RESUMEN
A 1,5-year-old intact male German Hunting Terrier was initially presented 2018 with hematuria. An abdominal ultrasound revealed multiple hyperechogenic structures in the urinary bladder. A urinalysis indicated severe crystalluria (ammonium urate or xanthine). Following cystotomy and urinary calculus analysis, ammonium urate urolithiasis was diagnosed in 2019. The patient was tested homozygous at the SLC2A9:p.C188F variant, which results in severe hyperuricemia and hyperuricosuria. This case report presents the first incidence of the SLC2A9:p.C188F gene variant being detected in a German Hunting Terrier. Veterinary practitioners are encouraged to consider the possibility of this gene defect presenting in breeds beyond the Dalmatian.
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Enfermedades de los Perros , Proteínas Facilitadoras del Transporte de la Glucosa , Ácido Úrico , Urolitiasis , Perros , Masculino , Animales , Enfermedades de los Perros/genética , Enfermedades de los Perros/diagnóstico , Urolitiasis/veterinaria , Urolitiasis/genética , Urolitiasis/diagnóstico , Ácido Úrico/orina , Proteínas Facilitadoras del Transporte de la Glucosa/genéticaRESUMEN
Primary renal hypouricemia (RHUC) is a rare autosomal recessive disorder with a mean duration of end-stage acute kidney injury (EIAKI) of 14 days. The pathogenesis of EIAKI in patients with RHUC remains unclear. Several hypotheses have been proposed, including those related to the renal vasoconvulsive effect and the elevating effect of xanthine oxidase (XO). The effect of xanthine oxidase (XO) is most often observed following strenuous anaerobic exercise, which is frequently accompanied by low back pain, nausea, and acute kidney injury (AKI). Consequently, we postulate that EIAKI could be prevented by avoiding strenuous exercise, thus preventing the onset and recurrence of EIAKI. In this paper, we present a case of recurrent EIAKI in a patient with RHUC and a mutation in the SLC2A9 gene.
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Lesión Renal Aguda , Ejercicio Físico , Defectos Congénitos del Transporte Tubular Renal , Humanos , Lesión Renal Aguda/etiología , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Adolescente , Masculino , Recurrencia , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Xantina Oxidasa , Cálculos Urinarios/genética , Cálculos Urinarios/etiología , Cálculos Urinarios/complicaciones , China , Mutación , Pueblos del Este de AsiaRESUMEN
BACKGROUND/AIM: Over-expression of glucose transporters (GLUTs), membrane proteins that facilitate glucose transport, has been implicated in cutaneous melanomas. Our prior studies have demonstrated increased expression of GLUT1 and GLUT3 in melanomas and their association with poorer prognosis. This study aimed to investigate the expression of GLUT isoforms 4 and 8 in melanocytic lesions, examine the co-expression status of multiple GLUTs, and evaluate their prognostic significance. MATERIALS AND METHODS: We analyzed 171 melanocytic lesions (97 primary melanomas, 19 metastatic melanomas, and 55 nevi) using a tissue microarray and immunohistochemistry using antibodies against GLUT4 and GLUT8. Membranous expression of GLUTs was scored using a semi-quantitative method. A combined GLUT total score was generated by summing scores from GLUT1, GLUT3, GLUT4, and GLUT8 (including data from previous studies). RESULTS: A significant up-regulation of GLUT4 and GLUT8 expression was found in melanomas compared to nevi (p<0.0001 for both). Concurrent over-expression of multiple GLUTs was more prevalent in melanomas compared to nevi (p<0.0001), and it was also more frequent in metastatic melanomas compared to primary melanomas (p=0.047). Importantly, high total GLUT expression scores were significantly correlated with negative prognostic factors, such as ulceration and mitoses (p=0.03 and p=0.008 respectively). Additionally, Kaplan-Meier survival curves revealed that patients with elevated GLUT total score in their melanomas had a lower disease-specific survival (p=0.006). Furthermore, analysis of multiple GLUTs improved diagnostic sensitivity. CONCLUSION: Similar to GLUT1 and GLUT3, melanoma exhibits up-regulation of GLUT 4 and GLUT8 compared to nevi. Evaluation of multiple GLUT isoforms improves diagnostic and prognostic values.
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Proteínas Facilitadoras del Transporte de la Glucosa , Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/metabolismo , Melanoma/patología , Melanoma/mortalidad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/mortalidad , Pronóstico , Femenino , Masculino , Persona de Mediana Edad , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Anciano , Adulto , Biomarcadores de Tumor/metabolismo , Anciano de 80 o más Años , Melanoma Cutáneo Maligno , Inmunohistoquímica , Análisis de Matrices Tisulares , Adulto JovenRESUMEN
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
CD8+ T cell activation leads to the rapid proliferation and differentiation of effector T cells (Teffs), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8+ Teffs, the mechanisms that regulate CD8+ T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8+ T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8+ T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8+ T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8+ T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8+ T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti-programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8+ T cells and identify that TME accumulated lactic acid inhibits CD8+ T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8+ T cell-mediated antitumor effects.
