RESUMEN
Hypertension (HP) is a health condition that overloads the heart and increases the risk of heart attack and stroke. In an infarction, the lack of oxygen causes an exclusive use of glycolysis, which becomes a crucial source of ATP for the heart with a higher glucose uptake mediated by glucose transporters (GLUTs). Due to the unpleasant effects of antihypertensives, new drugs need to be researched to treat this disease. This study aimed to evaluate the cardioprotective effect of three novel antihypertensive compounds (LQMs, "Laboratorio de Química Medicinal") synthesized from Changrolin under hypoxic conditions with the participation of two primary cardiac GLUT1 and GLUT4 using a high-salt diet HP model. The model used a diet with 10% salt to increase arterial blood pressure in Wistar rats. In isolated cardiomyocytes from these rats, glucose uptake was measured during hypoxia, evaluating the participation of GLUTs with or without the animals' previous treatment with LQM312, 319, and 345 compounds. In silico calculations were performed to understand the affinity of the compounds for the trafficking of GLUTs. Results: Control cells do shift to glucose uptake exclusively in hypoxia (from 1.84 ± 0.09 µg/g/h to 2.67 ± 0.1 µg/g/h). Meanwhile, HP does not change its glucose uptake (from 2.38 ± 0.24 µg/g/h to 2.33 ± 0.26 µg/g/h), which is associated with cardiomyocyte damage. The new compounds lowered the systolic blood pressure (from 149 to 120 mmHg), but only LQM312 and LQM319 improved the metabolic state of hypoxic cardiomyocytes mediated by GLUT1 and GLUT4. In silico studies suggested that Captopril and LQM312 may mimic the interaction with the AMPK γ-subunit. Therefore, these compounds could activate AMPK, promoting the GLUT4 trafficking signaling pathway. These compounds are proposed to be cardioprotective during hypoxia under HP.
Asunto(s)
Antihipertensivos , Transportador de Glucosa de Tipo 4 , Glucosa , Hipertensión , Miocitos Cardíacos , Ratas Wistar , Animales , Ratas , Antihipertensivos/farmacología , Hipertensión/metabolismo , Hipertensión/tratamiento farmacológico , Glucosa/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Transportador de Glucosa de Tipo 4/metabolismo , Masculino , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Transportador de Glucosa de Tipo 1/metabolismo , Cloruro de Sodio Dietético/efectos adversos , Hipoxia/metabolismo , Hipoxia/tratamiento farmacológico , Transporte Biológico/efectos de los fármacos , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Presión Sanguínea/efectos de los fármacosRESUMEN
OBJECTIVE: Glucose transporter-1 is a marker involved in energy transport in cancer cells. It has been shown to be a poor prognostic factor in many cancer types, including breast cancer. However, there is no satisfactory parameter predicting treatment in breast cancer patients receiving neoadjuvant therapy. This study investigated the effect of glucose transporter-1 in predicting the treatment response of patients receiving neoadjuvant therapy. METHODS: In this study, glucose transporter-1 immunohistochemistry was applied to tru-cut biopsy of patients who were diagnosed with breast cancer and received neoadjuvant therapy between 2010 and 2021. A built-in scoring system was used to evaluate both the pattern and intensity of glucose transporter-1 immunohistochemistry staining. The relationship between glucose transporter-1 immunohistochemistry staining and other clinicopathological parameters was examined. In addition, the relationship of glucose transporter-1 with response to treatment was investigated. RESULTS: A relationship was found between high glucose transporter-1 expression and other clinicopathological parameters (such as estrogen and progesterone receptor negativity, high Ki-67, triple-negative, and Her2 status). Cases with high glucose transporter-1 expression had either a complete or a partial pathologic response. The result was statistically significant. CONCLUSION: Glucose transporter-1 has the potential to be a biomarker that can be evaluated more objectively as an alternative to Ki-67 labeling index in evaluating the response to treatment in patients receiving neoadjuvant therapy.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Antígeno Ki-67/metabolismo , Terapia Neoadyuvante , Receptor ErbB-2/metabolismo , Receptor ErbB-2/uso terapéutico , Inmunohistoquímica , Proteínas Facilitadoras del Transporte de la Glucosa/uso terapéutico , Receptores de Progesterona/metabolismo , Receptores de Progesterona/uso terapéutico , Biomarcadores de Tumor/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , PronósticoRESUMEN
Gain-of-function mutations of dynamin-2, a mechano-GTPase that remodels membrane and actin filaments, cause centronuclear myopathy (CNM), a congenital disease that mainly affects skeletal muscle tissue. Among these mutations, the variants p.A618T and p.S619L lead to a gain of function and cause a severe neonatal phenotype. By using total internal reflection fluorescence microscopy (TIRFM) in immortalized human myoblasts expressing the pH-sensitive fluorescent protein (pHluorin) fused to the insulin-responsive aminopeptidase IRAP as a reporter of the GLUT4 vesicle trafficking, we measured single pHluorin signals to investigate how p.A618T and p.S619L mutations influence exocytosis. We show here that both dynamin-2 mutations significantly reduced the number and durations of pHluorin signals induced by 10 µM ionomycin, indicating that in addition to impairing exocytosis, they also affect the fusion pore dynamics. These mutations also disrupt the formation of actin filaments, a process that reportedly favors exocytosis. This altered exocytosis might importantly disturb the plasmalemma expression of functional proteins such as the glucose transporter GLUT4 in skeletal muscle cells, impacting the physiology of the skeletal muscle tissue and contributing to the CNM disease.
