OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance.

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensing O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

Rolling out physical exercise and energy homeostasis: Focus on hypothalamic circuitries.

Energy balance is the fine regulation of energy expenditure and energy intake. Negative energy balance causes body weight loss, while positive energy balance promotes weight gain. Modern societies offer a maladapted way of life, where easy access to palatable foods and the lack of opportunities to perform physical activity are considered the roots of the obesity pandemic. Physical exercise increases energy expenditure and, consequently, is supposed to promote weight loss. Paradoxically, physical exercise acutely drives anorexigenic-like effects, but the mechanisms are still poorly understood. Using an evolutionary background, this review aims to highlight the potential involvement of the melanocortin system and other hypothalamic neural circuitries regulating energy balance during and after physical exercise. The physiological significance of these changes will be explored, and possible signalling agents will be addressed. The knowledge discussed here might be important for clarifying obesity aetiology as well as new therapeutic approaches for body weight loss.

Coupling of GABA Metabolism to Mitochondrial Glucose Phosphorylation.

Glucose and oxygen (O2) are vital to the brain. Glucose metabolism and mitochondria play a pivotal role in this process, culminating in the increase of reactive O2 species. Hexokinase (HK) is a key enzyme on glucose metabolism and is coupled to the brain mitochondrial redox modulation by recycling ADP for oxidative phosphorylation (OXPHOS). GABA shunt is an alternative pathway to GABA metabolism that increases succinate levels, a Krebs cycle intermediate. Although glucose and GABA metabolisms are intrinsically connected, their interplay coordinating mitochondrial function is poorly understood. Here, we hypothesize that the HK and the GABA shunt interact to control mitochondrial metabolism differently in the cortex and the hypothalamus. The GABA shunt stimulated mitochondrial O2 consumption and H2O2 production higher in hypothalamic synaptosomes (HSy) than cortical synaptosomes (CSy). The GABA shunt increased the HK coupled to OXPHOS activity in both population of synaptosomes, but the rate of activation was higher in HSy than CSy. Significantly, malonate and vigabatrin blocked the effects of the GABA shunt in the HK activity coupled to OXPHOS. It indicates that the glucose phosphorylation is linked to GABA and Krebs cycle reactions. Together, these data shed light on the HK and SDH role on the metabolism of each region fed by GABA turnover, which depends on the neurons' metabolic route.

Intense physical exercise potentiates glucose inhibitory effect over food intake of male Wistar rats.

NEW FINDINGS: What is the central question of this study? How does an acute session of exercise affect food intake of male Wistar rats? What is the main finding and its importance? Food intake in male Wistar rats is decreased in the first hour after physical exercise independent of the intensity. Moreover, high-intensity exercise potentiates the anorexic effect of peripheral glucose administration. This work raises new feeding-related targets that would explain how exercise drives body weight loss. ABSTRACT: Obesity has emerged as a critical metabolic disorder in modern society. An adequate lifestyle with a well-oriented programme of diet and physical exercise (PE) can prevent or potentially even cure obesity. Additionally, PE might lead to weight loss by increasing energy expenditure and decreasing hunger perception. In this article, we hypothesize that an acute exercise session would potentiate the glucose inhibitory effects on food intake in male Wistar rats. Our data show that moderate- or high-intensity PE significantly decreased food intake, although no changes in the expression of feeding-related neuropeptide in the arcuate nucleus of the hypothalamus were found. Exercised animals demonstrated a reduced glucose tolerance and increased blood insulin concentration. Intraperitoneal administration of glucose decreased food intake in control animals. In the animals submitted to moderate-intensity PE, the decrease in food intake promoted by glucose was similar to controls; however, an interaction was observed when glucose was injected in the high-intensity PE group, in which food intake was significantly lower than the effect produced by glucose alone. A different pattern of expression was observed for the monocarboxylate transporter isoforms (MCT1, 2 and 4) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFBP3) in the hypothalamus, which was dependent on the exercise intensity. In conclusion, PE decreases food intake independently of the intensity. However, an interaction between PE and the anorexic effect of glucose is only observed when a high-intensity exercise is performed. These data show an essential role of exercise intensity in the modulation of the glucose inhibitory effect on food intake.

small ORFs: A new class of essential genes for development.

