Scielo RSS <![CDATA[Brazilian Journal of Medical and Biological Research]]> vol. 50 num. 12 lang. pt <![CDATA[SciELO Logo]]> <![CDATA[Physical exercise-induced fatigue: the role of serotonergic and dopaminergic systems]]> Brain serotonin and dopamine are neurotransmitters related to fatigue, a feeling that leads to reduced intensity or interruption of physical exercises, thereby regulating performance. The present review aims to present advances on the understanding of fatigue, which has recently been proposed as a defense mechanism instead of a “physiological failure” in the context of prolonged (aerobic) exercises. We also present recent advances on the association between serotonin, dopamine and fatigue. Experiments with rodents, which allow direct manipulation of brain serotonin and dopamine during exercise, clearly indicate that increased serotoninergic activity reduces performance, while increased dopaminergic activity is associated with increased performance. Nevertheless, experiments with humans, particularly those involving nutritional supplementation or pharmacological manipulations, have yielded conflicting results on the relationship between serotonin, dopamine and fatigue. The only clear and reproducible effect observed in humans is increased performance in hot environments after treatment with inhibitors of dopamine reuptake. Because the serotonergic and dopaminergic systems interact with each other, the serotonin-to-dopamine ratio seems to be more relevant for determining fatigue than analyzing or manipulating only one of the two transmitters. Finally, physical training protocols induce neuroplasticity, thus modulating the action of these neurotransmitters in order to improve physical performance. <![CDATA[Propranolol inhibits the proliferation, migration and tube formation of hemangioma cells through HIF-1α dependent mechanisms]]> The aim of this study was to investigate the mechanism of propranolol on the regression of hemangiomas. Propranolol-treated hemangioma tissues were collected and the expression of hypoxia inducible factor-1α (HIF-1α) was examined. We also established HIF-1α overexpression and knockdown hemangioma cells, and determined the effects of HIF-1α on the hemangioma cells proliferation, apoptosis, migration and tube formation. Significantly increased HIF-1α level was found in the hemangioma tissues compared to that in normal vascular tissues, whereas propranolol treatment decreased the HIF-1α level in hemangioma tissues in a time- and dose-dependent manner. Moreover, propranolol treatment significantly decreased cell proliferation, migration and tube formation as well as promoted cell apoptosis in HIF-1α overexpression and knockdown hemangioma cells. Propranolol suppressed the cells proliferation, migration and tube formation of hemangioma cells through HIF-1α dependent mechanisms. HIF-1α could serve as a novel target in the treatment of hemangiomas. <![CDATA[Effects of vacuum sealing drainage on the treatment of cranial bone-exposed wounds in rabbits]]> This study was designed to assess the efficacy of vacuum sealing drainage (VSD) on skull exposure wounds in rabbits and to investigate the underlying mechanism of the process. Full-thickness excisional circular wounds 2×2 cm with or without periosteum involvement were created in 88 New Zealand white rabbits (mean body weight: 3.0±0.65 kg). Animals were randomly divided into 4 groups: periosteum-intact wounds treated with traditional dressing (p+control), periosteum-intact wounds treated with VSD (p+VSD), periosteum-lacking wounds treated with traditional dressing (p–control) and periosteum-lacking wounds treated with VSD (p–VSD). The wounds treated with traditional dressing were covered with Vaseline gauze, while VSD treatment was accompanied with continuous –120 mmHg pressure. Finally, wound tissues were harvested for analysis of hydroxyproline content and histologic detection. VSD hastened the wound healing process significantly (P&lt;0.05) compared to the corresponding control groups. VSD alleviated the inflammation reaction, accelerated re-epithelialization and facilitated the organization of collagen fibers into neat rows. During the wound healing process, the hydroxyproline content increased overtime [i.e., postoperative days (POD) 7, POD 10 and POD 15] in all four groups, and it peaked in the p+VSD group. VSD also promoted angiogenesis via increasing number and quality of collagen. We concluded that VSD can promote healing in bone-exposed wounds via increasing hydroxyproline content and vessel density, reducing inflammatory responses and generating ordered collagen arrangement. <![CDATA[A practical approach to assess leg muscle