A Mechanism of Action of Metformin in the Brain: Prevention of Methylglyoxal-Induced Glutamatergic Impairment in Acute Hippocampal Slices.

Metformin, a biguanide compound (N-1,1-dimethylbiguanide), is widely prescribed for diabetes mellitus type 2 (T2D) treatment. It also presents a plethora of properties, such as anti-oxidant, anti-inflammatory, anti-apoptosis, anti-tumorigenic, and anti-AGE formation activity. However, the precise mechanism of action of metformin in the central nervous system (CNS) needs to be clarified. Herein, we investigated the neuroprotective role of metformin in acute hippocampal slices exposed to methylglyoxal (MG), a highly reactive dicarbonyl compound and a key molecule in T2D developmental pathophysiology. Metformin protected acute hippocampal slices from MG-induced glutamatergic neurotoxicity and neuroinflammation by reducing IL-1ß synthesis and secretion and RAGE protein expression. The drug also improved astrocyte function, particularly with regard to the glutamatergic system, increasing glutamate uptake. Moreover, we observed a direct effect of metformin on glutamate transporters, where the compound prevented glycation, by facilitating enzymatic phosphorylation close to Lys residues, suggesting a new neuroprotective role of metformin via PKC ζ in preventing dysfunction in glutamatergic system induced by MG. Proposed neuroprotection role of metformin in acute hippocampal slices against impairment in glutamatergic system induced in a model of methylglyoxal glycotoxicity. Metformin reversed methylglyoxal (MG)-induced neuroinflammation by reducing pro-inflammatory IL-1ß synthesis and secretion and RAGE protein expression. Metformin did not alter the effect of MG on S100B secretion (1). Both MG and metformin also influenced astrocyte function in hippocampal slices. Metformin did not reverse the elevation in GLO1 activity induced by glycotoxicity; however, it abrogated the high GSH level and the expression of the co-factor of GLO1 (2). Both treatments per se changed bioenergetic metabolism and increased glucose uptake, extracellular lactate content, and pyruvate kinase (PK) activity. The increment in glucose uptake and lactate levels ceased during the co-incubation of MG with metformin. Metformin reversed the elevation of hexokinase activity by MG (3). We suggest a new role of metformin in the glutamate system, whereby it protects the hippocampus against the derangements of the glutamatergic system induced by MG, possibly by phosphorylation via PKC ζ (4). The neuroprotective action of metformin may be mediated by the phosphorylation of specific amino acid residues (Lysine) of the glutamate transporters (GLAST and GLT-1), since metformin activated the PKC ζ signaling and promoted cascades of phosphorylation in p38 MAPK and Akt proteins. The transporter protein phosphorylation prevented the Lys-glycation and the impairment of glutamate uptake induced by MG (5).

Ketogenic diets, exercise performance, and training adaptations.

PURPOSE OF REVIEW: The ketogenic diet has been proposed as a nutritional strategy in sports. This review was undertaken to provide an overview of the recent literature concerning the effects of ketogenic diet on exercise performance and training adaptations. RECENT FINDINGS: Most recent literature on the ketogenic diet and exercise performance showed no beneficial effects, especially for trained individuals. During a period of intensified training, performance was clearly impaired during the ketogenic intervention, while a diet with high carbohydrates maintained physical performance. The main effect of the ketogenic diet resides in metabolic flexibility, inducing the metabolism to oxidize more fat for ATP resynthesis regardless of submaximal exercise intensities. SUMMARY: The ketogenic diet is not a reasonable nutritional strategy, as it has no advantage over normal/high carbohydrate-based diets on physical performance and training adaptations even when used only in a specific training/nutritional periodization stage.

Effects of physical training on functional, clinical, morphological, behavioural and psychosocial outcomes in post-COVID-19 infection: COVID-19 and REhabilitation study (CORE-study)-a study protocol for a randomised controlled clinical trial.

