RESUMO
Maternal Zika virus (ZIKV) infection during pregnancy has been associated with severe intrauterine growth restriction (IUGR), placental damage, metabolism disturbances, and newborn neurological abnormalities. Here, we investigated the impact of maternal ZIKV infection on placental nutrient transporters and nutrient-sensitive pathways. Immunocompetent (C57BL/6) mice were injected with Low (103 PFU-ZIKVPE243) or High (5 × 107 PFU-ZIKVPE243) ZIKV titers at gestational day (GD) 12.5, and tissue was collected at GD18.5 (term). Fetal-placental growth was impaired in male fetuses, which exhibited higher placental expression of the ZIKV infective marker, eukaryotic translation initiation factor 2 (eIF2α), but lower levels of phospho-eIF2α. There were no differences in fetal-placental growth in female fetuses, which exhibited no significant alterations in placental ZIKV infective markers. Furthermore, ZIKV promoted increased expression of glucose transporter type 1 (Slc2a1/Glut1) and decreased levels of glucose-6-phosphate in female placentae, with no differences in amino acid transport potential. In contrast, ZIKV did not impact glucose transporters in male placentae but downregulated sodium-coupled neutral amino acid 2 (Snat2) transporter expression. We also observed sex-dependent differences in the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation in ZIKV-infected pregnancies, showing that ZIKV can disturb placental nutrient sensing. Our findings highlight molecular alterations in the placenta caused by maternal ZIKV infection, shedding light on nutrient transport, sensing, and availability. Our results also suggest that female and male placentae employ distinct coping mechanisms in response to ZIKV-induced metabolic changes, providing insights into therapeutic approaches for congenital Zika syndrome.
Assuntos
Desenvolvimento Fetal , Camundongos Endogâmicos C57BL , Placenta , Transdução de Sinais , Infecção por Zika virus , Zika virus , Animais , Feminino , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia , Gravidez , Camundongos , Placenta/metabolismo , Placenta/virologia , Masculino , Desenvolvimento Fetal/fisiologia , Complicações Infecciosas na Gravidez/virologia , Complicações Infecciosas na Gravidez/metabolismo , Nutrientes/metabolismo , Transportador de Glucose Tipo 1/metabolismoRESUMO
Insulin resistance onset in skeletal muscle is characterized by the impairment of insulin signaling, which reduces the internalization of glucose, known as glucose uptake, into the cell. Therefore, there is a deficit of intracellular glucose, which is the main source for energy production in the cell. This may compromise cellular viability and functions, leading to pathological dysfunction. Skeletal muscle fibers continuously generate reactive oxygen and nitrogen species (RONS). An excess of RONS produces oxidative distress, which may evoke cellular damage and dysfunction. However, a moderate level of RONS, which is called oxidative eustress, is critical to maintain, modulate and regulate cellular functions through reversible interactions between RONS and the components of cellular signaling pathways that control those functions, such as the facilitation of glucose uptake. The skeletal muscle releases peptides called myokines that may have endocrine and paracrine effects. Some myokines bind to specific receptors in skeletal muscle fibers and might interact with cellular signaling pathways, such as PI3K/Akt and AMPK, and facilitate glucose uptake. In addition, there are cytokines, which are peptides produced by non-skeletal muscle cells, that bind to receptors at the plasma membrane of skeletal muscle cells and interact with the cellular signaling pathways, facilitating glucose uptake. RONS, myokines and cytokines might be acting on the same signaling pathways that facilitate glucose uptake in skeletal muscle. However, the experimental studies are limited and scarce. The aim of this review is to highlight the current knowledge regarding the role of RONS, myokines and cytokines as potential signals that facilitate glucose uptake in skeletal muscle. In addition, we encourage researchers in the field to lead and undertake investigations to uncover the fundamentals of glucose uptake evoked by RONS, myokines, and cytokines.
