133 results on '"Hirabara SM"'
Search Results
2. G-protein-coupled receptors as fat sensors.
- Author
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Vinolo MA, Hirabara SM, and Curi R
- Published
- 2012
3. Neutrophil death induced by a triathlon competition in elite athletes.
- Author
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Levada-Pires AC, Cury-Boaventura MF, Gorjão R, Hirabara SM, Puggina EF, Peres CM, Lambertucci RH, Curi R, and Pithon-Curi TC
- Published
- 2008
- Full Text
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4. S-nitrosylation of insulin receptor, insulin receptor substrate-1 and protein kinase B/Akt: A novel mechanism of insulin resistance
- Author
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Carvalho-Filho, Ma, Ueno, M., Hirabara, Sm, Seabra, Ab, Carvalheira, Jbc, Oliveira, Mg, Velloso, La, RUI CURI, and Saad, Mja
5. Insulin resistance in nonobese type 2 diabetic Goto Kakizaki rats is associated with a proinflammatory T lymphocyte profile.
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Lobato TB, Manoel R, Pereira ACG, Correa IS, Iser-Bem PN, Santos ESS, Pereira JNB, de Araújo MJL, Borges JCO, Pauferro JRB, Diniz VLS, Scervino MVM, Serdan TD, Pithon-Curi TC, Masi LN, Hirabara SM, Curi R, and Gorjão R
- Abstract
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., (© 2024 Federation of European Biochemical Societies.)
- Published
- 2024
- Full Text
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6. Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6.
- Author
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Guimarães DSPSF, Barrios NMF, de Oliveira AG, Rizo-Roca D, Jollet M, Smith JAB, Araujo TR, da Cruz MV, Marconato E Jr, Hirabara SM, Vieira AS, Krook A, Zierath JR, and Silveira LR
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- Animals, Mice, Humans, Cell Line, Male, Muscle, Skeletal metabolism, Muscle Contraction physiology
- Abstract
Background: The maintenance of skeletal muscle plasticity upon changes in the environment, nutrient supply, and exercise depends on regulatory mechanisms that couple structural and metabolic adaptations. The mechanisms that interconnect both processes at the transcriptional level remain underexplored. Nr2f6, a nuclear receptor, regulates metabolism and cell differentiation in peripheral tissues. However, its role in the skeletal muscle is still elusive. Here, we aimed to investigate the effects of Nr2f6 modulation on muscle biology in vivo and in vitro., Methods: Global RNA-seq was performed in Nr2f6 knockdown C2C12 myocytes (N = 4-5). Molecular and metabolic assays and proliferation experiments were performed using stable Nr2f6 knockdown and Nr2f6 overexpression C2C12 cell lines (N = 3-6). Nr2f6 content was evaluated in lipid overload models in vitro and in vivo (N = 3-6). In vivo experiments included Nr2f6 overexpression in mouse tibialis anterior muscle, followed by gene array transcriptomics and molecular assays (N = 4), ex vivo contractility experiments (N = 5), and histological analysis (N = 7). The conservation of Nr2f6 depletion effects was confirmed in primary skeletal muscle cells of humans and mice., Results: Nr2f6 knockdown upregulated genes associated with muscle differentiation, metabolism, and contraction, while cell cycle-related genes were downregulated. In human skeletal muscle cells, Nr2f6 knockdown significantly increased the expression of myosin heavy chain genes (two-fold to three-fold) and siRNA-mediated depletion of Nr2f6 increased maximal C2C12 myocyte's lipid oxidative capacity by 75% and protected against lipid-induced cell death. Nr2f6 content decreased by 40% in lipid-overloaded myotubes and by 50% in the skeletal muscle of mice fed a high-fat diet. Nr2f6 overexpression in mice resulted in an atrophic and hypoplastic state, characterized by a significant reduction in muscle mass (15%) and myofibre content (18%), followed by an impairment (50%) in force production. These functional phenotypes were accompanied by the establishment of an inflammation-like molecular signature and a decrease in the expression of genes involved in muscle contractility and oxidative metabolism, which was associated with the repression of the uncoupling protein 3 (20%) and PGC-1α (30%) promoters activity following Nr2f6 overexpression in vitro. Additionally, Nr2f6 regulated core components of the cell division machinery, effectively decoupling muscle cell proliferation from differentiation., Conclusions: Our findings reveal a novel role for Nr2f6 as a molecular transducer that plays a crucial role in maintaining the balance between skeletal muscle contractile function and oxidative capacity. These results have significant implications for the development of potential therapeutic strategies for metabolic diseases and myopathies., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)
- Published
- 2024
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7. Ganoderma lucidum dry extract supplementation modulates T lymphocyte function in older women.
- Author
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Iser-Bem PN, Lobato TB, Alecrim-Zeza AL, Dos Santos de Oliveira LC, Passos MEP, Manuel R, Diniz VLS, Correa IS, de Oliveira SP, Silva EBD, Almeida MM, Dias BB, Gritte RB, Levada-Pires AC, Masi LN, Hatanaka E, Pithon-Curi TC, Hirabara SM, Fabi JP, Curi R, and Gorjao R
- Abstract
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.- Published
- 2024
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8. Impact of Obesity on Cardiac Autonomic System Functioning in Military Police Officers.
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Lima TCP, Trevisan IR, Monma F, da Costa LT, Tinti JC, Ribeiro LTC, Pithon-Curi TC, Hirabara SM, Curi R, De Angelis K, De Souza DR, and Santa-Rosa FA
- Subjects
- Humans, Male, Cross-Sectional Studies, Adult, Brazil epidemiology, Heart innervation, Heart physiopathology, Occupational Health, Hemodynamics, Military Health, Adiposity, Risk Assessment, Military Personnel, Young Adult, Autonomic Nervous System physiopathology, Police, Obesity physiopathology, Obesity diagnosis, Obesity epidemiology, Heart Rate
- Abstract
Introduction: Cardiac autonomic system functioning may be altered by obesity leading to cardiovascular diseases and associated complications. Military police officers are exposed to traditional and occupational risk factors for the development of CVD, however data on the cardiovascular health in this population is still scarce., Aim: In this cross-sectional study, we investigated the impact of obesity on cardiac autonomic modulation and the hemodynamic profile in male active-duty military police officers., Methods: The body composition of the volunteers was assessed by octapolar electrical bioimpedance. Participants were classified as non-obese or obese in accordance with their body fat, with further subgroups as physically active obese or insufficiently active obese using International Physical Activity Questionnaire (IPAQ). Cardiac autonomic modulation was assessed by heart rate variability and the automatic oscillometric method allowed us to assess hemodynamic features., Results: 102 military police officers from the state of São Paulo participated in the study. Cardiac autonomic modulation revealed significant impairment in time and frequency domains and non-linear methods in the obese group compared to the non-obese (p < 0.05). A higher physical activity level did not alter these results in the obese group. However, no significant differences in the hemodynamic profile were observed between groups (p > 0.05)., Conclusion: These findings suggest a negative association between obesity and cardiac autonomic modulation in military police officers, unaffected by increased physical activity., (© 2024. The Author(s).)
- Published
- 2024
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9. Nutrition and Exercise Interventions on Skeletal Muscle Physiology, Injury and Recovery: From Mechanisms to Therapy.
- Author
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Hirabara SM, Marzuca-Nassr GN, and Cury-Boaventura MF
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- Humans, Nutritional Status, Aging, Exercise Therapy, Muscle, Skeletal, Sarcopenia prevention & control
- Abstract
Interventional strategies involving nutrition and physical exercise have been widely proposed to positively modulate skeletal muscle function, in both physiological and pathological states, such as obesity, T2DM, inflammatory diseases, cardiovascular diseases, aging, and sarcopenia [...].
- Published
- 2024
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10. Editorial: Spotlight on aging: physiology, prevention, and management of skeletal muscle atrophy.
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Marzuca-Nassr GN, Peñailillo L, Valladares-Ide D, Martinez-Huenchullan S, Curi R, Hirabara SM, and Vitzel KF
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2023
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11. Changes in Skeletal Muscle Protein Metabolism Signaling Induced by Glutamine Supplementation and Exercise.
