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Structural modifications of nonsteroidal anti-inflammatory drugs (NSAIDs) have successfully reduced the side effect of gastrointestinal ulceration without affecting anti-inflammatory activity, but they may increase the risk of myocardial infarction with chronic use. The fact that nitroxyl (HNO) reduces platelet aggregation, preconditions against myocardial infarction, and enhances contractility led us to synthesize a diazeniumdiolate-based HNO-releasing aspirin and to compare it to an NO-releasing analogue. Here, the decomposition mechanisms are described for these compounds. In addition to protection against stomach ulceration, these prodrugs exhibited significantly enhanced cytotoxcity compared to either aspirin or the parent diazeniumdiolate toward nonsmall cell lung carcinoma cells (A549), but they were not appreciably toxic toward endothelial cells (HUVECs). The HNO-NSAID prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase activity and triggered significant sarcomere shortening on murine ventricular myocytes compared to control. Together, these anti-inflammatory, antineoplasic, and contractile properties suggest the potential of HNO-NSAIDs in the treatment of inflammation, cancer, or heart failure.

Results from a previous study show that rats exposed to acute restraint display anxiogenic-like behavior, evidenced by facilitation of avoidance responses in the elevated T-maze (ETM) model of anxiety. In contrast, escape responses were unaltered by stress exposure. Since ETM avoidance and escape tasks seem to activate distinct sets of brain structures, it is possible that the differences observed with acute restraint are due to particularities in the neurobiological mechanisms which modulate these responses. In the present study, analysis of fos protein immunoreactivity (fos-ir) was used to map areas activated by exposure of male Wistar rats to restraint stress (30 min) previously (30 min) to the ETM. Corticosterone levels were also measured in stressed and non-stressed animals. Confirming previous observations restraint facilitated avoidance performance, an anxiogenic result, while leaving escape unaltered. Performance of the avoidance task increased fos-ir in the frontal cortex, intermediate lateral septum, basolateral amygdala, basomedial amygdala, lateral amygdala, anterior hypothalamus and dorsal raphe nucleus. In contrast, performance of escape increased fos-ir in the ventromedial hypothalamus, dorsolateral periaqueductal gray and locus ceruleus. Both behavioral tasks also increased fos-ir in the dorsomedial hypothalamus. Restraint significantly raised corticosterone levels. Additionally after restraint, fos-ir was predominantly seen in the basolateral amygdala and dorsal raphe of animals submitted to the avoidance task. This data confirms that different sets of brain structures are activated by ETM avoidance and escape tasks and suggests that acute restraint differently alters ETM behavior and the pattern of fos activation in the brain.

It has been suggested that access to high caloric food attenuates stress response. The present paper investigates whether access to commercial chow enriched with glucose and fat, here referred to as comfort food alters behavioral, metabolic, and hormonal parameters of rats submitted to three daily sessions of foot-shock stress. Food intake, anxiety-like behaviors, and serum levels of insulin, leptin, corticosterone, glucose and triglycerides were determined. The rats submitted to stress decreased the intake of commercial chow, but kept unaltered the intake of comfort food. During the elevated plus maze (EPM) test, stressed rats increased the number of head dipping, entries into the open arms, as well as the time spent there, and decreased the number of stretched-attend posture and risk assessment. These effects of stress were independent of the type of food consumed. Non-stressed rats ingesting comfort food decreased risk assessment as well. Stress and comfort food increased time spent in the center of the open field and delayed the first crossing to a new quadrant. Stress increased the plasma level of glucose and insulin, and reduced triglycerides, although consumption of comfort food increases glucose, triglyceride and leptin levels; no effect on leptin level was associated to stress. The stress induced increase in serum corticosterone was attenuated when rats had access to comfort food. It was concluded that foot-shock stress has an anorexigenic effect that is independent of leptin and prevented upon access to comfort food. Foot-shock stress also has an anxiolytic effect that is potentiated by the ingestion of comfort food and that is evidenced by both EPM and open field tests.

Background and aim: The goal of this study was to investigate whether physical stress is able to modulate apoptotic response in rat myocardial tissue. The effects of foot shock stress on the histopatological changes and immunohistochemistry for p53, bcl-2 and bax were evaluated. Methods: Male Wistar rats (n= 10) were distributed into two groups: group 1, control and group 2, stress. The stress protocol consisted of one daily foot-shock session applied on three consecutive days. Results: The results pointed out no remarkable changes of myocardial tissue between groups. Also, the foot shock stress was not able to modulate p53, bcl-2 or bax expression, as depicted by no significant statistically differences (P > 0.05) between groups for all immunomarkers evaluated. Conclusions: Taken together, our results suggest that foot shock stress did not induce histopathological changes in rat myocardial tissue. It seems that physical stress is not able to modulate apoptotic response in rats. Certainly, this finding offers new insights into the mechanisms underlying the relation between apoptosis and cardiac injury after stress.

Several cardiovascular disorders have been related to alterations in beta-adrenoceptor (beta-AR) signaling at or beyond the receptor level. During the stress reaction, the sympathetic-adrenal medullary system and the hypothalamus-pituitary-adrenal cortex axis are activated, causing beta-AR overstimulation and remodeling of the beta(1)/beta(2)/beta(3)-AR ratio in cardiomyocytes. In a model of foot-shock stress, we described decreased beta(1)-AR signaling occurring simultaneously with increased beta(2)-AR signaling, whereas the response to the nonconventional agonist, CGP12177, was not altered. These alterations may play an adaptive role to the increased sympathetic drive to the heart, protecting the cardiac tissue from the cardiotoxic effects mediated by beta(1)-ARs overstimulation without altering cardiac output, since this would be sustained by the beta(2)-AR, which would also protect myocytes from apoptosis. Moreover, the selective enhancement of the beta(2)-AR population might help to diminish the risk of overstimulation since this adrenoceptor subtype couples to both, stimulatory G (Gs) and inhibitory G (Gi) proteins. On the other hand, in the model of neurogenic hypertension, the decrease in beta(1)-AR-mediated response is not followed by increase in the beta(2)-AR-mediated response. However, the response to CGP12177, which was desensitized 48 h after the surgery, was normalized 7 days after that, when beta(1)-AR were downregulated. Therefore, both experimental models provided evidence that the classical isoform of beta(1)-AR and the recently described low-affinity isoform of beta(1)-AR show independent behavior and provide the heart with adaptive mechanisms to increased sympathetic stimulation during stress.

