Ganoderma lucidum dry extract supplementation modulates T lymphocyte function in older women.

Ganoderma lucidum (a mushroom used in traditional Chinese medicine) compounds may attenuate ageing-related physiological changes and restore normal immunity. However, studies on the physiological effects of Ganoderma lucidum dry extract food supplements are few. Therefore, here, we aimed to investigate the effects of Ganoderma lucidum dry extract food supplement on the lymphocyte function of older women. This was a double-blind clinical trial (n 60) with a final 39 older volunteers, divided into two groups Ganoderma lucidum (n 23) and placebo (n 16). The Ganoderma lucidum group received 2000 mg/d of Ganoderma lucidum dry extract for 8 weeks. We used flow cytometry to determine the lymphocyte profile. CD4+ lymphocyte gene expression was evaluated by real-time polymerase chain reaction. We observed that in the Ganoderma lucidum group, concanavalin A stimulation increased lymphocyte proliferation. Further, we observed an increase in expression of Forkhead box P3, transforming growth factor-beta, IL-10, IL-6, retinoic acid receptor-related orphan receptor gamma, GATA-binding protein 3 and interferon gamma genes in the Ganoderma lucidum group. Furthermore, in the Ganoderma lucidum group, ionomycin and phorbol 12-myristate 13-acetate stimulation led to decrease in Th17+ cells and increase in Th2+ cells. Thus, in older women, Ganoderma lucidum regulates T lymphocyte function leading to a predominant anti-inflammatory action but does not induce T lymphocyte proliferation through CD28 signalling pathway.

Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice.

AIMS/HYPOTHESIS: Athletes exhibit increased muscle insulin sensitivity, despite increased intramuscular triacylglycerol content. This phenomenon has been coined the 'athlete's paradox' and is poorly understood. Recent findings suggest that the subcellular distribution of sn-1,2-diacylglycerols (DAGs) in the plasma membrane leading to activation of novel protein kinase Cs (PKCs) is a crucial pathway to inducing insulin resistance. Here, we hypothesised that regular aerobic exercise would preserve muscle insulin sensitivity by preventing increases in plasma membrane sn-1,2-DAGs and activation of PKCε and PKCθ despite promoting increases in muscle triacylglycerol content. METHODS: C57BL/6J mice were allocated to three groups (regular chow feeding [RC]; high-fat diet feeding [HFD]; RC feeding and running wheel exercise [RC-EXE]). We used a novel LC-MS/MS/cellular fractionation method to assess DAG stereoisomers in five subcellular compartments (plasma membrane [PM], endoplasmic reticulum, mitochondria, lipid droplets and cytosol) in the skeletal muscle. RESULTS: We found that the HFD group had a greater content of sn-DAGs and ceramides in multiple subcellular compartments compared with the RC mice, which was associated with an increase in PKCε and PKCθ translocation. However, the RC-EXE mice showed, of particular note, a reduction in PM sn-1,2-DAG and ceramide content when compared with HFD mice. Consistent with the PM sn-1,2-DAG-novel PKC hypothesis, we observed an increase in phosphorylation of threonine1150 on the insulin receptor kinase (IRKT1150), and reductions in insulin-stimulated IRKY1162 phosphorylation and IRS-1-associated phosphoinositide 3-kinase activity in HFD compared with RC and RC-EXE mice, which are sites of PKCε and PKCθ action, respectively. CONCLUSIONS/INTERPRETATION: These results demonstrate that lower PKCθ/PKCε activity and sn-1,2-DAG content, especially in the PM compartment, can explain the preserved muscle insulin sensitivity in RC-EXE mice.

Essential metabolism required for T and B lymphocyte functions: an update.