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Rodrigues Junior CF, Murata GM, Gerlinger-Romero F, Nachbar RT, Marzuca-Nassr GN, Gorjão R, Vitzel KF, Hirabara SM, Pithon-Curi TC, and Curi R
- Subjects
- Rats, Animals, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Proto-Oncogene Proteins c-akt metabolism, Proteasome Endopeptidase Complex metabolism, Rats, Wistar, Muscle, Skeletal metabolism, Hypertrophy, Dietary Supplements, Glutamates pharmacology, Glutamine pharmacology, Glutamine metabolism, Physical Conditioning, Animal physiology
- Abstract
Aim: To evaluate the effects of resistance exercise training (RET) and/or glutamine supplementation (GS) on signaling protein synthesis in adult rat skeletal muscles., Methods: The following groups were studied: (1) control, no exercise (C); (2) exercise, hypertrophy resistance exercise training protocol (T); (3) no exercise, supplemented with glutamine (G); and (4) exercise and supplemented with glutamine (GT). The rats performed hypertrophic training, climbing a vertical ladder with a height of 1.1 m at an 80° incline relative to the horizontal with extra weights tied to their tails. The RET was performed three days a week for five weeks. Each training session consisted of six ladder climbs. The extra weight load was progressively increased for each animal during each training session. The G groups received daily L-glutamine by gavage (one g per kilogram of body weight per day) for five weeks. The C group received the same volume of water during the same period. The rats were euthanized, and the extensor digitorum longus (EDL) muscles from both hind limbs were removed and immediately weighed. Glutamine and glutamate concentrations were measured, and histological, signaling protein contents, and mRNA expression analyses were performed., Results: Supplementation with free L-glutamine increased the glutamine concentration in the EDL muscle in the C group. The glutamate concentration was augmented in the EDL muscles from T rats. The EDL muscle mass did not change, but a significant rise was reported in the cross-sectional area (CSA) of the fibers in the three experimental groups. The levels of the phosphorylated proteins (pAkt/Akt, pp70S6K/p70S6K, p4E-BP1/4E-BP1, and pS6/S6 ratios) were significantly increased in EDL muscles of G rats, and the activation of p4E-BP1 was present in T rats. The fiber CSAs of the EDL muscles in T, G, and GT rats were increased compared to the C group. These changes were accompanied by a reduction in the 26 proteasome activity of EDL muscles from T rats., Conclusion: Five weeks of GS and/or RET induced muscle hypertrophy, as indicated by the increased CSAs of the EDL muscle fibers. The increase in CSA was mediated via the upregulated phosphorylation of Akt, 4E-BP1, p70S6k, and S6 in G animals and 4E-BP1 in T animals. In the EDL muscles from T animals, a decrease in proteasome activity, favoring a further increase in the CSA of the muscle fibers, was reported.
- Published
- 2023
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12. Effectiveness of Whey Protein Supplementation during Resistance Exercise Training on Skeletal Muscle Mass and Strength in Older People with Sarcopenia: A Systematic Review and Meta-Analysis.
- Author
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Cuyul-Vásquez I, Pezo-Navarrete J, Vargas-Arriagada C, Ortega-Díaz C, Sepúlveda-Loyola W, Hirabara SM, and Marzuca-Nassr GN
- Subjects
- Adult, Humans, Aged, Whey Proteins, Muscle Strength, Muscle, Skeletal metabolism, Hand Strength, Dietary Supplements, Sarcopenia metabolism, Resistance Training
- Abstract
Objective: To determine the effectiveness of whey protein (WP) supplementation during resistance exercise training (RET) vs. RET with or without placebo supplementation on skeletal muscle mass, strength, and physical performance in older people with Sarcopenia., Methods: Electronic searches in the PubMed, Embase, Scopus, Web of Science, LILACS, SPORTDiscus, Epistemonikos, and CINAHL databases were performed until 20 January 2023. Randomized clinical trials conducted on sarcopenic adults aged 60 or older were included. The studies had to compare the effectiveness of the addition of supplements based on concentrated, isolated, or hydrolyzed whey protein during RET and compare it with RET with or without placebo supplementation on skeletal muscle mass and strength changes. The study selection process, data extraction, and risk of bias assessment were carried out by two independent reviewers., Results: Seven randomized clinical trials (591 participants) were included, and five of them provided data for quantitative synthesis. The overall pooled standardized mean difference (SMD) estimate showed a small effect size in favor of RET plus WP for skeletal muscle mass according to appendicular muscle index, with statistically significant differences compared with RET with or without the placebo group (SMD = 0.24; 95% CI, 0.05 to 0.42; p = 0.01; I
2 = 0%, p = 0.42). The overall pooled mean difference (MD) estimate showed a significant difference of +2.31 kg (MD = 2.31 kg; 95% CI, 0.01 to 4.6; p = 0.05; I2 = 81%, p < 0.001) in handgrip strength in the RET plus WP group compared with the RET group with or without placebo. The narrative synthesis revealed discordance between the results of the studies on physical performance., Conclusions: WP supplementation during RET is more effective in increasing handgrip strength and skeletal muscle mass in older people with Sarcopenia compared with RET with or without placebo supplementation. However, the effect sizes were small, and the MD did not exceed the minimally important clinical difference. The quality of the evidence was low to very low according, to the GRADE approach. Further research is needed in this field.- Published
- 2023
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13. Brain glucose hypometabolism and hippocampal inflammation in Goto-Kakizaki rats.
- Author
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Borges JCO, Oliveira VAB, Serdan TDA, Silva FLR, Santos CS, Pauferro JRB, Ribas ASF, Manoel R, Pereira ACG, Correa IS, Pereira JNB, Bazotte RB, Levada-Pires AC, Pithon-Curi TC, Gorjão R, Curi R, Hirabara SM, and Masi LN
- Subjects
- Rats, Animals, Rats, Wistar, Leptin, Blood Glucose metabolism, Neuroinflammatory Diseases, Brain metabolism, Obesity, Hippocampus metabolism, Inflammation, Insulin, Glucose metabolism, Diabetes Mellitus, Type 2 metabolism
- Abstract
Brain glucose hypometabolism and neuroinflammation are early pathogenic manifestations in neurological disorders. Neuroinflammation may also disrupt leptin signaling, an adipokine that centrally regulates appetite and energy balance by acting on the hypothalamus and exerting neuroprotection in the hippocampus. The Goto-Kakizaki (GK) rat is a non-obese type 2 diabetes mellitus (T2DM) animal model used to investigate diabetes-associated molecular mechanisms without obesity jeopardizing effects. Wistar and GK rats received the maintenance adult rodent diet. Also, an additional control group of Wistar rats received a high-fat and high-sugar diet (HFHS) provided by free consumption of condensed milk. All diets and water were provided ad libitum for eight weeks. Brain glucose uptake was evaluated by 2-deoxy-2-[fluorine-18] fluoro-D-glucose under basal (saline administration) or stimulated (CL316,243, a selective β3-AR agonist) conditions. The animals were fasted for 10-12 h, anesthetized, and euthanized. The brain was quickly dissected, and the hippocampal area was sectioned and stored at -80°C in different tubes for protein and RNA analyses on the same animal. GK rats exhibited attenuated brain glucose uptake compared to Wistar animals and the HFHS group under basal conditions. Also, the hippocampus of GK rats displayed upregulated leptin receptor, IL-1β, and IL-6 gene expression and IL-1β and the subunit of the transcription factor NF-κB (p-p65) protein expression. No significant alterations were detected in the hippocampus of HFHS rats. Our data indicated that a genetic predisposition to T2DM has significant brain deteriorating features, including brain glucose hypometabolism, neuroinflammation, and leptin signaling disruption in the hippocampal area.
- Published
- 2023
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14. Essential metabolism required for T and B lymphocyte functions: an update.
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Diniz VLS, Alvares-Saraiva AM, Serdan TDA, Dos Santos-Oliveira LC, Cruzat V, Lobato TB, Manoel R, Alecrim AL, Machado OA, Hirabara SM, Masi LN, Pithon-Curi TC, Curi R, Gorjão R, and Newsholme P
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- Glycosylation, Biological Transport, Antibodies, Glucose, B-Lymphocytes, Lipid Metabolism
- Abstract
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., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2023
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15. Fish Oil Supplementation Improves the Repeated-Bout Effect and Redox Balance in 20-30-Year-Old Men Submitted to Strength Training.
- Author
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Barquilha G, Dos Santos CMM, Caçula KG, Santos VC, Polotow TG, Vasconcellos CV, Gomes-Santos JAF, Rodrigues LE, Lambertucci RH, Serdan TDA, Levada-Pires AC, Hatanaka E, Cury-Boaventura MF, de Freitas PB, Pithon-Curi TC, Masi LN, Barros MP, Curi R, Gorjão R, and Hirabara SM
- Subjects
- Humans, Fish Oils pharmacology, Dietary Supplements, Oxidation-Reduction, Muscle, Skeletal, Muscle Strength, Resistance Training methods, Muscular Diseases
- Abstract
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.
- Published
- 2023
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16. Editorial: Nutritional modulation of inflammation and insulin resistance.
- Author
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Hirabara SM, Gorjao R, Curi R, Leandro CG, and Marzuca-Nassr GN
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2023
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17. Editorial: Molecular and cellular mechanisms involved in inflammation, metabolism and oxidative stress induced by coronaviruses.
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Hirabara SM, Gorjao R, Marzuca-Nassr GN, Vitzel KF, Vinolo MAR, and Masi LN
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2023
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18. Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice.