BACKGROUND: The COVID-19 pandemic remains ongoing, with a significant number of survivors who have experienced moderate to severe clinical conditions and who have suffered losses of great magnitude, especially in functional capacity, triggering limitations to daily autonomy and quality of life. Among the possibilities of intervention for disease rehabilitation, physical exercise training stands out, which can benefit several health outcomes and favours the adoption of healthier behaviours. Therefore, the aim of the study will be to analyse the effects of physical training on the functional, clinical, morphological, behavioural and psychosocial status in adults and the elderly following COVID-19 infection. METHODS: A randomised controlled clinical trial is to be conducted in parallel, with the experimental group undergoing an intervention involving a multicomponent physical rehabilitation programme, carried out at the Sports Center in partnership with the Academic Hospital of the Federal University of Santa Catarina, in Florianópolis, Brazil. Participants will be adults and the elderly, of both sexes, in a post-COVID-19-infection state, who were hospitalised during the infection. The intervention will have a total duration of 24 weeks and will include a multicomponent physical training programme, which will have gradual progression in frequency, duration and intensity over time. Regarding the outcomes, before, at the 12th and after 24 weeks of intervention, functional (primary outcome = functional index of aerobic capacity), clinical, morphological, behavioural and psychosocial outcomes will be assessed. DISCUSSION: This study will contribute to a greater understanding of the safety, adherence and benefits of physical training in the rehabilitation of post-COVID-19 patients. The results of this study will be disseminated through presentations at congresses, workshops, peer-reviewed publications and local and international conferences, especially with a view to proposing a post-COVID-19 rehabilitation care protocol. TRIAL REGISTRATION: ReBEC, RBR-10y6jhrs . Registered on 22 February 2022. 2015.

Effects of the ketogenic diet on performance and body composition in athletes and trained adults: a systematic review and Bayesian multivariate multilevel meta-analysis and meta-regression.

This systematic review with meta-analysis aimed to determine the effects of the ketogenic diet (KD) against carbohydrate (CHO)-rich diets on physical performance and body composition in trained individuals. The MEDLINE, EMBASE, CINAHL, SPORTDiscus, and The Cochrane Library were searched. Randomized and non-randomized controlled trials in athletes/trained adults were included. Meta-analytic models were carried out using Bayesian multilevel models. Eighteen studies were included providing estimates on cyclic exercise modes and strength one-maximum repetition (1-RM) performances and for total, fat, and free-fat masses. There were more favorable effects for CHO-rich than KD on time-trial performance (mode [95% credible interval]; -3.3% [-8.5%, 1.7%]), 1-RM (-5.7% [-14.9%, 2.6%]), and free-fat mass (-0.8 [-3.4, 1.9] kg); effects were more favorable to KD on total (-2.4 [-6.2, 1.8] kg) and fat mass losses (-2.4 [-5.4, 0.2] kg). Likely modifying effects on cyclic performance were the subject's sex and VO2max, intervention and performance durations, and mode of exercise. The intervention duration and subjects' sex were likely to modify effects on total body mass. KD can be a useful strategy for total and fat body losses, but a small negative effect on free-fat mass was observed. KD was not suitable for enhancing strength 1-RM or high-intensity cyclic performances.

Inflammatory cytokines and alcohol use disorder: systematic review and meta-analysis

Objective: To assess differences in blood inflammatory cytokines between people with alcohol use disorder (AUD) and healthy controls (HC). Methods: Searches were performed from inception through April 14, 2021. Meta-analyses with random-effects models were used to calculate the standardized mean difference ([SMD], 95%CI), and potential sources of heterogeneity were explored trough meta-regressions and subgroup analysis. Results: The meta-analysis included 23 studies on the following 14 cytokines: tumor necrosis factor (TNF)-α, IL-1, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, IL15, interferon (IFN)-γ and sCD14. There were significantly higher concentrations of IL-6 (n=462 AUD and 408 HC; SMD = 0.523; 95%CI 0.136-0.909; p = 0.008) in AUD than HC. No significant differences were found in the other 13 cytokines. Conclusion: We found that IL-6 levels were significantly higher in individuals with AUD than HC and that other cytokines were not altered. This can be explained by the small number of studies, their methodological heterogeneity, and confounding factors (active use, abstinence, quantity, and physical or psychiatric illnesses, for example). Despite a great deal of evidence about alcohol and inflammatory diseases, studies assessing the role of neuroimmune signaling in the development and severity of AUD are still lacking.