Assuntos
Resistência à Insulina , Humanos , Resistência à Insulina/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Citocinas/metabolismo , Oxigênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Músculo Esquelético/metabolismo , Glucose/metabolismoRESUMO
BACKGROUND: Fed-batch mode is the standard culture technology for industrial bioprocesses. Nevertheless, most of the early-stage cell and process development is carried out in batch cultures, which can bias the initial selection of expression systems. Cell engineering can provide an alternative to fed-batch cultures for high-throughput screening and host selection. We have previously reported a library of Escherichia coli strains with single and multiple deletions of genes involved in glucose transport. Compared to their wild type (W3110), the mutant strains displayed lower glucose uptake, growth and aerobic acetate production rates. Therefore, when cultured in batch mode, such mutants may perform similar to W3110 cultured in fed-batch mode. To test that hypothesis, we evaluated the constitutive expression of the green fluorescence protein (GFP) in batch cultures in microbioreactors using a semi defined medium supplemented with 10 or 20 g/L glucose + 0.4 g yeast extract/g glucose. RESULTS: The mutant strains cultured in batch mode displayed a fast-growth phase (growth rate between 0.40 and 0.60 h-1) followed by a slow-growth phase (growth rate between 0.05 and 0.15 h-1), similar to typical fed-batch cultures. The phase of slow growth is most probably caused by depletion of key amino acids. Three mutants attained the highest GFP fluorescence. Particularly, a mutant named WHIC (ΔptsHIcrr, ΔmglABC), reached a GFP fluorescence up to 14-fold greater than that of W3110. Strain WHIC was cultured in 2 L bioreactors in batch mode with 100 g/L glucose + 50 g/L yeast extract. These cultures were compared with exponentially fed-batch cultures of W3110 maintaining the same slow-growth of WHIC (0.05 h-1) and using the same total amount of glucose and yeast extract than in WHIC cultures. The WHIC strain produced approx. 450 mg/L GFP, while W3110 only 220 mg/L. CONCLUSION: The combination of cell engineering and high throughput screening allowed the selection of a particular mutant that mimics fed-batch behavior in batch cultures. Moreover, the amount of GFP produced by the strain WHIC was substantially higher than that of W3110 under both, batch and fed-batch schemes. Therefore, our results represent a valuable technology for accelerated bioprocess development.
Assuntos
Técnicas de Cultura Celular por Lotes , Escherichia coli , Transporte Biológico , Reatores Biológicos , Escherichia coli/metabolismo , Glucose/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismoRESUMO
Given obesity and its associated metabolic disorders have reached epidemic proportions, the study of therapeutic strategies targeting white adipose tissue (WAT) are of main research interest. We previously shown that α-linolenic acid-rich chia seed was able to ameliorate a wide range of metabolic disorders including body fat accretion in sucrose-rich diet (SRD)-fed rats, an experimental model of visceral adiposity and insulin resistance. However, the mechanisms involved are not fully clarified. The aim of this study was to evaluate the effect of chia seed administration upon WAT remodeling and key enzymes that controls lipolysis, insulin signaling (tAKT, pAKT), and GLUT-4 levels in different visceral fat pad depots (epididymal -eWAT- and retroperitoneal -rWAT- adipose tissues) of SRD-fed rats. Results showed that chia seed reduces adipocytes hypertrophy, the increased lipid content and collagen deposition in both WAT. These changes were accompanied by a significant reduction of HSL and ATGL protein levels in eWAT and HSL protein levels in rWAT. Moreover, chia seed restored the altered expression pattern of the pAKT observed in SRD-fed rats, and modulated GLUT-4 levels. Chia seed could be a dietary intervention of great relevance with potential beneficial effects in the management of body fat excess and WAT function.