- Author
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Gaspar RC, Lyu K, Hubbard BT, Leitner BP, Luukkonen PK, Hirabara SM, Sakuma I, Nasiri A, Zhang D, Kahn M, Cline GW, Pauli JR, Perry RJ, Petersen KF, and Shulman GI
- Subjects
- Mice, Animals, Protein Kinase C-theta metabolism, Protein Kinase C-epsilon metabolism, Chromatography, Liquid, Phosphatidylinositol 3-Kinases metabolism, Mice, Inbred C57BL, Tandem Mass Spectrometry, Insulin metabolism, Muscle, Skeletal metabolism, Triglycerides metabolism, Ceramides metabolism, Insulin Resistance physiology
- Abstract
Aims/hypothesis: Athletes exhibit increased muscle insulin sensitivity, despite increased intramuscular triacylglycerol content. This phenomenon has been coined the 'athlete's paradox' and is poorly understood. Recent findings suggest that the subcellular distribution of sn-1,2-diacylglycerols (DAGs) in the plasma membrane leading to activation of novel protein kinase Cs (PKCs) is a crucial pathway to inducing insulin resistance. Here, we hypothesised that regular aerobic exercise would preserve muscle insulin sensitivity by preventing increases in plasma membrane sn-1,2-DAGs and activation of PKCε and PKCθ despite promoting increases in muscle triacylglycerol content., Methods: C57BL/6J mice were allocated to three groups (regular chow feeding [RC]; high-fat diet feeding [HFD]; RC feeding and running wheel exercise [RC-EXE]). We used a novel LC-MS/MS/cellular fractionation method to assess DAG stereoisomers in five subcellular compartments (plasma membrane [PM], endoplasmic reticulum, mitochondria, lipid droplets and cytosol) in the skeletal muscle., Results: We found that the HFD group had a greater content of sn-DAGs and ceramides in multiple subcellular compartments compared with the RC mice, which was associated with an increase in PKCε and PKCθ translocation. However, the RC-EXE mice showed, of particular note, a reduction in PM sn-1,2-DAG and ceramide content when compared with HFD mice. Consistent with the PM sn-1,2-DAG-novel PKC hypothesis, we observed an increase in phosphorylation of threonine
1150 on the insulin receptor kinase (IRKT1150 ), and reductions in insulin-stimulated IRKY1162 phosphorylation and IRS-1-associated phosphoinositide 3-kinase activity in HFD compared with RC and RC-EXE mice, which are sites of PKCε and PKCθ action, respectively., Conclusions/interpretation: These results demonstrate that lower PKCθ/PKCε activity and sn-1,2-DAG content, especially in the PM compartment, can explain the preserved muscle insulin sensitivity in RC-EXE mice., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2023
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19. Hydrolyzed whey protein enriched with glutamine dipeptide attenuates skeletal muscle damage and improves physical exhaustion test performance in triathletes.
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Peres FP, Levada-Pires AC, Vieira M, Hatanaka E, Cury-Boaventura MF, Folador A, Gorjão R, Hirabara SM, Santos-Silva PR, Deuster PA, Curi R, and Pithon-Curi TC
- Abstract
Purpose: To investigate the effects of hydrolyzed whey protein enriched with glutamine dipeptide on the percentage of oxygen consumption, second ventilatory threshold, duration and total distance covered, and skeletal muscle damage during an exhaustion test in elite triathletes., Methods: The study was a randomized, double-blinded, placebo-controlled, crossover trial. Nine male triathletes performed a progressive incremental test on a treadmill ergometer (1.4 km h
-1 ·3 min-1 ) 30 min after ingesting either 50 g of maltodextrin plus four tablets of 700 mg hydrolyzed whey protein enriched with 175 mg of glutamine dipeptide diluted in 250 ml of water (MGln) or four tablets of 700 mg maltodextrin plus 50 g maltodextrin diluted in 250 ml of water (M). Each athlete was submitted to the two dietary treatments and two corresponding exhaustive physical tests with an interval of one week between the interventions. The effects of the two treatments were then compared within the same athlete. Maximal oxygen consumption, percentage of maximal oxygen consumption, second ventilatory threshold, and duration and total distance covered were measured during the exhaustion test. Blood was collected before and immediately after the test for the determination of plasma lactate dehydrogenase (LDH) and creatine kinase (CK) activities and lactate concentration (also measured 6, 10, and 15 min after the test). Plasma cytokines (IL-6, IL-1β, TNF-α, IL-8, IL-10, and IL-1ra) and C-reactive protein levels were also measured., Results: A single dose of MGln increased the percentage of maximal oxygen consumption, second ventilatory threshold duration, and total distance covered during the exhaustion test and augmented plasma lactate levels 6 and 15 min after the test. MGln also decreased plasma LDH and CK activities indicating muscle damage protection. Plasma cytokine and C-reactive protein levels did not change across the study periods., Conclusion: Conditions including overnight fasting and a single dose of MGln supplementation resulted in exercising at a higher percentage of maximal oxygen consumption, a higher second ventilatory threshold, blood lactate levels, and reductions in plasma markers of muscle damage during an exhaustion test in elite triathletes. These findings support oral glutamine supplementation's efficacy in triathletes, but further studies require., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Peres, Levada-Pires, Vieira, Hatanaka, Cury-Boaventura, Folador, Gorjão, Hirabara, Santos-Silva, Deuster, Curi and Pithon-Curi.)- Published
- 2023
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20. Molecular and cellular mechanisms involved in tissue-specific metabolic modulation by SARS-CoV-2.
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Dos Santos AAC, Rodrigues LE, Alecrim-Zeza AL, de Araújo Ferreira L, Trettel CDS, Gimenes GM, da Silva AF, Sousa-Filho CPB, Serdan TDA, Levada-Pires AC, Hatanaka E, Borges FT, de Barros MP, Cury-Boaventura MF, Bertolini GL, Cassolla P, Marzuca-Nassr GN, Vitzel KF, Pithon-Curi TC, Masi LN, Curi R, Gorjao R, and Hirabara SM
- Abstract
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-1β, INF-α and INF-β, 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Santos, Rodrigues, Alecrim-Zeza, de Araújo Ferreira, Trettel, Gimenes, Silva, Sousa-Filho, Serdan, Levada-Pires, Hatanaka, Borges, de Barros, Cury-Boaventura, Bertolini, Cassolla, Marzuca-Nassr, Vitzel, Pithon-Curi, Masi, Curi, Gorjao and Hirabara.)
- Published
- 2022
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21. Leukocyte metabolism in obese type 2 diabetic individuals associated with COVID-19 severity.
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Lobato TB, Gennari-Felipe M, Pauferro JRB, Correa IS, Santos BF, Dias BB, de Oliveira Borges JC, Dos Santos CS, de Sousa Santos ES, de Araújo MJL, Ferreira LA, Pereira SA, Serdan TDA, Levada-Pires AC, Hatanaka E, Borges L, Cury-Boaventura MF, Vinolo MAR, Pithon-Curi TC, Masi LN, Curi R, Hirabara SM, and Gorjão R
- Abstract
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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lobato, Gennari-Felipe, Pauferro, Correa, Salgado, Dias, de Oliveira Borges, dos Santos, de Sousa Santos, de Araújo, Ferreira, Pereira, Serdan, Levada-Pires, Hatanaka, Borges, Cury-Boaventura, Vinolo, Pithon-Curi, Masi, Curi, Hirabara and Gorjao.)
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- 2022
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22. Updating futsal physiology, immune system, and performance.
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Borges L, Dermargos A, Gorjão R, Cury-Boaventura MF, Hirabara SM, Abad CC, Pithon-Curi TC, Curi R, Barros MP, and Hatanaka E
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- Humans, Immune System, Inflammation, Oxidative Stress, Athletic Performance physiology, Soccer physiology
- Abstract
Futsal promotes stress by handling the ball, physical contact, and exhaustive muscle contractions, elevating the risks for injury, oxidative stress, and inflammation after a training session or a match. In this review, we critically evaluate the more recent advances in the performance and health of futsal players. We searched the effects of futsal on performance, physiological parameters, muscle injury, inflammation, and oxidative stress. Although the stressful factors apply to all futsal players, goalkeepers require special attention during the competition and the recovery phase. We also show that the FIFA injury prevention programme, called The 11+ , is effective in improving athletic performance and avoiding injury in futsal players. Research with different training durations and intensities and a wider range of studies involving oxidative stress, inflammation, and physiological mechanisms are of interest to design a more precise map of the biochemical regulation of training load and competition season in futsal.
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- 2022
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23. Maternal low-protein diet reduces skeletal muscle protein synthesis and mass via Akt-mTOR pathway in adult rats.
