Activation of p38MAPK Contributes to Expanded Polyglutamine-Induced Cytotoxicity

The signaling pathways that may modulate the pathogenesis of diseases induced by expanded polyglutamine proteins are not well understood.Herein we demonstrate that expanded polyglutamine protein cytotoxicity is mediated primarily through activation of p38MAPK and that the atypical PKC iota (PKCiota) enzyme antagonizes polyglutamine-induced cell death through induction of the ERK signaling pathway. We show that pharmacological blockade of p38MAPK rescues cells from polyglutamine-induced cell death whereas inhibition of ERK recapitulates the sensitivity observed in cells depleted of PKCiota by RNA interference. We provide evidence that two unrelated proteins with expanded polyglutamine repeats induce p38MAPK in cultured cells, and demonstrate induction of p38MAPK in an in vivo model of neurodegeneration (spinocerebellar ataxia 1, or SCA-1).Taken together, our data implicate activated p38MAPK in disease progression and suggest that its inhibition may represent a rational strategy for therapeutic intervention in the polyglutamine disorders

Effects of a recreational physical activity and healthy habits orientation program, using an illustrated diary, on the cardiovascular risk profile of overweight and obese schoolchildren: a pilot study in a public school in Brasilia, Federal District, Brazil

Angeliete Garcez Milit&atilde;o,1,2 Marg&ocirc; Gomes de Oliveira Karnikowski,3 Fernanda Rodrigues da Silva,4 Elba Sancho Garcez Milit&atilde;o,3 Raiane Maiara dos Santos Pereira,5 Carmen Silvia Grubert Campbell,2,5 1Department of Physical Education, Federal University of Rondonia, Brazil; 2Post-Graduate Program in Physical Education, Catholic University of Brasilia, Brazil; 3University of Brasilia, Brazil; 4Laboratory of Physical Evaluation and Training, 5Laboratory of Physical Education and Health Studies, Catholic University of Brasilia, Brazil Introduction: Educative strategies need to be adopted to encourage the consumption of healthy foods and to promote physical activity in childhood and adolescence. The effects of recreational physical activity and a health-habit orientation program using an illustrated diary on the cardiovascular risk profile of overweight and obese children was investigated. Methods: The weight and height of 314 schoolchildren aged between 9 and 11 years old, in a public school in Brasilia, Federal District, Brazil, were recorded. According to the body mass index (BMI) classification proposed by the World Health Organization, 84 were overweight or obese for their age and sex. Of these children, 34 (40%) participated in the study. Students were divided into two groups matched for sex, age, BMI, percent body fat (%BF): the intervention group (IG, n = 17) and the control group (CG, n = 17). The IG underwent a program of 10 weeks of exercise with recreational activities and health-habit orientation using an illustrated diary of habits, while no such interventions were used with the CG during the study period. Before and after the intervention, the children&#39;s weight, height, BMI, %BF, waist circumference (WC), maximum oxygen intake (VO2max), total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides, glucose, eating habits, and physical activity level (PAL) were assessed. In analyzing the data, we used descriptive statistics and paired and unpaired t-tests, using a significance level of 0.05. For assessment of dietary habits, a questionnaire, contingency tables, and the chi-squared test were used, with <0.05 set as the significance level. Results: After 10 weeks of intervention, the IG showed a reduction in BMI (pre: 22.2 &plusmn; 2.1 kg/m2 versus [vs] post: 21.6 &plusmn; 2.1 kg/m2, P< 0.01); WC (pre: 70.1 &plusmn; 6.1 cm vs post: 69.1 &plusmn; 5.8 cm, P< 0.01); %BF (pre: 29.2% &plusmn; 4.6% vs post: 28.0% &plusmn; 4.8%, P < 0.01); systolic blood pressure (P < 0.01); VO2max (P = 0.014); TC (P < 0.01); LDL (P < 0.01); triglycerides (P < 0.01); and intake of candy (P < 0.01) and soda drinks (P < 0.01), while an increase in the consumption of fruit (P < 0.01) and PAL (P < 0.01) were observed. The CG did not show any change in the health parameters assessed. Conclusion: The program was effective in reducing risk factors for cardiovascular disease and the use of an illustrative diary may have been the key to this result, since students were motivated to change their poor eating habits and to increase their physical activity level. Keywords: obesity, cardiovascular disease, physical activity level, body mass index, risk factor, motivation, children, change of habit

Blood glucose responses in humans mirror lactate responses for individual anaerobic threshold and for lactate minimum in track tests