Genes that contain small open reading frames (smORFs) constitute a new group of eukaryotic genes and are expected to represent 5% of the Drosophila melanogaster transcribed genes. In this review we provide a historical perspective of their recent discovery, describe their general mechanism and discuss the importance of smORFs for future genomic and transcriptomic studies. Finally, we discuss the biological role of the most studied smORF so far, the Mlpt/Pri/Tal gene in arthropods. The pleiotropic action of Mlpt/Pri/Tal in D. melanogaster suggests a complex evolutionary scenario that can be used to understand the origins, evolution and integration of smORFs into complex gene regulatory networks.

Type 2 iodothyronine deiodinase is upregulated in rat slow- and fast-twitch skeletal muscle during cold exposure.

During cold acclimation, shivering is progressively replaced by nonshivering thermogenesis. Brown adipose tissue (BAT) and skeletal muscle are relevant for nonshivering thermogenesis, which depends largely on thyroid hormone. Since the skeletal muscle fibers progressively adapt to cold exposure through poorly defined mechanisms, our intent was to determine whether skeletal muscle type 2 deiodinase (D2) induction could be implicated in the long-term skeletal muscle cold acclimation. We demonstrate that in the red oxidative soleus muscle, D2 activity increased 2.3-fold after 3 days at 4°C together with the brown adipose tissue D2 activity, which increased 10-fold. Soleus muscle and BAT D2 activities returned to the control levels after 10 days of cold exposure, when an increase of 2.8-fold in D2 activity was detected in white glycolytic gastrocnemius but not in red oxidative gastrocnemius fibers. Propranolol did not prevent muscle D2 induction, but it impaired the decrease of D2 in BAT and soleus after 10 days at 4°C. Cold exposure is accompanied by increased oxygen consumption, UCP3, and PGC-1α genes expression in skeletal muscles, which were partialy prevented by propranolol in soleus and gastrocnemius. Serum total and free T3 is increased during cold exposure in rats, even after 10 days, when BAT D2 is already normalized, suggesting that skeletal muscle D2 activity contributes significantly to circulating T3 under this adaptive condition. In conclusion, cold exposure is accompanied by concerted changes in the metabolism of BAT and oxidative and glycolytic skeletal muscles that are paralleled by type 2 deiodinase activation.

Brown spiders (Loxosceles) are taking hold in Pernambuco, Brazil: a case series, 2018-2022.

OBJECTIVE: To describe accidents involving brown spider (genus Loxosceles) bites notified by the Pernambuco Poison Information and Care Center (CIATox-PE), Brazil, from January 2018 to December 2022. METHODS: This was a case series study of brown spider bites notified by the CIATox-PE. RESULTS: The study included 22 cases with median age of 35 years, the majority being female (13); the cases occurred in rural and urban areas (12 versus 10), at night (10); Petrolina was the municipality with the highest number of notifications (6); spider bites occurred mainly in the lower (11) and upper (9) limbs, almost exclusively inside households (21); specific serum therapy was not indicated for 8 cases because the time for its effectiveness had already elapsed. CONCLUSION: Loxoscelism cases occurred more frequently in females, in both rural and urban areas and mainly at home, with delays in seeking medical care. MAIN RESULTS: The 22 cases described represent an alert for the presence of a venomous species not reported in previous studies in Pernambuco. The severity of cases may be associated with delays in seeking medical care, especially due to the population's lack of information. IMPLICATIONS FOR SERVICES: Identify the presence of brown spiders in households in the region and the potential severity of poisonings. Alert health professionals to recognize the clinical picture with a view to appropriate early treatment. PERSPECTIVES: Develop research on poisoning by venomous animals and educational actions alerting the population to prevent these accidents and updating health professionals on care.

Perception of lower back pain associated with use of body armor in police officers of the countryside specialized battalion of Ceará, Brazil.