Lymphocytes act as regulatory and effector cells in inflammation and infection situations. A metabolic switch towards glycolytic metabolism predominance occurs during T lymphocyte differentiation to inflammatory phenotypes (Th1 and Th17 cells). Maturation of T regulatory cells, however, may require activation of oxidative pathways. Metabolic transitions also occur in different maturation stages and activation of B lymphocytes. Under activation, B lymphocytes undergo cell growth and proliferation, associated with increased macromolecule synthesis. The B lymphocyte response to an antigen challenge requires an increased adenosine triphosphate (ATP) supply derived mainly through glycolytic metabolism. After stimulation, B lymphocytes increase glucose uptake, but they do not accumulate glycolytic intermediates, probably due to an increase in various metabolic pathway 'end product' formation. Activated B lymphocytes are associated with increased utilization of pyrimidines and purines for RNA synthesis and fatty acid oxidation. The generation of plasmablasts and plasma cells from B lymphocytes is crucial for antibody production. Antibody production and secretion require increased glucose consumption since 90% of consumed glucose is needed for antibody glycosylation. This review describes critical aspects of lymphocyte metabolism and functional interplay during activation. We discuss the primary fuels for the metabolism of lymphocytes and the particularities of T and B cell metabolism, including the differentiation of lymphocytes, stages of development of B cells, and the production of antibodies.

The paradoxical lean phenotype of hypothyroid mice is marked by increased adaptive thermogenesis in the skeletal muscle.

Obesity is a major health problem worldwide, given its growing incidence and its association with a variety of comorbidities. Weight gain results from an increase in energy intake without a concomitant increase in energy expenditure. To combat the obesity epidemic, many studies have focused on the pathways underlying satiety and hunger signaling, while other studies have concentrated on the mechanisms involved in energy expenditure, most notably adaptive thermogenesis. Hypothyroidism in humans is typically associated with a decreased basal metabolic rate, lower energy expenditure, and weight gain. However, hypothyroid mouse models have been reported to have a leaner phenotype than euthyroid controls. To elucidate the mechanism underlying this phenomenon, we used a drug-free mouse model of hypothyroidism: mice lacking the sodium/iodide symporter (NIS), the plasma membrane protein that mediates active iodide uptake in the thyroid. In addition to being leaner than euthyroid mice, owing in part to reduced food intake, these hypothyroid mice show signs of compensatory up-regulation of the skeletal-muscle adaptive thermogenic marker sarcolipin, with an associated increase in fatty acid oxidation (FAO). Neither catecholamines nor thyroid-stimulating hormone (TSH) are responsible for sarcolipin expression or FAO stimulation; rather, thyroid hormones are likely to negatively regulate both processes in skeletal muscle. Our findings indicate that hypothyroidism in mice results in a variety of metabolic changes, which collectively lead to a leaner phenotype. A deeper understanding of these changes may make it possible to develop new strategies against obesity.

Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice.

Adiponectin has emerged as a potential therapy for type 2 diabetes mellitus, but the molecular mechanism by which adiponectin reverses insulin resistance remains unclear. Two weeks of globular adiponectin (gAcrp30) treatment reduced fasting plasma glucose, triglyceride (TAG), and insulin concentrations and reversed whole-body insulin resistance, which could be attributed to both improved insulin-mediated suppression of endogenous glucose production and increased insulin-stimulated glucose uptake in muscle and adipose tissues. These improvements in liver and muscle sensitivity were associated with ∼50% reductions in liver and muscle TAG and plasma membrane (PM)-associated diacylglycerol (DAG) content and occurred independent of reductions in total ceramide content. Reductions of PM DAG content in liver and skeletal muscle were associated with reduced PKCε translocation in liver and reduced PKCθ and PKCε translocation in skeletal muscle resulting in increased insulin-stimulated insulin receptor tyrosine1162 phosphorylation, IRS-1/IRS-2-associated PI3-kinase activity, and Akt-serine phosphorylation. Both gAcrp30 and full-length adiponectin (Acrp30) treatment increased eNOS/AMPK activation in muscle and muscle fatty acid oxidation. gAcrp30 and Acrp30 infusions also increased TAG uptake in epididymal white adipose tissue (eWAT), which could be attributed to increased lipoprotein lipase (LPL) activity. These data suggest that adiponectin and adiponectin-related molecules reverse lipid-induced liver and muscle insulin resistance by reducing ectopic lipid storage in these organs, resulting in decreased plasma membrane sn-1,2-DAG-induced nPKC activity and increased insulin signaling. Adiponectin mediates these effects by both promoting the storage of TAG in eWAT likely through stimulation of LPL as well as by stimulation of AMPK in muscle resulting in increased muscle fat oxidation.

Updating futsal physiology, immune system, and performance.