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de Vasconcelos DAA, Nachbar RT, Pinheiro CH, do Amaral CL, Crisma AR, Vitzel KF, Abreu P, Alonso-Vale MI, Lopes AB, Bento-Santos A, Falcão-Tebas F, de Santana DF, do Nascimento E, Curi R, Pithon-Curi TC, Hirabara SM, and Leandro CG
- Abstract
Several studies have demonstrated that a maternal low-protein diet induces long-term metabolic disorders, but the involved mechanisms are unclear. This study investigated the molecular effects of a low-protein diet during pregnancy and lactation on glucose and protein metabolism in soleus muscle isolated from adult male rats. Female rats were fed either a normal protein diet or low-protein diet during gestation and lactation. After weaning, all pups were fed a normal protein diet until the 210th day postpartum. In the 7th month of life, mass, contractile function, protein and glucose metabolism, and the Akt-mTOR pathway were measured in the soleus muscles of male pups. Dry weight and contractile function of soleus muscle in the low-protein diet group rats were found to be lower compared to the control group. Lipid synthesis was evaluated by measuring palmitate incorporation in white adipose tissue. Palmitate incorporation was higher in the white adipose tissue of the low-protein diet group. When incubated soleus muscles were stimulated with insulin, protein synthesis, total amino acid incorporation and free amino acid content, glucose incorporation and uptake, and glycogen synthesis were found to be reduced in low-protein diet group rats. Fasting glycemia was higher in the low-protein diet group. These metabolic changes were associated with a decrease in Akt and GSK-3β signaling responses to insulin and a reduction in RPS6 in the absence of the hormone. There was also notably lower expression of Akt in the isolated soleus muscle of low-protein diet group rats. This study is the first to demonstrate how maternal diet restriction can reduce skeletal muscle protein and mass by downregulating the Akt-mTOR pathway in adulthood., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 de Vasconcelos, Nachbar, Pinheiro, do Amaral, Crisma, Vitzel, Abreu, Alonso-Vale, Lopes, Bento-Santos, Falcão-Tebas, de Santana, do Nascimento, Curi, Pithon-Curi, Hirabara and Leandro.)
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- 2022
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24. Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism.
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Katashima CK, de Oliveira Micheletti T, Braga RR, Gaspar RS, Goeminne LJE, Moura-Assis A, Crisol BM, Brícola RS, Silva VRR, de Oliveira Ramos C, da Rocha AL, Tavares MR, Simabuco FM, Matheus VA, Buscaratti L, Marques-Souza H, Pazos P, Gonzalez-Touceda D, Tovar S, Del Carmen García M, Neto JCR, Curi R, Hirabara SM, Brum PC, Prada PO, de Moura LP, Pauli JR, da Silva ASR, Cintra DE, Velloso LA, and Ropelle ER
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- Animals, Fatty Acids metabolism, Humans, Hypothalamus metabolism, Mice, Muscle, Skeletal metabolism, Oxidation-Reduction, AMP-Activated Protein Kinases genetics, AMP-Activated Protein Kinases metabolism, Interleukin-6 genetics, Interleukin-6 metabolism
- Abstract
Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation- and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.
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- 2022
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25. Poor prognosis indicators of type-2 diabetic COVID-19 patients.
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Gorjão R, Hirabara SM, Masi LN, Serdan TDA, Gritte RB, Hatanaka E, Souza-Siqueira T, Pithon-Curi AC, Lima TM, Pithon-Curi TC, Marchini JFM, Machado MCC, Souza HP, and Curi R
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- Hospital Mortality, Humans, Intensive Care Units, Organ Dysfunction Scores, ROC Curve, Retrospective Studies, COVID-19 complications, Diabetes Mellitus, Type 2 complications, Sepsis diagnosis
- Abstract
Diabetes is associated with a worse prognosis and a high risk of morbidity and mortality in COVID-19 patients. We aimed to evaluate the main factors involved in the poor prognosis in diabetic patients. A total of 984 patients diagnosed with COVID-19 admitted to the hospital were included in this study. Patients were first divided into type-2 diabetic (DM+) and non-diabetic (DM-) groups. The participants were analyzed based on the National Early Warning Score (NEWS) and on the Quick-Sequential Organ Failure Assessment (qSOFA) to find the best prognostic risk score for our study. The DM+ and DM- groups were divided into non-severe and severe groups. Comparative and correlative analyses were used to identify the physiological parameters that could be employed for creating a potential risk indicator for DM+ COVID-19 patients. We found a poorer prognosis for the DM+ COVID-19 patients with a higher ICU admission rate, mechanical ventilation rate, vasopressor use, dialysis, and longer treatment times compared with the DM- group. DM+ COVID-19 patients had increased plasma glucose, lactate, age, urea, NEWS, and D-dimer levels, herein referred to as the GLAUND set, and worse prognosis and outcomes when compared with infected DM- patients. The NEWS score was a better indicator for assessing COVID-19 severity in diabetic patients than the q-SOFA score. In conclusion, diabetic COVID-19 patients should be assessed with the NEWS score and GLAUND set for determining their prognosis COVID-19 prognosis.
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- 2022
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26. Reviewing physical exercise in non-obese diabetic Goto-Kakizaki rats.
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Galán BSM, Serdan TDA, Rodrigues LE, Manoel R, Gorjão R, Masi LN, Pithon-Curi TC, Curi R, and Hirabara SM
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- Animals, Muscle, Skeletal metabolism, Obesity metabolism, Quality of Life, Rats, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 therapy, Insulin Resistance
- Abstract
There is a high incidence of non-obese type 2 diabetes mellitus (non-obese-T2DM) cases, particularly in Asian countries, for which the pathogenesis remains mainly unclear. Interestingly, Goto-Kakizaki (GK) rats spontaneously develop insulin resistance (IR) and non-obese-T2DM, making them a lean diabetes model. Physical exercise is a non-pharmacological therapeutic approach to reduce adipose tissue mass, improving peripheral IR, glycemic control, and quality of life in obese animals or humans with T2DM. In this narrative review, we selected and analyzed the published literature on the effects of physical exercise on the metabolic features associated with non-obese-T2DM. Only randomized controlled trials with regular physical exercise training, freely executed physical activity, or skeletal muscle stimulation protocols in GK rats published after 2008 were included. The results indicated that exercise reduces plasma insulin levels, increases skeletal muscle glycogen content, improves exercise tolerance, protects renal and myocardial function, and enhances blood oxygen flow in GK rats.
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- 2022
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27. Corrigendum to "Impaired brown adipose tissue is differentially modulated in insulin-resistant obese wistar and type 2 diabetic Goto-Kakizaki rats" [Biomed. Pharmacother. 142 (2021) 112019].
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Serdan TDA, Mais LN, Pereira JNB, Rodrigues LE, Alecrim AL, Scervino MVM, Diniz VLS, Carneiro Dos Santos AA, Sousa Filho CPB, Alba-Loureiro TC, Marzuca-Nassr GN, Bazotte RB, Gorjão R, Pithon-Curi TC, Curi R, and Hirabara SM
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- 2022
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28. SARS-COV-2 Variants: Differences and Potential of Immune Evasion.
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Hirabara SM, Serdan TDA, Gorjao R, Masi LN, Pithon-Curi TC, Covas DT, Curi R, and Durigon EL
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- Antibodies, Neutralizing, Antibodies, Viral, Humans, Immune Evasion, Mutation, Pandemics, COVID-19, SARS-CoV-2
- Abstract
The structural spike (S) glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) plays an essential role in infection and is an important target for neutralizing antibody recognition. Mutations in the S gene can generate variants of concern (VOCs), which improve "viral fitness" through selective or survival advantages, such as increased ACE-2 receptor affinity, infectivity, viral replication, higher transmissibility, resistance to neutralizing antibodies and immune escape, increasing disease severity and reinfection risk. Five VOCs have been recognized and include B.1.1.7 (U.K.), B.1.351 (South Africa), P.1 (Brazil), B.1.617.2 (India), and B.1.1.529 (multiple countries). In this review, we addressed the following critical points concerning VOCs: a) characteristics of the SARS-CoV-2 VOCs with mutations in the S gene; b) possible evasion of variants from neutralizing antibodies generated through vaccination, previous infection, or immune therapies; c) potential risk of new pandemic waves induced by the variants worldwide; and d) perspectives for further studies and actions aimed at preventing or reducing the impact of new variants during the current COVID-19 pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hirabara, Serdan, Gorjao, Masi, Pithon-Curi, Covas, Curi and Durigon.)
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- 2022
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29. Impaired brown adipose tissue is differentially modulated in insulin-resistant obese wistar and type 2 diabetic Goto-Kakizaki rats.