Assuntos
Salvia , Ácido alfa-Linolênico , Adiposidade , Animais , Colágeno , Dieta , Insulina/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Extratos Vegetais , Ratos , Ratos Wistar , Roedores/metabolismo , Salvia/metabolismo , Salvia hispanica , Ácido alfa-Linolênico/farmacologiaRESUMO
Paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride; PQ) is a widely used herbicide in Brazilian crops, despite its banishment in many other countries. The present study investigated the effects of repeated dose of PQ on glutamate system, energy metabolism and redox parameters in the hippocampus of prepubertal rats. Twenty-two-day-old rats received daily intraperitoneal injections of PQ (10 mg/Kg) during 5 consecutive days and the effects of the pesticide were assessed 24 h after the last injection. The PQ exposure provoked cytotoxicity associated to decreased cell viability and increased glutamate excitotoxicity, as demonstrated by decreased 14C-glutamate uptake and increased 45Ca2+ uptake. Downregulated glutamine synthetase (GS) activity, further supports disrupted glutamate metabolism compromising the glutamate-glutamine cycle. Downregulated 14C-2-Deoxy-D-glucose indicates energy failure and upregulated lactate dehydrogenase (LDH) suggests the relevance of lactate as energy fuel. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) upregulation suggest Krebs cycle replenishment and piruvate production. In addition, PQ disturbed the redox status inducing lipid peroxidation, evaluated by increased TBARS and imbalanced antioxidant system. Downregulated glutathione reductase (GR), gamma-glutamyltransferase (GGT), glutathione-S-transferase (GST) and glucose-6-P-dehydrogenase (G6PD) activities together with upregulated superoxide dismutase (SOD) and catalase activities corroborate the oxidative imbalance. The mechanisms underlying PQ-induced neurotoxicity involves the modulation of GSK-3ß, NF-κB and NMDA receptors. These neurochemical and oxidative events observed may contribute to neuroinflammation and neurotoxic effects of PQ on hippocampal cells.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Herbicidas/toxicidade , Hipocampo/metabolismo , Paraquat/toxicidade , Maturidade Sexual/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Metabolismo Energético/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Técnicas de Cultura de Órgãos , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Maturidade Sexual/fisiologiaRESUMO
Among multiple mechanisms, low-grade inflammation is critical for the development of insulin resistance as a feature of type 2 diabetes. The nucleotide-binding oligomerization domain-like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been linked to the development of insulin resistance in various tissues; however, its role in the development of insulin resistance in the skeletal muscle has not been explored in depth. Currently, there is limited evidence that supports the pathological role of NLRP3 inflammasome activation in glucose handling in the skeletal muscle of obese individuals. Here, we have centered our focus on insulin signaling in skeletal muscle, which is the main site of postprandial glucose disposal in humans. We discuss the current evidence showing that the NLRP3 inflammasome disturbs glucose homeostasis. We also review how NLRP3-associated interleukin and its gasdermin D-mediated efflux could affect insulin-dependent intracellular pathways. Finally, we address pharmacological NLRP3 inhibitors that may have a therapeutical use in obesity-related metabolic alterations.
Assuntos
Inflamassomos/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Animais , Transporte Biológico , Doença Crônica , Glucose/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Interleucina-1beta/metabolismo , Metabolismo dos Lipídeos , Músculo Esquelético/patologia , Obesidade/tratamento farmacológico , Obesidade/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake-via AMP-activated protein kinase (AMPK)-after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.
Assuntos
Proteínas Quinases Ativadas por AMP , Glucose/metabolismo , Miócitos Cardíacos , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Células Cultivadas , Hipertrofia , Masculino , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Transdução de SinaisRESUMO
The acute rise in interstitial K+ that accompanies neural activity couples the energy demand of neurons to the metabolism of astrocytes. The effects of elevated K+ on astrocytes include activation of aerobic glycolysis, inhibition of mitochondrial respiration and the release of lactate. Using a genetically encoded FRET glucose sensor and a novel protocol based on 3-O-methylglucose trans-acceleration and numerical simulation of glucose dynamics, we report that extracellular K+ is also a potent and reversible modulator of the astrocytic glucose transporter GLUT1. In cultured mouse astrocytes, the stimulatory effect developed within seconds, engaged both the influx and efflux modes of the transporter, and was detected even at 1 mM incremental K+ . The modulation of GLUT1 explains how astrocytes are able to maintain their glucose pool in the face of strong glycolysis stimulation. We propose that the stimulation of GLUT1 by K+ supports the production of lactate by astrocytes and the timely delivery of glucose to active neurons.