Acute Methylglyoxal-Induced Damage in Blood-Brain Barrier and Hippocampal Tissue.

Methylglyoxal (MG) is a reactive dicarbonyl compound formed mostly via the glycolytic pathway. Elevated blood glucose levels can cause MG accumulation in plasma and cerebrospinal fluid in patients with diabetes mellitus and Alzheimer's disease. Under these disease conditions, the high reactivity of MG leads to modification of proteins and other biomolecules, generating advanced glycation end products (AGEs), which are considered mediators in neurodegenerative diseases. We investigated the integrity of the blood-brain barrier (BBB) and astrocyte response in the hippocampus to acute insult induced by MG when it was intracerebroventricularly administered to rats. Seventy-two hours later, BBB integrity was lost, as assessed by the entry of Evans dye into the brain tissue and albumin in the cerebrospinal fluid, and a decrease in aquaporin-4 and connexin-43 in the hippocampal tissue. MG did not induce changes in the hippocampal contents of RAGE in this short interval, but decreased the expression of S100B, an astrocyte-secreted protein that binds RAGE. The expression of two important transcription factors of the antioxidant response, NF-κB and Nrf2, was unchanged. However, hemeoxigenase-1 was upregulated in the MG-treated group. These data corroborate the idea that hippocampal cells are targets of MG toxicity and that BBB dysfunction and specific glial alterations induced by this compound may contribute to the behavioral and cognitive alterations observed in these animals.

Nine weeks of combined training improve functional and morphological outcomes in trained older people with cardiometabolic risk factors.

BACKGROUND: The study is characterized as a single group experiment, with the aim of verifying the responses of functional capacity and body composition, after a combined training program with undulating periodization, of low cost and easy applicability, in volunteers with cardiovascular risk factors. METHODS: Experimental study carried out with individuals of both sexes, with cardiometabolic risk factors, members of a Cardiorespiratory Rehabilitation Program (PROCOR) of the Federal University of Santa Catarina (UFSC). A combined physical training program (aerobic and strength) with load training progression was used, performed at a frequency of three weekly sessions, on alternate days, for nine weeks and using shin guards, elastic bands or just body weight. Functional capacity, anthropometric profile and body composition of individuals were evaluated before and after the intervention. The comparison of data before and after the intervention period was performed using the Student's t-test for paired samples and the Wilcoxon test. RESULTS: Improvements statistically significant were observed in the tests related to functional capacity, "Sit and Stand", "8-foot-up-and-go" at usual and maximum speeds and "March", along with a decrease in anthropometric measurements of hip circumference, body fat percentage, waist-to-hip ratio, and fat mass in the android region. In addition, the program was well-tolerated with a low rate of sample losses. CONCLUSION: The results of this study suggest that only 9 weeks of combined training at low cost and easy applicability is able to promote improvement in parameters related to functional capacity, anthropometric profile, and body composition of trained older people with cardiovascular risk factors.

Inflammatory cytokines and alcohol use disorder: systematic review and meta-analysis.

OBJECTIVE: To assess differences in blood inflammatory cytokines between people with alcohol use disorder (AUD) and healthy controls (HC). METHODS: Searches were performed from inception through April 14, 2021. Meta-analyses with random-effects models were used to calculate the standardized mean difference ([SMD], 95%CI), and potential sources of heterogeneity were explored trough meta-regressions and subgroup analysis. RESULTS: The meta-analysis included 23 studies on the following 14 cytokines: tumor necrosis factor (TNF)-a, IL-1, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, IL15, interferon (IFN)-g and sCD14. There were significantly higher concentrations of IL-6 (n=462 AUD and 408 HC; SMD = 0.523; 95%CI 0.136-0.909; p = 0.008) in AUD than HC. No significant differences were found in the other 13 cytokines. CONCLUSION: We found that IL-6 levels were significantly higher in individuals with AUD than HC and that other cytokines were not altered. This can be explained by the small number of studies, their methodological heterogeneity, and confounding factors (active use, abstinence, quantity, and physical or psychiatric illnesses, for example). Despite a great deal of evidence about alcohol and inflammatory diseases, studies assessing the role of neuroimmune signaling in the development and severity of AUD are still lacking.