oxygenation during ramp-incremental cycle ergometry in heart failure]]> Heart failure is characterized by the inability of the cardiovascular system to maintain oxygen (O2) delivery (i.e., muscle blood flow in non-hypoxemic patients) to meet O2 demands. The resulting increase in fractional O2 extraction can be non-invasively tracked by deoxygenated hemoglobin concentration (deoxi-Hb) as measured by near-infrared spectroscopy (NIRS). We aimed to establish a simplified approach to extract deoxi-Hb-based indices of impaired muscle O2 delivery during rapidly-incrementing exercise in heart failure. We continuously probed the right vastus lateralis muscle with continuous-wave NIRS during a ramp-incremental cardiopulmonary exercise test in 10 patients (left ventricular ejection fraction &lt;35%) and 10 age-matched healthy males. Deoxi-Hb is reported as % of total response (onset to peak exercise) in relation to work rate. Patients showed lower maximum exercise capacity and O2 uptake-work rate than controls (P&lt;0.05). The deoxi-Hb response profile as a function of work rate was S-shaped in all subjects, i.e., it presented three distinct phases. Increased muscle deoxygenation in patients compared to controls was demonstrated by: i) a steeper mid-exercise deoxi-Hb-work rate slope (2.2±1.3 vs 1.0±0.3% peak/W, respectively; P&lt;0.05), and ii) late-exercise increase in deoxi-Hb, which contrasted with stable or decreasing deoxi-Hb in all controls. Steeper deoxi-Hb-work rate slope was associated with lower peak work rate in patients (r=–0.73; P=0.01). This simplified approach to deoxi-Hb interpretation might prove useful in clinical settings to quantify impairments in O2 delivery by NIRS during ramp-incremental exercise in individual heart failure patients. <![CDATA[Myostatin promotes distinct responses on protein metabolism of skeletal and cardiac muscle fibers of rodents]]> Myostatin is a novel negative regulator of skeletal muscle mass. Myostatin expression is also found in heart in a much less extent, but it can be upregulated in pathological conditions, such as heart failure. Myostatin may be involved in inhibiting protein synthesis and/or increasing protein degradation in skeletal and cardiac muscles. Herein, we used cell cultures and isolated muscles from rats to determine protein degradation and synthesis. Muscles incubated with myostatin exhibited an increase in proteolysis with an increase of Atrogin-1, MuRF1 and LC3 genes. Extensor digitorum longus muscles and C2C12 myotubes exhibited a reduction in protein turnover. Cardiomyocytes showed an increase in proteolysis by activating autophagy and the ubiquitin proteasome system, and a decrease in protein synthesis by decreasing P70S6K. The effect of myostatin on protein metabolism is related to fiber type composition, which may be associated to the extent of atrophy mediated effect of myostatin on muscle. <![CDATA[MicroRNA profiling identifies miR-7-5p and miR-26b-5p as differentially expressed in hypertensive patients with left ventricular hypertrophy]]> Recent evidence suggests that cell-derived circulating miRNAs may serve as biomarkers of cardiovascular diseases. However, a few studies have investigated the potential of circulating miRNAs as biomarkers for left ventricular hypertrophy (LVH). In this study, we aimed to characterize the miRNA profiles that could distinguish hypertensive patients with LHV, hypertensive patients without LVH and control subjects, and identify potential miRNAs as biomarkers of LVH. LVH was defined by left ventricular mass indexed to body surface area &gt;125 g/m2 in men and &gt;110 g/m2 in women and patients were classified as hypertensive when presenting a systolic blood pressure of 140 mmHg or more, or a diastolic blood pressure of 90 mmHg or more. We employed miRNA PCR array to screen serum miRNAs profiles of patients with LVH, essential hypertension and healthy subjects. We identified 75 differentially expressed miRNAs, including 49 upregulated miRNAs and 26 downregulated miRNAs between LVH and control patients. We chose 2 miRNAs with significant differences for further testing in 59 patients. RT-PCR analysis of serum samples confirmed that miR-7-5p and miR-26b-5p were upregulated in the serum of LVH hypertensive patients compared with healthy subjects. Our findings suggest that these miRNAs may play a role in the pathogenesis of hypertensive LVH and may represent novel biomarkers for this disease. <![CDATA[Effect of a rosmarinic acid supplemented hemodialysis fluid on inflammation of human vascular endothelial cells]]> Chronic systemic inflammation and repetitive damage of vascular endothelia by incompatible dialysis system are probable