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Dinamina II , Miopatías Estructurales Congénitas , Dinamina II/genética , Dinamina II/metabolismo , Exocitosis , Mutación con Ganancia de Función , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Ionomicina , Músculo Esquelético/metabolismo , Mutación , Mioblastos/metabolismo , Miopatías Estructurales Congénitas/metabolismoRESUMEN
Prostate cancer (PCa) is the second leading cause of cancer deaths in men. Unfortunately, a very limited number of drugs are available for the relapsed and advanced stages of PCa, adding only a few months to survival; therefore, it is vital to develop new drugs. 5´ AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism. It plays a significant role in the metabolism of PCa; hence, it can serve well as a treatment option for the advanced stages of PCa. However, whether this pathway contributes to cancer cell survival or death remains unknown. The present study reviews the possible pathways by which AMPK plays role in the advanced stages of PCa, drug resistance, and metastasis: (1) AMPK has a contradictory role in promoting glycolysis and the Warburg effect which are correlated with cancer stem cells (CSCs) survival and advanced PCa. It exerts its effect by interacting with hypoxia-induced factor 1 (HIF1) α, pyruvate kinase 2 (PKM2), glucose transporter (GLUT) 1 and pyruvate dehydrogenase complex (PDHC), which are key regulators of glycolysis; however, whether it promotes or discourage glycolysis is not conclusive. It can also exert an anti-CSC effect by negative regulation of NANOG and epithelial-mesenchymal transition (EMT) transcription factors, which are the major drivers of CSC maintenance; (2) the regulatory effect of AMPK on autophagy is also noticeable. Androgen receptors' expression increases AMPK activation through Calcium/calmodulin-dependent protein kinase 2 (CaMKK2) and induces autophagy. In addition, AMPK itself increases autophagy by downregulating the mammalian target of rapamycin complex (mTORC). However, whether increased autophagy inhibits or promotes cell death and drug resistance is contradictory. This study reveals that there are numerous pathways other than cell metabolism by which AMPK exerts its effects in the advanced stages of PCa, making it a priceless treatment target. Finally, we mention some drugs developed to treat the advanced stages of PCa by acting on AMPK.
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Proteínas Quinasas Activadas por AMP , Neoplasias de la Próstata , Autofagia , Calcio/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/farmacología , Proteínas Facilitadoras del Transporte de la Glucosa/uso terapéutico , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Complejo Piruvato Deshidrogenasa/metabolismo , Complejo Piruvato Deshidrogenasa/farmacología , Complejo Piruvato Deshidrogenasa/uso terapéutico , Piruvato Quinasa/metabolismo , Piruvato Quinasa/farmacología , Piruvato Quinasa/uso terapéutico , Receptores Androgénicos/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Random-walk models are frequently used to model distinct natural phenomena such as diffusion processes, stock-market fluctuations, and biological systems. Here, we present a random-walk model to describe the dynamics of glucose uptake by the sodium-glucose transporter of type 2, SGLT2. Our starting point is the canonical alternating-access model, which suggests the existence of six states for the transport cycle. We propose the inclusion of two new states to this canonical model. The first state is added to implement the recent discovery that the Na+ion can exit before the sugar is released into the proximal tubule epithelial cells. The resulting model is a seven-state mechanism with stochastic steps. Then we determined the transition probabilities between these seven states and used them to write a set of master equations to describe the time evolution of the system. We showed that our model converges to the expected equilibrium configuration and that the binding of Na+and glucose to SGLT2 in the inward-facing conformation must be necessarily unordered. After that, we added another state to implement inhibition in the model. Our results reproduce the experimental dependence of glucose uptake on the inhibitor concentration and they reveal that the inhibitors act by decreasing the number of available SGLT2s, which increases the chances of glucose escaping reabsorption.
