CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction.

BACKGROUND: Modulated by differences in genetic and environmental factors, laboratory mice often show progressive weight gain, eventually leading to obesity and metabolic dyshomeostasis. Since the geroneuroprotector CMS121 has a positive effect on energy metabolism in a mouse model of type 2 diabetes, we investigated the potential of CMS121 to counteract the metabolic changes observed during the ageing process of wild type mice. METHODS: Control or CMS121-containing diets were supplied ad libitum for 6 months, and mice were sacrificed at the age of 7 months. Blood, adipose tissue, and liver were analyzed for glucose, lipids, and protein markers of energy metabolism. RESULTS: The CMS121 diet induced a 40% decrease in body weight gain and improved both glucose and lipid indexes. Lower levels of hepatic caspase 1, caspase 3, and NOX4 were observed with CMS121 indicating a lower liver inflammatory status. Adipose tissue from CMS121-treated mice showed increased levels of the transcription factors Nrf1 and TFAM, as well as markers of mitochondrial electron transport complexes, levels of GLUT4 and a higher resting metabolic rate. Metabolomic analysis revealed elevated plasma concentrations of short chain acylcarnitines and butyrate metabolites in mice treated with CMS121. CONCLUSIONS: The diminished de novo lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term.

Exercise Improves Lung Inflammation, but Not Lung Remodeling and Mechanics in a Model of Bleomycin-Induced Lung Fibrosis.

INTRODUCTION: Moderate aerobic exercise training accelerates the resolution of lung fibrosis in a model of bleomycin-induced pulmonary fibrosis. However, whether it can inhibit the development of lung fibrosis is unknown. MATERIALS AND METHODS: C57Bl/6 mice were distributed into four groups: Control (Co), Exercise (Exe), Bleomycin (Bleo), and Bleomycin+Exercise (Bleo+Exe). A single bleomycin dose (1.5 UI/kg) was administered orotracheally and treadmill exercise started in the same day, enduring for 4 weeks, 5x/week, 60 minutes/session, at moderate intensity. Lung mechanics, systemic and pulmonary inflammation, and lung remodeling were evaluated. Lung homogenates were used to evaluate the antioxidant status. RESULTS: Total cells, macrophages, lymphocytes, and neutrophils numbers, in agreement with IL-6 levels, were higher in the BAL and serum of Bleo group, compared to other groups. In addition, lung levels of LTB4 in Bleo were higher than other groups, whereas SOD activity and nitric oxide levels in exercised groups (Exe and Exe+Bleo) compared to the Bleo group. Lung GPX activity was lower in Bleo and Exe+Bleo groups compared to others. Exe and Exe+Bleo groups also showed higher IL-10 expression by lung macrophages than other groups, whereas TGF-ß expression was higher in Exe, Bleo, and Exe+Bleo groups compared to control. CCR7 expression was induced only in the Exe group. However, exercise did not improve lung remodeling and mechanics, or serum and pulmonary levels of VEGF, IGF-1, and TGF-ß. CONCLUSION: Aerobic exercise training initiated concomitantly with induction of pulmonary fibrosis reduces lung and systemic inflammation but fails to inhibit lung fibrosis and mechanics impairment.

Pulmonary and muscle profile in pneumosepsis: A temporal analysis of inflammatory markers.

In sepsis, greater understanding of the inflammatory mechanism involved would provide insights into the condition and into its extension to the muscular apparatus in critically ill patients. Therefore, this study evaluates the inflammatory profile of pneumosepsis induced by Klebsiella pneumoniae (K.p.) in lungs and skeletal muscles during the first 72 h. Male BALB/c mice were divided into 4 groups, submitted to intratracheal inoculation of K.p. at a concentration of 2 × 108 (PS) or PBS, and assessed after 24 (PS24), 48 (PS48) and 72 (PS72) hours. The Maximum Physical Capacity Test (MPCT) was performed before and after induction. Pulmonary inflammation was assessed by total cell number, nitric oxide levels (NOx), IL-1ß and TNF-α levels in bronchoalveolar lavage fluid (BALF); inflammation and muscle trophism were evaluated by the levels of TNF-α, IL-6, TGF-ß and BDNF by ELISA and NF-κB by western blotting in muscle tissue. Cells and colony forming units (CFU) were also analyzed in blood samples. The PS groups showed an increase in total cells in the BALF (p < 0.05), as well in the number of granulocytes in the blood (p < 0.05) and a decrease in performance in the MPCT (p < 0.05). NOx levels showed significant increase in PS72, when compared to Control group (p = 0.03). The PS24 showed a significant increase lung in TNF-α levels (p < 0.001) and in CFU (p = 0.013). We observed an increase in muscular IL-6 and nuclear NF-κB levels in PS24 group, when compared to PS48 and Control groups (p < 0.05). Nevertheless, mild signs of injury in the skeletal muscle tissue does not support the idea of an early muscular injury in this experimental model, suggesting that the low performance of the animals during the MPCT may be related to lung inflammation.

High-Intensity Exercise Prevents Disturbances in Lung Inflammatory Cytokines and Antioxidant Defenses Induced by Lipopolysaccharide.

In this study, we evaluated the effects of high-intensity swimming in an experimental model of acute lung injury (ALI) induced by lipopolysaccharide (LPS) on lung inflammation and antioxidant defenses. Balb/C male mice were submitted to exercise (30 min/day, 5 days/week, for a period of 3 weeks) prior to LPS instillation in the lung. Twenty-four hours after delivery of LPS (10 µg/animal), mice were euthanized and bronchoalveolar fluid (BALF) was obtained for cell counting and analysis of cytokines by ELISA. Lung tissue was used to evaluate antioxidant defenses. LPS instillation resulted in an increase in total and mononuclear cells, IL-1ß, TNF-α, and IL-6 in BALF. LPS instillation also altered IL-10 and IL-ra levels in BALF and induced antioxidant defenses (glutathione, superoxide dismutase, catalase, and glutathione peroxidase) in the lung. Protein carbonyl increased in the LPS-treated animals. High-intensity swimming prevented all these changes induced by LPS. Significance: Therefore, this experimental protocol of high-intensity swimming showed a protective effect on ALI, decreasing inflammatory processes and preventing disturbances in antioxidant defenses into the lungs.