Evidence for a Pro-Inflammatory State of Macrophages from Non-Obese Type-2 Diabetic Goto-Kakizaki Rats.

Obesity causes insulin resistance (IR) through systemic low-grade inflammation and can lead to type 2 diabetes mellitus (T2DM). However, the mechanisms that cause IR and T2DM in non-obese individuals are unclear. The Goto-Kakizaki (GK) rat develops IR spontaneously and is a model of non-obese T2DM. These rats exhibit hyperglycemia beginning at weaning and exhibit lower body mass than control Wistar rats. Herein, we tested the hypothesis that macrophages of GK rats are permanently in a pro-inflammatory state, which may be associated with a systemic inflammation condition that mimics the pathogenesis of obesity-induced T2DM. Using eighteen-week-old GK and control Wistar rats, we investigated the proportions of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages isolated from the peritoneal cavity. Additionally, the production of inflammatory cytokines and reactive oxygen species (ROS) in cultured macrophages under basal and stimulated conditions was assessed. It was found that phorbol myristate acetate (PMA) stimulation increased GK rat macrophage ROS production 90-fold compared to basal levels. This response was also three times more pronounced than in control cells (36-fold). The production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), tended to be upregulated in cultured macrophages from GK rats under basal conditions. Macrophages from GK rats produced 1.6 times more granulocyte-macrophage colony-stimulating factor (GM-CSF), 1.5 times more monocyte chemoattractant protein-1 (MCP-1) and 3.3 times more TNF-α than control cells when stimulated with lipopolysaccharide (LPS) (p = 0.0033; p = 0.049; p = 0.002, respectively). Moreover, compared to control cells, GK rats had 60% more M1 (p = 0.0008) and 23% less M2 (p = 0.038) macrophages. This study is the first to report macrophage inflammatory reprogramming towards a pro-inflammatory state in GK rats.

Insulin resistance in nonobese type 2 diabetic Goto Kakizaki rats is associated with a proinflammatory T lymphocyte profile.

Goto-Kakizaki (GK) rats develop a well-defined insulin resistance (IR) and type 2 diabetes mellitus (T2DM) without presenting obesity. The lymphocyte profile in nonobese diabetic conditions is not yet characterized. Therefore, GK rats were chosen to explore T lymphocyte (TL) dynamics at various stages (21, 60, and 120 days) compared to Wistar rats. GK rats exhibit progressive disruption of glucose regulation, with early glucose intolerance at 21 days and reduced insulin sensitivity at 60 days, confirming IR. Glucose transporter 1 (GLUT1) expression was consistently elevated in GK rats, suggesting heightened TL activation. T-regulatory lymphocyte markers diminished at 21 days. However, GK rats showed increased Th1 markers and reduced Gata-3 expression (crucial for Th2 cell differentiation) at 120 days. These findings underscore an early breakdown of anti-inflammatory mechanisms in GK rats, indicating a proinflammatory TL profile that may worsen chronic inflammation in T2DM.

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.

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.

Fish Oil Supplementation Improves the Repeated-Bout Effect and Redox Balance in 20-30-Year-Old Men Submitted to Strength Training.

Herein, we investigated the effect of fish oil supplementation combined with a strength-training protocol, for 6 weeks, on muscle damage induced by a single bout of strength exercise in untrained young men. Sixteen men were divided into two groups, supplemented or not with fish oil, and they were evaluated at the pre-training period and post-training period. We investigated changes before and 0, 24, and 48 h after a single hypertrophic exercise session. Creatine kinase (CK) and lactate dehydrogenase (LDH) activities, plasma interleukin-6 (IL-6) and C-reactive protein (CRP) levels, and the redox imbalance were increased in response to the single-bout session of hypertrophic exercises at baseline (pre-training period) and decreased during the post-training period in the control group due to the repeated-bout effect (RBE). The fish oil supplementation exacerbated this reduction and improved the redox state. In summary, our findings demonstrate that, in untrained young men submitted to a strength-training protocol, fish oil supplementation is ideal for alleviating the muscle injury, inflammation, and redox imbalance induced by a single session of intense strength exercises, highlighting this supplementation as a beneficial strategy for young men that intend to engage in strength-training programs.