The objective of this study was to evaluate the perceived stress index, quality of life, and hypothalamus-pituitary-adrenal axis activity in women with endometriosis and chronic pelvic pain. For the study, 93 women with endometriosis and 82 healthy women volunteered. The visual analogue scale (VAS) (0=no pain; 10=severe pain) was used to determine pain intensity; the perceived stress questionnaire (PSQ) defined stress index, and the health-related quality-of-life (HRQOL)-SF-36 questionnaire was used to evaluate quality of life. Salivary cortisol was measured at 0800, 1600, and 2000 h and the awakening cortisol response was assessed to evaluate the hypothalamus-pituitary-adrenal axis activity. The results show that women with endometriosis and chronic pelvic pain of moderate intensity (4.1+/-0.58, mean+/-SEM) have higher levels of perceived stress (0.55+/-0.01 versus 0.42+/-0.01, p

We investigated the ability of S-nitroso-N-acetylcyseine (SNAC) to prevent structural and functional myocardial alterations in hypercholesterolemic mice. C57BL6 wild-type (WT) and LDL-R-/- male mice (S) were fed a standard diet for 15 days. LDL-R-/- mice (S) showed an 11% increase in blood pressure, 62% decrease in left atrial contractility, and lower CD40L and eNOS expression relative to WT. LDL-R-/- mice fed an atherogenic diet for 15 days (Chol) showed significant increased left ventricular mass compared to S, which was characterized by: (1) 1.25-fold increase in the LV weight/body weight ratio and cardiomyocyte diameter; (2) enhanced expression of the NOS isoforms, CD40L, and collagen amount; and (3) no alteration in the atrial contractile performance. Administration of SNAC to Chol mice (Chol + SNAC) (0.51 micromol/kg/day for 15 day, IP) prevented increased left ventricular mass, collagen deposit, NOS isoforms, and CD40L overexpression, but it had no effect on the increased blood pressure or atrial basal hypocontractility. Deletion of the LDL receptor gene in mice resulted in hypertension and a marked left atrial contractile deficit, which may be related to eNOS underexpression. Our data show that SNAC treatment has an antiinflammatory action that might contribute to prevention of structural and functional myocardial alterations in atherosclerotic mice independently of changes in blood pressure.

In this study, we investigated whether the responses of right atria from sinoaortic denervated rats to CGP12177 (4(3-t-butylamino-2-hydroxypropoxy benzidimidazole-2 one, hydrochloride)), isoprenaline and norepinephrine desensitized in parallel and whether CGP12177 interacted with distinct conformations of beta-adrenoceptors. Right atria from rats 48 h after sinoaortic denervation were subsensitive to isoprenaline, norepinephrine and CGP12177. One week after sinoaortic denervation, the sensitivity to CGP12177 had recovered whereas the responses to isoprenaline and norepinephrine were still subsensitive, suggesting that the binding sites for these molecules showed independent behavior. In atria from 48 h sinoaortic-denervated rats, propranolol or 3 microM CGP20712A (2-hydroxy-5(2-((2-hydroxy-3-(4-((methyl-4-trifluormethyl)1H imidazole-2-yl)-phenoxypropyl) amino) ethoxy)-benzamide monomethane sulphonate)) blocked the responses to 10 nM-1 microM CGP12177 and steepened the curves. The concentration-response curves to CGP12177 in the presence of ICI118,551 (erythro-DL-1(-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol) were biphasic, suggesting that CGP12177 interacted with at least two conformations of beta-adrenoceptors that showed negative cooperativism, one acting through beta(2)-adrenoceptor-Gi and the other via beta(1)-adrenoceptor-Gs. This hypothesis was confirmed in right atria from sinoaortic-denervated rats treated with pertussis toxin.

Adipocytes isolated from epididymal adipose tissue of foot-shock stressed rats are supersensitive to isoprenaline and subsensitive to norepinephrine. These alterations are probably mediated by a stress-induced increase in plasma corticosterone levels. We investigated whether foot-shock stress modifies the expression of glucocorticoid receptors (GRs) and beta-adrenergic protein receptors (beta-ARs) in epididymal adipose tissue from rats submitted to one daily foot-shock session on three consecutive days. This stress protocol caused decreases in GR, beta(1)-AR, and beta(3)-AR protein levels, but caused an increase in beta(2)-AR. These results confirm and support previous functional studies. The alterations in protein expression may be modulated by the high corticosterone levels that downregulate the glucocorticoid receptor.

The aim of this work was to assess whether stress and estrous cycle phases affected the β-adrenoceptor (β-AR) site activated by CGP12177 in the right atria of rats. The chronotropic response to CGP12177 in the absence or presence of antagonists was determined in atria from rats submitted to one daily foot-shock session for 3 consecutive days. Blood was collected for hormonal assays. The pD2 for CGP12177 in atria from females was lower than in atria from males and was unaltered by stress or the estrous cycle. Propranolol (200 nM) or CGP20712A (3 μM) shifted the concentration–response curves to CGP12177 to the right in control and stressed estrus or control diestrus rats. Atria from stressed diestrus rats were resistant to blockade by propranolol or CGP20712A, indicating that the effect of β-adrenoceptor antagonists on the response to CGP12177 is influenced by estrous cycle phases. The stress-induced increase in serum corticosterone levels was independent of the estrous cycle or gender, but the estradiol/progesterone ratio was affected differently in the two groups of female rats. In the diestrus group, serum estradiol levels decreased after the first foot-shock session and remained low until the day of sacrifice, whereas in the estrus group the serum levels of estradiol did not decrease after stress and peaked on the second day, which corresponded to proestrus. These data do not indicate whether there is a direct or indirect effect of stress hormones and (or) sex steroids on cardiac β-AR sensitivity. However, they do show that the classic and low-affinity binding sites of the β-AR are independently regulated and that the β-AR atypical site affinity for antagonists depends on the estrous cycle.Key words: allosterism, β-adrenoceptor, β-adrenoceptor, receptor active site, steroid hormones, stress.