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Serdan TDA, Masi LN, Pereira JNB, Rodrigues LE, Alecrim AL, Scervino MVM, Diniz VLS, Dos Santos AAC, Filho CPBS, Alba-Loureiro TC, Marzuca-Nassr GN, Bazotte RB, Gorjão R, Pithon-Curi TC, Curi R, and Hirabara SM
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- Animals, Diabetes Mellitus, Experimental metabolism, Diet, High-Fat, Fluorodeoxyglucose F18, Glucose metabolism, Male, Positron-Emission Tomography, Rats, Rats, Wistar, Adipose Tissue, Brown metabolism, Diabetes Mellitus, Type 2 metabolism, Insulin Resistance physiology, Obesity metabolism
- Abstract
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 β3-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., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
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- 2021
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30. Physical exercise increases global and gene-specific (interleukin-17 and interferon-γ) DNA methylation in lymphocytes from aged women.
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Machado OAS, Diniz VLS, Passos MEP, de Oliveira HH, Santos-Oliveira LC, Alecrim AL, Bertola Lobato T, Manoel R, Correa I, Silva EB, de Oliveira Poma S, Mendes de Almeida M, Pithon-Curi TC, Diniz S, Levada-Pires AC, Curi R, Masi LN, Hirabara SM, and Gorjão R
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- Aged, Cross-Sectional Studies, DNA Methylation, Exercise, Female, Humans, Lymphocytes metabolism, Interferon-gamma metabolism, Interleukin-17 genetics, Interleukin-17 metabolism
- Abstract
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., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)- Published
- 2021
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31. A simple mathematical model for the evaluation of the long first wave of the COVID-19 pandemic in Brazil.
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Tang Y, Serdan TDA, Alecrim AL, Souza DR, Nacano BRM, Silva FLR, Silva EB, Poma SO, Gennari-Felipe M, Iser-Bem PN, Masi LN, Tang S, Levada-Pires AC, Hatanaka E, Cury-Boaventura MF, Borges FT, Pithon-Curi TC, Curpertino MC, Fiamoncini J, Leandro CG, Gorjao R, Curi R, and Hirabara SM
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- Brazil epidemiology, COVID-19 transmission, Cities epidemiology, Humans, Models, Statistical, Pandemics, SARS-CoV-2 isolation & purification, Time Factors, COVID-19 epidemiology
- Abstract
We propose herein a mathematical model to predict the COVID-19 evolution and evaluate the impact of governmental decisions on this evolution, attempting to explain the long duration of the pandemic in the 26 Brazilian states and their capitals well as in the Federative Unit. The prediction was performed based on the growth rate of new cases in a stable period, and the graphics plotted with the significant governmental decisions to evaluate the impact on the epidemic curve in each Brazilian state and city. Analysis of the predicted new cases was correlated with the total number of hospitalizations and deaths related to COVID-19. Because Brazil is a vast country, with high heterogeneity and complexity of the regional/local characteristics and governmental authorities among Brazilian states and cities, we individually predicted the epidemic curve based on a specific stable period with reduced or minimal interference on the growth rate of new cases. We found good accuracy, mainly in a short period (weeks). The most critical governmental decisions had a significant temporal impact on pandemic curve growth. A good relationship was found between the predicted number of new cases and the total number of inpatients and deaths related to COVID-19. In summary, we demonstrated that interventional and preventive measures directly and significantly impact the COVID-19 pandemic using a simple mathematical model. This model can easily be applied, helping, and directing health and governmental authorities to make further decisions to combat the pandemic., (© 2021. The Author(s).)
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- 2021
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32. Recreational Dance Practice Modulates Lymphocyte Profile and Function in Diabetic Women.
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Passos MEP, Borges L, Dos Santos-Oliveira LC, Alecrim-Zeza AL, Lobato TB, de Oliveira HH, Santos CMM, Diniz VLS, Iser-Bem PN, Manoel R, Murata GM, Hirabara SM, Curi R, Pithon-Curi TC, Hatanaka E, and Gorjao R
- Subjects
- Aged, Blood Glucose analysis, Body Composition, C-Reactive Protein analysis, Case-Control Studies, Cell Proliferation, Cytokines metabolism, Diabetes Mellitus, Type 2 immunology, Female, Humans, Interleukins blood, Lipids blood, Lymphocytes cytology, Lymphocytes physiology, Middle Aged, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory metabolism, T-Lymphocytes, Regulatory physiology, Time Factors, CD28 Antigens blood, Dancing physiology, Diabetes Mellitus, Type 2 blood, Exercise physiology, Interleukin-2 Receptor alpha Subunit blood, Lymphocytes metabolism
- Abstract
This study aimed to investigate the impact of a 16-week dance-based aerobic exercise program on lymphocyte function in healthy and type 2 diabetes mellitus (T2DM) women. We enrolled 23 women: 11 with T2DM and 12 non-diabetic controls. Initially, we performed anthropometry and body composition measurements, afterwards, plasma levels of C-reactive protein, lipids, and glucose were determined. We used flow cytometry to measure the CD25 and CD28 expression in circulating lymphocytes, T-regulatory (Treg) cell percentage, lymphocyte proliferation, and cytokines released by cultured lymphocytes. The T2DM group had a lower proportion of CD28+ cells and a higher percentage of Treg lymphocytes and proliferative capacity at the baseline compared with the control group. After 16 weeks of the program, differences in lymphocytes between the T2DM and the control groups disappeared. The dance program promoted IL-10 increase in both groups. We found decreased IL-4, IL-2, and IL-6 secretion in lymphocytes from the control group and increased IL-17 secretion and IL-10/IL-17 ratio in the T2DM group after the program. The program promoted marked changes in lymphocytes in diabetic women, leading to a balance between the different profiles., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)
- Published
- 2021
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33. L-arginine Improves Plasma Lipid Profile and Muscle Inflammatory Response in Trained Rats After High-Intense Exercise.
- Author
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Silva EPD Jr, Borges L, Bachi ALL, Hirabara SM, and Lambertucci RH
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- Animals, Chemokine CXCL1 metabolism, Cytokines metabolism, Male, Muscle, Skeletal drug effects, Muscle, Skeletal injuries, Rats, Wistar, Vascular Endothelial Growth Factor A metabolism, Rats, Arginine administration & dosage, Dietary Supplements, Lipids blood, Muscle, Skeletal metabolism, Myositis metabolism, Physical Conditioning, Animal physiology
- Abstract
Purpose : This study aimed to evaluate whether supplementation with L-arginine alone or in combination with physical exercise training can modulate rats' lipid and inflammatory profiles after a single intense exercise session. Methods : Male Wistar rats were divided into four different groups: control (C), trained (T), supplemented with L-arginine (C + A) and trained and supplemented (T + A). Animals from supplemented groups (C + A and T + A groups) received 300 mg/kg animal body weight L-arginine diluted in 30 mL of drinking water for 8 weeks. Exercise training protocol (moderate intensity-70% achieved in the maximum effort test) was held 5 days/week for 8 weeks. Results : Exercise training induced a decrease in the amount of plasma, cholesterol and triglyceride totals, and skeletal muscle VEGF and CINC. Supplementation alone showed a benefit by reducing LDL levels. Conclusion : Training combined with supplementation showed a pronounced reduction in skeletal muscle VEGF and CINC amount. L-arginine supplementation, especially when associated with the regular aerobic physical exercise at moderate intensity was able to improve not only plasma lipid profile but also the inflammatory response of skeletal muscle immediately after an exhaustive physical exercise session.
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- 2021
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34. 4-Aminoquinoline compounds from the Spanish flu to COVID-19.
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Bazotte RB, Hirabara SM, Serdan TAD, Gritte RB, Souza-Siqueira T, Gorjao R, Masi LN, Antunes MM, Cruzat V, Pithon-Curi TC, and Curi R
- Subjects
- Aminoquinolines pharmacology, Antimalarials pharmacology, Antimalarials therapeutic use, Antiviral Agents pharmacology, Humans, SARS-CoV-2 physiology, Virus Replication drug effects, Virus Replication physiology, Aminoquinolines therapeutic use, Antiviral Agents therapeutic use, COVID-19 epidemiology, Influenza Pandemic, 1918-1919 prevention & control, SARS-CoV-2 drug effects, COVID-19 Drug Treatment
- Abstract
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., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2021
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35. Profiling plasma-extracellular vesicle proteins and microRNAs in diabetes onset in middle-aged male participants in the ELSA-Brasil study.
