Exercise training induces alteration of clock genes and myokines expression in tumor-bearing mice.

To investigate the impact of different exercise training schedules (following a fixed schedule or at random times of the day) on clock genes and myokine expression patterns in the skeletal muscle of tumor-bearing mice. Mice were divided into three groups: tumor (LLC), tumor + exercise training (LLC + T) always performed at the same time of the day (ZT2) and exercise training at random times of the day (ZTAlt). Mice were inoculated subcutaneously with Lewis lung carcinoma cells. The gastrocnemius muscle was dissected and the clock gene expression (Clock/Per1/Per2/Per3/Rev-Erbα/GAPDH) was investigated by quantitative reverse transcription polymerase chain reaction with SYBR® Green. Myokine content in muscle (tumour necrosis factor alpha/IL-10/IL-4) was assessed by enzyme-linked immunosorbent assay. At the end of the protocol, the trained groups showed a reduction in total weight, when compared to Lewis lung carcinoma. Tumor weight was lower in the LLC + T (ZTAlt), when compared to LLC. Clock gene mRNA expression showed a significant increase for ZT20 in the groups that performed physical exercise at LLC + T (ZTAlt), when compared with LLC. The Per family showed increased mRNA expression in ZT4 in both trained mice groups, when compared with LLC. LLC + T (ZTAlt) presented reduction of the expression of anti-inflammatory myokines (Il-10/IL-4) during the night, compared with LLC + T(ZT2). Exercise training is able to induce marked modification of clock gene expression and of the production of myokines, in a way that is dependent on schedule exercise training strategy. Taken together, the results show that exercise is a potent Zeitgeber and may thus contribute to change clock genes expression and myokines that are able to reduce the tumor weight.

Immunometabolism-fit: How exercise and training can modify T cell and macrophage metabolism in health and disease.

BACKGROUND: The term immunometabolism describes cellular and molecular metabolic processes that control the immune system and the associated immune responses. Acute exercise and regular physical activity have a substantial influence on the metabolism and the immune system, so that both processes are closely associated and influence each other bidirectionally. SCOPE OF REVIEW: We limit the review here to focus on metabolic phenotypes and metabolic plasticity of T cells and macrophages to describe the complex role of acute exercise stress and regular physical activity on these cell types. The metabolic and immunological consequences of the social problem of inactivity and how, conversely, an active lifestyle can break this vicious circle, are then described. Finally, these aspects are evaluated against the background of an aging society. MAJOR CONCLUSIONS: T cells and macrophages show high sensitivity to changes in their metabolic environment, which indirectly or directly affects their central functions. Physical activity and sedentary behaviour have an important influence on metabolic status, thereby modifying immune cell phenotypes and influencing immunological plasticity. A detailed understanding of the interactions between acute and chronic physical activity, sedentary behaviour, and the metabolic status of immune cells, can help to target the dysregulated immune system of people who live in a much too inactive society.

Type and Intensity as Key Variable of Exercise in Metainflammation Diseases: A Review.

Monocyte and lymphocyte subpopulations exhibit functions that vary between the anti- and pro-inflammatory spectrum, such as classic CD16- and non-classical CD16+monocytes, as well as T helper 2 lymphocytes (Th2), the Th1/Th17 lymphocytes ratio, and T regulatory lymphocytes (Treg). Metabolic disease-associated inflammation is accompanied by an imbalance in monocyte and lymphocyte phenotypes and functionality, as well as a stronger proportion of inflammatory subpopulations. These changes appear to be important for the development and progression of diseases like diabetes and cardiovascular disease. On the other hand, the regular practice of physical exercise is an important tool to restore the functionality of monocytes and lymphocytes, and to balance the subtypes ratio. However, key variables regarding exercise prescription, such as the type of exercise, intensity, and volume differentially impact on the acute and chronic immune response in individuals diagnosed with meta-inflammation diseases. Here, we discuss the impact of different physical exercise protocols, acutely and chronically, on monocytes and lymphocytes of individuals with metabolic disease-associated inflammation. In this review, we focus on the best effects of different exercise protocols to dose the "exercise pill" in different inflammatory status.

Improvement in the anti-inflammatory profile with lifelong physical exercise is related to clock genes expression in effector-memory CD4+ T cells in master athletes.