Futsal promotes stress by handling the ball, physical contact, and exhaustive muscle contractions, elevating the risks for injury, oxidative stress, and inflammation after a training session or a match. In this review, we critically evaluate the more recent advances in the performance and health of futsal players. We searched the effects of futsal on performance, physiological parameters, muscle injury, inflammation, and oxidative stress. Although the stressful factors apply to all futsal players, goalkeepers require special attention during the competition and the recovery phase. We also show that the FIFA injury prevention programme, called The 11+, is effective in improving athletic performance and avoiding injury in futsal players. Research with different training durations and intensities and a wider range of studies involving oxidative stress, inflammation, and physiological mechanisms are of interest to design a more precise map of the biochemical regulation of training load and competition season in futsal.

Host cell glutamine metabolism as a potential antiviral target.

A virus minimally contains a nucleic acid genome packaged by a protein coat. The genome and capsid together are known as the nucleocapsid, which has an envelope containing a lipid bilayer (mainly phospholipids) originating from host cell membranes. The viral envelope has transmembrane proteins that are usually glycoproteins. The proteins in the envelope bind to host cell receptors, promoting membrane fusion and viral entry into the cell. Virus-infected host cells exhibit marked increases in glutamine utilization and metabolism. Glutamine metabolism generates ATP and precursors for the synthesis of macromolecules to assemble progeny viruses. Some compounds derived from glutamine are used in the synthesis of purines and pyrimidines. These latter compounds are precursors for the synthesis of nucleotides. Inhibitors of glutamine transport and metabolism are potential candidate antiviral drugs. Glutamine is also an essential nutrient for the functions of leukocytes (lymphocyte, macrophage, and neutrophil), including those in virus-infected patients. The increased glutamine requirement for immune cell functions occurs concomitantly with the high glutamine utilization by host cells in virus-infected patients. The development of antiviral drugs that target glutamine metabolism must then be specifically directed at virus-infected host cells to avoid negative effects on immune functions. Therefore, the aim of this review was to describe the landscape of cellular glutamine metabolism to search for potential candidates to inhibit glutamine transport or glutamine metabolism.

Physical exercise increases global and gene-specific (interleukin-17 and interferon-γ) DNA methylation in lymphocytes from aged women.

NEW FINDINGS: What is the central question of this study? Is lymphocyte DNA methylation differentially modulated by resistance training and aerobic exercise in older women? What is the main finding and its importance? The practice of resistance training led to an increased global DNA methylation in lymphocytes. The exercise-induced increase of inflammatory genes methylation may be associated with immune function impairment during ageing. ABSTRACT: Ageing-induced increase in inflammatory gene expression through a reduction in DNA methylation might contribute to chronic diseases. Regular physical exercise practices, in turn, are associated with a decrease in the incidence of inflammatory diseases. We herein evaluated the effects of three exercise modalities on lymphocyte global and gene-specific (interferon γ (IFN-γ) and interleukin 17A (IL-17A) DNA methylation in aged women (68 ± 7.5 years). This cross-sectional study included 86 women, divided into four groups according to the physical exercise practice: 20 were practicing resistance training (RT); 24 were practicing water aerobics exercise (W); 22 were practicing water aerobics and resistance exercise (RWT), and 20 did not practice any physical exercise (CON). We evaluated volunteer functional capability using the Timed Up and Go (TUG) test, global lymphocyte DNA methylation by enzyme-linked immunosorbent assay, IFN-γ and IL-17A methylation by qPCR and CD4+ IFN-γ+ and CD4+ IL-17+ cell percentage by flow cytometry. The three physically exercised groups performed functional capability tests in a shorter period and showed a higher global lymphocyte DNA methylation and methylated CpGs of IL-17A and IFN-γ promoter regions than the control group. The practice of resistance training (RT and RWT groups) lead to high global DNA methylation. The combination of resistance training and aerobic exercise led to the increase of lymphocyte IL-17A and IFN-γ gene methylation induced by each separately. However, the percentage of IFN-γ+ and IL-17+ cells was lower only in the RT group. The exercise-induced increase of inflammatory-gene methylation may be associated with gene expression changes and immune function impairment during ageing.

COVID-19 Pandemic in Brazil: History, Characteristics, and Evolution.