Vitamin D is associated with body composition and fat intake, but not with cardiometabolic parameters in adults with obesity.

Adults with obesity are at higher risk for developing hypovitaminosis D. Some studies suggest that reduced levels of serum 25-hydroxyvitamin D (25(OH)D) may also be related to disorders in cardiometabolic parameters. However, because of the association between 25(OH)D and obesity, we hypothesized that body composition can be a confounding factor in the association of 25(OH)D with cardiometabolic parameters, and that 25(OH)D is inversely associated with body composition and cardiometabolic parameters and directly associated with fat intake. The aim of this study was to analyze the associations between 25(OH)D with body composition, fat intake, and cardiometabolic parameters in adults with obesity. This cross-sectional study consisted of 52 adults with obesity (61.53% female; 37.50 ± 6.88 years; body mass index [BMI]: 33.60 ± 2.89 kg/m2). Cardiometabolic parameters (fasting blood glucose, insulin resistance index, C-reactive protein, blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and cholesterol), body mass, BMI, waist circumference, body fat percentage, and fat intake were evaluated. Body mass was negatively associated with 25(OH)D (ß = -0.108; P = .048; and R² = 0.090) and BMI (ß = -0.621; P = .031; and R² = 0.103), both adjusted for fat intake. 25(OH)D was positively associated with fat intake (ß = 0.129; P = .045 and R² = 0.078) adjusted for sex, age, and skin color. Cardiometabolic parameters were not associated with 25(OH)D, even after adjusted by body composition variables. However, the high prevalence of hypovitaminosis D (75%) and the negative association between 25(OH)D and body composition reinforce the importance of analyzing and monitoring vitamin D status in this population.

Metabolically unhealthy and overweight phenotypes are associated with increased levels of inflammatory cytokines: a population-based study.

OBJECTIVE: The aim of this study was to determine the association between cytokine levels in metabolic phenotypes. Our hypothesis was that an unhealthy metabolic profile is associated to higher levels of proinflammatory cytokines. METHODS: The study sample was composed of 743 Brazilian adults classified in four phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), and metabolically unhealthy overweight (MUOW). Sociodemographic, anthropometric, clinical, and biochemical parameters were collected. Six different cytokines were analyzed from blood samples using the CBA Human Inflammatory cytokines kit and the values divided in quartiles for analysis. Logistic regression models were constructed to assess the association between metabolic phenotypes and cytokines concentrations, adjusted for potential confounders and P < 0.05 was used. RESULTS: The MUOW phenotype showed a higher risk for increased levels of all cytokines analyzed compared with the reference group (MHNW). CONCLUSIONS: These results indicated that excess weight and altered metabolic profile are related to inflammation, especially when both conditions are associated, possibly linked to visceral adiposity. Therefore, the categorization of metabolic phenotypes in populations is an important factor for prevention of chronic diseases, as inflammation is associated with cardiovascular risk and obesity is not the only influencing factor.

Fruit-Derived Anthocyanins: Effects on Cycling-Induced Responses and Cycling Performance.

Previous evidence has shown that the consumption of fruit-derived anthocyanins may have exercise benefits. This review aimed to summarize the effects of fruit-derived anthocyanins on cycling-induced responses and cycling performance. Medline, Science Direct, Cochrane Library, and SPORTDiscus online databases were searched. Nineteen articles met the inclusion criteria. The fruit-derived anthocyanins used in these studies were from cherry (n = 6), blackcurrant (n = 8), pomegranate (n = 2), açai (n = 1), and juçara fruit (n = 2), and were offered in juice, pulp, powder, freeze-dried powder, and extract form. The supplementation time ranged from acute consumption to 20 days, and the amount of anthocyanins administered in the studies ranged from 18 to 552 mg/day. The studies addressed effects on oxidative stress (n = 5), inflammation (n = 4), muscle damage (n = 3), fatigue (n = 2), nitric oxide biomarkers (n = 2), vascular function (n = 2), muscle oxygenation (n = 2), performance (n = 14), substrate oxidation (n = 6), and cardiometabolic markers (n = 3). The potential ergogenic effect of anthocyanin supplementation on cycling-induced responses seems to be related to lower oxidative stress, inflammation, muscle damage, and fatigue, and increased production of nitric oxide, with subsequent improvements in vascular function and muscle oxygenation leading to improved performance. In addition, the observed increase in fat oxidation can direct nutritional strategies to change the use of substrate and improve performance.