PURPOSE: Ageing is associated with alterations in the immune system as well as with alterations of the circadian rhythm. Immune cells show rhythmicity in execution of their tasks. Chronic inflammation (inflammaging), which is observed in the elderly, is mitigated by lifelong exercise. The aimed this study was to determine the acute effect of a maximal exercise test on clock genes, regulatory proteins and cytokine expression, and evaluate the effect of lifelong exercise on the expression of clock genes in subpopulations of effector-memory (EM) CD4+ and CD8+T cells and the association of these processes with the inflammatory profile. Therefore, this study aimed to investigate the expression of clock genes in subpopulations of effector memory (EM) CD4+ and CD8+ T cells in master athletes and healthy controls and further associate them with systemic inflammatory responses to acute exercise. METHODS: The study population comprised national and international master athletes (n = 18) involved in three sports (athletics, swimming and judo). The control group (n = 8) comprised untrained healthy volunteers who had not participated in any regular and competitive physical exercise in the past 20 years. Anthropometric measurements and blood samples were taken before (Pre), 10 min after (Post) and 1 h after (1 h Post) a maximal cycle ergometer test for the determination of maximum oxygen consumption (VO2 max). The subpopulations of EM CD4+ and CD8+ T cells were purified using fluorescenceactivated cell sorting. RNA extraction of clock genes (CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, REV-ERBα, REV-ERBß, RORa, RORb and RORc) in EM CD4+ and EM CD8+ T cells as well as regulatory proteins (IL-4, IFN-γ, Tbx21, PD-1, Ki67, NF-kB, p53 and p21) in EM CD4+ T cells was performed. The serum concentration of cytokines (IL-8, IL-10, IL-12p70 and IL-17A) was measured. RESULTS: The master athletes showed better physiological parameters than the untrained healthy controls (P < 0.05). The levels of cytokines increased in master athletes at Post compared with those at Pre. The IL-8 level was higher at 1 h Post, whereas the IL-10 and IL-12p70 levels returned to baseline. There was no change in IL-17A levels (P < 0.05). The clock genes were modulated differently in CD4+ T cells after an acute session of exercise in a training status-dependent manner. CONCLUSION: The synchronization of clock genes, immune function and ageing presents new dimensions with interesting challenges. Lifelong athletes showed modified expression patterns of clock genes and cytokine production associated with the physical fitness level. Moreover, the acute bout of exercise altered the clock machinery mainly in CD4+ T cells; however, the clock gene expressions induced by acute exercise were different between the master athletes and control group.

The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes.

Macrophages and lymphocytes demonstrate metabolic plasticity, which is dependent partly on their state of activation and partly on the availability of various energy yielding and biosynthetic substrates (fatty acids, glucose, and amino acids). These substrates are essential to fuel-based metabolic reprogramming that supports optimal immune function, including the inflammatory response. In this review, we will focus on metabolism in macrophages and lymphocytes and discuss the role of fatty acids in governing the phenotype, activation, and functional status of these important cells. We summarize the current understanding of the pathways of fatty acid metabolism and related mechanisms of action and also explore possible new perspectives in this exciting area of research.

Moderate aerobic exercise-induced cytokines changes are disturbed in PPARα knockout mice.

The nuclear transcriptional factor peroxisome proliferator activated receptor alpha (PPARα) plays a role in regulating genes involved in lipid metabolism, adipogenesis and inflammation. We aimed to assess the role of PPARα on exercise-mediated locally produced cytokines in adipose fat deposits and skeletal muscle. C57BL/6 (WT) and PPARα knockout (PPARα-/-) mice were examined. Each genotype was randomly subdivided into three groups: non-exercised, and euthanized 2 or 24 h after a moderate aerobic exercise session (run on a treadmill at 60% of maximum speed for 1 h). Fat content in gastrocnemius muscle and lipolytic activity in isolated adipose tissue from mesenteric (MEAT) and retroperitoneal (RPAT) adipose tissue were evaluated. In addition, Interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) content were evaluated by ELISA. WT mice showed a maximum lipolysis rate, as well as higher IL-6, IL-10, and IL10/TNF-α ratio values 2 h post-exercise (RPAT only) compared with PPARα-/- mice. Taken together, our data suggests that PPARα knockout mice exhibited reduced lipolysis and anti-inflammatory response in adipose tissue following exercise, PPARα appears to play an important role in immunomodulatory and lipolysis signaling after acute moderate exercise.