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Linfocitos T CD8-positivos , Proteínas Facilitadoras del Transporte de la Glucosa , Glucosa , Ácido Láctico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Ácido Láctico/metabolismo , Animales , Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Activación de Linfocitos/efectos de los fármacos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Glucólisis/efectos de los fármacosRESUMEN
Insects and their gut bacteria form a tight and beneficial relationship, especially in utilization of host nutrients. The red turpentine beetle (RTB), a destructive and invasive pine pest, employs mutualistic microbes to facilitate its invasion success. However, the molecular mechanism underlying the utilization of nutrients remains unknown. In this study, we found that gut bacteria are crucial for the utilization of D-glucose, a main carbon source for RTB development. Downstream assays revealed that gut bacteria-induced gut hypoxia and the secretion of riboflavin are responsible for RTB development by regulating D-glucose transport via the activation of a hypoxia-induced transcription factor 1 (Hif-1α). Further functional investigations confirmed that Hif-1α mediates glucose transport by direct upregulation of two glucose transporters (ST10 and ST27), thereby promoting RTB development. Our findings reveal how gut bacteria regulate the development of RTB, and promote our understanding of the mutualistic relationship of animals and their gut bacteria.
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Escarabajos , Microbioma Gastrointestinal , Glucosa , Animales , Glucosa/metabolismo , Escarabajos/microbiología , Escarabajos/metabolismo , Microbioma Gastrointestinal/fisiología , Simbiosis/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Transporte Biológico , Pinus/parasitología , Pinus/microbiología , Pinus/metabolismo , Especies Introducidas , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Bacterias/metabolismo , Bacterias/genéticaRESUMEN
Glucose uptake by lymphocytes is dependent on the facilitative glucose transporters (GLUT1, GLUT3, GLUT4, and GLUT6) of the GLUT family and the Na+-coupled glucose transporter SGLT1. GLUTs and SGLTs are widely expressed in mammals, and their expression and functions may affect cell development, homeostasis, activation, and differentiation. This article details the important functions of several GLUTs and SGLTs in lymphocytes and points out that glucose transporters play a key role in supplying energy for lymphocytes, maintaining intracellular glucose homeostasis, and improving the efficiency of immune responses, which reflect their key roles in signal transduction. Probing into the effects of glucose transporters on lymphocyte functions will help to decipher the functioning mechanisms of lymphocytes in diseases. Furthermore, this paper prospects the application values of glucose transporters in lymphocytes from molecular biology, aiming to provide better strategies for the clinical treatment of lymphocyte-related diseases and promote the research and development of targeted therapeutic drugs.
Asunto(s)
Proteínas Facilitadoras del Transporte de la Glucosa , Linfocitos , Linfocitos/inmunología , Linfocitos/metabolismo , Humanos , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Glucosa/metabolismo , Animales , Transportador de Glucosa de Tipo 3/metabolismo , Transportador de Glucosa de Tipo 3/genética , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 1/genéticaRESUMEN
BACKGROUND: The liver fluke Clonorchis sinensis imports large amounts of glucose to generate energy and metabolic intermediates through glycolysis. We hypothesized that C. sinensis absorbs glucose through glucose transporters and identified four subtypes of glucose transporter (CsGTP) and one sodium glucose co-transporter (CsSGLT) in C. sinensis. METHODOLOGY/PRINCIPAL FINDINGS: Expressed sequence tags encoding CsGTPs were retrieved from the C. sinensis transcriptome database, and their full-length cDNA sequences were obtained by rapid amplification of cDNA ends (RACE). The tissue distribution of glucose transporters in C. sinensis adults was determined using immunohistochemical staining. Developmental expression was measured using RT-qPCR. The transport and distribution of glucose into living C. sinensis were monitored using confocal microscopy. Membrane topology and key functional residues of CsGTPs were homologous to their counterparts in animals and humans. CsGTP1, 2, and 4 were transcribed 2.4-5.5 times higher in the adults than metacercariae, while CsGTP3 was transcribed 2.1 times higher in the metacercariae than adults. CsSGLT transcription was 163.6 times higher in adults than in metacercariae. In adults, CsSGLT was most abundant in the tegument; CsGTP3 and CsSGLT were localized in the vitelline gland, uterine wall, eggs, mesenchymal tissue, and testes; CsGTP4 was found in sperm and mesenchymal tissue; and CsGTP1 was mainly in the sperm and testes. In C. sinensis adults, exogenous glucose is imported in a short time and is present mainly in the middle and posterior body, in which the somatic and reproductive organs are located. Of the exogenous glucose, 53.6% was imported through CsSGLT and 46.4% through CsGTPs. Exogenous glucose import was effectively inhibited by cytochalasin B and phlorizin. CONCLUSIONS/SIGNIFICANCE: We propose that CsSGLT cooperates with CsGTPs to import exogenous glucose from the environmental bile, transport glucose across mesenchymal tissue cells, and finally supply energy-demanding organs in C. sinensis adults. Studies on glucose transporters may pave the way for the development of new anthelmintic drugs.