Introduction: The strict demands of the military environment, associated with the increase in violence, as well as the frequent use of body armor, can further aggravate health problems. Objectives: To investigate the perception of police officers of the Countryside Specialized Police Battalion in relation to comfort, fatigue, and lower back pain, resulting from the use of body armor. Methods: This was a cross-sectional study conducted with 260 male military police officers (34.62 ± 5.83 years old) belonging to the ostensive rural police battalion in the state of Ceará, Brazil. The questionnaire related to comfort, fatigue, and lower back pain was used to identify the perception of pain from the use of body armor, with staggered responses, and the results were analyzed using the SPSS 21.0 software. Results: Regarding the use of body armor, 41.5% of participants perceived it to be little comfortable in general; furthermore, 45 and 47.5% of military police officers considered it little comfortable in relation to weight and use during operational activities, respectively. With regard to body measurements, 48.5% reported being little comfortable, and 70% perceived that the body armor is adjustable to the body. At the end of the work shift, 37.3% complained of lower back pain, and 45.8% felt moderate fatigue. Moreover, 70.1% felt pain in the lower back after the work shift. Conclusions: Military police officers reported lower back pain at the end and after the work shift due to use of body armor, as well as little comfort of the protective equipment and moderate fatigue at the end of the work shift.

Introdução: As rigorosas exigências do ambiente militar associadas ao aumento da violência, bem como ao uso frequente do colete balístico, podem agravar ainda mais os problemas de saúde. Objetivos: Investigar a associação do uso de colete balístico em relação ao conforto, à fadiga e à queixa de lombalgia em policiais do batalhão especializado do Ceará. Métodos: Tratou-se de um estudo transversal realizado com 260 policiais militares do sexo masculino (34,62 ± 5,83 anos) pertencentes ao batalhão de policiamento ostensivo rural do estado do Ceará. O questionário relacionado a conforto, fadiga e dores na região lombar foi utilizado para identificar a percepção de dor pelo uso do colete balístico, com respostas escalonadas, e seus resultados foram analisados no software SPSS 21.0. Resultados: Quanto ao uso do colete, 41,5% perceberam ser pouco confortável no geral; e 45 e 47,5% dos policiais militares consideraram ser pouco confortável em relação ao peso e em relação ao uso durante as atividades operacionais, respectivamente. No que se refere às medidas corporais, 48,5% reportaram ser confortável, e 70% percebem o colete como ajustável ao corpo. No momento da finalização do turno de trabalho, 37,3% apresentam dores na região lombar e 45,8% sentem fadiga moderada. Após o encerramento do turno de trabalho, 70,1% sentem dores na região lombar. Conclusões: Os policiais militares perceberam dores na região lombar ao final e depois do turno de trabalho pelo uso do colete balistico, além de relatarem sobre o pouco conforto do equipamento de proteção e sobre a fadiga moderada ao fim do turno de trabalho.

Modelling premature cardiac aging with induced pluripotent stem cells from a hutchinson-gilford Progeria Syndrome patient.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder that causes accelerated aging and a high risk of cardiovascular complications. However, the underlying mechanisms of cardiac complications of this syndrome are not fully understood. This study modeled HGPS using cardiomyocytes (CM) derived from induced pluripotent stem cells (iPSC) derived from a patient with HGPS and characterized the biophysical, morphological, and molecular changes found in these CM compared to CM derived from a healthy donor. Electrophysiological recordings suggest that the HGPS-CM was functional and had normal electrophysiological properties. Electron tomography showed nuclear morphology alteration, and the 3D reconstruction of electron tomography images suggests structural abnormalities in HGPS-CM mitochondria, however, there was no difference in mitochondrial content as measured by Mitotracker. Immunofluorescence indicates nuclear morphological alteration and confirms the presence of Troponin T. Telomere length was measured using qRT-PCR, and no difference was found in the CM from HGPS when compared to the control. Proteomic analysis was carried out in a high-resolution system using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). The proteomics data show distinct group separations and protein expression differences between HGPS and control-CM, highlighting changes in ribosomal, TCA cycle, and amino acid biosynthesis, among other modifications. Our findings show that iPSC-derived cardiomyocytes from a Progeria Syndrome patient have significant changes in mitochondrial morphology and protein expression, implying novel mechanisms underlying premature cardiac aging.

Subacute and sublethal ingestion of microcystin-LR impairs lung mitochondrial function by an oligomycin-like effect.

Microcystin-LR (MC-LR) is a potent cyanotoxin that can reach several organs. However subacute exposure to sublethal doses of MC-LR has not yet well been studied. Herein, we evaluated the outcomes of subacute and sublethal MC-LR exposure on lungs. Male BALB/c mice were exposed to MC-LR by gavage (30 µg/kg) for 20 consecutive days, whereas CTRL mice received filtered water. Respiratory mechanics was not altered in MC-LR group, but histopathology disclosed increased collagen deposition, immunological cell infiltration, and higher percentage of collapsed alveoli. Mitochondrial function was extensively affected in MC-LR animals. Additionally, a direct in vitro titration of MC-LR revealed impaired mitochondrial function. In conclusion, MC-LR presented an intense deleterious effect on lung mitochondrial function and histology. Furthermore, MC-LR seems to exert an oligomycin-like effect in lung mitochondria. This study opens new perspectives for the understanding of the putative pulmonary initial mechanisms of damage resulting from oral MC-LR intoxication.