Asunto(s)
Inhibidores del Cotransportador de Sodio-Glucosa 2 , Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa , Sodio/metabolismo , Proteínas de Transporte de Sodio-Glucosa , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
Chitosan is a polycationic amino-sugar polymer soluble in acidic pH. As a potential antifungal, it has been tested against several fungi. Its main mode of action is the permeabilization of cell membrane by the interaction with specific membrane sites. Ustilago maydis, an attractive fungal model used in biochemical and biotechnology research, is highly sensitive to chitosan, with extensive membrane destruction that results in cell death. Using the Golden Gate system, several mutant strains with deletions in monosaccharide transporters were obtained and tested against chitosan in order to know the implications of these membrane proteins in the sensitivity of the fungus against chitosan. Δum11514/03895 strain, a mutant with a deletion in a hypothetical high affinity glucose transporter, showed resistance to chitosan. Morphological characterization of the mutant displayed an apparent increase in mitochondrial content, but oxygen consumption as well as growth rate were not affected by the gene deletion. Alteration in cell wall surface was observed in the mutant strain. In contrast to wild type, the Δum11514/03895 strain showed integrity of cell wall and cell membrane in the presence of chitosan. The resistance against chitosan is likely associated to the modification of cell wall architecture and is not related to energy-depend process.
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Saccharomyces cerevisiae , Basidiomycota , Quitosano , Proteínas Facilitadoras del Transporte de la GlucosaRESUMEN
Clinical localization of primary tumors and sites of metastasis by PET is based on the enhanced cellular uptake of 2-deoxy-2-[18F]-fluoro-D-glucose (FDG). In prostate cancer, however, PET-FDG imaging has shown limited clinical applicability, suggesting that prostate cancer cells may utilize hexoses other than glucose, such as fructose, as the preferred energy source. Our previous studies suggested that prostate cancer cells overexpress fructose transporters, but not glucose transporters, compared with benign cells. Here, we focused on validating the functional expression of fructose transporters and determining whether fructose can modulate the biology of prostate cancer cells in vitro and in vivo. Fructose transporters, Glut5 and Glut9, were significantly upregulated in clinical specimens of prostate cancer when compared with their benign counterparts. Fructose levels in the serum of patients with prostate cancer were significantly higher than healthy subjects. Functional expression of fructose transporters was confirmed in prostate cancer cell lines. A detailed kinetic characterization indicated that Glut5 represents the main functional contributor in mediating fructose transport in prostate cancer cells. Fructose stimulated proliferation and invasion of prostate cancer cells in vitro. In addition, dietary fructose increased the growth of prostate cancer cell line-derived xenograft tumors and promoted prostate cancer cell proliferation in patient-derived xenografts. Gene set enrichment analysis confirmed that fructose stimulation enriched for proliferation-related pathways in prostate cancer cells. These results demonstrate that fructose promotes prostate cancer cell growth and aggressiveness in vitro and in vivo and may represent an alternative energy source for prostate cancer cells. SIGNIFICANCE: This study identifies increased expression of fructose transporters in prostate cancer and demonstrates a role for fructose as a key metabolic substrate supporting prostate cancer cells, revealing potential therapeutic targets and biomarkers.
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Biomarcadores de Tumor/metabolismo , Dieta/efectos adversos , Fructosa/farmacología , Regulación Neoplásica de la Expresión Génica , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Transportador de Glucosa de Tipo 5/metabolismo , Neoplasias de la Próstata/patología , Animales , Apoptosis , Biomarcadores de Tumor/genética , Ciclo Celular , Movimiento Celular , Proliferación Celular , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Transportador de Glucosa de Tipo 5/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Significance: Vitamin C is a powerful antioxidant that has an intricate relationship with cancer and has been studied for more than 60 years. However, the specific mechanisms that allow malignant cells to uptake, metabolize, and compartmentalize vitamin C remain unclear. In normal human cells, two different transporter systems are responsible for its acquisition: glucose transporters (GLUTs) transport the oxidized form of vitamin C (dehydroascorbic acid) and sodium-coupled ascorbic acid transporters (SVCTs) transport the reduced form (ascorbic acid [AA]). In this study, we review the mechanisms described for vitamin C uptake and metabolization in cancer. Recent Advances: Several studies performed recently in vivo and in vitro have provided the scientific community a better understanding of the differential capacities of cancer cells to acquire vitamin C: tumors from different origins do not express SVCTs in the plasma membrane and are only able to acquire vitamin C in its oxidized form. Interestingly, cancer cells differentially express a mitochondrial form of SVCT2. Critical Issues: Why tumors have reduced AA uptake capacity at the plasma membrane, but develop the capacity of AA transport within mitochondria, remains a mystery. However, it shows that understanding vitamin C physiology in tumor survival might be key to decipher the controversies in its relationship with cancer. Future Directions: A comprehensive analysis of the mechanisms by which cancer cells acquire, compartmentalize, and use vitamin C will allow the design of new therapeutic approaches in human cancer. Antioxid. Redox Signal. 35, 61-74.