High- and moderate-intensity training modify LPS-induced ex-vivo interleukin-10 production in obese men in response to an acute exercise bout.

The aim of this study was to evaluate the inflammatory (peripheral and lipopolysaccharide (LPS)-stimulated released from whole blood) and metabolic (glucose and insulin) profile of inactive obese men in response to two isoenergetic models of aerobic exercise training (~300  kcal each exercise session). Twenty-two participants (28.7 ± 1.6 years; BMI = 34.4 ± 0.1 kg/m2) were randomized into two groups: I) HIIT: high-intensity interval training (10× 1 bout: 1 min - 100% Maximal Aerobic Velocity) or II) MICT: moderate-intensity continuous training (65% Maximal Aerobic Velocity; kcal equal to HIIT). Both groups trained three times per week for 6-weeks. Fasting blood samples were collected before and 0, 30, and 60 min after exercise during the first and last training sessions for evaluation of: I) MIP-1ɑ, insulin, glucose, visceral and subcutaneous fat depots, oral glucose tolerance test, and homeostatic model assessment of insulin resistance (HOMA-IR) index; II) Peripheral (TNF-α, IL-6, and IL-10) and LPS-stimulated release of TNF-α and IL-10 were analyzed before, 0, and 60 min after sessions. IL-6 concentration remained elevated up to 60-min after the acute exercise session (p < 0.001), and IL-10 concentration was higher after 30 and 60-min (p = 0.001) compared to rest, independent of training period and protocol. AUC of IL-10 presented effect of type of training (p = 0.023) with MICT group showed significantly higher values than the HIIT. The ex-vivo assay showed higher IL-10 secretion in response to LPS immediately (p = 0.003) after both acute MICT and HIIT exercise sessions, independent of training period. Fifteen subjects presented decreased HOMA-IR after 6-weeks and seven presented an increase in this index. When we excluded the two least responsive subjects, it was possible to observe a decrease in HOMA-IR (p = 0.020) after training. Taken together, our results suggest that both HIIT and MICT (with same energy expenditure) promote similar effects on HOMA-IR and led to elevations in IL-10 production in LPS-stimulated whole blood, suggesting that leukocytes had an enhanced ability to secrete anti-inflammatory cytokines after the exercise bout.

Macrophage immunophenotype but not anti-inflammatory profile is modulated by peroxisome proliferator-activated receptor gamma (PPARγ) in exercised obese mice.

Moderate aerobic training may be therapeutic for chronic low-grade inflammatory diseases due to the associated anti-inflammatory response that is mediated by immune cells. The peroxisome proliferator-activated receptor gamma (PPARγ) regulates the M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization, as well as the immunometabolic response of macrophages. Against this background, the present study seeks to clarify whether the conditional deletion of PPARγ in macrophages would have any effect on the anti-inflammatory role of moderate aerobic training. To test this hypothesis, two mice strains were used: PPARγ LyzCre+/+ (KO) and littermates control animals (WT). Each genotype was divided into 1) sedentary high-fat diet (HF) and 2) high-fat diet and moderate aerobic training (HFT) (n = 5-8 per group). The experimental protocol lasted for 12 weeks, comprising 4 weeks of HF diet only and 8 weeks of HF diet and aerobic training (5 times/week, 50-60 minutes/day at 60% of maximum speed). Metabolic analyses were carried out on the serum glucose homeostase, adipose tissue morphology and cytokine content, and macrophage cytokine production.Immunophenotyping and gene expression were also performed. KO male mice were more prone to hypertrophy in the subcutaneous adipose tissue, though only the IL-1ß (p = 0.0049) was higher compared to the values observed in WT animals. Peritoneal macrophages from KO animals exhibited a marked inflammatory environment with an increase in TNF-α (p = 0.0008), IL- 1ß (p = 0.0017), and IL-6 (p < 0.0001) after lipopolysaccharide stimulation. The moderate aerobic training protected both genotypes from weight gain and reduced the caloric intake in the KO animals. Despite the attenuation of the M2 marker CD206 (p < 0.001) in the absence of PPAR-γ, the aerobic training modulated cytokine production in LPS stimulated peritoneal macrophages from both genotypes, reducing proinflammatory cytokines such as TNF-α (p = 0.0002) and IL-6 (p < 0.0001). Overall, our findings demonstrate the essential role of PPARγ in macrophage immunophenotypes. However, the deletion of PPARγ did not inhibit the exercise-mediated anti-inflammatory effect, underscoring the important role of exercise in modulating inflammation.