The aim of this study was to investigate the profile of metabolites in male rats subjected to 50-60 min of swimming on three protocols: group A, a single 50 min swimming session; group B, one session a day for three days (5 min on day 1, 15 min on day 2 and 30 min on day 3); and group C, one session a day for 5 days, with increasing duration from 5 min on day 1, 15, 30, 45 and 60 min on consecutive days. The interval between sessions was 24 h. Measurements were made after the last swimming session. Controls did not swim. The glycogen content of liver and gastrocnemius and soleus muscle was depleted in the three groups that swam, but blood glucose concentration was significantly increased only in group B. Serum lactate concentrations were greater than the controls in groups A and B. There were significant increases in serum free fatty acid concentrations in all groups that swam. The increases in plasma free fatty acids may have resulted from lipolysis stimulated by endogenous catecholamines in groups A and C, since basal lipolysis measured in vitro was unchanged by swimming. The large increase in basal lipolysis in group B may have contributed to the rise in plasma free fatty acids. Adipocytes from rats in groups A and B were supersensitive to epinephrine, whereas those from group C were not. We conclude that the metabolic alterations were less pronounced after the last of five swimming sessions over 5 days than after a single session, even though session duration and the contribution of the physical component were similar. Glucose mobilization, but probably not utilization, was similar in the three groups that swam. The mechanisms of lipid mobilization from adipose tissue differed, depending on the stress paradigm. The metabolic changes in groups A and B indicated that three daily swimming sessions were insufficient to cause adaptation. The results contrast with previous findings for foot-shock stress, which leads to sensitization rather than adaptation in response to repeated stimuli.

We examined the effect of three daily foot-shock stress sessions on glucose homeostasis, insulin secretion by isolated pancreatic islets, insulin sensitivity of white adipocytes, and glycogen stores in the liver and soleus muscle of rats. Stressed rats had plasma glucose (128.3 ± 22.9 mg/dL) and insulin (1.09 ± 0.33 ng/mL) levels higher than the controls (glucose, 73.8 ± 3.5 mg/dL; insulin, 0.53 ± 0.11 ng/mL, ANOVA plus Fisher's test; p < 0.05). After a glucose overload, the plasma glucose, but not insulin, levels remained higher (area under the curve 8.19 ± 1.03 vs. 4.84 ± 1.33 g/dL 30 min and 102.7 ± 12.2 vs. 93.2 ± 16.1 ng/mL 30 min, respectively). Although, the area under the insulin curve was higher in stressed (72.8 ± 9.8 ng/mL) rats than in control rats (34.9 ± 6.9 ng/mL) in the initial 10 min after glucose overload. The insulin release stimulated by glucose in pancreatic islets was not modified after stress. Adipocytes basal lipolysis was higher (stressed, 1.03 ± 0.14; control, 0.69 ± 0.11 µmol of glycerol in 60 min/100 mg of total lipids) but maximal lipolysis stimulated by norepinephrine was not different (stressed, 1.82 ± 0.35; control, 1.46 ± 0.09 µmol of glycerol in 60 min/100 mg of total lipids) after stress. Insulin dose-dependently inhibited the lipolytic response to norepinephrine by up to 35% in adipocytes from control rats but had no effect on adipocytes from stressed rats. The liver glycogen content was unaltered by stress, but was lower in soleus muscle from stressed rats than in control rats (0.45 ± 0.04 vs. 0.35 ± 0.04 mg/100 mg of wet tissue). These results suggest that rats submitted to foot-shock stress develop hyperglycemia along with hyperinsulinemia as a consequence of insulin subsensitivity in adipose tissue, with no alteration in the pancreatic sensitivity to glucose. Foot-shock stress may therefore provide a useful short-term model of insulin subsensitivity.Key words: glucose tolerance test, white adipocytes, lipolysis, pancreatic islets, insulin release, soleus muscle, liver glycogen.

The long-term effects of comfort food in an anxiogenic model of stress have yet to be analyzed. Here, we evaluated behavioral, endocrine and metabolic parameters in rats submitted or not to chronic unpredictable mild stress (CUMS), with access to commercial chow alone or to commercial chow and comfort food. Stress did not alter the preference for comfort food but decreased food intake. In the elevated plus-maze (EPM) test, stressed rats were less likely to enter/remain in the open arms, as well as being more likely to enter/remain in the closed arms, than were control rats, both conditions being more pronounced in the rats given access to comfort food. In the open field test, stress decreased the time spent in the centre, independent of diet; neither stress nor diet affected the number of crossing, rearing or grooming episodes. The stress-induced increase in serum corticosterone was attenuated in rats given access to comfort food. Serum concentration of triglycerides were unaffected by stress or diet, although access to comfort food increased total cholesterol and glucose. It is concluded that CUMS has an anorexigenic effect. Chronic stress and comfort food ingestion induced an anxiogenic profile although comfort food attenuated the endocrine stress response. The present data indicate that the combination of stress and access to comfort food, common aspects of modern life, may constitute a link among stress, feeding behavior and anxiety.