Assuntos
Astrócitos , Glicólise , Animais , Glucose , Transportador de Glucose Tipo 1/genética , Ácido Láctico , CamundongosRESUMO
Cerebral glucose hypometabolism is a common pathophysiological characteristic of many neurodegenerative diseases. This metabolic dysfunction includes alterations in glucose transport from the blood into the neurons by the facilitative glucose transporters (GLUTs). Several studies suggest that metabolic disturbances precede clinical symptoms and correlate with disease progression. Some groups have started to explore the use of therapeutic strategies that target decreased cerebral glucose metabolism to promote its availability. We selected Andrographolide (Andro), a natural product obtained from Andrographis paniculate that has both anti-hyperglycemic and anti-diabetic effects. Although it was shown to promote glucose uptake in vivo, the underlying mechanisms remain unclear. Here, we evaluated the acute effects of Andro on glucose transport and metabolism using primary rat hippocampal neuronal cultures. Our results showed that Andro enhances neuronal glucose uptake and stimulates glucose metabolism by inducing GLUT3 and 4 expression in neurons, as well as by promoting glycolysis. We also observed that Andro-mediated effects depend on the activity of AMP-activated protein kinase (AMPK), one of the central regulators of glucose metabolism. Our studies open the possibility to use Andro as a drug to restore glucose levels in neurodegenerative diseases.
Assuntos
Diterpenos/farmacologia , Glucose/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Células Cultivadas , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptakevia AMP-activated protein kinase (AMPK)after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.
Assuntos
Animais , Masculino , Ratos , Testosterona/farmacologia , Receptores Androgênicos/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Glucose/metabolismo , Transdução de Sinais , Células Cultivadas , Hipertrofia , Miocárdio/patologiaRESUMO
Astrocytes take up glucose via the 45â¯kDa isoform of the Glucose Transporter 1 (GLUT-1), and in this work we have investigated whether histamine regulates GLUT-1 expression in rat cerebro-cortical astrocytes in primary culture. Cultured astrocytes expressed histamine H1 and H3 receptors (H1Rs and H3Rs) as evaluated by radioligand binding. Receptor functionality was confirmed by the increase in the intracellular concentration of Ca2+ (H1R) and the inhibition of forskolin-induced cAMP accumulation (H3R). Quantitative RT-PCR showed that histamine and selective H1R and H3R agonists (1â¯h incubation) significantly increased GLUT-1 mRNA to 153⯱â¯7, 163⯱â¯2 and 168⯱â¯13% of control values, respectively. In immunoblot assays, incubation (3â¯h) with histamine or H1R and H3R agonists increased GLUT-1 protein levels to 224⯱â¯12, 305⯱â¯11 and 193⯱â¯13% of control values, respectively, an action confirmed by inmunocytochemistry. The effects of H1R and H3R agonists were blocked by the selective antagonists mepyramine (H1R) and clobenpropit (H3R). The pharmacological inhibition of protein kinase C (PKC) prevented the increase in GLUT-1 protein induced by either H1R or H3R activation. Furthermore, histamine increased ERK-1/2 phosphorylation, and the effect of H1R and H3R activation on GLUT-1 protein levels was reduced or prevented, respectively, by MEK-1/2 inhibition. These results indicate that by activating H1Rs and H3Rs histamine regulates the expression of GLUT-1 by astrocytes. The effect appears to involve the phospholipase C (PLC) â diacylglycerol (DAG)/Ca2+â PKC and PLC â DAG/Ca2+ â PKC â MAPK pathways.
