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Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats.

Renin-angiotensin system is involved in homeostasis processes linked to renal and cardiovascular system and recently has been linked to metabolic syndrome. We analyzed the influence of long term angiotensin I converting enzyme (ACE) inhibitor enalapril treatment in normotensive adult Wistar rats fed with standard or palatable hyperlipidic diets. Our results show that long term enalapril treatment decreases absolute food intake, serum leptin concentration and body weight gain. Moreover, in adipose tissue, enalapril treatment led to decreased ACE activity, enhanced the expression of peroxisome proliferator activated receptor gamma, adiponectin, hormone-sensitive lipase, fatty acid synthase, catalase and superoxide dismutase resulting in prolonged life span. On the other hand, the ACE inhibitor was not able to improve the transport of leptin through the blood brain barrier or to alter the sensitivity of this hormone in the central nervous system. The effect of enalapril in decreasing body weight gain was also observed in older rats. In summary, these results extend our previous findings and corroborate data from the literature regarding the beneficial metabolic effects of enalapril and show for the first time that this ACE inhibitor prolongs life span in rats also fed with palatable hyperlipidic diet, an action probably correlated with adipose tissue metabolic modulation and body weight reduction.

Consequences of subchronic and chronic exposure to intermittent hypoxia and sleep deprivation on cardiovascular risk factors in rats

Since studies suggest that both hypoxia and sleep fragmentation are related to cardiovascular alterations induced by obstructive sleep apnea, the present study was designed to evaluate the effects of hypoxia, sleep deprivation, and their combination on biochemical blood parameters in rats. In subchronic experiments (4 days), rats were exposed to intermittent hypoxia (IH) during the light period (2min room air-2min 10% O(2) for 12h/day) and/or paradoxical sleep deprivation (PSD, 24h/day). Consequences of chronic intermittent hypoxia (CIH) exposure were examined after 21 consecutive days of hypoxia protocol from 10:00 to 16:00 followed by a sleep restriction (SR) period of 18h (16:00-10:00). Rats were randomly assigned to seven treatment groups: (1) control (2) IH (3) PSD (4) IH-PSD (5) SR (6) CIH and (7) CIH-SR. PSD reduced triglycerides and very low-density lipoprotein (VLDL) cholesterol concentrations and increased total cholesterol and high-density lipoprotein (HDL) cholesterol. IH did not alter any of these parameters. The combination of IH-PSD did not modify the values of total cholesterol and HDL compared to control group. In the chronic experiment, the animals exposed to CIH displayed a reduction of Vitamin B(6) and an increase of triglycerides and VLDL. Our findings show a duration-dependent effect of hypoxia on triglycerides. Rats in the SR and CIH-SR groups showed a diminished concentration of triglycerides and VLDL. SR rats showed a reduction in the concentration of homocysteine but the animals in the CIH-SR treatment condition did not display any alterations in this parameter. In this latter group, an augmentation of cysteine concentration was observed. These results suggest that sleep deprivation and hypoxia modify biochemical blood parameters in distinct ways.

Diagnosing mucopolysaccharidosis IVA

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process.

Intermittent hypoxia and sleep restriction: motor, cognitive and neurochemical alterations in rats.

The present study evaluated the effects of intermittent hypoxia (IH) and sleep restriction (SR) upon motor and cognitive function in rats. Also evaluated were catecholamine concentrations and tyrosine hydroxylase (TH) protein expression in different regions of the forebrain. Wistar Hannover rats were submitted to IH for 4 days or 21 days (2 min room air to 2 min 10% O(2) for 10:00-16:00 h), followed by SR for 18 h (16:00-10:00 h). Rats were randomly assigned into four experimental groups: (1) control (2) IH (3) SR and (4) IH-SR. In the inhibitory avoidance task, an additional group of rats was submitted to paradoxical sleep deprivation (PSD) for 96 consecutive hours. Results showed that SR induced an increase in motor activity without modifying catecholaminergic turnover in the frontal cortex and striatum. The increase in exploratory activity in SR rats could be the result of impaired habituation. Neither SR periods induced cognitive deficits in the inhibitory avoidance task after 5 or 21 days. However, 96 h of PSD impaired acquisition/retention in rats. Exposure to IH did not affect motor and cognitive function but IH was associated with SR in increased motor activity. After 21 days, IH and IH-SR reduced striatal norepinephrine concentration although neither SR nor IH affected TH protein expression. The results presented here suggest that hypoxia and sleep loss exert distinct deleterious effects upon the central nervous system.

The beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling is impaired by anabolic androgenic steroids

Previous studies have shown that strength exercise improves memory and increases expression of a myriad of proteins involved on neuronal survival and synaptic plasticity in the hippocampus. Conversely, chronic exposure to supraphysiological levels of anabolic androgenic steroids (AAS) can induce psychiatric abnormalities, cognitive deficits, impair neurotransmission, alter the levels of neurotrophic factors, decrease cell proliferation and neurogenesis, and enhance neuronal cell death. In the present study, we investigated the effects of the AAS nandrolone decanoate (ND) administration during a strength exercise program on cell proliferation, apoptotic status and brain-derived neurotrophic factor (BDNF) expression in the rat hippocampus. Adult male Wistar rats were subjected to 4 weeks of progressive strength exercise in a vertical ladder apparatus with or without daily doses (5.0 mg/kg, SC) of ND. Immunohistochemistry analysis revealed that strength exercise increased significantly the number of Ki-67-positive cells (a cell proliferation marker) in dentate gyrus (DG) of hippocampus. However, this effect was abrogated when strength exercise was combined with ND. Although western blot analysis of whole hippocampus showed no significant differences in Bax and Bcl-2 protein expression among groups, the immunoreactivity of the pro-apoptotic protein Bax was significantly increased in DG, CA1 and CA3 hippocampal subfields of sedentary rats treated with ND. Moreover, the increase in the immunoreactivity of anti-apoptotic protein Bcl-2 (DG and CA3) induced by strength exercise was diminished by ND. There were no significant differences in BDNF expression among experimental groups. Therefore, the present findings suggest that the beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling are impaired by ND.

Metabolic syndrome and associated factors in children and adolescents of a Brazilian municipality.

BACKGROUND the risk factors associated to metabolic syndrome (MS) have been extensively studied in adults, but in children and adolescents it is poorly explored. OBJECTIVE To identify the prevalence of MS and associated factors in children and adolescents. METHODS A cross-sectional study with 540 children and adolescents from 7 to 14 years of age. The socioeconomic, demographic and lifestyle data and the family history of chronic diseases were reported by the individual and/or guardian and recorded in a structured questionnaire. Biochemical tests (fasting blood glucose, triacylglycerols, reduced high-density lipoprotein, very-low-density lipoprotein, homocysteine and cysteine), an anthropometric assessment and a blood pressure measurement were performed. MS was defined according to the criteria of The National Cholesterol Education Program Adult Treatment Panel III adapted by Ferranti. A Poisson regression was used to identify the factors statistically associated with MS. RESULTS The MS prevalence was 12.8%, in which the most frequent component was a decreased high-density lipoprotein level (58.2%), followed by hypertriglyceridemia (41.8%), elevated blood pressure (29.1%), increased waist circumference (26.7%) and hyperglycemia (7.2%). Associations between metabolic syndrome and overweight [prevalence ratio (PR): 2.2 (1.22-3.95)], father education [PR: 2.19 (1.10-4.37)], serum very low-density lipoprotein concentration [PR: 1.08 (1.04-1.11)] and concomitantly increased serum homocysteine and cysteine concentrations [PR: 2.58 (1.32-5.04)] were observed. CONCLUSIONS The MS prevalence is high in children and adolescents and it is increased in patients with overweight, higher father education, increased serum very-low-density lipoprotein concentrations and a concomitant serum homocysteine and cysteine high levels.

Kinin B1 Receptor in Adipocytes Regulates Glucose Tolerance and Predisposition to Obesity

Background Kinins participate in the pathophysiology of obesity and type 2 diabetes by mechanisms which are not fully understood. Kinin B1 receptor knockout mice (B1 −/−) are leaner and exhibit improved insulin sensitivity. Methodology/Principal Findings Here we show that kinin B1 receptors in adipocytes play a role in controlling whole body insulin action and glucose homeostasis. Adipocytes isolated from mouse white adipose tissue (WAT) constitutively express kinin B1 receptors. In these cells, treatment with the B1 receptor agonist des-Arg9-bradykinin improved insulin signaling, GLUT4 translocation, and glucose uptake. Adipocytes from B1 −/− mice showed reduced GLUT4 expression and impaired glucose uptake at both basal and insulin-stimulated states. To investigate the consequences of these phenomena to whole body metabolism, we generated mice where the expression of the kinin B1 receptor was limited to cells of the adipose tissue (aP2-B1/B1 −/−). Similarly to B1 −/− mice, aP2-B1/B1 −/− mice were leaner than wild type controls. However, exclusive expression of the kinin B1 receptor in adipose tissue completely rescued the improved systemic insulin sensitivity phenotype of B1 −/− mice. Adipose tissue gene expression analysis also revealed that genes involved in insulin signaling were significantly affected by the presence of the kinin B1 receptor in adipose tissue. In agreement, GLUT4 expression and glucose uptake were increased in fat tissue of aP2-B1/B1 −/− when compared to B1 −/− mice. When subjected to high fat diet, aP2-B1/B1 −/− mice gained more weight than B1 −/− littermates, becoming as obese as the wild types. Conclusions/Significance Thus, kinin B1 receptor participates in the modulation of insulin action in adipocytes, contributing to systemic insulin sensitivity and predisposition to obesity.