This chapter describes the eruption and spread of the SARS-COV-2 virus throughout Brazil. We also describe the governmental measures used to combat the virus, the regional influences impacting viral spreading, and the prevalence of the disease in different Brazilian subpopulations. It is hoped that such information will contribute to the control of the virus and help to prepare the region for future pandemics.

Recreational Dance Practice Modulates Lymphocyte Profile and Function in Diabetic Women.

This study aimed to investigate the impact of a 16-week dance-based aerobic exercise program on lymphocyte function in healthy and type 2 diabetes mellitus (T2DM) women. We enrolled 23 women: 11 with T2DM and 12 non-diabetic controls. Initially, we performed anthropometry and body composition measurements, afterwards, plasma levels of C-reactive protein, lipids, and glucose were determined. We used flow cytometry to measure the CD25 and CD28 expression in circulating lymphocytes, T-regulatory (Treg) cell percentage, lymphocyte proliferation, and cytokines released by cultured lymphocytes. The T2DM group had a lower proportion of CD28+ cells and a higher percentage of Treg lymphocytes and proliferative capacity at the baseline compared with the control group. After 16 weeks of the program, differences in lymphocytes between the T2DM and the control groups disappeared. The dance program promoted IL-10 increase in both groups. We found decreased IL-4, IL-2, and IL-6 secretion in lymphocytes from the control group and increased IL-17 secretion and IL-10/IL-17 ratio in the T2DM group after the program. The program promoted marked changes in lymphocytes in diabetic women, leading to a balance between the different profiles.

Myotube Protein Content Associates with Intracellular L-Glutamine Levels.

BACKGROUND/AIMS: Skeletal mass loss is reported in several catabolic conditions and it has been associated with a reduced intracellular L-glutamine content. We investigated the association of intracellular L-glutamine concentration with the protein content in skeletal muscle cells. METHODS: We cultivated C2C12 myotubes in the absence or presence of 2 (reference condition), 8 or 16 mM L-glutamine for 48 hours, and the variations in the contents of amino acids and proteins measured. We used an inhibitor of L-glutamine synthesis (L-methionine sulfoximine - MSO) to promote a further reduction in intracellular L-glutamine levels. Amino acids contents in cells and media were measured using LC-MS/MS. We measured changes in phosphorylated Akt, RP-S6, and 4E-BP1contents in the absence or presence of insulin by western blotting. RESULTS: Reduced intracellular L-glutamine concentration was associated with decreased protein content and increased protein breakdown. Low intracellular glutamine levels were also associated with decreased p-Akt contents in the presence of insulin. A further decrease in intracellular L-glutamine caused by glutamine synthetase inhibitor reduced protein content and levels of amino acids generated from glutamine metabolism and increased bAib still further. Cells exposed to high medium glutamine levels did not have any change in protein content but exhibited increased contents of the amino acids derived from L-glutamine metabolism. CONCLUSION: Intracellular L-glutamine levels per se play a role in the control of protein content in skeletal muscle myotubes.

Fenofibrate reverses changes induced by high-fat diet on metabolism in mice muscle and visceral adipocytes.

The effect of fenofibrate on the metabolism of skeletal muscle and visceral white adipose tissue of diet-induced obese (DIO) mice was investigated. C57BL/6J male mice were fed either a control or high-fat diet for 8 weeks. Fenofibrate (50 mg/Kg BW, daily) was administered by oral gavage during the last two weeks of the experimental period. Insulin-stimulated glucose metabolism in soleus muscles, glucose tolerance test, insulin tolerance test, indirect calorimetry, lipolysis of visceral white adipose tissue, expression of miR-103-3p in adipose tissue, and miR-1a, miR-133a/b, miR-206, let7b-5p, miR-23b-3p, miR-29-3p, miR-143-3p in soleus muscle, genes related to glucose and fatty acid metabolism in adipose tissue and soleus muscle, and proteins (phospho-AMPKα2, Pgc1α, Cpt1b), intramuscular lipid staining, and activities of fatty acid oxidation enzymes in skeletal muscle were investigated. In DIO mice, fenofibrate prevented weight gain induced by HFD feeding by increasing energy expenditure; improved whole body glucose homeostasis, and in skeletal muscle, increased insulin dependent glucose uptake, miR-1a levels, reduced intramuscular lipid accumulation, and phospho-AMPKα2 levels. In visceral adipose tissue of obese mice, fenofibrate decreased basal lipolysis rate and visceral adipocytes hypertrophy, and induced the expression of Glut-4, Irs1, and Cav-1 mRNA and miR-103-3p suggesting a higher insulin sensitivity of the adipocytes. The evidence is presented herein that beneficial effects of fenofibrate on body weight, glucose homeostasis, and muscle metabolism might be related to its action in adipose tissue. Moreover, fenofibrate regulates miR-1a-3p in soleus and miR-103-3p in adipose tissue, suggesting these microRNAs might contribute to fenofibrate beneficial effects on metabolism.

