Exercise-induced anti-inflammatory effects in overweight/obese women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by exacerbated inflammation, which is implicated in cardiometabolic dysfunction. This study aimed to examine the potential effects of acute exercise on inflammatory responses in obese/overweight PCOS women and their controls. Participants underwent a single bout of moderate-intensity aerobic exercise (30 min at ∼65% of VO2peak). Blood and muscle samples were collected immediately before (PRE) and 60 min after the exercise session. Cytokines (i.e., IL-1ß, IL-6, IL-4, IL-10, TNF-α) were measured both in plasma and in skeletal muscle, and proteins related to inflammatory signaling (IKKα/ß and JNK) were assessed in skeletal muscle. At PRE, PCOS showed elevated muscle TNF-α (+62%, p = 0.0012) and plasma IL-1ß (+76%, p = 0.0010) compared to controls. In PCOS, exercise decreased plasma and muscle TNF-α (-14%, p = 0.0003 and -46%, p = 0.0003), as well as increased plasma and muscle IL-4 (+147%, p = 0.0018 and +62%, p = 0.0474) and plasma IL-10 (+38%, p = 0.0029). Additionally, IKKα/ß and JNK phosphorylation in skeletal muscle, which was higher in PCOS at PRE, was significantly reduced by exercise (-58%, p < 0.0001 and -46%, p < 0.0001, respectively), approaching control levels. Person's correlations between PRE values and delta changes (i.e., exercise effect) showed significant, negative associations for plasma IL-1ß (r = -0.92, p < 0.0001), TNF-α (r = -0.72, p = 0.0100) and IL-6 (r = -0.58, p = 0.05), and muscle TNF-α (r = -0.95, p < 0.0001), IKKα/ß (r = -0.75, p = 0.005), and JNK (r = -0.94, p < 0.0001) in PCOS. In conclusion, exercise can mitigate the inflammatory milieu in women with PCOS. The anti-inflammatory role of exercise could underlie its cardiometabolic protection in PCOS.

Diastereomers of Coibamide A Show Altered Sec61 Client Selectivity and Ligand-Dependent Activity against Patient-Derived Glioma Stem-like Cells.

Coibamide A (CbA) is a cyanobacterial lariat depsipeptide that selectively inhibits multiple secreted and integral membrane proteins from entering the endoplasmic reticulum secretory pathway through binding the alpha subunit of the Sec61 translocon. As a complex peptide-based macrocycle with 13 stereogenic centers, CbA is presumed to adopt a conformationally restricted orientation in the ligand-bound state, resulting in potent antitumor and antiangiogenic bioactivity. A stereochemical structure-activity relationship for CbA was previously defined based on cytotoxicity against established cancer cell lines. However, the ability of synthetic isomers to inhibit the biosynthesis of specific Sec61 substrates was unknown. Here, we report that two less toxic diastereomers of CbA, [L-Hiv2]-CbA and [L-Hiv2, L-MeAla11]-CbA, are pharmacologically active Sec61 inhibitors. Both compounds inhibited the expression of a secreted reporter (Gaussia luciferase), VEGF-A, and a Type 1 membrane protein (VCAM1), while [L-Hiv2]-CbA also decreased the expression of ICAM1 and BiP/GRP78. Analysis of 43 different chemokines in the secretome of SF-268 glioblastoma cells revealed different inhibitory profiles for the two diastereomers. When the cytotoxic potential of CbA compounds was compared against a panel of patient-derived glioblastoma stem-like cells (GSCs), Sec61 inhibitors were remarkably toxic to five of the six GSCs tested. Each ligand showed a distinct cytotoxic potency and selectivity pattern for CbA-sensitive GSCs, with IC50 values ranging from subnanomolar to low micromolar concentrations. Together, these findings highlight the extreme sensitivity of GSCs to Sec61 modulation and the importance of ligand stereochemistry in determining the spectrum of inhibited Sec61 client proteins.

Exercise training reverses cancer-induced oxidative stress and decrease in muscle COPS2/TRIP15/ALIEN.