Assuntos
Astrócitos/metabolismo , Córtex Cerebral/metabolismo , Transportador de Glucose Tipo 1/biossíntese , Agonistas dos Receptores Histamínicos/farmacologia , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , AMP Cíclico/metabolismo , Histamina/metabolismo , Imuno-Histoquímica , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Wistar , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H3/efeitos dos fármacos , Receptores Histamínicos H3/metabolismoRESUMO
ABSTRACT Purpose: Glucose is a major energy resource for tumor cell survival and growth, and its influx into cells is mainly carried out by facilitative glucose transporters (GLUTs). Sodium - dependent glucose transporters (SGLTs) have been highlighted as playing important roles in diabetic treatment. However, their potential roles in cancer remain unclear. We examined expression patterns of SGLTs in tumor tissues together with conventional pathological variables to determine prognostic significance in patients with renal cell carcinoma (RCC). Materials and Methods: Nephrectomy specimens were obtained from 68 patients. GLUT - 1, - 2 and SGLT - 1, - 2 expression in tumor and adjacent normal tissues were analyzed by immunohistochemical staining, and intensity was quantified using an image analyzer. Results: The four glucose transporters evaluated were broadly distributed in tumor tissues as well as throughout the normal parenchyma. There was no significant correlation between transporter expression and conventional pathological variables. However, increased SGLT - 2 expression was significantly associated with shorter overall survival (p < 0.01), regardless of metastatic status. Conclusions: We propose possible prognostic significance of SGLT - 2 expression in human RCC. Given that glucose is a major energy resource for tumor cells and that glucose transport is largely mediated by SGLT, SGLT - 2 may serve as a possible therapeutic target in RCC.
Assuntos
Carcinoma de Células Renais/metabolismo , Proteínas de Transporte de Sódio-Glucose/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Neoplasias Renais/metabolismo , Prognóstico , Imuno-Histoquímica , Análise de Sobrevida , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
PURPOSE: Glucose is a major energy resource for tumor cell survival and growth, and its influx into cells is mainly carried out by facilitative glucose transporters (GLUTs). Sodium - dependent glucose transporters (SGLTs) have been highlighted as playing important roles in diabetic treatment. However, their potential roles in cancer remain unclear. We examined expression patterns of SGLTs in tumor tissues together with conventional pathological variables to determine prognostic significance in patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: Nephrectomy specimens were obtained from 68 patients. GLUT - 1, - 2 and SGLT - 1, - 2 expression in tumor and adjacent normal tissues were analyzed by immunohistochemical staining, and intensity was quantified using an image analyzer. RESULTS: The four glucose transporters evaluated were broadly distributed in tumor tissues as well as throughout the normal parenchyma. There was no significant correlation between transporter expression and conventional pathological variables. However, increased SGLT - 2 expression was significantly associated with shorter overall survival (p < 0.01), regardless of metastatic status. CONCLUSIONS: We propose possible prognostic significance of SGLT - 2 expression in human RCC. Given that glucose is a major energy resource for tumor cells and that glucose transport is largely mediated by SGLT, SGLT - 2 may serve as a possible therapeutic target in RCC.
Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Proteínas de Transporte de Sódio-Glucose/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de SobrevidaRESUMO
Resveratrol-a polyphenol of natural origin-has been the object of massive research in the past decade because of its potential use in cancer therapy. However, resveratrol has shown an extensive range of cellular targets and effects, which hinders the use of the molecule for medical applications including cancer and type 2 diabetes. Here, we review the latest advances in understanding how resveratrol modulates glucose uptake, regulates cellular metabolism, and how this may be useful to improve current therapies. We discuss challenges and findings regarding the inhibition of glucose uptake by resveratrol and other polyphenols of similar chemical structure. We review alternatives that can be exploited to improve cancer therapies, including the use of other polyphenols, or the combination of resveratrol with other molecules and their impact on glucose homeostasis in cancer and diabetes.