Validity of body fat percentage through different methods of body composition assessment in elite soccer referees / Validação do percentual de gordura de árbitros de futebol de elite por diferentes métodos de composição corporal

abstract The arbitration exercise in a soccer game requires high physical fitness and all federations apply physical tests to referees, including anthropometric tests, classifying them as fit or not for the role. The aim of this study was to assess the validity of the total body fat percentage (%BF) through different evaluation methods of body composition referenced in a four-compartment (4C) model. Cross-sectional study performed in 2018 with 21 elite male referees. %BF was estimated by 4 methods: anthropometry; bioelectrical impedance analysis (BIA); Dual X-ray absorptiometry (DXA) and air displacement plethysmography (ADP). Moreover, three and four-compartment (3 and 4C) models were calculated. Bland-Altman and intraclass correlations (ICC) analysis were performed to determine validity of all methods compared to a 4C reference. The results of one-way ANOVA revealed that there was no significant difference (F=1.541; p=0.182) between %BF analyzed by 4C model (15.98 ± 6.20), anthropometry (mean ± SD, 18.46 ± 7.03), ADP (16.19 ± 6.24), BIA (16.67 ± 5.30), DXA (20.33 ± 6.56) and 3C (16.92 ± 5.53). The Bland-Altman analysis showed that all methods analyzed overestimate %BF compared to the 4C model. The best agreement was obtained from the ADP evaluation (bias=-0.2), followed by BIA (bias=-0.6), 3C (bias=-0.9), anthropometry (bias=-2.4) and DXA (bias=-4.3). Validation assessed by ICC was excellent (ICC≥0.90) in most methods, except for anthropometry (ICC=0.80) and DXA (ICC=0.71). Overall, the results suggest that ADP, BIA and 3C were the best method to %BF evaluation. Nevertheless, anthropometry remains as a feasible method to monitor %BF of elite soccer referees.

resumo A arbitragem no futebol exige alto preparo físico. As federações aplicam testes antropométricos para classificar os árbitros como aptos ou não para a função. O presente trabalho teve como objetivo avaliar a validade do percentual de gordura corporal (%GC) aferido por meio de diferentes métodos de avaliação referenciado em um modelo de quatro compartimentos (4C). O %GC foi estimado por seis métodos: antropometria; bioimpedância elétrica (BIA); absortometria dupla de raios-X (DXA); pletismografia por deslocamento de ar (ADP); modelo de três e quatro compartimentos (3 e 4C). Bland-Altman e correlações intraclasse (ICC) foram realizadas para determinar a validade de todos os métodos em comparação com o modelo de referência 4C. Os resultados da ANOVA revelaram que não houve diferença significativa (F = 1,541; p = 0,182) entre o %GC analisado pelo modelo 4C (15,98 ± 6,20), antropometria (média ± DP, 18,46 ± 7,03), ADP (16,19 ± 6,24), BIA (16,67 ± 5,30), DXA (20,33 ± 6,56) e 3C (16,92 ± 5,53). Segundo Bland-Altman todos os métodos ​​superestimam o %GC em comparação com o 4C. A melhor concordância foi obtida na ADP (viés= -0,2), seguida da BIA (bias = -0,6), 3C (viés = -0,9), antropometria (viés = -2,4) e DXA (viés = -4,3). O ICC foi excelente (ICC≥0,90) na maioria dos métodos, exceto para antropometria (ICC = 0,80) e DXA (ICC = 0,71). Os resultados sugerem que ADP, BIA e 3C foram os melhores métodos para avaliação do %GC. No entanto, a antropometria continua sendo um método válido para monitorar o %GC.