Physical exercise improves mitochondrial function in ovariectomized rats.

Estrogen deficiency causes metabolic disorders in humans and rodents, including in part due to changes in energy expenditure. We have shown previously that skeletal muscle mitochondrial function is compromised in ovariectomized (Ovx) rats. Since physical exercise is a powerful strategy to improve skeletal muscle mitochondrial content and function, we hypothesize that exercise training would counteract the deficiency-induced skeletal muscle mitochondrial dysfunction in Ovx rats. We report that exercised Ovx rats, at 60-65% of maximal exercise capacity for 8 weeks, exhibited less fat accumulation and body weight gain compared with sedentary controls. Treadmill exercise training decreased muscle lactate production, indicating a shift to mitochondrial oxidative metabolism. Furthermore, reduced soleus muscle mitochondrial oxygen consumption confirmed that estrogen deficiency is detrimental to mitochondrial function. However, exercise restored mitochondrial oxygen consumption in Ovx rats, achieving similar levels as in exercised control rats. Exercise-induced skeletal muscle peroxisome proliferator-activated receptor-γ coactivator-1α expression was similar in both groups. Therefore, the mechanisms by which exercise improves mitochondrial oxygen consumption appears to be different in Ovx-exercised and sham-exercised rats. While there was an increase in mitochondrial content in sham-exercised rats, demonstrated by a greater citrate synthase activity, no induction was observed in Ovx-exercised rats. Normalizing mitochondrial respiratory capacity by citrate synthase activity indicates a better oxidative phosphorylation efficiency in the Ovx-exercised group. In conclusion, physical exercise sustains mitochondrial function in ovarian hormone-deficient rats through a non-conventional mitochondrial content-independent manner.

Hypothalamic AgRP neurons exert top-down control on systemic TNF-α release during endotoxemia.

Loss of appetite and negative energy balance are common features of endotoxemia in all animals and are thought to have protective roles by reducing nutrient availability to host and pathogen metabolism. Accordingly, fasting and caloric restriction have well-established anti-inflammatory properties. However, in response to reduced nutrient availability at the cellular and organ levels, negative energy balance also recruits distinct energy-sensing brain circuits, but it is not known whether these neuronal systems have a role in its anti-inflammatory effects. Here, we report that hypothalamic AgRP neurons-a critical neuronal population for the central representation of negative energy balance-have parallel immunoregulatory functions. We found that when endotoxemia occurs in fasted mice, the activity of AgRP neurons remains sustained, but this activity does not influence feeding behavior and endotoxemic anorexia. Furthermore, we found that endotoxemia acutely desensitizes AgRP neurons, which also become refractory to inhibitory signals. Mimicking this sustained AgRP neuron activity in fed mice by chemogenetic activation-a manipulation known to recapitulate core behavioral features of fasting-results in reduced acute tumor necrosis factor alpha (TNF-α) release during endotoxemia. Mechanistically, we found that endogenous glucocorticoids play an important role: glucocorticoid receptor deletion from AgRP neurons prevents their endotoxemia-induced desensitization, and importantly, it counteracts the fasting-induced suppression of TNF-α release, resulting in prolonged sickness. Together, these findings provide evidence directly linking AgRP neuron activity to the acute response during endotoxemia, suggesting that these neurons are a functional component of the immunoregulatory effects associated with negative energy balance and catabolic metabolism.

Isolation of Mitochondria From Fresh Mice Lung Tissue.

Direct analysis of isolated mitochondria enables a better understanding of lung dysfunction. Despite well-defined mitochondrial isolation protocols applicable to other tissues, such as the brain, kidney, heart, and liver, a robust and reproductive protocol has not yet been advanced for the lung. We describe a protocol for the isolation of mitochondria from lung tissue aiming for functional analyses of mitochondrial O2 consumption, transmembrane potential, reactive oxygen species (ROS) formation, ATP production, and swelling. We compared our protocol to that used for heart mitochondrial function that is well-established in the literature, and achieved similar results.