Molecular and cellular mechanisms involved in tissue-specific metabolic modulation by SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is triggered by the SARS-CoV-2, which is able to infect and cause dysfunction not only in lungs, but also in multiple organs, including central nervous system, skeletal muscle, kidneys, heart, liver, and intestine. Several metabolic disturbances are associated with cell damage or tissue injury, but the mechanisms involved are not yet fully elucidated. Some potential mechanisms involved in the COVID-19-induced tissue dysfunction are proposed, such as: (a) High expression and levels of proinflammatory cytokines, including TNF-α IL-6, IL-1ß, INF-α and INF-ß, increasing the systemic and tissue inflammatory state; (b) Induction of oxidative stress due to redox imbalance, resulting in cell injury or death induced by elevated production of reactive oxygen species; and (c) Deregulation of the renin-angiotensin-aldosterone system, exacerbating the inflammatory and oxidative stress responses. In this review, we discuss the main metabolic disturbances observed in different target tissues of SARS-CoV-2 and the potential mechanisms involved in these changes associated with the tissue dysfunction.

Linseed Oil Attenuates Liver Inflammation, Fatty Acid Accumulation, and Lipid Distribution in Periportal and Perivenous Hepatocytes Induced by a High-Carbohydrate Diet in Mice.

We evaluated whether linseed oil (LO) modulates the effects of a high-carbohydrate diet (HCD) on liver inflammation, fatty acid (FA) accumulation, and lipid distribution in periportal and perivenous hepatocytes. The control group (control high-carbohydrate diet [HCD-C]) received an HCD with lard and soybean oil as the lipid source. The L10 and L100 groups received the HCD with 10% and 100% of LO as the lipid source, respectively. The animals were killed by decapitation before (day 0) and after receiving the diets. Liver FA composition, inflammation, and fibrogenesis gene expression were evaluated. Also, the percentage of lipid-occupied area in periportal end perivenous hepatocytes were measured. The L100 group exhibited a higher (P < .05) liver amount of omega-3 polyunsaturated FA (n-3 PUFA) and lower (P < .05) amounts of saturated FA (SFA), monounsaturated FA (MUFA), and omega-6 polyunsaturated FA (n-6 PUFA) compared with L10 or HCD-C mice. On day 56, interleukin 10 and type IV collagen gene expression were significantly upregulated and downregulated, respectively in L100. Also, the L100 group showed lower (P < .05) FA accumulation (i.e., total FA, SFA, MUFA, and n-6 PUFA). Also, L10 and L100 presented lower (P < .05) percentage of high lipid-containing portion in periportal and perivenous hepatocytes. We concluded that LO attenuation of liver inflammation promoted by an HCD is associated with increased liver n-3 PUFA levels, so modulating FA composition, deposition, and distribution in periportal and perivenous hepatocytes.

Leukocyte metabolism in obese type 2 diabetic individuals associated with COVID-19 severity.

Recent studies show that the metabolic characteristics of different leukocytes, such as, lymphocytes, neutrophils, and macrophages, undergo changes both in the face of infection with SARS-CoV-2 and in obesity and type 2 diabetes mellitus (DM2) condition. Thus, the objective of this review is to establish a correlation between the metabolic changes caused in leukocytes in DM2 and obesity that may favor a worse prognosis during SARS-Cov-2 infection. Chronic inflammation and hyperglycemia, specific and usual characteristics of obesity and DM2, contributes for the SARS-CoV-2 replication and metabolic disturbances in different leukocytes, favoring the proinflammatory response of these cells. Thus, obesity and DM2 are important risk factors for pro-inflammatory response and metabolic dysregulation that can favor the occurrence of the cytokine storm, implicated in the severity and high mortality risk of the COVID-19 in these patients.

Evidence for Monocyte Reprogramming in a Long-Term Postsepsis Study.