Phase angle association with metabolic profile in adults: A population-based study.

OBJECTIVE: This study assesses the association of the phase angle (PhA) with the metabolic profile in adults of both sexes. METHODS: This is a cross-sectional, population-based study including 949 adults 20 to 59 y of age living in the Viçosa, Minas Gerais, Brazil - urban zone. The PhA was measured based on electrical bioimpedance analysis. The metabolic profile comprised the following components: waist circumference, glucose, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, C-reactive protein, homeostatic model assessment index-insulin resistance (HOMA-IR), serum uric acid, systolic blood pressure, and diastolic blood pressure. Linear regression models (crude and adjusted) were used to determine the association between each independent and dependent variable; statistical significance was analyzed at 5%. RESULTS: Multiple analyses showed that the increase in the values of waist circumference (ß: -0.01; 95%CI: -0.03; -0.01) represented lower values in the PhA. For the glucose, non-HDL-C, triglycerides, CRP, HOMA-IR and uric acid there was no association with PhA in the adjusted models. . CONCLUSION: Low PhA was directly associated with grater values of the waist circumference, even after adjustments were made in the sociodemographic, lifestyle variables and body mass index; this outcome suggests that PhA is a promising cardiometabolic profile biomarker in adults.

Does the relationship between 25-hydroxyvitamin D status and bone mass vary according to skin color in adults? Results of a Brazilian population-based study.

Skin color has been indicated as an important factor in determining serum concentrations of 25-hydroxyvitamin D [25(OH)D], and consequently bone health. However, studies are controversial and scarce for mixed populations. PURPOSE/INTRODUCTION: To analyze the association of 25(OH)D with bone mineral content (BMC) and bone mineral density (BMD); and to investigate the presence of interaction with skin color in Brazilian adults. METHODS: This is a cross-sectional, population-based study conducted with adult individuals (20-59 years) of both genders. Bone health was assessed by dual energy radiological absortometry. Vitamin D status was measured using serum 25(OH)D. Skin color and other variables in the adjusted model were collected using a questionnaire and anthropometric assessment. Associations and interactions were evaluated using linear regression models stratified according to gender. RESULTS: Non-white men with vitamin D deficiency (< 20.0 ng/mL) have less bone mass than those with insufficiency and sufficiency for the femoral neck and hip sites. According to the adjusted regression analysis, the deficient status of 25(OH)D in men was associated with worse bone health for the lumbar spine sites (ß = - 0.1; p = 0.006), femoral neck (ß = - 0.08; p = 0.006), and hip (ß = - 0.08; p = 0.009). No statistically significant associations were observed between 25(OH)D and bone health in women. In addition, no statistical interaction was identified between skin color and vitamin D status in relation to bone health (p > 0.05 for all tests) in either gender and for all bone sites evaluated. CONCLUSION: Deficient vitamin D status is associated with lower bone mass in adults with differences observed according to gender, but not according to skin color.

Meal and snack patterns of 7-13-year-old schoolchildren in southern Brazil.

OBJECTIVE: The aim of the current study was to identify and describe the meal and snack patterns (breakfast, mid-morning snack, lunch, mid-afternoon snack, dinner and evening snack) of public schoolchildren. DESIGN: Cross-sectional study. Information on the previous day's food intake was obtained through the Web-CAAFE (Food Intake and Physical Activity of Schoolchildren), an interactive questionnaire, which divides daily food consumption into three meals (breakfast, lunch and dinner) and three snacks (mid-morning, mid-afternoon and evening). Each meal contains thirty-one food items and the schoolchildren clicked on the food items consumed in each meal. Factor analysis was used to identify meal and snack patterns. The descriptions of the dietary patterns (DP) were based on food items with factor loads ≥ 0·30 that were considered representative of each DP. SETTING: Schoolchildren, Florianopolis, Brazil. PARTICIPANTS: Children (n 1074) aged 7-13 years. RESULTS: Lunch was the most consumed meal (96·0 %), followed by dinner (86·4 %), breakfast (85·3 %) and mid-afternoon snack (81·7 %). Four DP were identified for breakfast, mid-morning snack, lunch, dinner and evening snack, and three for mid-afternoon snack. Breakfast, lunch and dinner patterns included traditional Brazilian foods. DP consisting of fast foods and sugary beverages were also observed, mainly for the evening snack. CONCLUSIONS: The results of the current study provide important information regarding the meal and snack patterns of schoolchildren to guide the development of nutrition interventions in public health.