Endurance Exercise Mitigates Immunometabolic Adipose Tissue Disturbances in Cancer and Obesity.

Adipose tissue is considered an endocrine organ whose complex biology can be explained by the diversity of cell types that compose this tissue. The immune cells found in the stromal portion of adipose tissue play an important role on the modulation of inflammation by adipocytokines secretion. The interactions between metabolic active tissues and immune cells, called immunometabolism, is an important field for discovering new pathways and approaches to treat immunometabolic diseases, such as obesity and cancer. Moreover, physical exercise is widely known as a tool for prevention and adjuvant treatment on metabolic diseases. More specifically, aerobic exercise training is able to increase the energy expenditure, reduce the nutrition overload and modify the profile of adipocytokines and myokines with paracrine and endocrine effects. Therefore, our aim in this review was to cover the effects of aerobic exercise training on the immunometabolism of adipose tissue in obesity and cancer, focusing on the exercise-related modification on adipose tissue or immune cells isolated as well as their interaction.

Peptides from Natural or Rationally Designed Sources Can Be Used in Overweight, Obesity, and Type 2 Diabetes Therapies.

Overweight and obesity are among the most prominent health problems in the modern world, mostly because they are either associated with or increase the risk of other diseases such as type 2 diabetes, hypertension, and/or cancer. Most professional organizations define overweight and obesity according to individual body-mass index (BMI, weight in kilograms divided by height squared in meters). Overweight is defined as individuals with BMI from 25 to 29, and obesity as individuals with BMI ≥30. Obesity is the result of genetic, behavioral, environmental, physiological, social, and cultural factors that result in energy imbalance and promote excessive fat deposition. Despite all the knowledge concerning the pathophysiology of obesity, which is considered a disease, none of the existing treatments alone or in combination can normalize blood glucose concentration and prevent debilitating complications from obesity. This review discusses some new perspectives for overweight and obesity treatments, including the use of the new orally active cannabinoid peptide Pep19, the advantage of which is the absence of undesired central nervous system effects usually experienced with other cannabinoids.

Regulation of autophagy as a therapy for immunosenescence-driven cancer and neurodegenerative diseases: The role of exercise.

Aging is one of the risk factors for the development of low-grade inflammation morbidities, such as several types of cancer and neurodegenerative diseases, due to changes in the metabolism, hormonal secretion, and immunosenescence. The senescence of the immune system leads to improper control of infections and tissue damage increasing age-related diseases. One of the mechanisms that maintain cellular homeostasis is autophagy, a cell-survival mechanism, and it has been proposed as one of the most powerful antiaging therapies. Regular exercise can reestablish autophagy, probably through AMP-activated protein kinase activation, and help in reducing the age-related senescence diseases. Therefore, in this study, we discuss the effects of exercise training in immunosenescence and autophagy, preventing the two main age-related disease, cancer and neurodegeneration.

Exercise rescues the immune response fine-tuned impaired by peroxisome proliferator-activated receptors γ deletion in macrophages.