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Ácido Ascórbico/metabolismo , Ácido Deshidroascórbico/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Neoplasias/metabolismo , Transportadores de Sodio Acoplados a la Vitamina C/metabolismo , Antioxidantes/metabolismo , Humanos , Mitocondrias/metabolismoRESUMEN
The development of new models to study diabetes in invertebrates is important to ensure adherence to the 3R's principle and to expedite knowledge of the complex molecular events underlying glucose toxicity. Streptozotocin (STZ)-an alkylating and highly toxic agent that has tropism to mammalian beta cells-is used as a model of type 1 diabetes in rodents, but little is known about STZ effects in insects. Here, the cockroach; Nauphoeta cinerea was used to determine the acute toxicity of 74 and 740 nmol of STZ injection per cockroach. STZ increased the glucose content, mRNA expression of glucose transporter 1 (GLUT1) and markers of oxidative stress in the head. Fat body glycogen, insect survival, acetylcholinesterase activity, triglyceride content and viable cells in head homogenate were reduced, which may indicate a disruption in glucose utilization by the head and fat body of insects after injection of 74 and 740 nmol STZ per nymph. The glutathione S-transferase (GST) activity and reduced glutathione levels (GSH) were increased, possibly via activation of nuclear factor erythroid 2 related factor as a compensatory response against the increase in reactive oxygen species. Our data present the potential for metabolic disruption in N. cinerea by glucose analogues and opens paths for the study of brain energy metabolism in insects. We further phylogenetically demonstrated conservation between N. cinerea glucose transporter 1 and the GLUT of other insects in the Neoptera infra-class.
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Encéfalo/metabolismo , Cucarachas/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Glucosa/metabolismo , Estrés Oxidativo , Filogenia , Estreptozocina/farmacología , Animales , Antibióticos Antineoplásicos/farmacología , Encéfalo/efectos de los fármacos , Cucarachas/efectos de los fármacos , Cucarachas/genética , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Glutatión/metabolismo , Glutatión Transferasa/metabolismoRESUMEN
Diabetes is a metabolic condition associated with hyperglycemia manifested by the elevation of blood glucose levels occurring when the pancreas decreases or stops the production of insulin, in case of insulin resistance or both. The current literature supports that insulin resistance may be responsible for the memory decline associated with diabetes. Glucose transporters (GLUTs) are a family of proteins involved in glucose transport across biological membranes. GLUT-1 and GLUT-3 are involved in glucose delivery to the brain. Evidence suggests that both transporters are downregulated in chronic peripheral hyperglycemia. Here we show the mechanisms of glucose transport and its influence on cognitive function, including a hypothesis of how peripheral hyperglycemia related genes network interactions may lead to glucose transporters downregulation and its possible consequences.
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Proteínas Facilitadoras del Transporte de la Glucosa , Hiperglucemia , Encéfalo/metabolismo , Glucosa , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Hiperglucemia/complicaciones , Insulina/metabolismoRESUMEN
The discovery and synthesis of insulin has been vital in the study and treatment of diabetes mellitus. From the studies carried by Dr. Nicolae C. Paulescu in 1921 and descriptions of the pancrein, before those published by Banting and Macleod, the Nobel Prize winners in 1923, more metabolic and non-metabolic actions have been discovered and that are fundamental for life, growth and development of different organs and systems. Diverse studies in animal models have shown the participation in the development of the central nervous system, regeneration, neuronal apoptosis, and synaptic transmission, as well as the effects of its dysregulation in the pathophysiology of diseases such as dementia. Different researchers have demonstrated the synthesis of insulin at the brain, the mechanisms through which the blood-brain barrier crosses and how it regulates non-metabolic systems linked with the nueromodulation. This document to integrate these findings in the cerebral insulin circuit and the translation in clinical practice.
El descubrimiento y la síntesis de la insulina ha sido vitales en el estudio y el tratamiento de la diabetes mellitus. Desde los estudios realizados por el Dr. Nicolae C. Paulescu en 1921 y sus descripciones de la pancreína, antes de los publicados por Banting y Macleod, galardonados con el Premio Nobel en 1923, se han descubierto cada vez más acciones metabólicas y no metabólicas fundamentales para la vida, el crecimiento y el desarrollo de diferentes órganos y sistemas. En la actualidad, el estudio de esta hormona se nutre con más evidencia científica de su utilidad en blancos terapéuticos no metabólicos. Diversos estudios en modelos animales han demostrado su participación en el desarrollo del sistema nervioso central, la regeneración, la apoptosis neuronal y la transmisión sináptica, así como los efectos de su disregulación en la fisiopatología de enfermedades como la demencia. En la actualidad, diferentes investigadores han demostrado la síntesis de insulina en el cerebro, los mecanismos por los cuales atraviesa la barrera hematoencefálica y cómo regula sistemas no metabólicos ligados con la nueromodulación. Este documento trata de integrar estos hallazgos en un sistema insulinérgico cerebral y su posible traducción en la práctica clínica.