OBJECTIVE: We tested the hypothesis that exercise training would attenuate metabolic impairment in a model of severe cancer cachexia. METHODS: We used multiple in vivo and in vitro methods to explore the mechanisms underlying the beneficial effects induced by exercise training in tumor-bearing rats. RESULTS: Exercise training improved running capacity, prolonged lifespan, reduced oxidative stress, and normalized muscle mass and contractile function in tumor-bearing rats. An unbiased proteomic screening revealed COP9 signalosome complex subunit 2 (COPS2) as one of the most downregulated proteins in skeletal muscle at the early stage of cancer cachexia. Exercise training normalized muscle COPS2 protein expression in tumor-bearing rats and mice. Lung cancer patients with low endurance capacity had low muscle COPS2 protein expression as compared to age-matched control subjects. To test whether decrease in COPS2 protein levels could aggravate or be an intrinsic compensatory mechanism to protect myotubes from cancer effects, we performed experiments in vitro using primary myotubes. COPS2 knockdown in human myotubes affected multiple cellular pathways, including regulation of actin cytoskeleton. Incubation of cancer-conditioned media in mouse myotubes decreased F-actin expression, which was partially restored by COPS2 knockdown. Direct repeat 4 (DR4) response elements have been shown to positively regulate gene expression. COPS2 overexpression decreased the DR4 activity in mouse myoblasts, and COPS2 knockdown inhibited the effects of cancer-conditioned media on DR4 activity. CONCLUSIONS: These studies demonstrated that exercise training may be an important adjuvant therapy to counteract cancer cachexia and uncovered novel mechanisms involving COPS2 to regulate myotube homeostasis in cancer cachexia.

GLUT4 translocation is not impaired after acute exercise in skeletal muscle of women with obesity and polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to examine the effects of acute exercise on insulin signaling in skeletal muscle of women with polycystic ovary syndrome (PCOS) and controls (CTRL). METHODS: Fifteen women with obesity and PCOS and 12 body mass index-matched CTRL participated in this study. Subjects performed a 40-min single bout of exercise. Muscle biopsies were performed before and 60 min after exercise. Selected proteins were assessed by Western blotting. RESULTS: CTRL, but not PCOS, showed a significant increase in PI3-k p85 and AS160 Thr 642 after a single bout of exercise (P = 0.018 and P = 0.018, respectively). Only PCOS showed an increase in Akt Thr 308 and AMPK phosphorylation after exercise (P = 0.018 and P = 0.018, respectively). Total GLUT4 expression was comparable between groups (P > 0.05). GLUT4 translocation tended to be significantly higher in both groups after exercise (PCOS: P = 0.093; CTRL: P = 0.091), with no significant difference between them (P > 0.05). CONCLUSIONS: A single bout of exercise elicited similar GLUT4 translocation in skeletal muscle of PCOS and CTRL, despite a slightly differential pattern of protein phosphorylation. The absence of impairment in GLUT4 translocation suggests that PCOS patients with obesity and insulin resistance may benefit from exercise training.

Associação entre o nível de atividade física de lazer e o desempenho cognitivo em crianças saudáveis / Association between physical activity level of leisure and cognitive performance in healthy children

O objetivo do presente estudo foi avaliar a associação da atividade física de lazer sobre o desempenho cognitivo em crianças saudáveis. Foi conduzido um estudo transversal, no qual 100 crianças (10,8 ± 0,6 anos) foram divididas em dois grupos: "Insuficientemente Ativos" (IA) e "Ativos" (A). O desempenho cognitivo foi avaliado pelo Teste de Memória e Aprendizagem de Figuras, o Teste de Stroop e o Teste de Trilhas. Foi observada uma diferença estatisticamente significante entre os grupos para a condição de memória incidental do Teste de Memória e Aprendizagem de Figuras (IA: 6,6 ± 1,37 versus A: 7,1 ± 1,24; p = 0,03). Entretanto, não foram observadas diferenças estatisticamente significativas entre os grupos para todas as outras variáveis. Esses achados revelam uma influência positiva da atividade física de lazer sobre a memória incidental de crianças saudáveis, mas não a memória tardia, a flexibilidade mental e o controle inibitório. Estudos com maiores amostras e medidas diretas de avaliação de nível de atividade física precisam ser conduzidos para confirmar esses achados...

The aim of this study was to assess the association of leisure physical activity on cognitive performance in healthy children. It was performed a cross-sectional study in which 100 children (10.8 ± 0.6 years of age) were divided into two groups as follows: "Insufficiently actives" (IA) and "Actives" (A). The cognitive performance was assessed by Memory and Learning of Figure Test, Stroop Test, Trail Making Test. It was observed a significant difference between groups for an incidental memory task from Memory and Learning of Figure Test (IA: 6.6 ± 1.4 versus A: 7.1 ± 1.2; p = 0.03). However, no significant differences were noted for any other variables. These findings reveal a positive influence of leisure physical activity on the incidental memory, but not long-term memory, mental flexibility, and inhibitory control in healthy children. Future studies with larger samples and direct measures of physical activity levels must be conducted to confirm these results...