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Masi LN, Lotufo PA, Ferreira FM, Rodrigues AC, Serdan TDA, Souza-Siqueira T, Braga AA, Saldarriaga MEG, Alba-Loureiro TC, Borges FT, Cury DP, Hirata MH, Gorjão R, Pithon-Curi TC, Lottenberg SA, Fedeli LMG, Nakaya HTI, Bensenor IJM, Curi R, and Hirabara SM
- Subjects
- Adult, Age Factors, Aged, Blood Glucose analysis, Brazil epidemiology, Diabetes Mellitus diagnosis, Diabetes Mellitus epidemiology, Gene Expression Profiling, Humans, Incidence, Male, Middle Aged, Proteomics, Risk Assessment, Risk Factors, Sex Factors, Blood Proteins analysis, Diabetes Mellitus blood, Diabetes Mellitus genetics, Extracellular Vesicles genetics, Extracellular Vesicles metabolism, MicroRNAs genetics, Proteome, Transcriptome
- Abstract
We measured plasma-derived extracellular vesicle (EV) proteins and their microRNA (miRNA) cargos in normoglycemic (NG), glucose intolerant (GI), and newly diagnosed diabetes mellitus (DM) in middle-aged male participants of the Brazilian Longitudinal Study of Adult Health (ELSA-Brazil). Mass spectrometry revealed decreased IGHG-1 and increased ITIH2 protein levels in the GI group compared with that in the NG group and higher serotransferrin in EVs in the DM group than in those in the NG and GI groups. The GI group also showed increased serum ferritin levels, as evaluated by biochemical analysis, compared with those in both groups. Seventeen miRNAs were differentially expressed (DEMiRs) in the plasma EVs of the three groups. DM patients showed upregulation of miR-141-3p and downregulation of miR-324-5p and -376c-3p compared with the NG and GI groups. The DM and GI groups showed increased miR-26b-5p expression compared with that in the NG group. The DM group showed decreased miR-374b-5p levels compared with those in the GI group and higher concentrations than those in the NG group. Thus, three EV proteins and five DEMiR cargos have potential prognostic importance for diabetic complications mainly associated with the immune function and iron status of GI and DM patients., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
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- 2021
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36. Host cell glutamine metabolism as a potential antiviral target.
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Hirabara SM, Gorjao R, Levada-Pires AC, Masi LN, Hatanaka E, Cury-Boaventura MF, da Silva EB, Santos-Oliveira LCD, Sousa Diniz VL, Serdan TAD, de Oliveira VAB, de Souza DR, Gritte RB, Souza-Siqueira T, Zambonatto RF, Pithon-Curi TC, Bazotte RB, Newsholme P, and Curi R
- Subjects
- Cell Line, Tumor, Host-Pathogen Interactions, Humans, Neoplasms metabolism, Neoplasms virology, Virulence drug effects, Viruses drug effects, Viruses pathogenicity, Antiviral Agents pharmacology, Glutamine metabolism, Metabolic Networks and Pathways drug effects, Virus Replication drug effects
- Abstract
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., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
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- 2021
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37. COVID-19 Pandemic in Brazil: History, Characteristics, and Evolution.
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Serdan TDA, Tang Y, Lobato TB, da Silva FLR, Tang S, Masi LN, Gorjao R, Palacios R, Pithon-Curi TC, Curi R, and Hirabara SM
- Subjects
- Brazil epidemiology, Humans, Prevalence, SARS-CoV-2, COVID-19, Pandemics
- Abstract
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., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2021
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38. Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice.
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Li X, Zhang D, Vatner DF, Goedeke L, Hirabara SM, Zhang Y, Perry RJ, and Shulman GI
- Subjects
- AMP-Activated Protein Kinases metabolism, Adiponectin genetics, Adiponectin metabolism, Adipose Tissue, White drug effects, Adipose Tissue, White metabolism, Animals, Diglycerides metabolism, Insulin metabolism, Lipid Metabolism, Lipoprotein Lipase metabolism, Liver metabolism, Male, Mice, Inbred C57BL, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, Nitric Oxide Synthase Type III metabolism, Protein Kinase C metabolism, Recombinant Proteins genetics, Recombinant Proteins metabolism, Recombinant Proteins pharmacology, Adiponectin pharmacology, Diet, High-Fat adverse effects, Insulin Resistance physiology
- Abstract
Adiponectin has emerged as a potential therapy for type 2 diabetes mellitus, but the molecular mechanism by which adiponectin reverses insulin resistance remains unclear. Two weeks of globular adiponectin (gAcrp30) treatment reduced fasting plasma glucose, triglyceride (TAG), and insulin concentrations and reversed whole-body insulin resistance, which could be attributed to both improved insulin-mediated suppression of endogenous glucose production and increased insulin-stimulated glucose uptake in muscle and adipose tissues. These improvements in liver and muscle sensitivity were associated with ∼50% reductions in liver and muscle TAG and plasma membrane (PM)-associated diacylglycerol (DAG) content and occurred independent of reductions in total ceramide content. Reductions of PM DAG content in liver and skeletal muscle were associated with reduced PKCε translocation in liver and reduced PKCθ and PKCε translocation in skeletal muscle resulting in increased insulin-stimulated insulin receptor tyrosine1162 phosphorylation, IRS-1/IRS-2-associated PI3-kinase activity, and Akt-serine phosphorylation. Both gAcrp30 and full-length adiponectin (Acrp30) treatment increased eNOS/AMPK activation in muscle and muscle fatty acid oxidation. gAcrp30 and Acrp30 infusions also increased TAG uptake in epididymal white adipose tissue (eWAT), which could be attributed to increased lipoprotein lipase (LPL) activity. These data suggest that adiponectin and adiponectin-related molecules reverse lipid-induced liver and muscle insulin resistance by reducing ectopic lipid storage in these organs, resulting in decreased plasma membrane sn -1,2-DAG-induced nPKC activity and increased insulin signaling. Adiponectin mediates these effects by both promoting the storage of TAG in eWAT likely through stimulation of LPL as well as by stimulation of AMPK in muscle resulting in increased muscle fat oxidation., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)
- Published
- 2020
- Full Text
- View/download PDF
39. Epidemiology of COVID-19 in Brazil: using a mathematical model to estimate the outbreak peak and temporal evolution.
- Author
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Tang Y, Serdan TDA, Masi LN, Tang S, Gorjao R, and Hirabara SM
- Subjects
- Brazil epidemiology, COVID-19, Epidemiologic Studies, Humans, Pandemics, Coronavirus Infections epidemiology, Disease Outbreaks, Models, Statistical, Pneumonia, Viral epidemiology
- Published
- 2020
- Full Text
- View/download PDF
40. COVID-19 in Brazil: Historical cases, disease milestones, and estimated outbreak peak.
- Author
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Serdan TDA, Masi LN, Gorjao R, Pithon-Curi TC, Curi R, and Hirabara SM
- Subjects
- Brazil epidemiology, COVID-19 prevention & control, COVID-19 transmission, Communicable Disease Control legislation & jurisprudence, Communicable Disease Control statistics & numerical data, Disease Outbreaks prevention & control, Humans, Program Evaluation, SARS-CoV-2, COVID-19 epidemiology, Disease Outbreaks statistics & numerical data
- Abstract
Competing Interests: All authors declare no conflict of interest.
- Published
- 2020
- Full Text
- View/download PDF
41. A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance.
- Author
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Lyu K, Zhang Y, Zhang D, Kahn M, Ter Horst KW, Rodrigues MRS, Gaspar RC, Hirabara SM, Luukkonen PK, Lee S, Bhanot S, Rinehart J, Blume N, Rasch MG, Serlie MJ, Bogan JS, Cline GW, Samuel VT, and Shulman GI
- Subjects
- Animals, Cell Membrane metabolism, Diglycerides chemistry, Humans, Insulin Resistance, Male, Phosphorylation, Rats, Rats, Sprague-Dawley, Receptor, Insulin metabolism, Cell Membrane chemistry, Diglycerides metabolism, Liver metabolism, Protein Kinase C-epsilon metabolism
- Abstract
Nonalcoholic fatty liver disease is strongly associated with hepatic insulin resistance (HIR); however, the key lipid species and molecular mechanisms linking these conditions are widely debated. We developed a subcellular fractionation method to quantify diacylglycerol (DAG) stereoisomers and ceramides in the endoplasmic reticulum (ER), mitochondria, plasma membrane (PM), lipid droplets, and cytosol. Acute knockdown (KD) of diacylglycerol acyltransferase-2 in liver induced HIR in rats. This was due to PM sn-1,2-DAG accumulation, which promoted PKCϵ activation and insulin receptor kinase (IRK)-T1160 phosphorylation, resulting in decreased IRK-Y1162 phosphorylation. Liver PM sn-1,2-DAG content and IRK-T1160 phosphorylation were also higher in humans with HIR. In rats, liver-specific PKCϵ KD ameliorated high-fat diet-induced HIR by lowering IRK-T1160 phosphorylation, while liver-specific overexpression of constitutively active PKCϵ-induced HIR by promoting IRK-T1160 phosphorylation. These data identify PM sn-1,2-DAGs as the key pool of lipids that activate PKCϵ and that hepatic PKCϵ is both necessary and sufficient in mediating HIR., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
42. The paradoxical lean phenotype of hypothyroid mice is marked by increased adaptive thermogenesis in the skeletal muscle.