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Barrera Hematoencefálica , Encéfalo/metabolismo , Insulina/fisiología , Receptor de Insulina/metabolismo , Glucemia , Diabetes Mellitus/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Insulina/biosíntesis , Insulina/genética , ARN Mensajero/metabolismo , Receptor de Insulina/genéticaRESUMEN
Risk of hyperuricemia is modified by genetic and environmental factors. Our aim was to identify factors associated with serum uric acid levels and hyperuricemia in Mexicans. A pilot Genome-wide association study GWAS was performed in a subgroup of participants (n = 411) from the Health Workers Cohort Study (HWCS). Single nucleotide polymorphisms (SNPs) associated with serum uric acid levels were validated in all the HWCS participants (n = 1939) and replicated in independent children (n = 1080) and adult (n = 1073) case-control studies. The meta-analysis of the whole HWCS and replication samples identified three SLC2A9 SNPs: rs1014290 (p = 2.3 × 10-64), rs3775948 (p = 8.2 × 10-64) and rs11722228 (p = 1.1 × 10-17); and an ABCG2 missense SNP, rs2231142 (p = 1.0 × 10-18). Among the non-genetic factors identified, the visceral adiposity index, smoking, the metabolic syndrome and its components (waist circumference, blood pressure, glucose and hyperlipidemia) were associated with increased serum uric acid levels and hyperuricemia (p < 0.05). Among the female HWCS participants, the odds ratio for hyperuricemia was 1.24 (95% CI, 1.01-1.53) per unit increase in soft drink consumption. As reported in other studies, our findings indicate that diet, adiposity and genetic variation contribute to the elevated prevalence of hyperuricemia in Mexico.
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Hiperuricemia , Ácido Úrico/sangre , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Adolescente , Adulto , Niño , Femenino , Estudio de Asociación del Genoma Completo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Humanos , Hiperuricemia/sangre , Hiperuricemia/epidemiología , Hiperuricemia/genética , Masculino , México/epidemiología , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
The mammary gland increases energy requirements during pregnancy and lactation to support epithelial proliferation and milk nutrients synthesis. Lactose, the principal carbohydrate of the milk, is synthetized in the Golgi of mammary epithelial cells by lactose synthase from glucose and UPD galactose. We studied the temporal changes in the expression of GLUT1 and GLUT8 in mammary gland and their association with lactose synthesis and proliferation in BALB/c mice. Six groups were used: virgin, pregnant at 2 and 17 days, lactating at 2 and 10 days, and weaning at 2 days. Temporal expression of GLUT1 and GLUT8 transporters by qPCR, western blot and immunohistochemistry, and its association with lactalbumin, Ki67, and cytokeratin 18 within mammary tissue was studied, along with subcellular localization. GLUT1 and GLUT8 transporters increased their expression during mammary gland progression, reaching 20-fold increasing in GLUT1 mRNA at lactation (p < 0.05) and 2-fold at protein level for GLUT1 and GLUT8 (p < 0.05 and 0.01, respectively). The temporal expression pattern was shared with cytokeratin 18 and Ki67 (p < 0.01). Endogenous GLUT8 partially co-localized with 58 K protein and α-lactalbumin in mammary tissue and with Golgi membrane-associated protein 130 in isolated epithelial cells. The spatial-temporal synchrony between expression of GLUT8/GLUT1 and alveolar cell proliferation, and its localization in cis-Golgi associated to lactose synthase complex, suggest that both transporters are involved in glucose uptake into this organelle, supporting lactose synthesis.