The equilibrium point between blood lactate production and removal (La-min(-)) and the individual anaerobic threshold (IAT) protocols have been used to evaluate exercise. During progressive exercise, blood lactate [La-](b), catecholamine and cortisol concentrations, show exponential increases at upper anaerobic threshold intensities. Since these hormones enhance blood glucose concentrations [Glc](b), this study investigated the [Glc] and [La-](b) responses during incremental tests and the possibility of considering the individual glucose threshold (IGT) and glucose minimum;(Glc(min)) in addition to IAT and La-min(-) in evaluating exercise. A group of 15 male endurance runners ran in four tests on the track 3000 m run (v(3km)); IAT and IGT- 8 x 800 m runs at velocities between 84% and 102% of v(3km); La-min(-) and Glc(min) - after lactic acidosis induced by a 500-m sprint, the subjects ran 8 x 800 m at intensities between 87% and 97% of v(3km); endurance test (ET)- 30 min at the velocity of IAT. Capillary blood (25 mu l) was collected for [La-](b) and [Glc](b) measurements. The TAT and IGT were determined by [La-](b) and [Glc](b) kinetics during the second test. The La-min(-) and Glc(min) were determined considering the lowest [La-] and [Glc](b) during the third test. No differences were observed (P 0.05). We concluded that for these subjects it was possible to evaluate the aerobic capacity by IGT and Glc(min), as well as by IAT and La-min(-)

The phosphatidylinositol/AKT/atypical PKC pathway is involved in the improved insulin sensitivity by DHEA in muscle and liver of rats in vivo

DHEA improves insulin sensitivity and has anti-obesity effect in animal models and men. However, the molecular mechanisms by which DHEA improves insulin action have not been clearly understood. In the present study, we examined the protein levels and phosphorylation state of insulin receptor (IR), IRS-1 and IRS-2, the association between IRSs and PI3K and SHP2, the insulin-induced IRSs associated PI 3-kinase activities, and the phosphorylation status of AKT and atypical PKCzeta/lambda in the liver and the muscle of 6 month-old Wistar rats treated with DHEA. There was no change in IR, IRS-1 and IRS-2 protein levels in both tissues of treated rats analysed by immunoblotting. On the other hand, insulin-induced, IRS-1 tyrosine phosphorylation was increased in both tissues While IRS-2 tyrosyl phosphorylation was increased in liver of DHEA treated group. The PI3-kinase/AKT pathway was increased in the liver and the PI3K/atypical PKCzeta/lambda pathway was increased in the muscle of DHEA treated rats. These data indicate that these regulations of early steps of insulin action may play a role in the intracellular mechanism for the improved insulin sensitivity observed in this animal model. (C) 2004 Elsevier Inc. All rights reserved.761577

Relationships and significance of lactate minimum, critical velocity, heart rate deflection and 3 000 m track-tests for running

The running velocities associated to lactate minimum (V-lm), heart rate deflection (V-HRd), critical velocity (CV), 3000 M (V-3000) and 10000 m performance (V-10km) were compared. Additionally the ability of V-lm and VHRd on identifying sustainable velocities was investigated.Methods. Twenty runners (28.5 +/- 5.9 y) performed 1) 3000 m running test for V3000; 2) an all-out 500 in sprint followed by 6x800 m incremental bouts with blood lactate ([lac]) measurements for V-lm; 3) a continuous velocity-incremented test with heart rate measurements at each 200 m for V-HRd; 4) participants attempted to 30 min of endurance test both at V-lm(ETVlm) and V-HRd(ETVHRd). Additionally, the distance-time and velocity-1/time relationships produced CV by 2 (500 m and 3000 m) or 3 predictive trials (500 m, 3000 m and distance reached before exhaustion during ETVHRd), and a 10 km race was recorded for V-10km.Results. The CV identified by different methods did not differ to each other. The results (m(.)min(-1)) revealed that V-.(lm) (281 +/- 14.8)< CV (292.1 +/- 17.5)=V-10km (291.7 +/- 19.3)< V-HRd (300.8 +/- 18.7)=V-3000 (304 +/- 17.5) with high correlation among parameters (P < 0.001). During ETVlm participants completed 30 min of running while on the ETVHRd they lasted only 12.5 +/- 8.2 min with increasing [lac].Conclusion. We evidenced that CV and Vim track-protocols are valid for running evaluation and performance prediction and the parameters studied have different significance. The V-lm reflects the moderate-high intensity domain (below CV), can be sustained without [lac] accumulation and may be used for long-term exercise while the V-HRd overestimates a running intensity that can be sustained for long-time. Additionally, V-3000 and V-HRd reflect the severe intensity domain (above CV)