This study sought to identify monocyte alterations from septic patients after hospital discharge by evaluating gene expression of inflammatory mediators and monocyte polarization markers. It was hypothesized that sepsis reprograms the inflammatory state of monocytes, causing effects that persist after hospital discharge and influencing patient outcomes. DESIGN: The gene expression patterns of inflammatory receptors, M1 and M2 macrophage polarization markers, NLRP3 inflammasome components, and pro- and anti-inflammatory cytokines in monocytes were assessed. PATIENTS: Thirty-four patients from the University of São Paulo Hospital, during the acute sepsis phase (phase A), immediately after ICU discharge (phase B), and 3 months (phase C), 6 months (phase D), 1 year (phase E), and 3 years (phase F) after discharge, were included. Patients that died during phases A and B were grouped separately, and the remaining patients were collectively termed the survivor group. MEASUREMENTS AND MAIN RESULTS: The gene expression of toll-like receptor (TLR)2 and TLR4 (inflammatory receptors), NLRP3, NFκB1, adaptor molecule apoptosis-associated speck-like protein containing a CARD, caspase 1, caspase 11, and caspase 12 (NLRP3 inflammasome components), interleukin-1α, interleukin-1ß, interleukin-18, and high-mobility group box 1 protein (proinflammatory cytokines), interleukin-10 (anti-inflammatory cytokine), C-X-C motif chemokine ligand 10, C-X-C motif chemokine ligand 11, and interleukin-12p35 (M1 inflammatory polarization markers), and C-C motif chemokine ligand 14, C-C motif chemokine ligand 22, transforming growth factor-beta (TGF-ß), SR-B1, and peroxisome proliferator-activated receptor γ (M2 anti-inflammatory polarization and tissue repair markers) was upregulated in monocytes from phase A until phase E compared with the control group. CONCLUSIONS: Sepsis reprograms the inflammatory state of monocytes, probably contributing to postsepsis syndrome development and mortality.

Prefrontal Cortex and Hippocampus Inflammation in Mice Fed High-Carbohydrate or High-Fat Diets.

We previously reported that a high-carbohydrate diet (HCD) induced systemic inflammation and higher gene expression of proinflammatory mediators in the liver, skeletal muscle, and brain than a high-fat diet (HFD). However, the differences between the groups were less pronounced in the brain. In this study, we extended the evaluation of inflammation to specific areas of the brain. In this study, we evaluated the gene expression of caspase 2, caspase 3, caspase 9, cyclooxygenase-2 (Cox 2), inducible nitric oxide synthase (iNOS), interleukin (IL), IL-6, IL-1ß, IL-10, IL-4, tumor necrosis factor-alpha (TNF-α), integrin subunit alpha m (Itgam), S100 protein (S100), allograft inflammatory factor 1 (Aif1), and glial fibrillary acidic protein (Gfap) in the prefrontal cortex and hippocampus of male Swiss mice that were fed with HCD or HFD for 8 weeks. The HCD group exhibited higher IL-1ß expression, whereas the HFD group showed higher TNF-α expression in the prefrontal cortex. In the hippocampus, TNF-α expression was higher in the HFD group. IL-1ß and TNF-α are proinflammatory cytokines that have been associated with impaired brain function and numerous brain disorders. Our results indicate that both HCD and HFD promote prefrontal cortex inflammation; however, the hippocampus seems more sensitive to a HFD than HCD.

Impaired brown adipose tissue is differentially modulated in insulin-resistant obese wistar and type 2 diabetic Goto-Kakizaki rats.

