT animals, male and female ob/ob mice showed marked hyperglycemia and insulin resistance, whereas fluid intake remained unaltered. Levels of total AGEs, MGO-derived hydroimidazolone 1, and RAGE in bladder tissues, as well as fluorescent AGEs in serum, were significantly elevated in ob/ob mice of either sex. Collagen content was also markedly elevated in the bladders of ob/ob mice. Void spot assays in filter paper in conscious mice revealed significant increases in total void volume and volume per void in ob/ob mice with no alterations of spot number. Treatment with ALT-711 significantly reduced the levels of MGO, AGEs, RAGE, and collagen content in ob/ob mice. In addition, ALT-711 treatment normalized the volume per void and increased the number of spots in ob/ob mice. Activation of AGEs-RAGE pathways by MGO in the bladder wall may contribute to the pathogenesis of diabetes-associated bladder dysfunction.NEW & NOTEWORTHY The involvement of methylglyoxal (MGO) and advanced glycation end products (AGEs) in bladder dysfunction of diabetic ob/ob mice treated with the AGE breaker ALT-711 was investigated here. Diabetic mice exhibited high levels of MGO, AGEs, receptor for AGEs (RAGE), and collagen in serum and/or bladder tissues along with increased volume per void, all of which were reduced by ALT-711. Activation of the MGO-AGEs-RAGE pathway in the bladder wall contributes to the pathogenesis of diabetes-associated bladder dysfunction.

Periprostatic adipose tissue (PPAT) supernatant from obese mice releases anticontractile substances and increases human prostate epithelial cell proliferation: the role of nitric oxide and adenosine.

Background: The prostate gland is surrounded by periprostatic adipose tissue (PPAT) that can release mediators that interfere in prostate function. In this study, we examined the effect of periprostatic adipose tissue supernatant obtained from obese mice on prostate reactivity in vitro and on the viability of human prostatic epithelial cell lines. Methods: Male C57BL/6 mice were fed a standard or high-fat diet after which PPAT was isolated, incubated in Krebs-Henseleit solution for 30 min (without prostate) or 60 min (with prostate), and the supernatant was then collected and screened for biological activity. Total nitrate and nitrite (NOx-) and adenosine were quantified, and the supernatant was then collected and screened for biological activity. NOx- and adenosine were quantified. Concentration-response curves to phenylephrine (PE) were obtained in prostatic tissue from lean and obese mice incubated with or without periprostatic adipose tissue. In some experiments, periprostatic adipose tissue was co-incubated with inhibitors of the nitric oxide (NO)-cyclic guanosine monophosphate pathway (L-NAME, 1400W, ODQ), adenylate cyclase (SQ22536) or with adenosine A2A (ZM241385), and A2B (MRS1754) receptor antagonists. PNT1-A (normal) and BPH-1 (hyperplasic) human epithelial cells were cultured and incubated with supernatant from periprostatic adipose tissue for 24, 48, or 72 h in the absence or presence of these inhibitors/antagonists, after which cell viability and proliferation were assessed. Results: The levels of NOx- and adenosine were significantly higher in the periprostatic adipose tissue supernatant (30 min, without prostate) when compared to the vehicle. A trend toward an increase in the levels of NOX was observed after 60 min. PPAT supernatant from obese mice significantly reduced the PE-induced contractions only in prostate from obese mice. The co-incubation of periprostatic adipose tissue with L-NAME, 1400W, ODQ, or ZM241385 attenuated the anticontractile activity of the periprostatic adipose tissue supernatant. Incubation with the supernatant of periprostatic adipose tissue from obese mice significantly increased the viability of PNT1-A cells and attenuated expression of the apoptosis marker protein caspase-3 when compared to cells incubated with periprostatic adipose tissue from lean mice. Hyperplastic cells (BPH-1) incubated with periprostatic adipose tissue from obese mice showed greater proliferation after 24 h, 48 h, and 72 h compared to cells incubated with culture medium alone. BPH-1 cell proliferation in the presence of PPAT supernatant was attenuated by NO-signaling pathway inhibitors and by adenosine receptor antagonists after 72 h. Conclusion: NO and adenosine are involved in the anticontractile and pro-proliferative activities of periprostatic adipose tissue supernatant from obese mice. More studies are needed to determine whether the blockade of NO and/or adenosine derived from periprostatic adipose tissue can improve prostate function.