Short-Term Alterations in Behavior and Astroglial Function After Intracerebroventricular Infusion of Methylglyoxal in Rats.

Methylglyoxal (MG) is a by-product of glycolysis. In pathological conditions, particularly diabetes mellitus, this molecule is unbalanced, causing widespread protein glycation. In addition to protein glycation, other effects resulting from high levels of MG in the central nervous system may involve the direct modulation of GABAergic and glutamatergic neurotransmission, with evidence suggesting that the effects of MG may be related to behavioral changes and glial dysfunction. In order to evaluate the direct influence of MG on behavioral and biochemical parameters, we used a high intracerebroventricular final concentration (3 µM/µL) to assess acute effects on memory and locomotor behavior in rats, as well as the underlying alterations in glutamatergic and astroglial parameters. MG induced, 12 h after injection, a decrease in locomotor activity in the Open field and anxiolytic effects in rats submitted to elevated plus-maze. Subsequently, 36 h after surgery, MG injection also induced cognitive impairment in both short and long-term memory, as evaluated by novel object recognition task, and in short-term spatial memory, as evaluated by the Y-maze test. In addition, hippocampal glutamate uptake decreased and glutamine synthetase activity and glutathione levels diminished during seventy-two hours after infusion of MG. Interestingly, the astrocytic protein, S100B, was increased in the cerebrospinal fluid, accompanied by decreased hippocampal S100B mRNA expression, without any change in protein content. Taken together, these results may improve our understanding of how this product of glucose metabolism can induce the brain dysfunction observed in diabetic patients, as well as in other neurodegenerative conditions, and further defines the role of astrocytes in disease and therapeutics.

Modulation of neuropeptide Y levels is impaired in crack withdrawal patients.

Introduction The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has a key role in drug addiction susceptibility. In addition to the well-known relationship between cortisol and the HPA axis, other molecules are involved with stress response and could modify the HPA activation, such as the neuropeptide Y (NPY), which has anxiolytic proprieties. There are few studies evaluating the effect of NPY levels on addiction, especially in crack cocaine dependence. Objective To evaluate NPY in crack users during early withdrawal to determine its relationship with drug use and cortisol levels. Methods We analyzed 25 male inpatient crack users. Serum NPY levels were measured at admission and discharge (mean of 24 days). Morning salivary cortisol was measured at admission. Results Serum NPY levels at admission and discharge were very similar. Lower NPY levels at discharge were associated with higher lifetime crack use. Also, a negative correlation was found between morning cortisol and delta NPY (NPY discharge - NPY admission). Conclusion These preliminary findings indicate that crack use influences the modulation of NPY levels and modifies stress response. The NPY pathway may play an important role in the pathophysiology of crack addiction, and the anxiolytic effect of NPY may be impaired in crack users. Future studies should consider NPY as a measurable indicator of the biological state in addiction.

Phase angle associated with different indicators of health-related physical fitness in adults with obesity.