The aim of this study was to examine the state of anxiety and the 17beta-estradiol and progesterone levels in rats tested in the elevated plus-maze during the four phases of the estrous cycle. Male rats, female rats during each of the four phases of the estrous cycle, ovariectomized rats, and diestrus female rats treated with estradiol were tested in the elevated plus-maze between 8:00 and 10:00 a.m. Blood was collected from all rats for the determination of 17beta-estradiol and progesterone levels. Female rats in the proestrus group spent more time in the open arms than diestrus rats (P.05). There were no significant differences in the percentage of entries into the open arms or in the number of entries into the closed arms among the phases of the estrous cycle or between males and normal or ovariectomized females. Serum estradiol levels were higher (P.05) during proestrus compared to estrus, metestrus, and diestrus in control and plus-maze tested female rats, but there were no significant differences in progesterone levels. Treating diestrus female rats with estradiol to produce estradiol plasma concentrations similar to those seen during proestrus abolished the difference in the percentage of time spent in the open arms by proestrus and diestrus rats. Since the time spent in the open arms of the plus-maze is inversely related to anxiety, we conclude that the anxiety levels of female rats were lower in proestrus than during diestrus, and that the levels of estradiol modulate this response.

Stress hormones can alter metabolic functions in adipose tissue and liver, as well as the sensitivity of rat white adipocytes and rat atrial responses to beta-adrenergic agonists. In this study, we examined the effects of three daily footshock stress sessions on the plasma corticosterone, glucose, glycerol and triacylglycerol levels of fed, conscious male rats, and on the plasma glucose, glycerol and triacylglycerol levels of the same rats following iv infusions of beta-adrenergic agonists (isoproterenol: 0.4 nmol kg-1 min-1, noradrenaline: 5.0 microg kg-1 day-1, and BRL 37344 ([+/-]-[4-(2-[(2-[3-chlorophenyl]-2-hydroxyethyl)amino]propyl)phenoxy]acetic acid), a selective beta3-adrenoceptor agonist: 0.4 nmol kg-1 min-1). Plasma corticosterone levels increased significantly after each stress session, while triacylglycerol levels increased after the first session and glucose increased after the second and third sessions. Glycerol levels were unaltered after stress. These results suggest that repeated footshock stress may induce a metabolic shift from triacylglycerol biosynthesis to glucose release by hepatic tissue, with glycerol serving as one of the substrates in both pathways. Stressed rats were more sensitive to infusion of noradrenaline plus prazosin and to infusion of isoproterenol, with elevated plasma glucose, glycerol and triacylglycerol levels. The higher sensitivity of stressed rats to isoproterenol and noradrenaline was probably related to the permissive effect of plasma corticosterone. Only BRL 37344 increased plasma glycerol levels in stressed rats, probably because beta3-adrenoceptors are not involved in hepatic triacylglycerol synthesis, thus allowing glycerol to accumulate in plasma.

The purpose of the present study was to demonstrate a physiological response to TA2005, a potent β2-adrenoceptor (β2-AR) selective agonist, in right atria isolated from stressed female rats under the influence of the estrous cycle. We obtained concentration-response curves to the agonist in the presence and in the absence of selective antagonists in right atria isolated from female rats submitted to three daily foot-shock sessions (30 min duration, 120 pulses of 1.0 mA, 1.0 s, applied at random intervals of 5-25 s) and sacrificed at estrus or diestrus. Our results showed that the pD2 values of TA2005 were not influenced by estrous cycle phase or foot-shock stress. However, in right atria from stressed rats sacrificed during diestrus, the concentration-response curve to TA2005 was biphasic, with a response being obtained at concentrations of 0.1 nM, whereas during estrus no response was observed at doses lower than 3 nM. ICI118,551, a β2-AR antagonist, abolished the response to nanomolar concentrations of TA2005 in right atria from stressed rats at diestrus, with no changes in agonist pD2 values in right atria from control rats (7.47 ± 0.09, p > 0.05) but a 3-fold decrease in pD2 values of TA2005 in right atria from foot shock stressed rats (7.90 ± 0.07, p [Formula: see text] 0.05). Concentration-response curves to TA2005 in the presence of ICI118,551 were best fitted by a one-site model equation. The β1-AR antagonist, CGP20712A, shifted to the right only the second part of the concentration-response curves to the agonist, unmasking the putative β2-AR-mediated response to the agonist in tissues isolated from stressed rats at diestrus. Under this condition, concentration-response curves to the agonist were best fitted by a two-site model equation. pD2 and maximum response of TA2005 interaction with β1- and putative β2-adrenoceptor components were calculated. Schild analyses gave a pKB value for CGP20712A that was typical for the interaction with β1-AR in each experimental group. pKB values for ICI118,551 could not be obtained in stressed rats sacrificed at diestrus since Schild plot slopes were lower than 1.0. In right atria from control rats, ICI118,551 pKB values were similar to reported values for the interaction of the antagonist with β1-AR. These results confirm that a heterogenous β-AR population mediating the chronotropic response to catecholamines can be demonstrated in right atria from foot shock stressed female rats sacrificed at diestrus. The stress-induced response seems to be mediated by the β2-AR subtype. Right atria from rats sacrificed during estrus are protected against stress-induced alterations on the homogeneity of β-AR population.Key words: foot-shock stress, TA2005, ICI118,551, CGP20712A, estrus, diestrus.

In a previous study we showed that rats chronically treated with corticosterone (CORT) display anxiogenic behavior, evidenced by facilitation of avoidance responses in the elevated T-maze (ETM) model of anxiety. Treatment with the tricyclic antidepressant imipramine significantly reversed the anxiogenic effects of CORT, while inhibiting ETM escape, a response related to panic disorder. To better understand the neurobiological mechanisms underlying these behavioral effects, analysis of c-fos protein immunoreactivity (fos-ir) was used here to map areas activated by chronic CORT (200 mg pellets, 21-day release) and imipramine (15 mg/kg, IP) administration. We also evaluated the number of cells expressing the neurogenesis marker doublecortin (DCX) in the hippocampus and measured plasma CORT levels on the 21st day of treatment. Results showed that CORT increased fos-ir in the ventrolateral septum, medial amygdala and paraventricular hypothalamic nucleus and decreased fos-ir in the lateral periaqueductal gray. Imipramine, on the other hand, increased fos-ir in the medial amygdala and decreased fos-ir in the anterior hypothalamus. CORT also decreased the number of DCX-positive cells in the ventral and dorsal hippocampus, an effect antagonized by imipramine. CORT levels were significantly higher after treatment. These data suggest that the behavioral effects of CORT and imipramine are mediated through specific, at times overlapping, neuronal circuits, which might be of relevance to a better understanding of the physiopathology of generalized anxiety and panic disorder.