Physical activity influences heart rate variability in young adults, regardless of dextrose ingestion.

INTRODUCTION: Cardiac autonomic modulation can be altered by carbohydrate ingestion. On the other hand, some of the protective effects of physical activity may be due to its impact on the autonomic nervous system. PURPOSE: This cross-sectional study was conducted to evaluate whether physical activity level influences heart rate variability (HRV) under fasting and mainly, after dextrose ingestion. METHODS: Healthy adults aged 18-40 years ( n = 92; 54.35 % women) were separated into nonactive ( n = 47) and active groups ( n = 45), based on the physical activity level determined by International Physical Activity Questionnaire (IPAQ) and then compared. RESULTS: There were no significant differences ( P > 0.05) for age, body mass, BMI, abdominal circumference, blood pressure, fasting glucose and blood glucose at 60 min after dextrose ingestion between groups. Body fat (%) was lower in the active group ( P = 0.02). The time-domain indices (RMSSD, SDNN and pNN50) were higher in the physically active group compared to the nonactive group (main effect of group, P < 0.01). The SDNN index was higher at 60 min after dextrose ingestion compared to fasting (main effect of time, P ≤ 0.01). However, no HRV indices showed significantly interaction effect (group x time; P > 0.05). CONCLUSION: The magnitude of HRV responses to glucose was not influenced by physical activity status. Young adults who met at least the minimum physical activity recommendations showed a higher cardiac autonomic modulation, regardless of dextrose ingestion.

The Role of Periprostatic Adipose Tissue on Prostate Function in Vascular-Related Disorders.

The lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) are highly prevalent worldwide. Clinical and experimental data suggest that the incidence of LUTS-BPH is higher in patients with vascular-related disorders such as in pelvic ischemia, obesity and diabetes as well as in the ageing population. Obesity is an important risk factor that predisposes to glucose intolerance, insulin resistance, dyslipidemia, type 2 diabetes mellitus and cardiovascular disorders. Prospective studies showed that obese men are more likely to develop LUTS-BPH than non-obese men. Yet, men with greater waist circumferences were also at a greater risk of increased prostate volume and prostate-specific antigen than men with lower waist circumference. BPH is characterized by an enlarged prostate and increased smooth muscle tone, thus causing urinary symptoms. Data from experimental studies showed a significant increase in prostate and epididymal adipose tissue weight of obese mice when compared with lean mice. Adipose tissues that are in direct contact with specific organs have gained attention due to their potential paracrine role. The prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is believed to play a paracrine role by releasing growth factors, pro-inflammatory, pro-oxidant, contractile and anti-contractile substances that interfere in prostate reactivity and growth. Therefore, this review is divided into two main parts, one focusing on the role of adipokines in the context of obesity that can lead to LUTS/BPH and the second part focusing on the mediators released from PPAT and the possible pathways that may interfere in the prostate microenvironment.

Higher blood glucose impairs cardiac autonomic modulation in fasting and after carbohydrate overload in adults.

This study aimed to assess whether the blood glucose levels influence cardiac autonomic modulation under fasting and after carbohydrate overload conditions. Participants (n = 108) were separated into lower blood glucose and higher blood glucose groups, based on the median (90.5 mg·dL-1) of fasting glucose assessed. The SD2, SDNN, LF indices, and LF/HF increased, and HF decreased after dextrose overload compared with fasting (p < 0.05). Body mass (78.9 vs 69.7 kg), abdominal circumference (90.2 vs 82.2 cm), systolic (113 vs 108 mm Hg) and diastolic (72 vs 67 mm Hg) blood pressure were higher (p < 0.05) in the higher blood glucose group. Heart rate variability (HRV) indices (SD1: 21.0 vs 26.5; SD2: 76.8: vs 86.1; RMSSD: 28.7 vs 37.5; SDNN: 56.1 vs 62.5 ms; pNN50: 10.6 vs 18.9%, HF: 328.4 vs 506.0; LF: 982.8 vs 1259.0 ms2), and the area under the curve of these indices after dextrose overload were lower in the higher blood glucose group (p < 0.05). Additionally, glycemia after dextrose overload was correlated with HRV indices (ρ = -0.216 to -0.273, p < 0.05). Individuals with higher blood glucose, even in the normality range, showed impairment in the cardiac autonomic modulation both at fasting and after carbohydrate overload. Novelty: Higher fasting blood glucose impairs cardiac autonomic modulation. Carbohydrate overload impairs cardiac autonomic modulation.