causes of cardiovascular disease in patients on dialysis. The present study aimed to assess in vitro biocompatibility and anti-inflammatory effect of hemodialysis fluid supplemented with rosmarinic acid (RA) using human umbilical vein endothelial cells (HUVEC). HUVECs (5×106 cells/mL) were pre-exposed to 1 μg/mL of lipopolysaccharides (LPS) and incubated with RA-supplemented hemodialysis fluid (HDF). Cytotoxicity was assessed qualitatively by morphologic assessment and quantitatively by MTT assay. Expressions of proinflammatory mediators were assessed using quantitative real-time PCR and production of NO was quantified. Phosphorylation of AKT and nuclear localization of nuclear factor kappa B (NF-κB) were examined using western blotting. Exposure of HUVECs to RA-supplemented HDF had no influence on morphology and viability. Inhibition of proinflammatory mediator production in HUVECs by RA supplementation to HDF was significant in a dose-dependent manner. Exposure to RA-supplemented HDF resulted in a decrease in nitric oxide synthase expression and reduction of NO production in LPS-stimulated HUVECs. RA supplementation of HDF suppressed Akt activation in LPS-stimulated HUVECs. In addition, the level of cellular IκB was increased in parallel to a reduced nuclear translocation of NF-κB in LPS-induced endothelial cells. Our results suggest that RA-supplemented HDF is biocompatible and significantly suppressed inflammation induced in endothelial cells. In this respect, the use of HDF supplemented with RA could alleviate inflammation and improve long-term treatment of patients with renal failure on dialysis. Further clinical studies are required to confirm the effects. <![CDATA[Effects of N-acetylcysteine on spinal cord oxidative stress biomarkers in rats with neuropathic pain]]> N-acetylcysteine (NAC) inhibits nociceptive transmission. This effect has been associated partly with its antioxidant properties. However, the effect of NAC on the levels of lipid hydroperoxides (a pro-oxidant marker), content of ascorbic acid (a key antioxidant molecule of nervous tissue) and total antioxidant capacity (TAC) is unknown. Thus, our study assessed these parameters in the lumbosacral spinal cord of rats with chronic constriction injury (CCI) of the sciatic nerve, one of the most commonly employed animal models of neuropathic pain. Thirty-six male Wistar rats weighing 200–300 g were equally divided into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve). All rats received intraperitoneal injections of NAC (150 mg·kg−1·day−1) or saline for 1, 3, or 7 days. Rats were killed 1, 3, and 7 days after surgery. NAC treatment prevented the CCI-induced increase in lipid hydroperoxide levels only at day 1, although the amount was higher than that found in naive rats. NAC treatment also prevented the CCI-induced increase in ascorbic acid content, which occurred at days 1, 3, and 7. No significant change was found in TAC with NAC treatment. The changes observed here may be related to the antinociceptive effect of NAC because modulation of oxidative-stress parameters seemed to help normalize the spinal cord oxidative status altered by pain. <![CDATA[Different levels of brain-derived neurotrophic factor and cortisol in healthy heavy smokers]]> Studies suggest that brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis modulate dopaminergic activity in response to nicotine and that the concentrations of BDNF and cortisol seem to be dependent on the amount and duration of smoking. Therefore, we investigated BDNF and cortisol levels in smokers ranked by daily cigarette consumption. Twenty-seven adult males (13 non-smokers and 14 smokers) participated in the study. The smokers were divided in two groups: light (n=7) and heavy smokers (n=7). Anthropometric parameters and age were paired between the groups, and plasma BDNF and salivary cortisol levels were measured. Saliva samples were collected on awakening, 30 min after awakening, at 10:00 and 12:00 am, 5:00 and 10:00 pm. Additionally, cotinine serum levels were measured in smokers. Heavy smokers had higher mean values of BDNF compared to the control group (P=0.01), whereas no difference was observed in light smokers. Moreover, heavy smokers presented lower cortisol levels in the last collection (10:00 pm) than the control group (P=0.02) and presented statically higher values of cotinine than the light smokers (P=0.002). In conclusion, changes in BDNF and cortisol levels (10:00 pm) appear to be dependent on heavy cigarette smoking and can be involved in activation and in the relationship between the mesolimbic system and the HPA axis. <![CDATA[Total phenolic, flavonoid, alkaloid and iridoid