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1.
Exerc Immunol Rev ; 26: 10-22, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32139355

RESUMO

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.


Assuntos
Inflamação/imunologia , Macrófagos Peritoneais/imunologia , PPAR gama/imunologia , Condicionamento Físico Animal , Animais , Dieta Hiperlipídica , Imunofenotipagem , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Fator de Necrose Tumoral alfa/imunologia
2.
J Cell Physiol ; 234(7): 9956-9965, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30536945

RESUMO

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.


Assuntos
Exercício Físico/fisiologia , Interleucina-10/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Inflamação/fisiopatologia , Inflamação/prevenção & controle , Interleucina-10/imunologia , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Regulação para Cima , Adulto Jovem
3.
J Cachexia Sarcopenia Muscle ; 14(3): 1244-1248, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37130578

RESUMO

BACKGROUND: It is known that S-pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals. METHODS: Here, we tested 3 mg/kg/day of S-pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC). RESULTS: Treatment of mice with 3 mg/kg/day of S-pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo-treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (-0.9 ± 1.0 vs. -2.2 ± 1.4 g for S-pindolol and placebo, respectively, P < 0.05) and around a third of the lean mass lost by tumour-bearing controls (-0.4 ± 1.0 vs. -1.5 ± 1.5 g for S-pindolol and placebo, respectively, P < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S-pindolol tumour-bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S-pindolol-treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S-pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S-pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S-pindolol-treated mice improved by 32.7 ± 18.5 g, tumour-bearing mice only show minimal improvements (7.3 ± 19.4 g, P < 0.01). CONCLUSIONS: S-pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength.


Assuntos
Carcinoma Pulmonar de Lewis , Neoplasias Pulmonares , Camundongos , Animais , Caquexia/tratamento farmacológico , Caquexia/etiologia , Caquexia/patologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Músculo Esquelético/patologia , Carcinoma Pulmonar de Lewis/complicações , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/patologia , Pâncreas/patologia
4.
Front Oncol ; 13: 1237709, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38234397

RESUMO

Background: Even though doxorubicin (DOX) chemotherapy promotes intense muscle wasting, this drug is still widely used in clinical practice due to its remarkable efficiency in managing cancer. On the other hand, intense muscle loss during the oncological treatment is considered a bad prognosis for the disease's evolution and the patient's quality of life. In this sense, strategies that can counteract the muscle wasting induced by DOX are essential. In this study, we evaluated the effectiveness of formoterol (FOR), a ß2-adrenoceptor agonist, in managing muscle wasting caused by DOX. Methods and results: To evaluate the effect of FOR on DOX-induced muscle wasting, mice were treated with DOX (2.5 mg/kg b.w., i.p. administration, twice a week), associated or not to FOR treatment (1 mg/kg b.w., s.c. administration, daily). Control mice received vehicle solution. A combination of FOR treatment with DOX protected against the loss of body weight (p<0.05), muscle mass (p<0.001), and grip force (p<0.001) promoted by chemotherapy. FOR also attenuated muscle wasting (p<0.01) in tumor-bearing mice on chemotherapy. The potential mechanism by which FOR prevented further DOX-induced muscle wasting occurred by regulating Akt/FoxO3a signaling and gene expression of atrogenes in skeletal muscle. Conclusions: Collectively, our results suggest that FOR can be used as a pharmacological strategy for managing muscle wasting induced by DOX. This study provides new insights into the potential therapeutic use of FOR to improve the overall wellbeing of cancer patients undergoing DOX chemotherapy.

5.
J Biomed Biotechnol ; 2012: 945131, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22988427

RESUMO

High consumption of polyunsaturated fatty acids, such as sunflower oil has been associated to beneficial effects in plasma lipid profile, but its role on inflammation and insulin resistance is not fully elucidated yet. We evaluated the effect of sunflower oil supplementation on inflammatory state and insulin resistance condition in HFD-induced obese mice. C57BL/6 male mice (8 weeks) were divided in four groups: (a) control diet (CD), (b) HFD, (c) CD supplemented with n-6 (CD + n-6), and (d) HFD supplemented with n-6 (HFD + n-6). CD + n-6 and HFD + n-6 were supplemented with sunflower oil by oral gavage at 2 g/Kg of body weight, three times per week. CD and HFD were supplemented with water instead at the same dose. HFD induced whole and muscle-specific insulin resistance associated with increased inflammatory markers in insulin-sensitive tissues and macrophage cells. Sunflower oil supplementation was not efficient in preventing or reducing these parameters. In addition, the supplementation increased pro-inflammatory cytokine production by macrophages and tissues. Lipid profile, on the other hand, was improved with the sunflower oil supplementation in animals fed HFD. In conclusion, sunflower oil supplementation improves lipid profile, but it does not prevent or attenuate insulin resistance and inflammation induced by HFD in C57BL/6 mice.