Physical training prevent and treat hepatic lipid accumulation induced by fructose-rich diet / Treinamento físico previne e trata acumulação lipídica hepática induzida por dieta rica em frutose

This study aims to examine the effects of physical training performed in early (preventive) or late (therapeutic) protocols on body weight gain, glucose tolerance, and triglycerides accumulation in rats fed on a fructoserich diet. Wistar rats were allocated into two major groups according to the diet received: Control (C- standard diet) and Fructose (F- diet containing 60% fructose) fed during 120 days. Next, these two groups were distributed into six groups: C and F that were kept inactive; CTE (Control Trained Early) and FTE (Fructose Trained Early) that were submitted to Anaerobic Threshold (AnT) training from 28 to 120 days; CTL (Control Trained Late) and FTL (Fructose Trained Late) trained from 90 to 120 days. Physical Training was composed by swimming (5 days/week) at AnT determined by maximum lactate stead state (MLSS). The Oral Glucose Tolerance Test (oGTT) was performed 48h after the last in vivo analysis and did not showed differences between the groups. After, the animals were euthanized for heart, liver, and adipose tissue extraction. The early exercised animals had lower body weight compared to their sedentary littermates. Also, the fructose-rich diet increased liver lipids content in the sedentary animals and physical training successfully reduced this parameter in both major groups. These results suggests that physical training at the AnT performed in early or late protocols are effective to prevent and treat metabolic disorders related to fructose intake.

Este estudo tem como objetivo examinar os efeitos do treinamento físico realizado em protocolos precoce (preventivo) ou tardio (terapêutico) sobre o ganho de massa corporal, tolerância à glicose e acúmulo de triglicerídeos em ratos alimentados com dieta rica em frutose. Ratos Wistar foram alocados em dois grupos principais de acordo com a dieta recebida: Controle (C, dieta padrão) e Frutose (F, dieta contendo 60% de frutose) durante 120 dias. Em seguida, esses dois grupos foram distribuídos em seis grupos: C e F que foram mantidos inativos; CET (Controle Treinado Precoce) e FTE (Frutose Treinado Precoce) que foram submetidos ao treinamento no Limiar Anaeróbio (AnT) de 28 a 120 dias; CTL (controle treinado tardio) e FTL (frutose treinado tardio) treinados de 90 a 120 dias. O treinamento físico foi composto por natação (5 dias / semana) na AnT determinado pela Máxima Fase Estável de Lactato (MLSS). O Teste Oral de Tolerância à Glicose (oGTT) foi realizado 48 horas após a última análise in vivo e não mostrou diferenças entre os grupos. Depois, os animais foram eutanasiados para extração do coração, fígado e tecido adiposo. Os animais exercitados precocemente apresentaram menor massa corporal em comparação com os sedentários. Além disso, a dieta rica em frutose aumentou o conteúdo de lipídios do fígado nos animais sedentários e o treinamento físico reduziu com sucesso este parâmetro em ambos os grupos principais. Estes resultados sugerem que o treinamento físico no AnT realizado em protocolos precoce ou tardio são eficazes para prevenir e tratar distúrbios metabólicos relacionados à ingestão de frutose.

Hypothalamic S1P/S1PR1 axis controls energy homeostasis in Middle-Aged Rodents: the reversal effects of physical exercise.

Recently, we demonstrated that the hypothalamic S1PR1/STAT3 axis plays a critical role in the control of food consumption and energy expenditure in rodents. Here, we found that reduction of hypothalamic S1PR1 expression occurs in an age-dependent manner, and was associated with defective thermogenic signaling and weight gain. To address the physiological relevance of these findings, we investigated the effects of chronic and acute exercise on the hypothalamic S1PR1/STAT3 axis. Chronic exercise increased S1PR1 expression and STAT3 phosphorylation in the hypothalamus, restoring the anorexigenic and thermogenic signals in middle-aged mice. Acutely, exercise increased sphingosine-1-phosphate (S1P) levels in the cerebrospinal fluid (CSF) of young rats, whereas the administration of CSF from exercised young rats into the hypothalamus of middle-aged rats at rest was sufficient to reduce the food intake. Finally, the intracerebroventricular (ICV) administration of S1PR1 activators, including the bioactive lipid molecule S1P, and pharmacological S1PR1 activator, SEW2871, induced a potent STAT3 phosphorylation and anorexigenic response in middle-aged rats. Overall, these results suggest that hypothalamic S1PR1 is important for the maintenance of energy balance and provide new insights into the mechanism by which exercise controls the anorexigenic and thermogenic signals in the central nervous system during the aging process.