content and preventive effect of Lider-7-tang on lipopolysaccharide-induced acute lung injury in rats]]> Lider-7-tang, a medicine used for the treatment of respiratory diseases especially pneumonia and fever in Mongolian Traditional Medicine, was selected for this phytochemical and pharmacological study. The objectives of the study were to determine total biological active substances and analyze the effects of Lider-7-tang treatment in rats with acute lung injury (ALI). Quantitative determination of the total active constituents (phenolic, flavonoid, iridoid and alkaloid) of the methanol extract of Lider-7-tang was performed using Folin-Ciocalteu reagent, aluminum chloride reagent, Trim-Hill reagent, and Bromocresol green reagent, respectively. A total of fifty 8–10-week-old male Wistar rats (200–240 g) were randomized into three groups: control group, lipopolysaccharide (LPS) group (7.5 mg/kg) and LPS+Lider-7 group (90 mg/kg Lider-7-tang before LPS administration). The total content of alkaloids was 0.2±0.043%, total phenols 7.8±0.67%, flavonoids 3.12±0.206%, and iridoids 0.308±0.0095%. This study also evaluated the effects of Lider-7 on levels of inflammatory mediators by observing histopathological features associated with LPS-induced ALI. The rats pretreated with Lider-7 had significantly lower levels of IL-6 (at 3 and 6 h), and TNF-α (at 3, 6, 9, and 12 h). The current study showed that Lider-7 exerted a preventive effect against LPS-induced ALI, which appeared to be mediated by inhibiting the release of pro-inflammatory cytokines. <![CDATA[Monoterpenoids (thymol, carvacrol and S-(+)-linalool) with anesthetic activity in silver catfish (<em>Rhamdia quelen</em>): evaluation of acetylcholinesterase and GABAergic activity]]> This study evaluated the anesthetic potential of thymol and carvacrol, and their influence on acetylcholinesterase (AChE) activity in the muscle and brain of silver catfish (Rhamdia quelen). The AChE activity of S-(+)-linalool was also evaluated. We subsequently assessed the effects of thymol and S-(+)-linalool on the GABAergic system. Fish were exposed to thymol and carvacrol (25, 50, 75, and 100 mg/L) to evaluate time for anesthesia and recovery. Both compounds induced sedation at 25 mg/L and anesthesia with 50–100 mg/L. However, fish exposed to carvacrol presented strong muscle contractions and mortality. AChE activity was increased in the brain of fish at 50 mg/L carvacrol and 100 mg/L thymol, and decreased in the muscle at 100 mg/L carvacrol. S-(+)-linalool did not alter AChE activity. Anesthesia with thymol was reversed by exposure to picrotoxin (GABAA antagonist), similar to the positive control propofol, but was not reversed by flumazenil (antagonist of benzodiazepine binding site), as observed for the positive control diazepam. Picrotoxin did not reverse the effect of S-(+)-linalool. Thymol exposure at 50 mg/L is more suitable than carvacrol for anesthesia in silver catfish, because this concentration did not cause any mortality or interference with AChE activity. Thymol interacted with GABAA receptors, but not with the GABAA/benzodiazepine site. In contrast, S-(+)-linalool did not act in GABAA receptors in silver catfish. <![CDATA[Effects of <em>Lippia sidoides</em> essential oil, thymol, p-cymene, myrcene and caryophyllene on rat sciatic nerve excitability]]> Lippia sidoides Cham is a typical herb species of Northeast Brazil with widespread use in folk medicine. The major constituents of the essential oil of L. sidoides (EOLs) are thymol, p-cymene, myrcene, and caryophyllene. Several studies have shown that the EOLs and its constituents have pharmacological effects, including antibacterial, anti-inflammatory, antioxidant and neuroprotective activity. Therefore, this work aimed to investigate the effects of the EOLs and their main constituents on rat sciatic nerve excitability. The sciatic nerves of adult Wistar rats were dissected and mounted in a moist chamber. Nerves were stimulated by square wave pulses, with an amplitude of 40 V, duration of 100 μs to 0.2 Hz. Both EOLs and thymol inhibited compound action potential (CAP) in a concentration-dependent manner. Half maximal inhibitory concentration for CAP peak-to-peak amplitude blockade were 67.85 and 40 µg/mL for EOLs and thymol, respectively. CAP peak-to-peak amplitude was significantly reduced by concentrations ≥60 µg/mL for EOLs and ≥30 µg/mL for thymol. EOLs and thymol in the concentration of 60 µg/mL significantly increased chronaxie and rheobase. The conduction velocities of 1st and 2nd CAP components were also concentration-dependently reduced by EOLs and thymol in the range of 30-100 µg/mL. Differently from EOLs and