Granulocyte-colony stimulating factor treatment of chronic myocardial infarction.

PURPOSE: The aim of this study was to investigate the impact of granulocyte-colony stimulating factor (G-CSF) administration on cardiac function of rats with chronic myocardial infarction through two different protocols: high dose short term and low dose long term protocols. METHODS: Wistar rats were submitted to MI surgery and after 4 weeks they received recombinant human G-CSF (Filgrastim) or vehicle subcutaneously. We tested the classical protocol (50 microg/kg/day during 7 days) and the long term low dose treatment (four cycles of 5 days of 10 microg/kg/day). Cardiac performance was evaluated before, 4 and 6 weeks after G-CSF injections by electro- and echocardiography, hemodynamic and treadmill exercise test. RESULTS: All infarcted groups exhibited impaired function compared to sham operated animals. Moreover, all cardiac functional parameter were not different between G-CSF and Vehicle group at resting conditions as well as after treadmill exercise stress test, despite intense white blood cell mobilization in both protocols at all time points. Hypertrophy was not different and infarct size was similar in histological analysis CONCLUSIONS: These data clearly show that G-CSF treatment was unable to restore cardiac function impaired by myocardial infarction either with classical approach or long term low dose administration.

Regulation of substrate utilization and adiposity by Agrp neurons.

The type of nutrient utilized by the organism at any given time-substrate utilization-is a critical component of energy metabolism. The neuronal mechanisms involved in the regulation of substrate utilization in mammals are largely unknown. Here, we found that activation of hypothalamic Agrp neurons rapidly altered whole-body substrate utilization, increasing carbohydrate utilization, while decreasing fat utilization. These metabolic changes occurred even in the absence of caloric ingestion and were coupled to increased lipogenesis. Accordingly, inhibition of fatty acid synthase-a key enzyme that mediates lipogenesis-blunted the effects of Agrp neuron activation on substrate utilization. In pair-fed conditions during positive energy balance, activation of Agrp neurons improved metabolic efficiency, and increased weight gain and adiposity. Conversely, ablation of Agrp neurons impaired fat mass accumulation. These results suggest Agrp neurons regulate substrate utilization, contributing to lipogenesis and fat mass accumulation during positive energy balance.

Brown spiders (Loxosceles) are taking hold in Pernambuco, Brazil: a case series, 2018-2022 / Las arañas marrones (Loxosceles) están instalándose en Pernambuco, Brasil: serie de casos, 2018-2022 / As aranhas-marrons (Loxosceles) estão se estabelecendo em Pernambuco: série de casos, 2018-2022

ABSTRACT Objective To describe accidents involving brown spider (genus Loxosceles) bites notified by the Pernambuco Poison Information and Care Center (CIATox-PE), Brazil, from January 2018 to December 2022. Methods This was a case series study of brown spider bites notified by the CIATox-PE. Results The study included 22 cases with median age of 35 years, the majority being female (13); the cases occurred in rural and urban areas (12 versus 10), at night (10); Petrolina was the municipality with the highest number of notifications (6); spider bites occurred mainly in the lower (11) and upper (9) limbs, almost exclusively inside households (21); specific serum therapy was not indicated for 8 cases because the time for its effectiveness had already elapsed. Conclusion Loxoscelism cases occurred more frequently in females, in both rural and urban areas and mainly at home, with delays in seeking medical care.

RESUMEN Objetivo Describir accidentes causados ​​por arañas pardas (género Loxosceles) notificados por el Centro de Información de Asistencia Toxicológica de Pernambuco (CIATox-PE), Brasil, de enero de 2018 a diciembre de 2022. Métodos Reporte de 22 casos notificados de CIATox-PE. Resultados Casos con media de idade de 35 años, predominio femenino (13); los casos ocurrieron en área rural/urbana (12 versus 10), por la noche (10); Petrolina fue el municipio con más notificaciones (6); las picaduras fueron principalmente en los miembros inferiores (11) y superiores (9), casi exclusivamente en el interior de las viviendas (21); en 8 de los casos no se indicó sueroterapia específica por haber superado el tiempo de efecto. Conclusión Los casos de loxoscelismo ocurrieron con mayor frecuencia en el sexo femenino, en áreas rurales y urbanas, y principalmente en el hogar, con demoras en la búsqueda de atención médica.