BACKGROUND: Exercise is a powerful tool for prevention and treatment of many conditions related to the cardiovascular system and also chronic low-grade inflammation. Peroxisome proliferator-activated receptors γ (PPARγ) exerts an import role on the regulation of metabolic profile and subsequent inflammatory response, especially in macrophages. PURPOSE: To investigate the effects of 8-week moderate-exercise training on metabolic and inflammatory parameters in mice with PPARγ deficiency in myeloid cells. METHODS: Twelve-week old mice bearing PPARγ deletion exclusively in myeloid cells (PPARγlox/lox Lys Cre -/+ , knockout [KO]) and littermate controls (PPARγlox/lox Lys Cre -/- , wild type [WT]) were submitted to 8-week exercise training (treadmill running at moderate intensity, 5 days/week). Animals were evaluated for food intake, glucose homeostasis, serum metabolites, adipose tissue and peritoneal macrophage inflammation, and basal and stimulated cytokine secretion. RESULTS: Exercise protocol did not improve glucose metabolism or adiponectin concentrations in serum of KO mice. Moreover, the absence of PPARγ in macrophages exacerbated the proinflammatory profile in sedentary mice. Peritoneal cultured cells had higher tumor necrosis factor-α (TNF-α) secretion in nonstimulated and lipopolysaccharide (LPS)-stimulated conditions and higher Toll-4 receptor (TLR4) gene expression under LPS stimulus. Trained mice showed reduced TNF-α content in adipose tissue independently of the genotype. M2 polarization ability was impaired in KO peritoneal macrophages after exercise training, while adipose tissue-associated macrophages did not present any effect by PPARγ ablation. CONCLUSION: Overall, PPARγ seems necessary to maintain macrophages appropriate response to inflammatory stimulus and macrophage polarization, affecting also whole body lipid metabolism and adiponectin profile. Exercise training showed as an efficient mechanism to restore the immune response impaired by PPARγ deletion in macrophages.

Interleukin-10 responses from acute exercise in healthy subjects: A systematic review.

PURPOSE: Interleukin 10 (IL-10) is a cytokine that plays a critical role with potent anti-inflammatory properties when produced during exercise, limiting host immune response to pathogens and preventing tissue damage. The purpose of this systematic review was to assess the response of IL-10 after acute exercise session in healthy adults. METHODS: Databases of Ovid Medline (1978-2016), CINAHL (1998-2016), EMBASE (2003-2016), SportDiscus (1990-2016), and Web of Science library (1990-2016) were carefully screened. Clinical trials comparing exercise types in healthy individuals were included for pooled analysis. The trials of exercise were methodologically appraised by PEDro Scale. RESULTS: Twelve randomized controlled and crossover trials containing 176 individuals were identified for inclusion. The Kruskal-Wallis test showed no significant differences between type of exercise and the corresponding values in IL-10 [X2(4) = 2.878; p = 0.449]. The duration of exercise was significantly correlated with increase in IL-10 changes (Pearson's r = 1.00, 95%CI: 0.015-0.042, p < 0.0001) indicating that 48% of the variation in IL-10 levels can be explained by the duration of the exercise performed. In addition, despite a linear increase, we did not find a significant correlation with the intensity of exercise and IL-10 changes (Pearson's r = 0.218, 95%CI: -0.554-0.042, p < 0.035). CONCLUSION: Overall, the duration of the exercise is the single most important factor determining the magnitude of the exercise-induced increase of plasma IL-10.

Anti-inflammatory response to acute exercise is related with intensity and physical fitness.

PURPOSE: The relationship between inflammatory markers and energetic metabolism has been explored. However, the relationship between exercise intensity and fitness status is unclear, and it is necessary to understand this relationship to apply specific exercise guidance. The purpose of the study was to analyze metabolic and inflammatory responses imposed by acute exercise sessions performed at moderate, heavy, and severe intensities and their relationship with the physical fitness status. METHODS: Nineteen healthy male volunteers performed three acute exercise sessions until exhaustion or up to 60 minutes on a cycle ergometer at moderate (90% of first ventilatory threshold [VT1]), heavy (midpoint between VT1 and second ventilatory threshold [VT2]), and severe (midpoint between VT2 and maximal aerobic power) intensities. Blood lactate, glucose, NEFA, endotoxin, and cytokines were determined for each exercise session. Peripheral and lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-10 was analyzed before, after, and 60 minutes after sessions. RESULTS: In peripheral blood, severe intensity increased lactate, endotoxin, and TNF-α immediately after exercise and glucose at 60 min after exercise. There was a trend for IL-10 increase at 60 minutes after exercise in peripheral blood. Immediately after exercise, LPS-stimulated TNF-α, IL-6, IL-6/IL-10 ratio, and lactate levels were higher in the severe intensity while nonester fatty acid levels decreased at this time. At 60 minute after exercise, higher concentrations of glucose and a trend for increased IL-10 were observed in severe intensity. A positive correlation was observed between maximal aerobic power and IL-10 ( r = 0.513; P = 0.042), and negative correlations between maximal aerobic power and endotoxin ( r = -0.531; P = 0.034) and lactate ( r = -0.538; P = 0.031) in heavy intensity. CONCLUSION: Our data show a novel finding that higher cytokine responses occur at higher intensities, mainly in severe intensity. However, the anti-inflammatory (IL-10) response was physical fitness-dependent.