Assuntos
Gorduras na Dieta/efeitos adversos , Suplementos Nutricionais , Inflamação/induzido quimicamente , Resistência à Insulina , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Óleos de Plantas/administração & dosagem , Óleos de Plantas/efeitos adversos , Animais , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Óleo de Girassol
6.
Life Sci ; 266: 118868, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310034

RESUMO

Liver steatosis is one of the main drivers for the development of whole-body insulin resistance. Conversely, aerobic training (AT) has been suggested as non-pharmacological tool to improve liver steatosis, however, the underlying molecular mechanism remains unclear. Therefore, the aim of this study was to analyze the effect of 8-weeks AT in non-alcoholic liver disease (NAFLD) outcomes in obese mice. Male C57BL/6 J wild type (WT) were fed with standard (SD) or high-fat diet (HFD) for 12-weeks. Another group fed with HFD underwent 8-weeks of AT (60% of maximum velocity), initiated at the 5th week of experimental protocol. We measured metabolic, body composition parameters, protein and gene expression inflammatory and metabolic mediators. We found that AT attenuates the weight gain, but not body fat accumulation. AT improved triacylglycerol and non-esterified fatty acid plasma concentrations, and also whole-body insulin resistance. Regarding NAFLD, AT decreased the progression of macrovesicular steatosis and inflammation through the upregulation of AMPK Thr172 phosphorylation and PPAR-α protein expression. Moreover, although no effects of intervention in PPAR-γ protein concentration were observed, we found increased levels of its target genes Cd36 and Scd1 in exercised group, demonstrating augmented transcriptional activity. AT reduced liver cytokines concentrations, such as TNF-α, IL-10, MCP-1 and IL-6, regardless of increased Ser536 NF-κB phosphorylation. In fact, none of the interventions regulated NF-κB target genes Il1b and Cccl2, demonstrating its low transcriptional activity. Therefore, we conclude that AT attenuates the progression of liver macrovesicular steatosis and inflammation through AMPK-PPAR-α signaling and PPAR-γ activation, respectively, improving insulin resistance in obese mice.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Inflamação/prevenção & controle , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/complicações , PPAR alfa/metabolismo , Condicionamento Físico Animal , Proteínas Quinases Ativadas por AMP/genética , Animais , Biomarcadores/análise , Citocinas/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/genética , Transdução de Sinais
7.
J Cachexia Sarcopenia Muscle ; 7(5): 615-625, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27239415

RESUMO

BACKGROUND: Cancer is considered the second leading cause of death in the world, and for the treatment of this disease, pharmacological intervention strategies are frequently based on chemotherapy. Doxorubicin (DOX) is one of the most widely used chemotherapeutic agents in clinical practice for treating a number of solid tumours. The treatment with DOX mimics some effects of cancer cachexia, such as anorexia, asthenia, decreases in fat and skeletal muscle mass and fatigue. We observed that treatment with DOX increased the systemic insulin resistance and caused a massive increase in glucose levels in serum. Skeletal muscle is a major tissue responsible for glucose uptake, and the positive role of AMPk protein (AMP-activated protein kinase) in GLUT-4 (Glucose Transporter type 4) translocation, is well established. With this, our aim was to assess the insulin sensitivity after treatment with DOX and involvement of AMPk signalling in skeletal muscle in this process. METHODS: We used Wistar rats which received a single dose of doxorubicin (DOX group) or saline (CT group) intraperitoneally at a dose of 15 mg/kg b.w. The expression of proteins involved in insulin sensitivity, glucose uptake, inflammation, and activity of electron transport chain was assessed in extensor digitorum longus muscle, as well as the histological evaluation. In vitro assays were performed in L6 myocytes to assess glucose uptake after treatment with DOX. Agonist of AMPk [5-aminoimidazole-4-carboxamide (AICAR)] and the antioxidant n-acetyl cysteine were used in L6 cells to evaluate its effect on glucose uptake and cell viability. RESULTS: The animals showed a significant insulin resistance, hyperglycaemia, and hyperinsulinemia. A decrease in the expression of AMKP and GLUT-4 was observed in the extensor digitorum longus muscle. Also in L6 cells, DOX leads to a decrease in glucose uptake, which is reversed with AICAR. CONCLUSIONS: DOX leads to conditions similar to cachexia, with severe glucose intolerance both in vivo and in vitro. The decrease of AMPk activity of the protein is modulated negatively with DOX, and treatment with agonist of AMPk (AICAR) has proved to be a possible therapeutic target, which is able to recover glucose sensitivity in skeletal muscle.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Resistência à Insulina , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Animais , Anorexia/etiologia , Anorexia/metabolismo , Antibióticos Antineoplásicos/farmacologia , Glicemia , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Jejum , Glucose/metabolismo , Inflamação/metabolismo , Masculino , Células Musculares/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Ratos , Sarcopenia/etiologia , Sarcopenia/metabolismo , Sarcopenia/patologia
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