MCH levels in the CSF, brain preproMCH and MCHR1 gene expression during paradoxical sleep deprivation, sleep rebound and chronic sleep restriction.

Neurons that utilize melanin-concentrating hormone (MCH) as neuromodulator are located in the lateral hypothalamus and incerto-hypothalamic area. These neurons project throughout the central nervous system and play a role in sleep regulation. With the hypothesis that the MCHergic system function would be modified by the time of the day as well as by disruptions of the sleep-wake cycle, we quantified in rats the concentration of MCH in the cerebrospinal fluid (CSF), the expression of the MCH precursor (Pmch) gene in the hypothalamus, and the expression of the MCH receptor 1 (Mchr1) gene in the frontal cortex and hippocampus. These analyses were performed during paradoxical sleep deprivation (by a modified multiple platform technique), paradoxical sleep rebound and chronic sleep restriction, both at the end of the active (dark) phase (lights were turned on at Zeitgeber time zero, ZT0) and during the inactive (light) phase (ZT8). We observed that in control condition (waking and sleep ad libitum), Mchr1 gene expression was larger at ZT8 (when sleep predominates) than at ZT0, both in frontal cortex and hippocampus. In addition, compared to control, disturbances of the sleep-wake cycle produced the following effects: paradoxical sleep deprivation for 96 and 120 h reduced the expression of Mchr1 gene in frontal cortex at ZT0. Sleep rebound that followed 96 h of paradoxical sleep deprivation increased the MCH concentration in the CSF also at ZT0. Twenty-one days of sleep restriction produced a significant increment in MCH CSF levels at ZT8. Finally, sleep disruptions unveiled day/night differences in MCH CSF levels and in Pmch gene expression that were not observed in control (undisturbed) conditions. In conclusion, the time of the day and sleep disruptions produced subtle modifications in the physiology of the MCHergic system.

Central and systemic responses to methionine-induced hyperhomocysteinemia in mice.

Hyperhomocysteinemia has been considered a risk factor for neuropsychiatric disorders, but the mechanisms involved in this process have not been completely elucidated. The aim of this study was to analyze the influence of hyperhomocysteinemia induction by methionine supplementation considering different levels and periods of exposure in mice. For this purpose, methionine supplementation at concentrations of 0.5 and 1% were administered in water to increase homocysteinemia in male C57BL/6 mice, and was maintained for 3 time periods (2, 4 and 6 months of treatment). The results from one-carbon metabolism parameters, brain-derived neurotrophic factor (BDNF) concentrations and behavioral evaluation were compared. The 0.5% supplementation was efficient in increasing plasma homocysteine levels after 2 and 6 months. The 1% supplementation, increased plasma homocysteine after 2, 4 and 6 months. Little influence was observed in cysteine and glutathione concentrations. Frontal cortex BDNF levels showed a lack of treatment influence in all periods; only the expected decrease due to increasing age was observed. Moreover, the only behavioral alteration observed using a novel object recognition task was that which was expected with increasing age. We found that responses to hyperhomocysteinemia varied based on how it was reached, and the length of toxicity. Moreover, hyperhomocysteinemia can affect the normal pattern of one carbon metabolism during age increase in mice. These findings allow the establishment of a reliable animal model for studies in this field.

SKF 38393 reverses cocaine-conditioned place preference in mice.

Cocaine is a psychotropic drug with a high potential for abuse due to its euphoric effects. Efforts to develop medications for the treatment of cocaine dependence have not been clinically successful. Some studies using animal models have shown positive effects of dopaminergic agents such as partial agonists of the dopamine D1 receptor. Thus, this study aimed to examine the effect of the dopamine D1 receptor partial agonist SKF 38393 on cocaine craving. Adult male C57BL/6J mice were injected with cocaine for 10 days in a conditioned place preference apparatus using a biased procedure and subsequently treated for three consecutive days with SKF 38393. The results showed that SKF 38393 was able to block the preference of cocaine-conditioned animals for the compartment paired with the drug without showing effects on locomotor activity. The results of this study suggest that partial activation of D1 dopamine receptors may be necessary for the development of pharmacotherapies for cocaine addiction.