Exercise-induced AMPK activation and IL-6 muscle production are disturbed in adiponectin knockout mice.

BACKGROUND: Adiponectin exhibits anti-inflammatory actions and is mainly expressed in adipose tissue. However, recent studies have shown that adiponectin can also be secreted by skeletal muscle fibers with autocrine and paracrine effects. OBJECTIVES: To analyze the role of adiponectin in the metabolic and inflammatory response of skeletal muscle after acute exhaustive aerobic exercise. METHODS: C57BL/6 (WT) and adiponectin knockout (AdKO) mice underwent four days of treadmill running adaptation and at the fifth day, they performed an incremental maximum test to determine the maximum speed (Vmax). Acute exercise consisted of one hour at 60% Vmax. Mice were euthanatized 2 and 24 h after acute exercise session. RESULTS: Serum and gastrocnemius adiponectin increased after 2-hours of acute exercise. NEFA concentrations were lower in non-exercise AdKO, and decreased 2-hours after exercise only in WT. No differences were found in muscle triacylglycerol content; however, glycogen content was higher in AdKO in non-exercise (p-value = 0.005). WT showed an increase in AMP-activated protein kinase (AMPK) phosphorylation 2-hours after exercise and its level went back to normal after 24-hours. Otherwise, exercise was not able to modify AMPK in the same way as in AdKO. WT showed an increase in the phosphorylation of ACC (Ser79) 2-hours after exercise and return to normal after 24-hours of exercise (p-value < 0.05), kinects that was not observed in AdKO mice. IL-10 and IL-6 concentration was completely different among genotypes. In WT, these cytokines were increased at 2 (p-value < 0.01) and 24 h (p-value < 0.001) after exercise when compared with AdKO. NF-κBp65 protein and gene expression were not different between genotypes. CONCLUSION: Adiponectin influences muscle metabolism, mainly by the decrease in exercise-induced AMPK phosphorylation, inflammatory profile and IL-6 in the muscle.

Inflammatory features of obesity and smoke exposure and the immunologic effects of exercise.

Many lifestyle-related diseases, such as obesity and cigarette smoke-induced pulmonary diseases, are associated with chronic systemic inflammation, which has been shown to contribute to the disease initiation and progression, and also for co-morbidities of these diseases. While the source of inflammation in obese subjects is suggested to be mainly the visceral adipose tissue, smoke-induced inflammation originates in the pulmonary system. Here, chronic cigarette smoking induces oxidative stress, resulting in severe cellular damage. During obesity, metabolic stress pathways in adipocytes induce inflammatory cascades which are also accompanied by fibrotic processes and insulin resistance. In both diseases, local inflammatory signals induce progressive immune cell infiltration, release of cytokines and a subsequent spill-over of inflammation to the systemic circulation. Exercise training represents an effective therapeutic and immune regulating strategy for both obese patients, as well as for patients with smoke induced pulmonary inflammation. While the immuneregulating impact of exercise might primarily depend on the disease state, patients with pulmonary inflammation seem to be less responsive to exercise therapy. The current review tries to identify similarities and differences between inflammatory processes, and the consequences for the immunoregulatory effects of exercise as a therapeutic agent.

White adipose tissue IFN-γ expression and signalling along the progression of rodent cancer cachexia.