Influence of trans fatty acids on glucose metabolism in soleus muscle of rats fed diets enriched in or deprived of linoleic acid.

PURPOSE: Industrial trans fatty acid (TFA) intake leads to impaired glucose metabolism. However, the overall effects reported are inconsistent and vary with the dietary FA composition and TFA isomer type and levels. We investigated TFA effects on glucose uptake, incorporation and oxidation, and glycogen synthesis in incubated soleus muscle under basal conditions or after treatment with insulin and/or palmitate. METHODS: Male Wistar rats were fed either linoleic acid (LA)-enriched (+LA) or LA-deprived (-LA) diet, supplemented (+LA + TFA or -LA + TFA) or not with TFA, for 60 days. Soleus muscle glucose metabolism was assessed in the absence or presence of insulin and/or palmitic acid. RESULTS: Under basal conditions, TFA enhanced glucose uptake and oxidation regardless of the LA status. Both TFA-supplemented groups had lower insulin response to glucose metabolism. Under insulin-stimulated conditions, TFA prevented the palmitate inhibition of muscle glucose uptake and metabolism in the +LA + TFA group. CONCLUSION: Dietary TFA enhanced glucose utilization in incubated soleus muscle under basal conditions and prevented the palmitate-induced inhibition in insulin-stimulated conditions. However, TFA reduced the insulin response to glucose uptake and metabolism. The effects mentioned above were influenced by the FA profile modifications induced by the dietary LA levels, suggesting that lipid metabolization and incorporation into plasma membrane are important determining factors of glucose metabolism and insulin sensitivity.

Short-term treatment with metformin reduces hepatic lipid accumulation but induces liver inflammation in obese mice.

The study aimed to evaluate the metabolic and inflammatory effects of short-term treatments (10 days) with metformin (MET) on the NAFLD caused by a high-fat diet (HFD) in C57BL/6 mice. After the treatment, histological liver slices were obtained, hepatocytes and macrophages were extracted and cultured with phosphate buffered saline, LPS (2.5 µg/mL) and MET (1 µM) for 24 h. Cytokine levels were determined by ELISA. NAFLD caused by the HFD was partially reduced by MET. The lipid accumulation induced by the HFD was not associated with liver inflammation; however, MET seemed to promote pro-inflammatory effects in liver, since it increased hepatic concentration of IL-1ß, TNF-α, IL-6, MCP-1 and IFN-γ. Similarly, MET increased the concentration of IL-1ß, IL-6 in hepatocyte cultures. However, in macrophages culture, MET lowered levels of IL-1ß, IL-6 and TNF-α stimulated by LPS. Overall, MET reduced liver NAFLD but promoted hepatocyte increase in pro-inflammatory cytokines, thus, leading to liver inflammation.

Role of microRNAs on the Regulation of Mitochondrial Biogenesis and Insulin Signaling in Skeletal Muscle.

Mitochondria play a critical role in several cellular processes and cellular homeostasis. Mitochondrion dysfunction has been correlated with numerous metabolic diseases such as obesity and type 2 diabetes. MicroRNAs are non-coding RNAs that have emerged as key regulators of cell metabolism. The microRNAs act as central regulators of metabolic gene networks by leading to the degradation of their target messenger RNA or repression of protein translation. In addition, vesicular and non-vesicular circulating miRNAs exhibit a potential role as mediators of the cross-talk between the skeletal muscle and other tissues/organs. In this review, we will focus on the emerging knowledge of miRNAs controlling mitochondrial function and insulin signaling in skeletal muscle cells. J. Cell. Physiol. 232: 958-966, 2017. © 2016 Wiley Periodicals, Inc.