Assuntos
Metabolismo dos Carboidratos/efeitos dos fármacos , Glucose/metabolismo , Estilbenos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Transporte Biológico/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Sinergismo Farmacológico , Homeostase/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Polifenóis/química , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Estilbenos/química , Estilbenos/uso terapêuticoRESUMO
Dentre as lesões que levam à destruição óssea nos maxilares, os cistos odontogênicos são as mais comuns. A inflamação que participa na patogênese de alguns desses cistos pode estimular modificações no metabolismo celular energético, possibilitando a expressão do transportador de glicose-1 (GLUT-1). A partir deste contexto, o presente estudo objetiva analisar a imuno expressão do GLUT-1 em cistos radiculares (CR) e dentígeros (CD).A amostra foi constituída de 36 casos, sendo 18 de CR e 18 de CD. Foi realizado estudo morfológico para o diagnóstico histopatológico de coloração por hematoxilina & eosina (HE),bem como a análise da intensidade do infiltrado inflamatório dos CRs (leve/intenso) no aumento de 100x. Para avaliação imuno-histoquímica, foi utilizada a técnica da estreptoavidina-biotina, com o uso do anticorpo anti-GLUT-1 (GeneTex®, 1:300, citrato pH6, Pascal). A análise quantitativa foi realizada por meio de contagem percentual de células imunomarcadas em cinco campos fotografados no aumento de 400x; enquanto a análise da intensidade de imunomarcação (sem expressão/fraca expressão/forte expressão) ocorreu através da avaliação de um campo fotografado no aumento de 100x; para ambas as avaliações,utilizou-se o programa Image J. Os dados clínicos foram comparados entre grupos por meio do teste qui-quadrado de Pearson ou Exato de Fisher e por meio de Regressão Logística Multinomial. As contagens de células positivas foram analisadas por meio do teste de Mann Whineyou Kruskall-Wallis/Dunn (dados não paramétricos). Adicionalmente, utilizou-se a correlação de Spearman entre alguns grupos. Todos os testes estatísticos tiveram como baseos níveis de significância de 5%...
Odontogenic cysts are one of the most common osseous-destructive lesions in the jaws.Inflammation involved in the pathogenesis of some of these cysts can stimulate changes in theenergy cellular metabolism, enabling an increase of glucose transporter-1 expression (GLUT1).In this way, the present study aims to evaluate the immunohistochemical expression ofGLUT-1 in radicular cysts (RC) and dentigerous cysts (DC). The sample consists of 36 cases,18 RC and 18 cases of DC. Morphological study was conducted for histopathologic diagnosisby staining with HE as well as the intensity of the RCs inflammatory infiltrate analysis(slight/heavy) using 100x magnification. For immunohistochemical assessment, the techniquestreptavidin-biotin was used, with anti-GLUT-1 antibody (GeneTex®, 1: 300, Citrate pH 6).Quantitative analysis was performed by counting of immunostained cells in 05 photographedfields at 400x magnification. The analysis of immunostaining intensity (no expression / weakexpression / strong expression) occurred by evaluating 01 photographed field at 100xmagnification. The software Image J was used for both reviews. Clinical data between groupswere compared using Pearson's chi-square test or Fisher's exact test and through LogisticMultinomial Regression. Scores of positive cells were analyzed using the Mann-Whiney orKruskall-Wallis/Dunn test (nonparametric data). Additionally, the Spearman correlation wasused among some groups. All statistical tests were based on the significance level of 5%...