Fructose-rich diet leads to reduced aerobic capacity and to liver injury in rats.

The main purpose of this research was to investigate the alterations in the aerobic capacity and appearance of metabolic alterations in Wistar rats fed on fructose-rich diet. We separated twenty-eight rats into two groups according to diet: a control group (C) (balanced diet) and a fructose-rich diet group (F). The animals were fed these diets for 60 d (d 120 to 180). We performed insulin, glucose as well as a minimum lactate test, at d 120 and 180. At the end of the experiment, sixteen animals were euthanized, and the following main variables were analysed: aerobic capacity, the serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, serum and liver triglyceride concentrations, serum and liver thiobarbituric acid reactive substance (TBARS) concentrations, serum and liver catalase and superoxide dismutase (SOD) activity and haematoxylin-eosin histology (HE) in hepatocytes. The remaining twelve animals were submitted to an analysis of their hepatic lipogenic rate. The animals fed a fructose-rich diet exhibited a reduction in aerobic capacity, glucose tolerance and insulin sensitivity and increased concentrations of triglycerides and TBARS in the liver. Catalase and SOD activities were reduced in the livers of the fructose-fed animals. In addition, the serum AST/ALT ratio was higher than that of the C group, which indicates hepatic damage, and the damage was confirmed by histology. In conclusion, the fructose-rich diet caused significant liver damage and a reduction in insulin sensitivity in the animals, which could lead to deleterious metabolic effects.

Metabolic syndrome markers in wistar rats of different ages.

In recent decades, metabolic syndrome has become a public health problem throughout the world. Longitudinal studies in humans have several limitations due to the invasive nature of certain analyses and the size and randomness of the study populations. Thus, animal models that are able to mimic human physiological responses could aid in investigating metabolic disease. Thus, the present study was designed to analyze metabolic syndrome markers in albino Wistar rats (Rattus norvegicus) of different ages. The following parameters were assessed at two (young), four ( adult), six (adult), and twelve (mature) months of age: glucose tolerance (glucose tolerance test); insulin sensitivity (insulin tolerance test); fasting serum glucose, triglycerides, total cholesterol, HDL cholestero, and LDL cholesterol concentrations; glucose uptake in isolated soleus muscle; and total lipid concentration in subcutaneous, mesenteric, and retroperitoneal adipose tissue. We found that aging triggered signs of metabolic syndrome in Wistar rats. For example, mature rats showed a significant increase in body weight that was associated. In addition, mature rats showed an increase in the serum concentration of triglycerides, total cholesterol, and LDL cholesterol, which is characteristic of dyslipidemia. There was also an increase in serum glucose compared with the younger groups of animals. Therefore, aging Wistar rats appear to be an interesting model to study the changes related to metabolic syndrome.

Exercise and spirulina control non-alcoholic hepatic steatosis and lipid profile in diabetic Wistar rats.

BACKGROUND: Diabetes mellitus is associated with metabolic dysfunctions, including alterations in circulating lipid levels and fat tissue accumulation, which causes, among other pathologies, non-alcoholic fatty liver disease (NAFLD). AIM OF THE STUDY: The objective of this study was to analyse the effects of physical exercise and spirulina intake on the control of NAFLD in diabetic Wistar rats. METHODS: Diabetes was induced in the animals through intravenous administration of alloxan. The rats were divided into four groups: Diabetic Control (DC) - diabetic rats fed with a control diet and no physical exercise; Diabetic Spirulina (DS) - diabetic rats fed with a diet that included spirulina; Diabetic Spirulina and Exercise (DSE) - diabetic rats fed with a diet that included Spirulina and that exercised; and Diabetic Exercise (DE) - diabetic rats fed with a control diet and that exercised. RESULTS: The groups DS, DSE, and DE presented lower plasma concentrations of LDL cholesterol than DC, as well as lower levels of total liver lipids in groups DS, DSE, and DE in comparison to DC. CONCLUSION: Thus, spirulina appears to be effective in reducing total circulating levels of LDL-cholesterol and hepatic lipids, alone or in conjunction with physical exercise in diabetic rats.