Previous results show that elevated T-maze (ETM) avoidance responses are facilitated by acute restraint. Escape, on the other hand, was unaltered. To examine if the magnitude of the stressor is an important factor influencing these results, we investigated the effects of unpredictable chronic mild stress (UCMS) on ETM avoidance and escape measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to map areas activated by stress exposure in response to ETM avoidance and escape performance. Additionally, the effects of the UCMS protocol on the number of cells expressing the marker of migrating neuroblasts doublecortin (DCX) in the hippocampus were investigated. Corticosterone serum levels were also measured. Results showed that UCMS facilitates ETM avoidance, not altering escape. In unstressed animals, avoidance performance increases Fos-ir in the cingulate cortex, hippocampus (dentate gyrus) and basomedial amygdala, and escape increases Fos-ir in the dorsolateral periaqueductal gray and locus ceruleus. In stressed animals submitted to ETM avoidance, increases in Fos-ir were observed in the cingulate cortex, ventrolateral septum, hippocampus, hypothalamus, amygdala, dorsal and median raphe nuclei. In stressed animals submitted to ETM escape, increases in Fos-ir were observed in the cingulate cortex, periaqueductal gray and locus ceruleus. Also, UCMS exposure decreased the number of DCX-positive cells in the dorsal and ventral hippocampus and increased corticosterone serum levels. These data suggest that the anxiogenic effects of UCMS are related to the activation of specific neurobiological circuits that modulate anxiety and confirm that this stress protocol activates the hypothalamus-pituitary-adrenal axis and decreases hippocampal adult neurogenesis.

Introdução: O desenvolvimento positivo resulta em competências em diferentes domínios (cognitivos, afetivos, sociais) importantes para a proteção frente a problemas psicológicos e de comportamento que podem levar a disfunções, prejudicando a organização de ações, percepções, atitudes e interação com o meio. Objetivo: Avaliar de forma descritiva indicadores de estresse, competência social e problemas psicológicos e comportamentais em um grupo de adolescentes estudantes em jornada integral. Método: Este estudo incluiu 50 adolescentes (22 meninos e 28 meninas com idades de 12 a 18 anos). Os instrumentos usados foram o ASQ (Questionário de estresse para adolescentes) e o YSR (Inventário de autoavaliação para adolescentes). Dados relativos à competência social e a problemas psicológicos e de comportamento foram sistematizados com uso do software do YSR, enquanto a organização dos resultados do ASQ seguiu padrões descritivos de frequência dos dados da escala tipo Likert do instrumento. O estudo da associação entre ASQ e as variáveis do YSR foi feito a partir da observação de gráficos de dispersão e do cálculo do coeficiente de correlação linear de Pearson. Resultados: Verificou-se tendência geral à baixa intensidade de estresse e à faixa não clínica para problemas psicológicos e para competência total (que inclui competência social). No subgrupo dos meninos foi verificada correlação moderada entre problemas psicológicos e estresse. Conclusão: Embora tenham sido detectadas queixas relacionadas ao tempo de ficar na escola, a inserção escolar em período integral pode ter sido importante variável interveniente para os resultados positivos encontrados, o que aponta necessidades de ampliação de estudos na temática.

The aim of the present study was to comparatively evaluate genomic damage and cellular death in exfoliated oral mucosa cells and peripheral blood from car painters. A total of 24 car painters and 19 healthy controls (non-exposed individuals) were included in this setting. Individuals had epithelial cells from cheek mucosa (left and right side) mechanically exfoliated, placed in fixative and dropped in clean slides which were checked for the specific nuclear phenotypes. A total of 5 μL from peripheral blood was collected for the single cell gel (comet) assay. The results pointed out statistically significant differences (p0.05) of micronucleated oral mucosa cells from car painters. In addition, DNA damage was detected in peripheral blood cells by single cell gel (comet) assay. Nevertheless, exposure to car paints did not cause increases other nuclear alterations closely related to cytotoxicity such as karrhyorexis, pyknosis and karyolysis in buccal mucosa cells. In summary, the results of the present study suggest that car painters comprise a high risk group since paints can induce genotoxic and mutagenic effects in peripheral blood and oral mucosa cells, respectively.

In type 2 diabetes, hyperglycemia and increased sympathetic drive may alter mitochondria energetic/redox properties, decreasing the organelle’s functionality. These perturbations may prompt or sustain basal low-cardiac performance and limited exercise capacity. Yet the precise steps involved in this mitochondrial failure remain elusive. Here, we have identified dysfunctional mitochondrial respiration with substrates of complex I, II, and IV and lowered thioredoxin-2/glutathione (GSH) pools as the main processes accounting for impaired state 4→3 energetic transition shown by mitochondria from hearts of type 2 diabetic db/db mice upon challenge with high glucose (HG) and the β-agonist isoproterenol (ISO). By mimicking clinically relevant conditions in type 2 diabetic patients, this regimen triggers a major overflow of reactive oxygen species (ROS) from mitochondria that directly perturbs cardiac electro-contraction coupling, ultimately leading to heart dysfunction. Exogenous GSH or, even more so, the fatty acid palmitate rescues basal and β-stimulated function in db/db myocyte/heart preparations exposed to HG/ISO. This occurs because both interventions provide the reducing equivalents necessary to counter mitochondrial ROS outburst and energetic failure. Thus, in the presence of poor glycemic control, the diabetic patient’s inability to cope with increased cardiac work demand largely stems from mitochondrial redox/energetic disarrangements that mutually influence each other, leading to myocyte or whole-heart mechanical dysfunction.