Regulatory principles in metabolism-then and now.

The importance of metabolic pathways for life and the nature of participating reactions have challenged physiologists and biochemists for over a hundred years. Eric Arthur Newsholme contributed many original hypotheses and concepts to the field of metabolic regulation, demonstrating that metabolic pathways have a fundamental thermodynamic structure and that near identical regulatory mechanisms exist in multiple species across the animal kingdom. His work at Oxford University from the 1970s to 1990s was groundbreaking and led to better understanding of development and demise across the lifespan as well as the basis of metabolic disruption responsible for the development of obesity, diabetes and many other conditions. In the present review we describe some of the original work of Eric Newsholme, its relevance to metabolic homoeostasis and disease and application to present state-of-the-art studies, which generate substantial amounts of data that are extremely difficult to interpret without a fundamental understanding of regulatory principles. Eric's work is a classical example of how one can unravel very complex problems by considering regulation from a cell, tissue and whole body perspective, thus bringing together metabolic biochemistry, physiology and pathophysiology, opening new avenues that now drive discovery decades thereafter.

Regulation of Gene Expression by Exercise-Related Micrornas.

Gene expression control by microRNAs (miRs) is an important mechanism for maintenance of cellular homeostasis in physiological and pathological conditions as well as in response to different stimuli including nutritional factors and exercise. MiRs are involved in regulation of several processes such as growth and development, fuel metabolism, insulin secretion, immune function, miocardium remodeling, cell proliferation, differenciation, survival, and death. These molecules have also been proposed to be potential biomarkers and/or therapeutical targets in obesity, type 2 diabetes mellitus, cardiovascular diseases, metabolic syndrome, and cancer. MiRs are released by most cells and potentially act on intercellular communication to borderer or distant cells. Various studies have been performed to elucidate the involvement of miRs in exercise-induced effects. The aims of this review are: 1) to bring up the main advances for the comprehension of the mechanisms of action of miRs; 2) to present the main results on miR involvement in physical exercise; 3) to discuss the physiological effects of miRs modified by exercise. The state of the art and the perspectives on miRs associated with physical exercise will be presented. Thus, this review is important for updating recent advances and driving further strategies and studies on the exercise-related miR research.

Contractile function recovery in severely injured gastrocnemius muscle of rats treated with either oleic or linoleic acid.

NEW FINDINGS: What is the central question of this study? Oleic and linoleic acids modulate fibroblast proliferation and myogenic differentiation in vitro. However, their in vivo effects on muscle regeneration have not yet been examined. We investigated the effects of either oleic or linoleic acid on a well-established model of muscle regeneration after severe laceration. What is the main finding and its importance? We found that linoleic acid increases fibrous tissue deposition and impairs muscle regeneration and recovery of contractile function, whereas oleic acid has the opposite effects in severely injured gastrocnemius muscle, suggesting that linoleic acid has a harmful effect and oleic acid a potential therapeutic effect on muscle regeneration. Oleic and linoleic acids control fibroblast proliferation and myogenic differentiation in vitro; however, there was no study in skeletal muscle in vivo. The aim of this study was to evaluate the effects of either oleic or linoleic acid on the fibrous tissue content (collagen deposition) of muscle and recovery of contractile function in rat gastrocnemius muscle after being severely injured by laceration. Rats were supplemented with either oleic or linoleic acid for 4 weeks after laceration [0.44 g (kg body weight)-1 day-1 ]. Muscle injury led to an increase in oleic-to-stearic acid and palmitoleic-to-palmitic acid ratios, suggesting an increase in Δ9 desaturase activity. Increased fibrous tissue deposition and reduced isotonic and tetanic specific forces and resistance to fatigue were observed in the injured muscle. Supplementation with linoleic acid increased the content of eicosadienoic (20:2, n-6) and arachidonic (20:4, n-6) acids, reduced muscle mass and fibre cross-sectional areas, increased fibrous tissue deposition and further reduced the isotonic and tetanic specific forces and resistance to fatigue induced by laceration. Supplementation with oleic acid increased the content of docosahexaenoic acid (22:6, n-3) and abolished the increase in fibrous tissue area and the decrease in isotonic and tetanic specific forces and resistance to fatigue induced by muscle injury. We concluded that supplementation with linoleic acid impairs muscle regeneration and increases fibrous tissue deposition, resulting in impaired recovery of contractile function. Oleic acid supplementation reduced fibrous tissue deposition and improved recovery of contractile function, attenuating the tissue damage caused by muscle injury.