Brown adipose tissue (BAT) is a potential target to treat obesity and diabetes, dissipating energy as heat. Type 2 diabetes (T2D) has been associated with obesogenic diets; however, T2D was also reported in lean individuals to be associated with genetic factors. We aimed to investigate the differences between obese and lean models of insulin resistance (IR) and elucidate the mechanism associated with BAT metabolism and dysfunction in different IR animal models: a genetic model (lean GK rats) and obese models (diet-induced obese Wistar rats) at 8 weeks of age fed a high-carbohydrate (HC), high-fat (HF) diet, or high-fat and high-sugar (HFHS) diet for 8 weeks. At 15 weeks of age, BAT glucose uptake was evaluated by 18F-FDG PET under basal (saline administration) or stimulated condition (CL316,243, a selective ß3-AR agonist). After CL316, 243 administrations, GK animals showed decreased glucose uptake compared to HC animals. At 16 weeks of age, the animals were euthanized, and the interscapular BAT was dissected for analysis. Histological analyses showed lower cell density in GK rats and higher adipocyte area compared to all groups, followed by HFHS and HF compared to HC. HFHS showed a decreased batokine FGF21 protein level compared to all groups. However, GK animals showed increased expression of genes involved in fatty acid oxidation (CPT1 and CPT2), BAT metabolism (Sirt1 and Pgc1-α), and obesogenic genes (leptin and PAI-1) but decreased gene expression of glucose transporter 1 (GLUT-1) compared to other groups. Our data suggest impaired BAT function in obese Wistar and GK rats, with evidence of a whitening process in these animals.

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.

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.

Macrophage inflammatory state in Type 1 diabetes: triggered by NLRP3/iNOS pathway and attenuated by docosahexaenoic acid.

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic ß-cell destruction and hyperglycemia. While monocytes and NOD-like receptor family-pyrin domain containing 3 (NLRP3) are associated with T1D onset and development, the specific receptors and factors involved in NLRP3 inflammasome activation remain unknown. Herein, we evaluated the inflammatory state of resident peritoneal macrophages (PMs) from genetically modified non-obese diabetic (NOD), NLRP3-KO, wild-type (WT) mice and in peripheral blood mononuclear cells (PBMCs) from human T1D patients. We also assessed the effect of docosahexaenoic acid (DHA) on the inflammatory status. Macrophages from STZ-induced T1D mice exhibited increased inflammatory cytokine/chemokine levels, nitric oxide (NO) secretion, NLRP3 and iNOS protein levels, and augmented glycolytic activity compared to control animals. In PMs from NOD and STZ-induced T1D mice, DHA reduced NO production and attenuated the inflammatory state. Furthermore, iNOS and IL-1ß protein expression levels and NO production were lower in the PMs from diabetic NLRP3-KO mice than from WT mice. We also observed increased IL-1ß secretion in PBMCs from T1D patients and immortalized murine macrophages treated with advanced glycation end products and palmitic acid. The present study demonstrated that the resident PMs are in a proinflammatory state characterized by increased NLRP3/iNOS pathway-mediated NO production, up-regulated proinflammatory cytokine/chemokine receptor expression and altered glycolytic activity. Notably, ex vivo treatment with DHA reverted the diabetes-induced changes and attenuated the macrophage inflammatory state. It is plausible that DHA supplementation could be employed as adjuvant therapy for treating individuals with T1D.

4-Aminoquinoline compounds from the Spanish flu to COVID-19.

In 1918, quinine was used as one of the unscientifically based treatments against the H1N1 virus during the Spanish flu pandemic. Originally, quinine was extracted from the bark of Chinchona trees by South American natives of the Amazon forest, and it has been used to treat fever since the seventeenth century. The recent COVID-19 pandemic caused by Sars-Cov-2 infection has forced researchers to search for ways to prevent and treat this disease. Based on the antiviral potential of two 4-aminoquinoline compounds derived from quinine, known as chloroquine (CQ) and hydroxychloroquine (HCQ), clinical investigations for treating COVID-19 are being conducted worldwide. However, there are some discrepancies among the clinical trial outcomes.Thus, even after one hundred years of quinine use during the Spanish flu pandemic, the antiviral properties promoted by 4-aminoquinoline compounds remain unclear. The underlying molecular mechanisms by which CQ and HCQ inhibit viral replication open up the possibility of developing novel analogs of these drugs to combat COVID-19 and other viruses.

The Dietary Replacement of Soybean Oil by Canola Oil Does Not Prevent Liver Fatty Acid Accumulation and Liver Inflammation in Mice.