The aim of this study was to examine salivary cortisol and testosterone concentrations in professional male athletes during a short triathlon competition using non-invasive methods, and to determine whether these hormone concentrations could be accurate predictors of performance. Eight adult male athletes (age, mean ± SEM: 27.8 ± 3.2 years; body mass index: 21.66 ± 0.42) in a professional triathlon team volunteered to participate in this study. Saliva samples were taken on the competition day and 7 days after competition on a rest day. The performance of the athletes was assessed by their rank order in the competition. Salivary cortisol concentrations were greater on the competition day than on the rest day in the early morning, immediately after waking up, 30 min later, immediately before the start of the competition, and later in the evening. Testosterone concentrations were greater on the competition day in the morning and in the evening. The diurnal rhythm of both cortisol and testosterone concentrations was maintained on both days and the testosterone/cortisol ratio (T/C ratio) was similar between days. The performance of the athletes was positively correlated with salivary cortisol concentration in the early morning of the competition day, but was not correlated with testosterone concentrations at any of the time points. In conclusion, early morning salivary cortisol concentration, but not T/C ratio, could be used to predict performance in athletes during a professional triathlon competition.

Background Environmental stress plays an important role in the development of glucose intolerance influencing lipid and glucose metabolism through sympathetic nervous system, cytokines and hormones such as glucocorticoids, catecholamines and glucagon. Otherwise, fish oil prevents glucose intolerance and insulin resistance. Although the mechanisms involved are not fully understood, it is known that sympathetic and HPA responses are blunted and catecholamines and glucocorticoids concentrations can be modulated by fish consumption. The aim of the present study was to evaluate whether fish oil, on a normal lipidic diet: 1) could prevent the effect of footshock-stress on the development of glucose intolerance; 2) modified adiponectin receptor and serum concentration; and 3) also modified TNF-α, IL-6 and interleukin-10 (IL-10) levels in adipose tissue and liver. The study was performed in thirty day-old male Wistar randomly assigned into four groups: no stressed (C) and stressed (CS) rats fed with control diet, and no stressed (F) and stressed (FS) rats fed with a fish oil rich diet. The stress was performed as a three daily footshock stress sessions. Results Body weight, carcass fat and protein content were not different among groups. FS presented a reduction on the relative weight of RET. Basal serum glucose levels were higher in CS and FS but 15 min after glucose load just CS remained with higher levels than other groups. Serum corticosterone concentration was increased in CS, this effect was inhibited in FS. However, 15 min after footshock-stress, corticosterone levels were similar among groups. IL-6 was increased in EPI of CS but fish oil consumption prevented IL-6 increase in FS. Similar levels of TNF-α and IL-10 in RET, EPI, and liver were observed among groups. Adipo R1 protein concentration was not different among groups. Footshock-stress did not modify AdipoR2 concentration, but fish oil diet increases AdipoR2 protein concentration. Conclusions Footshock-stress promotes glucose intolerance associated to corticosterone serum level and epididymal white adipose tissue IL-6 concentration increase. The fish oil consumption by stressed rats normalized the stress responses. These results suggested that fish oil intake could be useful to minimize or prevent the development of diseases associated to the stress.

The goal of this study was to investigate whether daily administration of green tea is able to protect the liver injury induced by cholesterol. Male Wistar rats (n = 24) were distributed into four groups: group 1, negative control; group 2, cholesterol at 1% (w/w) in the diet treated for 5 weeks; group 3, cholesterol at 1% treated for 5 weeks and green tea at 1% (w/v) in drinking water in the last week only and group 4, cholesterol and green tea at 1% in drinking water for 5 weeks. The results pointed out that treatment with green tea in the last week (group 3) showed mild degenerative changes of liver tissue in cholesterol exposed group when compared to group 2. Green tea aqueous extract was not able to reduce cholesterol levels, that is, no significant statistical differences (p > 0.05) were noticed when compared to positive control group. Nevertheless, green tea was able to decrease oxidative deoxyribonucleic acid (DNA) damage either to peripheral blood or to liver cells as depicted by significant statistical differences (p

The aim of this study was to use the single cell gel (comet) assay to investigate whether blood, liver, heart, kidney, and brain are particularly sensitive organs for DNA damage in cirrhotic rats to predict genetic instability induced by cirrhosis.A total of 16 male Wistar rats (negative control, n = 8; experimental, n = 8) were submitted to bile duct ligation during 28 days.Cirrhosis was able to induce genetic damage in liver and brain cells, as depicted by the mean tail moment. No genetic damage was induced in blood, heart, or kidney cells (i.e., no significant statistically differences were noticed when compared with negative control).In conclusion, our results suggest that cirrhosis could contribute to DNA damage in liver and brain cells.

This study evaluated level of salivary cortisol and perceived burden, stress and health of mothers and primary caregivers of children (4-11 years of age) with cerebral palsy (purpose group, n=37) and those for mothers of children of the same age without developmental problems (control group, n=38). Anthropometric and socioeconomic data were collected from the participants, who also completed the perceived stress questionnaire, the Burden Interview and the 36-Item Short Form Health Survey (SF-36). Cortisol level was assayed in saliva samples collected at various times in a single day and the area under the cortisol curve was then determined. Both groups presented low socioeconomic level and high, although equivalent, perceived stress index. However, the purpose group showed lower cortisol levels, as well as lower scores for many of the SF-36 domains related to physical well-being (physical functioning, role-physical, vitality, and general health) and social functioning. Nevertheless, bodily pain was also reported to be lower. For the control group, the area under the cortisol curve correlated negatively with mental health and social functioning. For the purpose group, where the burden is greater, no such correlation was found. It was concluded that mothers of healthy children leaving in unfavorable socioeconomic conditions face high levels of stress with the hypothalamus-pituitary-adrenal cortex axis function preserved. However, to the mothers of children with cerebral palsy, who live in even worse socioeconomic conditions and also have the burden of caring for a disabled child, the level of stress was overwhelming, to an extent that it impaired the hypothalamus-pituitary-adrenal cortex axis function, as well as reflecting negatively on certain aspects of their physical and psychological well-being. This must receive consideration during the treatment of the child, an approach which is in line with present day tendencies towards family-centered models of assistance to disabled children.