- Author
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Kaspari RR, Reyna-Neyra A, Jung L, Torres-Manzo AP, Hirabara SM, and Carrasco N
- Subjects
- Animals, Disease Models, Animal, Eating physiology, Male, Mice, Mice, Knockout, Muscle Proteins metabolism, Phenotype, Proteolipids metabolism, Symporters genetics, Symporters metabolism, Hypothyroidism metabolism, Muscle, Skeletal metabolism, Thermogenesis physiology
- Abstract
Obesity is a major health problem worldwide, given its growing incidence and its association with a variety of comorbidities. Weight gain results from an increase in energy intake without a concomitant increase in energy expenditure. To combat the obesity epidemic, many studies have focused on the pathways underlying satiety and hunger signaling, while other studies have concentrated on the mechanisms involved in energy expenditure, most notably adaptive thermogenesis. Hypothyroidism in humans is typically associated with a decreased basal metabolic rate, lower energy expenditure, and weight gain. However, hypothyroid mouse models have been reported to have a leaner phenotype than euthyroid controls. To elucidate the mechanism underlying this phenomenon, we used a drug-free mouse model of hypothyroidism: mice lacking the sodium/iodide symporter (NIS), the plasma membrane protein that mediates active iodide uptake in the thyroid. In addition to being leaner than euthyroid mice, owing in part to reduced food intake, these hypothyroid mice show signs of compensatory up-regulation of the skeletal-muscle adaptive thermogenic marker sarcolipin, with an associated increase in fatty acid oxidation (FAO). Neither catecholamines nor thyroid-stimulating hormone (TSH) are responsible for sarcolipin expression or FAO stimulation; rather, thyroid hormones are likely to negatively regulate both processes in skeletal muscle. Our findings indicate that hypothyroidism in mice results in a variety of metabolic changes, which collectively lead to a leaner phenotype. A deeper understanding of these changes may make it possible to develop new strategies against obesity., Competing Interests: The authors declare no competing interest.
- Published
- 2020
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43. Tributyrin Attenuates Metabolic and Inflammatory Changes Associated with Obesity through a GPR109A-Dependent Mechanism.
- Author
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Sato FT, Yap YA, Crisma AR, Portovedo M, Murata GM, Hirabara SM, Ribeiro WR, Marcantonio Ferreira C, Cruz MM, Pereira JNB, Payolla TB, Guima SES, Thomas AM, Setubal JC, Alonso-Vale MIC, Santos MF, Curi R, Marino E, and Vinolo MAR
- Subjects
- Adipose Tissue drug effects, Adipose Tissue metabolism, Animals, Butyrates blood, Cytokines metabolism, Diet, High-Fat adverse effects, Gastrointestinal Microbiome, Gene Knockout Techniques, Inflammation drug therapy, Inflammation metabolism, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity etiology, Receptors, G-Protein-Coupled genetics, Triglycerides blood, Weight Gain drug effects, Obesity blood, Obesity drug therapy, Prodrugs administration & dosage, Receptors, G-Protein-Coupled metabolism, Signal Transduction drug effects, Triglycerides administration & dosage
- Abstract
Obesity is linked with altered microbial short-chain fatty acids (SCFAs), which are a signature of gut dysbiosis and inflammation. In the present study, we investigated whether tributyrin, a prodrug of the SCFA butyrate, could improve metabolic and inflammatory profiles in diet-induced obese mice. Mice fed a high-fat diet for eight weeks were treated with tributyrin or placebo for another six weeks. We show that obese mice treated with tributyrin had lower body weight gain and an improved insulin responsiveness and glucose metabolism, partly via reduced hepatic triglycerides content. Additionally, tributyrin induced an anti-inflammatory state in the adipose tissue by reduction of Il-1β and Tnf-a and increased Il-10 , Tregs cells and M2-macrophages. Moreover, improvement in glucose metabolism and reduction of fat inflammatory states associated with tributyrin treatment were dependent on GPR109A activation. Our results indicate that exogenous targeting of SCFA butyrate attenuates metabolic and inflammatory dysfunction, highlighting a potentially novel approach to tackle obesity.
- Published
- 2020
- Full Text
- View/download PDF
44. Microbiota determines insulin sensitivity in TLR2-KO mice.
- Author
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Guadagnini D, Rocha GZ, Santos A, Assalin HB, Hirabara SM, Curi R, Oliveira AG, Prada PO, and Saad MJA
- Subjects
- Animals, Endoplasmic Reticulum Stress, Gene Deletion, Glucose Intolerance genetics, Glucose Intolerance metabolism, Glucose Intolerance microbiology, Housing, Animal, Male, Mice, Inbred C57BL, Mice, Knockout, Toll-Like Receptor 2 metabolism, Gastrointestinal Microbiome, Insulin metabolism, Insulin Resistance genetics, Toll-Like Receptor 2 genetics
- Abstract
Introduction: Environmental factors have a key role in the control of gut microbiota and obesity. TLR2 knockout (TLR2
-/- ) mice in some housing conditions are protected from diet-induced insulin resistance. However, in our housing conditions these animals are not protected from diet-induced insulin-resistance., Aim: The aim of the present study was to investigate the influence of our animal housing conditions on the gut microbiota, glucose tolerance and insulin sensitivity in TLR2-/- mice., Material and Methods: The microbiota was investigated by metagenomics, associated with hyperinsulinemic euglycemic clamp and GTT associated with insulin signaling through immunoblotting., Results: The results showed that TLR2-/- mice in our housing conditions presented a phenotype of metabolic syndrome characterized by insulin resistance, glucose intolerance and increase in body weight. This phenotype was associated with differences in microbiota in TLR2-/- mice that showed a decrease in the Proteobacteria and Bacteroidetes phyla and an increase in the Firmicutesphylum, associated with and in increase in the Oscillospira and Ruminococcus genera. Furthermore there is also an increase in circulating LPS and subclinical inflammation in TLR2-/- . The molecular mechanism that account for insulin resistance was an activation of TLR4, associated with ER stress and JNK activation. The phenotype and metabolic behavior was reversed by antibiotic treatment and reproduced in WT mice by microbiota transplantation., Conclusions: Our data show, for the first time, that the intestinal microbiota can induce insulin resistance and obesity in an animal model that is genetically protected from these processes., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
45. Moderate physical exercise improves lymphocyte function in melanoma-bearing mice on a high-fat diet.
- Author
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Dos Santos CMM, Diniz VLS, Bachi ALL, Dos Santos de Oliveira LC, Ghazal T, Passos MEP, de Oliveira HH, Murata G, Masi LN, Martins AR, Levada-Pires AC, Curi R, Hirabara SM, Sellitti DF, Pithon-Curi TC, and Gorjão R
- Abstract
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., Competing Interests: Competing interestsThere are no competing interests.
- Published
- 2019
- Full Text
- View/download PDF
46. Oral L-glutamine pretreatment attenuates skeletal muscle atrophy induced by 24-h fasting in mice.
- Author
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de Vasconcelos DAA, Giesbertz P, de Souza DR, Vitzel KF, Abreu P, Marzuca-Nassr GN, Fortes MAS, Murata GM, Hirabara SM, Curi R, Daniel H, and Pithon-Curi TC
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Adipose Tissue metabolism, Administration, Oral, Animals, Cell Cycle Proteins metabolism, Male, Mice, Mice, Inbred C57BL, Ribosomal Protein S6 metabolism, Signal Transduction, gamma-Aminobutyric Acid metabolism, Fasting adverse effects, Glutamine administration & dosage, Muscle, Skeletal pathology, Muscular Atrophy prevention & control
- Abstract
L-Glutamine (L-Gln) supplementation has been pointed out as an anticatabolic intervention, but its effects on protein synthesis and degradation signaling in skeketal muscle are still poorly known. The effects of L-Gln pretreatment (1 g kg
-1 day-1 body weight for 10 days) on muscle fiber cross-sectional area (CSA), amino acid composition (measured by LC-MS/MS) and protein synthesis (Akt-mTOR) and degradation (ubiquitin ligases) signaling in soleus and extensor digitorum longus (EDL) muscles in 24-h-fasted mice were investigated. The fiber CSA of EDL muscle was not different between the L-Gln-fasted and L-Gln-fed groups. This finding was associated with reduced contents of L-Leu and L-Iso and activation of protein synthesis signaling (p-RPS6Ser240/244 and Akt-mTOR). The spectrum of soleus muscle fiber CSA distribution was larger in L-Gln-fasted as compared with placebo-fasted mice. This effect of L-Gln pretreatment was associated with changes in red fibers L-Gln metabolism as indicated by increased intracellular L-glutamine/L-glutamate ratio, L-aspartate and GABA levels. L-Gln supplementation reduced fasting-induced mass loss in tibialis anterior and gastrocnemius muscles. Evidence is presented that pretreatment with L-glutamine attenuates skeletal muscle atrophy induced by 24-h fasting through mechanisms that vary with the muscle fiber type., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