thymol, p-cymene, myrcene and caryophyllene did not reduce CAP in the higher concentrations of 10 mM. These data demonstrated that EOLs and thymol inhibited neuronal excitability and were promising agents for the development of new drugs for therapeutic use. <![CDATA[Effects of a 4-week high-intensity interval training on pacing during 5-km running trial]]> This study analyzed the influence of a 4-week high-intensity interval training on the pacing strategy adopted by runners during a 5-km running trial. Sixteen male recreational long-distance runners were randomly assigned to a control group (CON, n=8) or a high-intensity interval training group (HIIT, n=8). The HIIT group performed high-intensity interval-training twice per week, while the CON group maintained their regular training program. Before and after the training period, the runners performed an incremental exercise test to exhaustion to measure the onset of blood lactate accumulation, maximal oxygen uptake (VO2max), and peak treadmill speed (PTS). A submaximal constant-speed test to measure the running economy (RE) and a 5-km running trial on an outdoor track to establish pacing strategy and performance were also done. During the 5-km running trial, the rating of perceived exertion (RPE) and time to cover the 5-km trial (T5) were registered. After the training period, there were significant improvements in the HIIT group of ∼7 and 5% for RE (P=0.012) and PTS (P=0.019), respectively. There was no significant difference between the groups for VO2max (P=0.495) or onset of blood lactate accumulation (P=0.101). No difference was found in the parameters measured during the 5-km trial before the training period between HIIT and CON (P&gt;0.05). These findings suggest that 4 weeks of HIIT can improve some traditional physiological variables related to endurance performance (RE and PTS), but it does not alter the perception of effort, pacing strategy, or overall performance during a 5-km running trial. <![CDATA[Protective effects of deferasirox and N-acetyl-L-cysteine on iron overload-injured bone marrow]]> Using an iron overload mouse model, we explored the protective effect of deferasirox (DFX) and N-acetyl-L-cysteine (NAC) on injured bone marrow hematopoietic stem/progenitor cells (HSPC) induced by iron overload. Mice were intraperitoneally injected with 25 mg iron dextran every 3 days for 4 weeks to establish an iron overload (Fe) model. DFX or NAC were co-administered with iron dextran in two groups of mice (Fe+DFX and Fe+NAC), and the function of HSPCs was then examined. Iron overload markedly decreased the number of murine HSPCs in bone marrow. Subsequent colony-forming cell assays showed that iron overload also decreased the colony forming capacity of HSPCs, the effect of which could be reversed by DFX and NAC. The bone marrow hematopoiesis damage caused by iron overload could be alleviated by DFX and NAC. <![CDATA[Bone mineral density and inflammatory bowel disease severity]]> Inflammatory bowel disease (IBD) is associated with low bone mineral density (BMD). In this study, the association between disease severity and BMD in patients with IBD was evaluated. Associations between BMD and the Montreal classification, disease activity and drug therapy were also tested. A cross-sectional prevalence study with a comparison group was conducted. One hundred and twenty-eight patients were evaluated: 68 patients with ulcerative colitis (UC), and 60 with Crohn's disease (CD). The control group consisted of 67 healthy subjects. All patients and controls had BMD measured and in IBD patients, current medications, hospitalization, and disease location, extent and phenotype, according to the Montreal classification, were recorded. Multiple correspondence analysis was applied to evaluate categorical variables. In the CD group, most patients were diagnosed between 17–40 years of age. Ileocolonic and non-stricturing non-penetrating disease were the most frequent disease location and behavior, respectively. In UC patients, extensive colitis was the most frequent disease location. UC and CD patients were more likely to have osteopenia than controls (OR=14.93/OR=24.38, respectively). In the CD group, male patients, perianal disease, penetrating behavior and age at diagnosis &gt;40 years were associated with low BMD. Taking azathioprine and infliximab also seemed to be associated with osteopenia. In the UC group, we observed an association between low BMD and male patients, left colitis, corticosteroid use and hospitalization. Disease activity was not associated with osteopenia or osteoporosis in CD and UC patients. Disease severity seems to be associated with osteopenia in IBD patients.