RESUMO Objetivo Descrever os acidentes por picada de aranhas-marrons (gênero Loxosceles), notificados no Centro de Informação de Assistência Toxicológica de Pernambuco (CIATox-PE), Brasil, no período de 2018 a 2022. Métodos Estudo de série, sobre casos notificados no CIATox-PE. Resultados Foram incluídos 22 casos com mediana de idade de 35 anos e houve predomínio do sexo feminino (13); os casos ocorreram nas zonas rural e urbana (12 versus 10), durante a noite (10), e Petrolina foi o município com mais notificações (6); as picadas ocorreram, principalmente, nos membros inferiores (11) e superiores (9), quase exclusivamente dentro das residências (21); para 8 acidentados, não se prescreveu soroterapia específica por terem ultrapassado o tempo de efetividade. Conclusão Os casos de loxoscelismo ocorreram com maior frequência no sexo feminino, nas zonas rural e urbana indiferentemente, quase todos foram intradomiciliares e houve demora na procura por atendimento médico.

Mitochondria-Bound Hexokinase (mt-HK) Activity Differ in Cortical and Hypothalamic Synaptosomes: Differential Role of mt-HK in H2O2 Depuration.

Glucose and oxygen are vital for the brain, as these molecules provide energy and metabolic intermediates that are necessary for cell function. The glycolysis pathway and mitochondria play a pivotal role in cell energy metabolism, which is closely related to reactive oxygen species (ROS) production. Hexokinase (HK) is a key enzyme involved in glucose metabolism that modulates the level of brain mitochondrial ROS by recycling ADP for oxidative phosphorylation (OxPhos). Here, we hypothesize that the control of mitochondrial metabolism by hexokinase differs in distinct areas of the brain, such as the cortex and hypothalamus, in which ROS might function as signaling molecules. Thus, we investigated mitochondrial metabolism of synaptosomes derived from both brain regions. Cortical synaptosomes (CSy) show a predominance of glutamatergic synapses, while in the hypothalamic synaptosomes (HSy), the GABAergic synapses predominate. Significant differences of oxygen consumption and ROS production were related to higher mitochondrial complex II activity (succinate dehydrogenase-SDH) in CSy rather than to mitochondrial number. Mitochondrial HK (mt-HK) activity was higher in CSy than in HSy regardless the substrate added. Mitochondrial O2 consumption related to mt-HK activation by 2-deoxyglucose was also higher in CSy. In the presence of substrate for complex II, the activation of synaptosomal mt-HK promoted depuration of ROS in both HSy and CSy, while ROS depuration did not occur in HSy when substrate for complex I was used. The impact of the mt-HK inhibition by glucose-6-phosphate (G6P) was the same in synaptosomes from both areas. Together, the differences found between CSy and HSy indicate specific roles of mt-HK and SDH on the metabolism of each brain region, what probably depends on the main metabolic route that is used by the neurons.

Differential glycolytic profile and Warburg effect in papillary thyroid carcinoma cell lines.

Acceleration of glycolysis is a characteristic of neoplasia. Previous studies have shown that a metabolic shift occurs in many tumors and correlates with a negative prognosis. The present study aimed to investigate the glycolytic profile of thyroid carcinoma cell lines. We investigated glycolytic and oxidative parameters of two thyroid carcinoma papillary cell lines (BCPAP and TPC1) and the non-tumor cell line NTHY-ori. All carcinoma cell lines showed higher rates of glycolysis efficiency, when compared to NTHY-ori, as assessed by a higher rate of glucose consumption and lactate production. The BCPAP cell line presented higher rates of growth, as well as elevated intracellular ATP levels, compared to the TPC1 and NTHY-ori cells. We found that glycolysis and activities of pentose phosphate pathway (PPP) regulatory enzymes were significantly different among the carcinoma cell lines, particularly in the mitochondrial hexokinase (HK) activity which was higher in the BCPAP cells than that in the TPC1 cell line which showed a balanced distribution of HK activity between cytoplasmic and mitochondrial subcellular localizations. However, TPC1 had higher levels of glucose­6-phosphate dehydrogenase activity, suggesting that the PPP is elevated in this cell type. Using high resolution respirometry, we observed that the Warburg effect was present in the BCPAP and TPC1 cells, characterized by low oxygen consumption and high reactive oxygen species production. Overall, these results indicate that both thyroid papillary carcinoma cell lines showed a glycolytic profile. Of note, BCPAP cells presented some relevant differences in cell metabolism compared to TPC1 cells, mainly related to higher mitochondrial-associated HK activity.