Assuntos
Humanos , Odontologia , Cisto Radicular , Cisto Dentígero , ProteínasRESUMO
Introducción: el transporte de la glucosa y de muchos aminoácidos en el intestino es realizado por el cotransportador SGLT1 únicamente si esta unido al ion sodio. La sal aporta un ion sodio por cada molécula que se consume y en los humanos su ingesta comúnmente es de diez veces más de la cantidad necesaria y generalmente se acompaña de dietas ricas en carbohidratos. Este trabajo se planteo pensando en que una estrategia simple para reducir de peso sería el disminuir la cantidad de sal en los alimentos. Objetivo: estudiar el efecto que tiene la sal en la dinámica de la absorción de glucosa y el efecto de una dieta rica en carbohidratos y sal en el desarrollo de obesidad en ratas Wistar. Métodos: para corroborar la hipótesis se evaluó el efecto de la sal en la dinámica de la absorción de la glucosa en el intestino realizando curvas de tolerancia a la glucosa con sal y sin sal. También se analizó si una dieta rica en carbohidratos y sal favorece el desarrollo de obesidad en ratas Wistar. Resultados: los experimentos mostraron que la ingesta de sal no influye en la dinámica de la absorción intestinal de la glucosa, ni en el desarrollo de obesidad en la rata Wistar. Conclusión: el sodio que de manera natural recircula desde el citoplasma de los enterocitos hacia la luz del intestino mantiene saturado al cotransportador de la glucosa SGLT1 y garantiza en todo momento el transporte de la glucosa que se ingiere en la dieta.
Introduction: Intestinal transport of glucose and many amino acids is performed by the SGLT1 cotransporter only when the latter is bound to the sodium ion. Salt contributes a sodium ion per molecule ingested. Human salt intake is often tenfold the required amount, and is generally accompanied by a carbohydrate-rich diet. The present study is based on the assumption that reducing the amount of salt in foods is a simple weight-loss strategy. Objective: Study the effect of salt on glucose absorption dynamics and the effect of a diet rich in carbohydrates and salt on the development of obesity in Wistar rats. Methods: To corroborate the hypothesis, an evaluation was conducted of the effect of salt on intestinal glucose absorption, based on glucose tolerance curves with and without salt. An analysis was also made of whether a diet rich in carbohydrates and salt leads to the development of obesity in Wistar rats. Results: Experiments showed that salt intake does not influence intestinal glucose absorption or the development of obesity in Wistar rats. Conclusion: Sodium naturally recirculating from the cytoplasm of enterocytes to the intestinal lumen keeps the SGLT1 glucose cotransporter saturated and at all times ensures the transport of the glucose ingested in the diet.
RESUMO
Insulin and insulin-like growth factor 1 (IGF-I) are capable of activating similar intracellular pathways. Insulin acts mainly through its own receptor, but can also activate the IGF-I receptor (IGF-IR). The aim of this study was to investigate the involvement of the IGF-IR in the effects of insulin and IGF-I on the membrane potential of immature Sertoli cells in whole seminiferous tubules, as well as on calcium, amino acid, and glucose uptake in testicular tissue of immature rats. The membrane potential of the Sertoli cells was recorded using a standard single microelectrode technique. In calcium uptake experiments, the testes were pre-incubated with (45)Ca(2+), with or without JB1 (1 µg/mL), and then incubated with insulin (100 nM) or IGF-I (15 nM). In amino acid and glucose uptake experiments, the gonads were pre-incubated with or without JB1 (1 µg/mL) and then incubated with radiolabeled amino acid or glucose analogues in the presence of insulin (100 nM) or IGF-I (15 nM). The blockade of IGF-IR with JB1 prevented the depolarising effects of both insulin and IGF-I on membrane potential, as well as the effect of insulin on calcium uptake. JB1 also inhibited the effects of insulin and IGF-I on glucose uptake. The effect of IGF-I on amino acid transport was inhibited in the presence of JB1, whereas the effect of insulin was not. We concluded that while IGF-I seems to act mainly through its cognate receptor to induce membrane depolarisation and calcium, amino acid and glucose uptake, insulin appears to be able to elicit its effects through IGF-IR, in seminiferous tubules from immature rats.
Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Insulina/metabolismo , Receptor IGF Tipo 1/metabolismo , Túbulos Seminíferos/metabolismo , Aminoácidos/metabolismo , Animais , Transporte Biológico , Cálcio/metabolismo , Membrana Celular/metabolismo , Glucose/metabolismo , Masculino , Potenciais da Membrana , Ratos , Ratos Wistar , Células de Sertoli/metabolismoRESUMO
Objetivos: el transporte de la glucosa y de muchos aminoácidos en el intestino se realiza por el cotransportador SGLT1 únicamente si está unido al ion sodio. La sal aporta un ion sodio por cada molécula que se consume y en los humanos su ingesta comúnmente es de diez veces más de la cantidad necesaria y, por lo general, se acompaña de dietas ricas en carbohidratos. El presente proyecto evaluó, si el consumo abundante de sal en la dieta conlleva al desarrollo de obesidad. Este trabajo se planteó pensando en que una estrategia simple para reducir de peso sería el disminuir la cantidad de sal en los alimentos. Métodos: para corroborar la hipótesis se evaluó el efecto de la sal en la dinámica de la absorción de la glucosa en el intestino realizando curvas de tolerancia a la glucosa con sal y sin sal. También se analizó si una dieta rica en carbohidratos y sal favorece el desarrollo de obesidad en ratas wistar. Resultados: los experimentos mostraron que la ingesta de sal no influye en la dinámica de la absorción intestinal de la glucosa, ni en el desarrollo de obesidad en la rata wistar. Conclusión: el sodio que, de manera natural, recircula desde el citoplasma de los enterocitos hacia la luz del intestino mantiene saturado al cotransportador de la glucosa SGLT1 y garantiza, en todo momento, el transporte de la glucosa que se ingiere en la dieta.
Objectives: intestinal transport of glucose and many amino acids is performed by the SGLT1 cotransporter only when the latter is bound to the sodium ion. Salt contributes a sodium ion per molecule ingested. Human salt intake is often tenfold the required amount, and is generally accompanied by a carbohydrate-rich diet. The present paper evaluates whether an abundant salt intake leads to the development of obesity. It is based on the assumption that reducing the amount of salt in foods is a simple weight-loss strategy. Methods: to corroborate the hypothesis, an evaluation was conducted of the effect of salt on intestinal glucose absorption, based on tolerance curves for glucose with and without salt. An analysis was also made of whether a diet rich in carbohydrates and salt leads to the development of obesity in Wistar rats. Results: experiments showed that salt intake does not influence intestinal glucose absorption or the development of obesity in Wistar rats. Conclusion: sodium naturally recirculating from the cytoplasm of enterocytes to the intestinal lumen keeps the SGLT1 glucose cotransporter saturated and at all times ensures the transport of the glucose ingested in the diet.
RESUMO
The LmxGT1 glucose transporter is selectively targeted to the flagellum of the kinetoplastid parasite Leishmania mexicana, but the mechanism for targeting this and other flagella-specific membrane proteins among the Kinetoplastida is unknown. To address the mechanism of flagellar targeting, we employed in vivo cross-linking, tandem affinity purification, and mass spectrometry to identify a novel protein, KHARON1 (KH1), which is important for the flagellar trafficking of LmxGT1. Kh1 null mutant parasites are strongly impaired in flagellar targeting of LmxGT1, and trafficking of the permease was arrested in the flagellar pocket. Immunolocalization revealed that KH1 is located at the base of the flagellum, within the flagellar pocket, where it associates with the proximal segment of the flagellar axoneme. We propose that KH1 mediates transit of LmxGT1 from the flagellar pocket into the flagellar membrane via interaction with the proximal portion of the flagellar axoneme. KH1 represents the first component involved in flagellar trafficking of integral membrane proteins among parasitic protozoa. Of considerable interest, Kh1 null mutants are strongly compromised for growth as amastigotes within host macrophages. Thus, KH1 is also important for the disease causing stage of the parasite life cycle.