In obese populations, the exacerbated increase in adipose tissue results in a significant reduction of health-related physical fitness and can affect the phase angle (PhA), a promising health indicator of cell health and integrity. The aim of this study was to investigate the association of PhA with health-related physical fitness indicators in obese adults. This cross-sectional study had a non-probabilistic sample and was conducted from April to June 2018. The PhA was obtained by a bioelectrical impedance analysis, and the health-related physical fitness indicators evaluated were percentage of body fat (%BF), lower- and upper-body maximal strength, cardiorespiratory fitness (relative V̇O2peak), and flexibility. Pearson and Spearman´s linear correlations, crude and adjusted linear regression analyses were performed. A total of 69 obese adults (60.8% female; BMI = 33.5 ± 2.8 kg/m2) with a mean age of 34.6 ± 7.1 years were studied. The PhA means were 5.8 (±0.6º) and had an inverse correlation with %BF (r=-0.74; p<0.001) and positive correlation with V̇O2peak (r=0.50; p<0.001), lower- and upper-body maximal strength (r=0.65; r=0.70; p<0.001, respectively). After adjustment, %BF (ß=-0.065, adjusted R2=0.53; p<0.001), lower- and upper-body maximal strength (ß=0.004; adjusted R2=0.46; p<0.001, and ß=0.024; adjusted R2=0.50; p<0.001, respectively) were predictors of PhA. Our results suggest the favorable role of PhA as a clinically viable tool to screen and identify the physical fitness variables and functional status of obese adults.

Glutamatergic Alterations in STZ-Induced Diabetic Rats Are Reversed by Exendin-4.

Diabetes mellitus is a metabolic disorder that results in glucotoxicity and the formation of advanced glycated end products (AGEs), which mediate several systemic adverse effects, particularly in the brain tissue. Alterations in glutamatergic neurotransmission and cognitive impairment have been reported in DM. Exendin-4 (EX-4), an analogue of glucagon-like peptide-1 (GLP-1), appears to have beneficial effects on cognition in rats with chronic hyperglycemia. Herein, we investigated the ability of EX-4 to reverse changes in AGE content and glutamatergic transmission in an animal model of DM looking principally at glutamate uptake and GluN1 subunit content of the N-methyl-D-aspartate (NMDA) receptor. Additionally, we evaluated the effects of EX-4 on in vitro models and the signaling pathway involved in these effects. We found a decrease in glutamate uptake and GluN1 content in the hippocampus of diabetic rats; EX-4 was able to revert these parameters, but had no effect on the other parameters evaluated (glycemia, C-peptide, AGE levels, RAGE, and glyoxalase 1). EX-4 abrogated the decrease in glutamate uptake and GluN1 content caused by methylglyoxal (MG) in hippocampal slices, in addition to leading to an increase in glutamate uptake in astrocyte culture cells and hippocampal slices under basal conditions. The effect of EX-4 on glutamate uptake was mediated by the phosphatidylinositide 3-kinases (PI3K) signaling pathway, which could explain the protective effect of EX-4 in the brain tissue, since PI3K is involved in cell metabolism, inhibition of apoptosis, and reduces inflammatory responses. These results suggest that EX-4 could be used as an adjuvant treatment for brain impairment associated with excitotoxicity.

GABAA Modulation of S100B Secretion in Acute Hippocampal Slices and Astrocyte Cultures.

Astrocytes are the major glial cells in brain tissue and are involved, among many functions, ionic and metabolic homeostasis maintenance of synapses. These cells express receptors and transporters for neurotransmitters, including GABA. GABA signaling is reportedly able to affect astroglial response to injury, as evaluated by specific astrocyte markers such as glial fibrillary acid protein and the calcium-binding protein, S100B. Herein, we investigated the modulatory effects of the GABAA receptor on astrocyte S100B secretion in acute hippocampal slices and astrocyte cultures, using the agonist, muscimol, and the antagonists pentylenetetrazol (PTZ) and bicuculline. These effects were analyzed in the presence of tetrodotoxin (TTX), fluorocitrate (FLC), cobalt and barium. PTZ positively modify S100B secretion in hippocampal slices and astrocyte cultures; in contrast, bicuculline inhibited S100B secretion only in hippocampal slices. Muscimol, per se, did not change S100B secretion, but prevented the effects of PTZ and bicuculline. Moreover, PTZ-induced S100B secretion was prevented by TTX, FLC, cobalt and barium indicating a complex GABAA communication between astrocytes and neurons. The effects of two putative agonists of GABAA, ß-hydroxybutyrate and methylglyoxal, on S100B secretion were also evaluated. In view of the neurotrophic role of extracellular S100B under conditions of injury, our data reinforce the idea that GABAA receptors act directly on astrocytes, and indirectly on neurons, to modulate astroglial response.