Papel do imunometabolismo, receptores Toll-Like e ECA 2 na COVID-19 / Role of immunometabolism, Toll-Like receptors, and ACE-2 in COVID-19

No combate à infecção pelo coronavírus 2 da síndrome respiratória aguda grave (SARS-CoV-2), o organismo se utiliza de mecanismos da imunidade inata, dentre eles os receptores Toll- Like (TLR), responsáveis pela sinalização da inflamação através da liberação de mediadores químicos e recrutamento de células imunitárias. Na patologia causada pela doença do SARS-CoV-2 2019 (COVID-19), ganha especial importância o TLR-4, visto que a sua estimulação exacerbada vem sendo relacionada ao estado hiperinflamatório em fases avançadas da COVID-19. Outro receptor que desempenha um papel primordial na infecção pelo SARS-CoV-2, servindo como porta de entrada para o vírus e progressão da doença, é a enzima conversora de angiotensina 2 (ECA 2), cuja ligação com a proteína S viral causa desregulação de vários sistemas fundamentais para a homeostase, como o sistema renina-angiotensina-aldosterona. Pacientes com doenças cardiometabólicas como obesidade, diabetes, aterosclerose e hipertensão vêm sendo classificados como alto risco para desenvolver as formas graves da COVID-19, visto que o estado inflamatório, já existente nessas doenças, pode ser agravado pelo desequilíbrio metabólico causado pelo SARS-CoV-2. A elucidação desses e de outros mecanismos relacionados à fisiopatologia da COVID-19 é imprescindível para uma melhora na estratificação de risco, nas escolhas terapêuticas e no prognóstico desses pacientes. Desta forma, nesta revisão objetivamos discutir as relações entre TLR-4, ECA 2, doenças cardiometabólicas, infecção pelo SARS-CoV-2 e gravidade da COVID-19.

In the fight against the infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the body uses mechanisms from the innate immune system, such as Toll-Like receptors (TLR), responsible for inflammation signaling through release of chemical mediators and recruitment of immune cells. In the disease caused by SARS-CoV-2 (COVID-19), TLR-4 assumes special importance because its exacerbated stimulation has been related to a hyperinflammatory state in advanced stages of COVID-19. Another receptor that plays a major role in SARS-CoV-2 infection, serving as a gateway to the virus and impacting disease progression, is angiotensin-converting enzyme 2 (ACE-2), whose binding to the viral S protein causes dysregulation of several key systems for homeostasis, such as the renin-angiotensin-aldosterone system. The elucidation of these and other mechanisms related to the pathophysiology of COVID-19 is essential for an improvement in risk stratification, therapeutic choices, and prognosis for these patients. Thus, we aimed to discuss in this review the relationships between TLR-4, ACE-2, cardiometabolic diseases, SARS-CoV-2 infection, and severity of COVID-19.

Differential Expression of NADPH Oxidases Depends on Skeletal Muscle Fiber Type in Rats.

NADPH oxidases (NOX) are important sources of reactive oxygen species (ROS) in skeletal muscle, being involved in excitation-contraction coupling. Thus, we aimed to investigate if NOX activity and expression in skeletal muscle are fiber type specific and the possible contribution of this difference to cellular oxidative stress. Oxygen consumption rate, NOX activity and mRNA levels, and the activity of catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD), as well as the reactive protein thiol levels, were measured in the soleus (SOL), red gastrocnemius (RG), and white gastrocnemius (WG) muscles of rats. RG showed higher oxygen consumption flow than SOL and WG, while SOL had higher oxygen consumption than WG. SOL showed higher NOX activity, as well as NOX2 and NOX4 mRNA levels, antioxidant enzymatic activities, and reactive protein thiol contents when compared to WG and RG. NOX activity and NOX4 mRNA levels as well as antioxidant enzymatic activities were higher in RG than in WG. Physical exercise increased NOX activity in SOL and RG, specifically NOX2 mRNA levels in RG and NOX4 mRNA levels in SOL. In conclusion, we demonstrated that NOX activity and expression differ according to the skeletal muscle fiber type, as well as antioxidant defense.