47. New insights on the regulation of cancer cachexia by N-3 polyunsaturated fatty acids.
- Author
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Gorjao R, Dos Santos CMM, Serdan TDA, Diniz VLS, Alba-Loureiro TC, Cury-Boaventura MF, Hatanaka E, Levada-Pires AC, Sato FT, Pithon-Curi TC, Fernandes LC, Curi R, and Hirabara SM
- Subjects
- Animals, Fatty Acids, Omega-3 pharmacology, Humans, Cachexia drug therapy, Fatty Acids, Omega-3 therapeutic use, Neoplasms drug therapy
- Abstract
Cancer cachexia is a multifactorial syndrome that develops during malignant tumor growth. Changes in plasma levels of several hormones and inflammatory factors result in an intense catabolic state, decreased activity of anabolic pathways, anorexia, and marked weight loss, leading to cachexia development and/or accentuation. Inflammatory mediators appear to be related to the control of a highly regulated process of muscle protein degradation that accelerates the process of cachexia. Several mediators have been postulated to participate in this process, including TNF-α, myostatin, and activated protein degradation pathways. Some interventional therapies have been proposed, including nutritional (dietary, omega-3 fatty acid supplementation), hormonal (insulin), pharmacological (clenbuterol), and nonpharmacological (physical exercise) therapies. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid, are recognized for their anti-inflammatory properties and have been used in therapeutic approaches to treat or attenuate cancer cachexia. In this review, we discuss recent findings on cellular and molecular mechanisms involved in inflammation in the cancer cachexia syndrome and the effectiveness of n-3 PUFAs to attenuate or prevent cancer cachexia., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
48. Myotube Protein Content Associates with Intracellular L-Glutamine Levels.
- Author
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de Vasconcelos DAA, Giesbertz P, Murata GM, de Souza DR, Fiamoncini J, Duque-Guimaraes D, Leandro CG, Hirabara SM, Daniel H, Curi R, and Pithon-Curi TC
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins analysis, Cell Cycle Proteins, Cell Line, Chromatography, Liquid, Eukaryotic Initiation Factors, Glutamine analysis, Insulin analysis, Mice, Muscle Fibers, Skeletal chemistry, Phosphoproteins analysis, Phosphorylation, Proto-Oncogene Proteins c-akt analysis, Ribosomal Protein S6 analysis, Tandem Mass Spectrometry, Carrier Proteins metabolism, Glutamine metabolism, Insulin metabolism, Muscle Fibers, Skeletal metabolism, Phosphoproteins metabolism, Proto-Oncogene Proteins c-akt metabolism, Ribosomal Protein S6 metabolism
- Abstract
Background/aims: Skeletal mass loss is reported in several catabolic conditions and it has been associated with a reduced intracellular L-glutamine content. We investigated the association of intracellular L-glutamine concentration with the protein content in skeletal muscle cells., Methods: We cultivated C
2 C12 myotubes in the absence or presence of 2 (reference condition), 8 or 16 mM L-glutamine for 48 hours, and the variations in the contents of amino acids and proteins measured. We used an inhibitor of L-glutamine synthesis (L-methionine sulfoximine - MSO) to promote a further reduction in intracellular L-glutamine levels. Amino acids contents in cells and media were measured using LC-MS/MS. We measured changes in phosphorylated Akt, RP-S6, and 4E-BP1contents in the absence or presence of insulin by western blotting., Results: Reduced intracellular L-glutamine concentration was associated with decreased protein content and increased protein breakdown. Low intracellular glutamine levels were also associated with decreased p-Akt contents in the presence of insulin. A further decrease in intracellular L-glutamine caused by glutamine synthetase inhibitor reduced protein content and levels of amino acids generated from glutamine metabolism and increased bAib still further. Cells exposed to high medium glutamine levels did not have any change in protein content but exhibited increased contents of the amino acids derived from L-glutamine metabolism., Conclusion: Intracellular L-glutamine levels per se play a role in the control of protein content in skeletal muscle myotubes., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)- Published
- 2019
- Full Text
- View/download PDF
49. Short-term treatment with metformin reduces hepatic lipid accumulation but induces liver inflammation in obese mice.
- Author
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de Souza Teixeira AA, Souza CO, Biondo LA, Sanches Silveira L, Lima EA, Batatinha HA, Araujo AP, Alves MJ, Hirabara SM, Curi R, and Neto JCR
- Subjects
- Animals, Diet, High-Fat, Enzyme-Linked Immunosorbent Assay, Hepatocytes drug effects, Hepatocytes pathology, Inflammation pathology, Lipids chemistry, Liver drug effects, Liver metabolism, Liver pathology, Macrophages drug effects, Macrophages pathology, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Non-alcoholic Fatty Liver Disease pathology, Cytokines metabolism, Inflammation drug therapy, Metformin pharmacology, Non-alcoholic Fatty Liver Disease drug therapy
- Abstract
The study aimed to evaluate the metabolic and inflammatory effects of short-term treatments (10 days) with metformin (MET) on the NAFLD caused by a high-fat diet (HFD) in C57BL/6 mice. After the treatment, histological liver slices were obtained, hepatocytes and macrophages were extracted and cultured with phosphate buffered saline, LPS (2.5 µg/mL) and MET (1 µM) for 24 h. Cytokine levels were determined by ELISA. NAFLD caused by the HFD was partially reduced by MET. The lipid accumulation induced by the HFD was not associated with liver inflammation; however, MET seemed to promote pro-inflammatory effects in liver, since it increased hepatic concentration of IL-1β, TNF-α, IL-6, MCP-1 and IFN-γ. Similarly, MET increased the concentration of IL-1β, IL-6 in hepatocyte cultures. However, in macrophages culture, MET lowered levels of IL-1β, IL-6 and TNF-α stimulated by LPS. Overall, MET reduced liver NAFLD but promoted hepatocyte increase in pro-inflammatory cytokines, thus, leading to liver inflammation.
- Published
- 2018
- Full Text
- View/download PDF
50. Attenuation of obesity and insulin resistance by fish oil supplementation is associated with improved skeletal muscle mitochondrial function in mice fed a high-fat diet.
- Author
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Martins AR, Crisma AR, Masi LN, Amaral CL, Marzuca-Nassr GN, Bomfim LHM, Teodoro BG, Queiroz AL, Serdan TDA, Torres RP, Mancini-Filho J, Rodrigues AC, Alba-Loureiro TC, Pithon-Curi TC, Gorjao R, Silveira LR, Curi R, Newsholme P, and Hirabara SM
- Subjects
- Adiposity drug effects, Animals, Anti-Obesity Agents pharmacology, Catalase metabolism, Diet, High-Fat adverse effects, Dietary Supplements, Fatty Acids analysis, Fatty Acids metabolism, Fatty Acids, Omega-3 pharmacology, Hydrogen Peroxide metabolism, Male, Mice, Inbred C57BL, Mitochondria, Muscle drug effects, Muscle, Skeletal drug effects, Muscle, Skeletal physiology, Obesity etiology, Proteins genetics, Proteins metabolism, Fish Oils pharmacology, Insulin Resistance, Mitochondria, Muscle physiology, Obesity diet therapy
- Abstract
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to improve insulin sensitivity and glucose homeostasis in animal models of insulin resistance, but the involved mechanisms still remain unresolved. In this study, we evaluated the effects of fish oil (FO), a source of n-3 PUFAs, on obesity, insulin resistance and muscle mitochondrial function in mice fed a high-fat diet (HFD). C57Bl/6 male mice, 8 weeks old, were divided into four groups: control diet (C), high-fat diet (H), C+FO (CFO) and H+FO (HFO). FO was administered by oral gavage (2 g/kg b.w.), three times a week, starting 4 weeks before diet administration until the end of the experimental protocol. HFD-induced obesity and insulin resistance associated with impaired skeletal muscle mitochondrial function, as indicated by decreased oxygen consumption, tricarboxylic acid cycle intermediate (TCAi) contents (citrate, α-ketoglutarate, malate and oxaloacetate), oxidative phosphorylation protein content and mitochondrial biogenesis. These effects were associated with elevated reactive oxygen species production, decreased PGC1-a transcription and reduced Akt phosphorylation. The changes induced by the HFD were partially attenuated by FO, which decreased obesity and insulin resistance and increased mitochondrial function. In the H group, FO supplementation also improved oxygen consumption; increased TCAi content, and Akt and AMPK phosphorylation; and up-regulated mRNA expression of Gpat1, Pepck, catalase and mitochondrial proteins (Pgc1α, Pparα, Cpt1 and Ucp3). These results suggest that dietary FO attenuates the deleterious effects of the HFD (obesity and insulin resistance) by improving skeletal muscle mitochondrial function., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
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