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Células Epiteliales/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Aparato de Golgi/metabolismo , Glándulas Mamarias Animales/metabolismo , Animales , Células Epiteliales/inmunología , Femenino , Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Transportador de Glucosa de Tipo 1/genética , Queratina-18/metabolismo , Lactalbúmina/metabolismo , Lactancia , Lactosa/biosíntesis , Lactosa Sintasa/metabolismo , Ratones , Ratones Endogámicos BALB C , Péptidos/metabolismo , Embarazo , ARN Mensajero/metabolismo , Proteína p130 Similar a la del Retinoblastoma/metabolismo , Factores de Tiempo , DesteteRESUMEN
RESUMO: Importância do problema: A Síndrome da Deficiência do Transportador de Glicose tipo 1 (GLUT1DS), descrita pela primeira vez por De Vivo em 1991, é causada por um deficitário transporte de glicose na barreira hematoencefálica e nos astrócitos devido à mutações na maioria das vezes de novo heterozigóticas no gene SLC2A1, responsável pela codificação do transportador de glicose tipo 1 (GLUT-1). Essa mutação limita a disponibilidade de glicose cerebral, levando a sua deficiência energética, sendo o mecanismo gerador de suas manifestações clínicas. Os sintomas sugestivos são convulsões, atraso no desenvolvimento, microcefalia, hipotonia, espasticidade e complexas alterações no movimento, consistindo de ataxia e distonia. Em pacientes GLUT1DS, substratos energéticos alternativos são de fundamental importância. Inúmeros trabalhos recomendam a utilização da dieta cetogênica de maneira imperiosa como mecanismo padrão ouro de tratamento. Esta, nos primeiros anos de vida em pacientes com GLUT1DS, garante um melhor resultado cognitivo e melhora nos aspectos psicomotores. Comentários: A GLUT1DS, por ser uma doença de recente descoberta, ter poucos casos descritos na literatura, características clínicas heterogêneas e falta substancial de casuística é muitas vezes subdiagnosticada. Nesse sentido, critérios de suspeição e algoritmos diagnósticos se fazem necessários. Dessa maneira, o objetivo deste artigo é chamar a atenção da comunidade médica brasileira para essa síndrome, com vistas a incrementar seu diagnóstico e melhorar o prognóstico de epilepsias de difícil controle (AU)
ABSTRACT: Glut-1 deficiency syndrome (GLUT1DS), first described by De Vivo in 1991, is caused by a deficient glucose transport in the blood-brain barrier and astrocytes by heterozygous mutations, mostly de novo, in the gene SLC2A1 encoding the glucose transporter type 1 (GLUT-1). This mutation limits the availability of cerebral glucose leading to energy deficiency, which is the underlying mechanism of the clinical manifestations. The suggestive symptoms are convulsions, developmental delay, microcephaly, hypotonia, spasticity, and complex changes in movement consisting of ataxia and dystonia. In GLUT1DS patients, altern ative energy substrates are of fundamental importance. Numerous studies recommend the use of a ketogenic diet in an imperative manner as a gold standard therapy method. This diet, in the first years of life in patients with GLUT1DS, guarantees a better cognitive result and improvement in psychomotor aspects. Because GLUT1DS is a disease of recent discovery, with a few cases described in the literature, heterogeneous clinical features and a substantial lack of casuistry is often underdiagnosed. In this sense, suspicion criteria and diagnostic algorithms become necessary. Thus, the purpose of this article is to draw the attention of the Brazilian medical community to this syndrome to increase its diagnosis and improve the prognosis of difficult-to-control epilepsy (AU)
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Humanos , Masculino , Preescolar , Epilepsia , Proteínas Facilitadoras del Transporte de la Glucosa , Dieta CetogénicaRESUMEN
BACKGROUND: Escherichia coli W3110 and a group of six isogenic derivatives, each displaying distinct specific rates of glucose consumption were characterized to determine levels of GFP production and population heterogeneity. These strains have single or combinatory deletions in genes encoding phosphoenolpyruvate:sugar phosphotransferase system (PTS) permeases as PtsG and ManX, as well as common components EI, Hpr protein and EIIA, also the non-PTS Mgl galactose/glucose ABC transporter. They have been transformed for expressing GFP based on a lac-based expression vector, which is subject to bistability. RESULTS: These strains displayed specific glucose consumption and growth rates ranging from 1.75 to 0.45 g/g h and 0.54 to 0.16 h-1, respectively. The rate of acetate production was strongly reduced in all mutant strains when compared with W3110/pV21. In bioreactor cultures, wild type W3110/pV21 produced 50.51 mg/L GFP, whereas strains WG/pV21 with inactive PTS IICBGlc and WGM/pV21 with the additional inactivation of PTS IIABMan showed the highest titers of GFP, corresponding to 342 and 438 mg/L, respectively. Moreover, we showed experimentally that bistable expression systems, as lac-based ones, induce strong phenotypic segregation among microbial populations. CONCLUSIONS: We have demonstrated that reduction on glucose consumption rate in E. coli leads to an improvement of GFP production. Furthermore, from the perspective of phenotypic heterogeneity, we observed in this case that heterogeneous systems are also the ones leading to the highest performance. This observation suggests reconsidering the generally accepted proposition stating that phenotypic heterogeneity is generally unwanted in bioprocess applications.