A high-carbohydrate diet (HCD) is a well-established experimental model of accelerated liver fatty acid (FA) deposition and inflammation. In this study, we evaluated whether canola oil can prevent these physiopathological changes. We evaluated hepatic FA accumulation and inflammation in mice fed with a HCD (72.1% carbohydrates) and either canola oil (C group) or soybean oil (S group) as a lipid source for 0, 7, 14, 28, or 56 days. Liver FA compositions were analyzed by gas chromatography. The mRNA expression of acetyl-CoA carboxylase 1 (ACC1) was measured as an indicator of lipogenesis. The mRNA expression of F4/80, tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, and IL-10, as mediators of liver inflammation, were also measured. The C group stored less n-6 polyunsaturated FAs (n-6 PUFAs) and had more intense lipid deposition of monounsaturated FAs (MUFAs), n-3 PUFAs, and total FAs. The C group also showed higher ACC1 expression. Moreover, on day 56, the C group showed higher expressions of the inflammatory genes F4/80, TNF-α, IL-1ß, and IL-6, as well as the anti-inflammatory IL-10. In conclusion, a diet containing canola oil as a lipid source does not prevent the fatty acid accumulation and inflammation induced by a HCD.

Moderate physical exercise improves lymphocyte function in melanoma-bearing mice on a high-fat diet.

BACKGROUND: Obesity can lead to a chronic systemic inflammatory state that increases the risk of cancer development. Therefore, this study aimed to evaluate the alterations in tumor non-infiltrated lymphocytes function and melanoma growth in animals maintained on a high-fat diet and/or moderate physical exercise program in a murine model of melanoma. METHODS: Female mice were randomly divided into eight groups: 1) normolipidic control (N), 2) normolipidic + melanoma (NM), 3) high-fat control (H), 4) high-fat + melanoma (HM), 5) normolipidic control + physical exercise (NE), 6) normolipidic melanoma + physical exercise (NEM), 7) high-fat control + physical exercise (HE), and 8) high-fat melanoma + physical exercise (HEM). After 8 weeks of diet treatment and/or moderate physical exercise protocol, melanoma was initiated by explanting B16F10 cells into one-half of the animals. RESULTS: Animals fed a high-fat diet presented high-energy consumption (30%) and body weight gain (H and HE vs N and NE, 37%; HM and HEM vs NM and NEM, 73%, respectively), whether or not they carried melanoma explants. Although the tumor growth rate was higher in animals from the HM group than in animals from any other sedentary group, it was reduced by the addition of a physical exercise regimen. We also observed an increase in stimulated peripheral lymphocyte proliferation and a decrease in the T-helper 1 response in the HEM group. CONCLUSIONS: The results of the present study support the hypothesis that altering function of tumor non-infiltrated lymphocytes via exercise-related mechanisms can slow melanoma progression, indicating that the incorporation of a regular practice of moderate-intensity exercises can be a potential strategy for current therapeutic regimens in treating advanced melanoma.

Combination of a high-fat diet with sweetened condensed milk exacerbates inflammation and insulin resistance induced by each separately in mice.

Obesogenic diets increase body weight and cause insulin resistance (IR), however, the association of these changes with the main macronutrient in the diet remains to be elucidated. Male C57BL/6 mice were fed with: control (CD), CD and sweetened condensed milk (HS), high-fat (HF), and HF and condensed milk (HSHF). After 2 months, increased body weight, glucose intolerance, adipocyte size and cholesterol levels were observed. As compared with CD, HS ingested the same amount of calories whereas HF and HSHF ingested less. HS had increased plasma AST activity and liver type I collagen. HF caused mild liver steatosis and hepatocellular damage. HF and HSHF increased LDL-cholesterol, hepatocyte and adipocyte hypertrophy, TNF-α by macrophages and decreased lipogenesis and adiponectin in adipose tissue (AT). HSHF exacerbated these effects, increasing IR, lipolysis, mRNA expression of F4/80 and leptin in AT, Tlr-4 in soleus muscle and IL-6, IL-1ß, VCAM-1, and ICAM-1 protein in AT. The three obesogenic diets induced obesity and metabolic dysfunction. HS was more proinflammatory than the HF and induced hepatic fibrosis. The HF was more detrimental in terms of insulin sensitivity, and it caused liver steatosis. The combination HSHF exacerbated the effects of each separately on insulin resistance and AT inflammatory state.