Celecoxib and Ibuprofen Restore the ATP Content and the Gluconeogenesis Activity in the Liver of Walker-256 Tumor-Bearing Rats.

BACKGROUND/AIMS: The main purpose of this study was to investigate the effects of celecoxib and ibuprofen, both non-steroidal anti-inflammatory drugs (NSAIDs), on the decreased gluconeogenesis observed in liver of Walker-256 tumor-bearing rats. METHODS: Celecoxib and ibuprofen (both at 25 mg/Kg) were orally administered for 12 days, beginning on the same day when the rats were inoculated with Walker-256 tumor cells. RESULTS: Celecoxib and ibuprofen treatment reversed the reduced production of glucose, pyruvate, lactate and urea from alanine as well as the reduced production of glucose from pyruvate and lactate in perfused liver from tumor-bearing rats. Besides, celecoxib and ibuprofen treatment restored the decreased ATP content, increased triacylglycerol levels and reduced mRNA expression of carnitine palmitoyl transferase 1 (CPT1), while ibuprofen treatment restored the reduced mRNA expression of peroxisome proliferator-activated receptor alpha (PPARα) in the liver of tumor-bearing rats. Both treatments tended to decrease TNFα, IL6 and IL10 in the liver of tumor-bearing rats. Finally, the treatment with celecoxib, but not with ibuprofen, reduced the growth of Walker-256 tumor. CONCLUSION: Celecoxib and ibuprofen restored the decreased gluconeogenesis in the liver of Walker-256 tumor-bearing rats. These effects did not involve changes in tumor growth and probably occurred by anti-inflammatory properties of these NSAIDs, which increased expression of genes associated with fatty acid oxidation (PPARα and CPT1) and consequently the ATP production, normalizing the energy status in the liver of tumor-bearing rats.

PPARγ activation attenuates glucose intolerance induced by mTOR inhibition with rapamycin in rats.

mTOR inhibition with rapamycin induces a diabetes-like syndrome characterized by severe glucose intolerance, hyperinsulinemia, and hypertriglyceridemia, which is due to increased hepatic glucose production as well as reduced skeletal muscle glucose uptake and adipose tissue PPARγ activity. Herein, we tested the hypothesis that pharmacological PPARγ activation attenuates the diabetes-like syndrome associated with chronic mTOR inhibition. Rats treated with the mTOR inhibitor rapamycin (2 mg·kg(-1)·day(-1)) in combination or not with the PPARγ ligand rosiglitazone (15 mg·kg(-1)·day(-1)) for 15 days were evaluated for insulin secretion, glucose, insulin, and pyruvate tolerance, skeletal muscle and adipose tissue glucose uptake, and insulin signaling. Rosiglitazone corrected fasting hyperglycemia, attenuated the glucose and insulin intolerances, and abolished the increase in fasting plasma insulin and C-peptide levels induced by rapamycin. Surprisingly, rosiglitazone markedly increased the plasma insulin and C-peptide responses to refeeding in rapamycin-treated rats. Furthermore, rosiglitazone partially attenuated rapamycin-induced gluconeogenesis, as evidenced by the improved pyruvate tolerance and reduced mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Rosiglitazone also restored insulin's ability to stimulate glucose uptake and its incorporation into glycogen in skeletal muscle of rapamycin-treated rats, which was associated with normalization of Akt Ser(473) phosphorylation. However, the rapamycin-mediated impairments of adipose tissue glucose uptake and incorporation into triacylglycerol were unaffected by rosiglitazone. Our findings indicate that PPARγ activation ameliorates some of the disturbances in glucose homeostasis and insulin action associated with chronic rapamycin treatment by reducing gluconeogenesis and insulin secretion and restoring muscle insulin signaling and glucose uptake.