We have analyzed the perceived stress index, the basal salivary cortisol levels, and the awakening cortisol response (ACR) in 86 volunteers of low (LSES) and high socioeconomic status (HSES). The LSES presented higher perceived stress index and basal salivary cortisol levels, nonaltered ACR, or cortisol diurnal rhythm. We have concluded that the LSES is associated with high perceived stress index and salivary cortisol levels, which could impact negatively in health, and that it is related to the daily life stress experienced by individuals in the LSES group. Because the LSES corresponds to about 30% of the total Brazilian population, this conclusion might have a great impact on public health policies and costs.

Summary Background Cellulite or lipodystrophy involves the modification of the subcutaneous adipose tissue. A wide variety of topical products is available to combat cellulite, but these have difficulties in being absorbed through the skin. One option is the therapeutic use of the ultrasound to enhance the transdermic transport of these drugs. Aim The objective of this study was the analysis of the effect of caffeine on the morphology of the swine hypodermis, both when applied topically and in combination with ultrasound treatment. Methods The following treatments were applied to the dorsal areas of five pigs (Landrace × Large White, 35 days old, weighing 15 kg each): gel, gel + ultrasound, gel + caffeine (5%, w/w), and gel + caffeine + ultrasound, daily for 15 days. A fifth area received no topical application and was used as a control. Continuous ultrasound of 3 MHz with an intensity of 0.2 W/cm2 was applied at a rate of 1 min/cm2. After histological processing (hematoxylin and eosin), morphometric analyses were conducted to determine the thickness and numerical profile of the hypodermis. A one-way analysis variance using a Kolmogorov–Smirnov test was conducted, with a Tukey test used to identify significant differences. A confidence level of P ≤ 0.05 was adopted. Results Caffeine treatment was effective only when associated with ultrasound therapy; the combination resulted in a significant reduction in the thickness of the subcutaneous adipose tissue, as well as damage to the adipocytes, consequently decreasing the number of cells. Conclusion Ultrasound treatment was effective in increasing the cutaneous permeation of caffeine, as evidenced by the reduction in thickness of the hypodermis and number of adipocytes.

Most modern theories about stress recognize that although stress is not a disease, it may be the trigger for the majority of diseases when allostatic overload has been generated. During stress, the glucocorticoids and catecholamines play a key role in the regulation of physiological parameters and homeostasis during stress. In the heart, positive chronotropic, inotropic, and lusitropic responses to catecholamines are mediated by various subtypes of adrenergic receptors (beta-ARs), mainly beta1- and beta2-adrenergic receptors. beta-ARs also control cardiomyocyte growth and death, thus contributing to cardiac remodelling. The structural basis of each beta-AR subtype, as well as their signalling pathways, and adaptive responses to stress are discussed. The participation of beta3- and putative beta4-ARs in the control of cardiac function is also discussed, with emphasis on low affinity beta-AR isoforms and the role they play in the response to the catecholamines under stress. The changes in beta-AR signalling under pathogenic conditions as well as under stress are reviewed.

Background The pathophysiology of the NO/NO synthase system and dysfunctional changes in the endothelium in the early phases of the atherogenic process are incompletely understood. In this study, we investigated the effects of the nitrosothiol NO donor S -nitroso- N -acetylcysteine (SNAC) in the early prevention of plaque development in the hypercholesterolemic LDLr−/− mice as well as the changes in endothelium-dependent relaxation and NO synthase expression. Methods and results LDLr−/− mice were fed a 1.25% cholesterol-enriched diet for 15 days. Plasma cholesterol/triglyceride levels increased and this increase was accompanied by the development of aortic root lesions. Aortic vasorelaxation to acetylcholine was increased, although endothelium-independent relaxation in response to sodium nitroprusside did not change, which suggest stimulated NO release enhanced. This dysfunction was associated with enhanced aortic superoxide production and with increased levels of constitutive NOS isoform expression, particularly neuronal NOS. SNAC ( S -nitroso- N -acetylcysteine) administration (0.51 μmol/kg/day i.p. for 15 days) decreased the extent of the plaque by 55% in hypercholesterolemic mice, but had no effects on vasomotor changes. It did, however, lead to a decrease in constitutive NOS expression. The SNAC induced only minor changes in plasma lipid profile. Conclusion The present study has shown that, in early stages of plaque development in LDLr−/− mice, specific changes in NO/NO synthase system develop, that are characterized by increased endothelium-dependent vasorelaxation and increased constitutive NOS expression. Since the development of plaque and the indicator of endothelial cell dysfunction were prevented by SNAC, such treatment may constitute a novel strategy for the halting of progression of early plaque.

The [Ru II (Hedta)NO + ] complex is a diamagnetic species crystallizing in a distorted octahedral geometry, with the Ru–N(O) length 1.756(4) A and the RuNO angle 172.3(4)°. The complex contains one protonated carboxylate (p K a = 2.7 ± 0.1). The [Ru II (Hedta)NO + ] complex undergoes a nitrosyl-centered one-electron reduction (chemical or electrochemical), with E NO+/NO = −0.31 V vs SCE ( I = 0.2 M, pH 1), yielding [Ru II (Hedta)NO] − , which aquates slowly: k –NO = 2.1 ± 0.4 × 10 −3 s −1 (pH 1.0, I = 0.2 M, CF 3 COOH/NaCF 3 COO, 25 °C). At pHs > 12, the predominant species, [Ru II (edta)NO] − , reacts according to [Ru II (edta)NO] − + 2OH − ⇒ [Ru II (edta)NO 2 ] 3− , with K eq = 1.0 ± 0.4 × 10 3 M −2 ( I = 1.0 M, NaCl; T = 25.0 ± 0.1 °C). The rate-law is first order in each of the reactants for most reaction conditions, with k OH − = 4.35 ± 0.02 M −1 s −1 (25.0 °C), assignable mechanistically to the elementary step comprising the attack of one OH − on [Ru II (edta)NO] − , with subsequent fast deprotonation of the [Ru II (edta)NO 2 H] 2− intermediate. The activation parameters were Δ H # = 60 ± 1 kJ/mol, Δ S # = −31 ± 3 J/K mol, consistent with a nucleophilic addition process between likely charged ions. In the toxicity up-and-down tests performed with Swiss mice, no death was observed in all the doses administered (3–9.08 × 10 −5 mol/kg). The biodistribution tests performed with Wistar male rats showed metal in the liver, kidney, urine and plasma. Eight hours after the injection no metal was detected in the samples. The vasodilator effect of [Ru II (edta)NO] − was studied in aortic rings without endothelium, and was compared with sodium nitroprusside (SNP). The times of maximal effects of [Ru II (edta)NO] − and SNP were 2 h and 12 min, respectively, suggesting that [Ru II (edta)NO] − releases NO slowly to the medium in comparison with SNP.