Cachexia is associated with increased morbidity and mortality in cancer. The White adipose tissue (WAT) synthesizes and releases several pro-inflammatory cytokines that play a role in cancer cachexia-related systemic inflammation. IFN-γ is a pleiotropic cytokine that regulates several immune and metabolic functions. To assess whether IFN-γ signalling in different WAT pads is modified along cancer-cachexia progression, we evaluated IFN-γ receptors expression (IFNGR1 and IFNGR2) and IFN-γ protein expression in a rodent model of cachexia (7, 10, and 14days after tumour implantation). IFN-γ protein expression was heterogeneously modulated in WAT, with increases in the mesenteric pad and decreased levels in the retroperitoneal depot along cachexia progression. Ifngr1 was up-regulated 7days after tumour cell injection in mesenteric and epididymal WAT, but the retroperitoneal depot showed reduced Ifngr1 gene expression. Ifngr2 gene expression was increased 7 and 14days after tumour inoculation in mesenteric WAT. The results provide evidence that changes in IFN-γ expression and signalling may be perceived at stages preceding refractory cachexia, and therefore, might be employed as a means to assess the early stage of the syndrome.

Modulation of inflammatory response arising from high-intensity intermittent and concurrent strength training in physically active males.

The purposes of this study were to determine: (i) the extent of an acute session of high-intensity intermittent exercise (HIIE) followed by a concurrent strength session (Conc) on the increase of systemic inflammatory cytokines and chemokines, and (ii) whether eight weeks of high intensity interval training plus concurrent strength training alters the acute inflammatory response and immune status. Ten recreationally active males (aged 26.9±4.3years) performed two experimental exercise sessions interspersed by eight weeks of HIIT plus concurrent strength training. The experimental exercise session was composed of a 5-km run on a treadmill (1:1 at 100% of maximal aerobic speed (MAS)), and after 10min of passive recovery, back squat exercises were performed (80% 1RM, four sets until exhaustion). Serum samples were collected after fasting, pre-HIIE, post-HIIE, Pre-Conc, Post-Conc, and 30 and 60min post-exercise session. The comparison between both concurrent exercise sessions was performed using repeated measure ANOVA, with the Bonferroni Post-hoc when necessary. Interleukin-6 (IL-6) presented a moment effect (F=6.72; p<0.05), with Post-Conc significantly higher than pre-HIIE, Post-HIIE, and 60min, only a tendency was found between pre-HIIE and post-HIIE (difference=-5.99; p=0.09). MCP-1 and IL-1ra did not present effects for condition, moment, or interaction. Interleukin-10 (IL-10) presented both moment and interaction effects (F=5.31 and 2.50; p=0.005 and 0.036). Pre-Conc and Post-Conc were significantly higher than Pre-HIIE. The interaction between before and after eight weeks of concurrent training probably occurred at Post-Conc (11.42±3.09pgmL-1 and 8.88±1.29pgmL-1). In addition, maintenance of immune function was observed. Therefore, HIIE and concurrent strength exercise lead to an increase in cytokines response, but eight weeks of training program promoted anti-inflammatory response after an acute session of concurrent exercise.

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.

Hypothalamic energy metabolism is impaired by doxorubicin independently of inflammation in non-tumour-bearing rats.

We sought to explore the effects of doxorubicin on inflammatory profiles and energy metabolism in the hypothalamus of rats. To investigate these effects, we formed two groups: a control (C) group and a Doxorubicin (DOXO) group. Sixteen rats were randomly assigned to either the control (C) or DOXO groups. The hypothalamus was collected. The levels of interleukin (IL)-1ß, IL-6, IL-10, TNF-α and energy metabolism (malate dehydrogenase, complex I and III activities) were analysed in the hypothalamus. The DOXO group exhibited a decreased body weight (p < 0.01). Hypothalamic malate dehydrogenase activity was reduced when compared with control (p < 0.05). In addition, pro-inflammatory cytokine levels were unchanged. Therefore, our results demonstrate that doxorubicin leads to an impairment of \hypothalamic energy metabolism, but do not affect the inflammatory pathway. SIGNIFICANCE PARAGRAPH: The hypothalamus is a central organ that regulates a great number of functions, such as food intake, temperature and energy expenditure, among others. Doxorubicin can lead to deep anorexia and metabolic chaos; thus, we observed the effect of this chemotherapeutic drug on the inflammation and metabolism in rats after the administration of doxorubicin in order to understand the central effect in the hypothalamus. Drug treatment by doxorubicin is used as a cancer therapy; however the use of this drug may cause harmful alterations to the metabolism. Thus, further investigations are needed on the impact of drug therapy over the long term.