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Escherichia coli/genética , Glucosa/metabolismo , Ingeniería Metabólica/métodos , Acetatos/metabolismo , Transporte Biológico , Reactores Biológicos , Escherichia coli/crecimiento & desarrollo , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Citometría de Flujo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Fluorescentes Verdes/análisis , Cinética , Técnicas Analíticas MicrofluídicasRESUMEN
Glucose transporters are important for viability and infectivity of the disease-causing amastigote stages of Leishmania mexicana The Δgt1-3 null mutant, in which the 3 clustered glucose transporter genes, GT1, GT2, and GT3, have been deleted, is strongly impaired in growth inside macrophages in vitro We have now demonstrated that this null mutant is also impaired in virulence in the BALB/c murine model of infection and forms lesions considerably more slowly than wild-type parasites. Previously, we established that amplification of the PIFTC3 gene, which encodes an intraflagellar transport protein, both facilitated and accompanied the isolation of the original Δgt1-3 null mutant generated in extracellular insect-stage promastigotes. We have now isolated Δgt1-3 null mutants without coamplification of PIFTC3 These amplicon-negative null mutants are further impaired in growth as promastigotes, compared to the previously described null mutants containing the PIFTC3 amplification. In contrast, the GT3 glucose transporter plays an especially important role in promoting amastigote viability. A line that expresses only the single glucose transporter GT3 grows as well inside macrophages and induces lesions in animals as robustly as do wild-type amastigotes, but lines expressing only the GT1 or GT2 transporters replicate poorly in macrophages. Strikingly, GT3 is restricted largely to the endoplasmic reticulum in intracellular amastigotes. This observation raises the possibility that GT3 may play an important role as an intracellular glucose transporter in the infectious stage of the parasite life cycle.IMPORTANCE Glucose transport plays important roles for in vitro growth of insect-stage promastigotes and especially for viability of intramacrophage mammalian host-stage amastigotes of Leishmania mexicana However, the roles of the three distinct glucose transporters, GT1, GT2, and GT3, in parasite viability inside macrophages and virulence in mice have not been fully explored. Parasite lines expressing GT1 or GT2 alone were strongly impaired in growth inside macrophages, but lines expressing GT3 alone infected macrophages and caused lesions in mice as robustly as wild-type parasites. Notably, GT3 localizes to the endoplasmic reticulum of intracellular amastigotes, suggesting a potential role for salvage of glucose from that organelle for viability of infectious amastigotes. This study establishes the unique role of GT3 for parasite survival inside host macrophages and for robust virulence in infected animals.
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Retículo Endoplásmico/parasitología , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Leishmania mexicana/patogenicidad , Proteínas Protozoarias/genética , Animales , Línea Celular , Femenino , Técnicas de Inactivación de Genes , Leishmania mexicana/genética , Estadios del Ciclo de Vida , Macrófagos/parasitología , Ratones , Ratones Endogámicos BALB C , Microscopía Fluorescente , Mutación , VirulenciaRESUMEN
Stress hyperglycemia is frequently diagnosed in septic patients in critical care units (ICU) and it is associated with greater illness severity and higher morbimortality rates. In response to an acute injury, high levels of counterregulatory hormones such as glucocorticoids and catecholamines are released causing increased hepatic gluconeogenesis and insulin resistance. Furthermore, during sepsis, proinflammatory cytokines also participate in the pathogenesis of this phenomenon. Septic patients represent a subtype of the critical ill patients in the ICU: this metabolic disarrangement management strategies and insulin therapy recommendations had been inconsistent. In this article, we describe the pathophysiological mechanisms of stress hyperglycemia in critical patients including the action of hormones, inflammatory cytokines and tissue resistance to insulin. In addition, we analyzed the main published studies for the treatment of acute hyperglycemia in critical patients.
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Hiperglucemia/etiología , Sepsis/complicaciones , Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Hiperglucemia/metabolismo , Hiperglucemia/fisiopatología , Hiperglucemia/terapia , Unidades de Cuidados Intensivos , Sepsis/metabolismo , Sepsis/fisiopatología , Estrés FisiológicoRESUMEN
Stress hyperglycemia is frequently diagnosed in septic patients in critical care units (ICU) and it is associated with greater illness severity and higher morbimortality rates. In response to an acute injury, high levels of counterregulatory hormones such as glucocorticoids and catecholamines are released causing increased hepatic gluconeogenesis and insulin resistance. Furthermore, during sepsis, proinflammatory cytokines also participate in the pathogenesis of this phenomenon. Septic patients represent a subtype of the critical ill patients in the ICU: this metabolic disarrangement management strategies and insulin therapy recommendations had been inconsistent. In this article, we describe the pathophysiological mechanisms of stress hyperglycemia in critical patients including the action of hormones, inflammatory cytokines and tissue resistance to insulin. In addition, we analyzed the main published studies for the treatment of acute hyperglycemia in critical patients.