Aqueous extracts of Croton cajucara bark are used in folk medicine to treat hepatic and gastrointestinal disorders and as a coadjuvant in weight-loss programs. We examined the effect of treating rats for 15 days with a 5% aqueous extract of C. cajucara on body weight and food intake. The epididymal adipose pads were removed and the lipolytic responses of isolated adipocytes to isoprenaline, noradrenaline (norepinephrine), BRL37344 and adrenaline (epinephrine) were analysed in the absence or presence of metoprolol or ICI118,551. Treated rats had a significantly lower weight gain than control rats, with no difference in food and liquid intake, epididymal fat-pad weight or basal glycerol release. The sensitivity of the lipolytic response to isoprenaline and adrenaline was significantly higher in adipocytes from treated rats. The sensitivity to noradrenaline or BRL37344 was unaltered. Metoprolol shifted the dose-response curves to noradrenaline to the right in adipocytes from control and treated rats; the dose-response curve to isoprenaline in adipocytes from control rats was also shifted to the right. In adipocytes from treated rats, the dose-response curve to isoprenaline was unaltered by metoprolol but was shifted to the right by ICI118,551, a β2-adrenoceptor antagonist. We conclude that in adipocytes from treated rats there is an increase in the lipolytic response to non-selective agonists (isoprenaline and adrenaline) mediated by β2-adrenoceptors, with no alteration in the responses mediated by β1-adrenoceptors (noradrenaline) or β3-adrenoceptors (BRL37344). This effect could increase the role of adrenaline as an endogenous stimulator of lipolysis.

The decoction of Dalbergia monetaria L. is popularly used in Brazil for the treatment of gastric ulcer and the lyophilized aqueous extract (LAE) of D. monetaria has significant anti-ulcerogenic activity and inhibits gastric ulcer lesions induced by pylorus-ligature, ethanol and hypothermic-restraint stress. This work was conducted to identify the anti-ulcerogenic mechanisms of action of the LAE of D. monetaria. We analysed the effect of the LAE on prostaglandin E2 (PGE2) synthesis and on the characteristics (pH, volume and total acid content) of gastric juice. The antagonism between the LAE and histamine or carbachol was also analysed. The LAE increased gastric mucosal PGE2 synthesis compared with control (89.7 ± 21.5 and 52.6 ± 11.8 pg mg−1, respectively) as assayed by enzyme immunoassay in the rat stomach. The LAE reduced the total acid content of gastric juice, but did not modify pH or gastric volume significantly, in Shay rats. Dose-response curves to histamine were shifted to the right in guinea-pig isolated right atria (pD2 values were 5.77 ± 0.2 and 5.42 ± 0.3, respectively, in the absence and presence of the LAE), with a significant reduction in maximum response (140 ± 15.1 and 98 ± 13.0, respectively). The same effect was observed when the agonist was isoprenaline. The LAE had no effect on the dose-response curve to carbachol in rat fundus strips. Thus, the protective effect of the LAE on induced gastric lesions might be because of synergistic effects, e.g. increased PGE2 synthesis and antagonism of H2 histamine and β-adrenergic receptors, reducing gastric acid secretion. Increased PGE2 synthesis results in increased protection, and antagonism of H2 histamine and β-adrenergic receptors reduces aggressive factors against the gastric mucosa.

The bark of Croton cajucara Benth. is used in Brazilian folk medicine as an infusion to treat gastrointestinal disorders. The aim of the present study was to assess the mechanisms involved in the antiulcerogenic activity of dehydrocrotonin (DHC), a diterpene isolated from C. cajucara bark. We studied the effects of DHC on pylorus ligature (Shay) in mice treated with the drug (100 mg/kg) by the intraduodenal route. DHC did not induce any alteration in gastric volume in Shay mice but modified the pH and total acid concentration of gastric juice. Incubation of gastric juice with DHC did not reduce gastric acidity compared to control. We also investigated the effects of DHC on the response to histamine of right atria isolated from guinea pigs and on the response to carbachol of stomach fundus strips from rats. The concentration-response curves for the chronotropic effect of histamine in guinea pig right atria were shifted to the right, with a significant decrease in the maximum response, in the presence of DHC. Similar results were obtained with DHC (30 μM) for the concentration-response curves to carbachol in the isolated rat stomach. The ability of DHC to increase PGE2 release from rat stomach mucous cells was also studied. We observed that DHC induced a significant increase in PGE 2 production (60% compared to control). In addition, the effects of DHC on the healing of acetic acid-induced gastric ulcer in rats were evaluated 14 days after acid injection. Oral administration of DHC (100 mg/kg per day) for 14 consecutive days had no effect on gastric ulcer healing in rats. Thus, the protective effect of DHC on induced gastric lesions could be due to synergistic effects, e.g., an increase in PGE 2 release and non-competitive antagonism of H 2 -receptors and of muscarinic receptors. Whereas the former result represents an increase in the protective factors, the latter one shows a decrease in the aggressive factors against the gastric mucosa.