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Humanos , Sepsis/complicaciones , Hiperglucemia/etiología , Estrés Fisiológico , Sepsis/fisiopatología , Sepsis/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Glucosa/metabolismo , Hiperglucemia/fisiopatología , Hiperglucemia/metabolismo , Hiperglucemia/terapia , Unidades de Cuidados IntensivosRESUMEN
BACKGROUND AND AIMS: Little is known about specific genetic determinants of carotid-intima-media thickness (CIMT) and carotid plaque in subjects with rheumatoid arthritis (RA). We have used the Metabochip array to fine map and replicate loci that influence variation in these phenotypes in Mexican Americans (MAs) and European Americans (EAs). METHODS: CIMT and plaque were measured using ultrasound from 700 MA and 415 EA patients with RA and we conducted association analyses with the Metabochip single nucleotide polymorphism (SNP) data using PLINK. RESULTS: In MAs, 12 SNPs from 11 chromosomes and 6 SNPs from 6 chromosomes showed suggestive associations (p < 1 × 10-4) with CIMT and plaque, respectively. The strongest association was observed between CIMT and rs17526722 (SLC17A2 gene) (ß ± SE = -0.84 ± 0.18, p = 3.80 × 10-6). In EAs, 9 SNPs from 7 chromosomes and 7 SNPs from 7 chromosomes showed suggestive associations with CIMT and plaque, respectively. The top association for CIMT was observed with rs1867148 (PPCDC gene, ß ± SE = -0.28 ± 0.06, p = 5.11 × 10-6). We also observed strong association between plaque and two novel loci: rs496916 from COL4A1 gene (OR = 0.51, p = 3.15 × 10-6) in MAs and rs515291 from SLCA13 gene (OR = 0.50, p = 3.09 × 10-5) in EAs. CONCLUSIONS: We identified novel associations between CIMT and variants in SLC17A2 and PPCDC genes, and between plaque and variants from COL4A1 and SLCA13 that may pinpoint new candidate risk loci for subclinical atherosclerosis associated with RA.
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Artritis Reumatoide/etnología , Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/etnología , Enfermedades de las Arterias Carótidas/genética , Grosor Intima-Media Carotídeo , Americanos Mexicanos/genética , Placa Aterosclerótica , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Anciano , Artritis Reumatoide/diagnóstico , Carboxiliasas/genética , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Femenino , Perfilación de la Expresión Génica/métodos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo I/genética , Texas/epidemiologíaRESUMEN
INTRODUCTION: Molecular imaging of the earliest events related to the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) could facilitate therapeutic development and patient management. We previously reported that 18F-fluoro-2-deoxyglucose (18F-FDG) PET identifies ALI/ARDS prior to radiographic abnormalities. The purpose of this study was to establish the time courses of 18F-FDG uptake, edema and neutrophil recruitment in an endotoxin-induced acute lung injury model and to examine molecular events required for 14C-2DG uptake in activated neutrophils. METHODS: Lung uptake of 18F-FDG was measured by PET in control male Sprague Dawley rats and at 2, 6 and 24h following the intraperitoneal injection of 10mg/kg LPS. Lung edema (attenuation) was measured by microCT. Neutrophil influx into the lungs was measured by myeloperoxidase assay. Control and activated human donor neutrophils were compared for uptake of 14C-2DG, transcription and content of hexokinase and GLUT isoforms and for hexokinase (HK) activity. RESULTS: Significant uptake of 18F-FDG occurred by 2h following LPS, and progressively increased to 24h. Lung uptake of 18F-FDG preceded increased CT attenuation (lung edema). Myeloperoxidase activity in the lungs, supporting neutrophil influx, paralleled 18F-FDG uptake. Activation of isolated human neutrophils resulted in increased uptake of 14C-2DG, expression of GLUT 3 and GLUT 4 and expression and increased HK1 activity. CONCLUSION: Systemic endotoxin-induced ALI results in very early and progressive uptake of 18F-FDG, parallels neutrophil accumulation and occurs earlier than lung injury edema. Activated neutrophils show increased uptake of 14C-2DG, expression of specific GLUT3, GLUT4 and HK1 protein and HK activity. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: 18F-FDG pulmonary uptake is an early biomarker of neutrophil recruitment in ALI and is associated with specific molecular events that mediate 14C-2DG uptake in activated neutrophils. 18F-FDG PET may provide a potential mechanism for early diagnosis and therapeutic assessment of ALI/ARDS.