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Clonorchis sinensis , Proteínas Facilitadoras del Transporte de la Glucosa , Glucosa , Proteínas de Transporte de Sodio-Glucosa , Animales , Clonorchis sinensis/metabolismo , Clonorchis sinensis/genética , Glucosa/metabolismo , Proteínas de Transporte de Sodio-Glucosa/metabolismo , Proteínas de Transporte de Sodio-Glucosa/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Clonorquiasis/parasitología , Transporte BiológicoRESUMEN
Some glycoside drugs can be transported through intestinal glucose transporters (IGTs). The surfactants used in oral drug preparations can affect the function of transporter proteins. This study aimed to investigate the effect of commonly used surfactants, Poloxamer 188 and Tween 80, on the drug transport capacity of IGTs. Previous studies have shown that gastrodin is the optimal drug substrate for IGTs. Gastrodin was used as a probe drug to evaluate the effect of these two surfactants on intestinal absorption in SD rats through pharmacokinetic and in situ single-pass intestinal perfusion. Then, the effects of the two surfactants on the expression of glucose transporters and tight-junction proteins were examined using RT-PCR and western blotting. Additionally, the effect of surfactants on intestinal permeability was evaluated through hematoxylin-eosin staining. The results found that all experimental for Poloxamer 188 (0.5%, 2.0% and 8.0%) and Tween 80 (0.1% and 2.0%) were not significantly different from those of the blank group. However, the AUC(0-∞) of gastrodin increased by approximately 32% when 0.5% Tween 80 was used. The changes in IGT expression correlated with the intestinal absorption of gastrodin. A significant increase in the expression of IGTs was observed at 0.5% Tween 80. In conclusion, Poloxamer 188 had minimal effect on the drug transport capacity of IGTs within the recommended limits of use. However, the expression of IGTs increased in response to 0.5% Tween 80, which significantly enhanced the drug transport capacity of IGTs. However, 0.1% and 2.0% Tween 80 had no significant effect.
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Absorción Intestinal , Mucosa Intestinal , Poloxámero , Polisorbatos , Ratas Sprague-Dawley , Tensoactivos , Animales , Poloxámero/farmacología , Polisorbatos/farmacología , Ratas , Absorción Intestinal/efectos de los fármacos , Masculino , Tensoactivos/farmacología , Transporte Biológico/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Glucósidos/farmacologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: In recent years, in addition to hypertension, hyperglycemia, and hyperlipidemia, the prevalence of hyperuricemia (HUA) has increased considerably. Being the fourth major health risk factor, HUA can affect the kidneys and cardiovascular system. Chrysanthemi Indici Flos is a flavonoid-containing traditional Chinese patent medicine that exhibits a uric acid (UA)-lowering effect. However, the mechanisms underlying Chrysanthemi Indici Flos-enriched flavonoid part (CYM.E) mediated alleviation of HUA remain unelucidated. AIM OF THE STUDY: This study aimed to elucidate the efficacy of CYM.E in preventing and treating HUA and its specific effects on UA-related transport proteins, to explore possible mechanism. METHODS: The buddleoside content in CYM.E was determined through high-performance liquid chromatography. HUA was induced in mice models using adenine and potassium oxonate. Subsequently, mice were administered 10 mg/kg allopurinol, and 30, 60, and 90 mg/kg CYM.E to evaluate the effects of CYM.E on the of HUA mice model. Herein, plasma uric acid (UA), creatinine (CR), blood urea nitrogen (BUN), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) contents, along with serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities were measured. Additionally, xanthine oxidase (XOD) and adenosine deaminase (ADA) activities in the liver were determined. The histomorphologies of the liver and kidney tissues were examined through hematoxylin and eosin staining. The messenger RNA (mRNA) expression of facilitated glucose transporter 9 (GLUT9), organic anion transporter (OAT)1, OAT3, and adenosine triphosphate binding cassette subfamily G2 (ABCG2) in the kidney was assessed by real-time quantitative polymerase chain reaction. Furthermore, the expression of urate transporter 1 (URAT1), GLUT9, OAT1, and OAT3 in the kidney, OAT4, and ABCG2 proteins was determined by immunohistochemistry and western blotting. RESULTS: The buddleoside content in CYM.E was approximately 32.77%. CYM.E improved body weight and autonomous activity in HUA mice. Additionally, it reduced plasma UA, BUN, and CR levels and serum ALT and AST activities, thus improving hepatic and renal functions, which further reduced the plasma UA content. CYM.E reduced histopathological damage to the kidneys. Furthermore, it lowered plasma TC, TG, and LDL-c levels, thereby improving lipid metabolism disorder. CYM.E administration inhibited hepatic XOD and ADA activities and reduced the mRNA expression of renal GLUT9. CYM.E inhibited the protein expression of renal URAT1, GLUT9, and OAT4, and increased the mRNA and protein expression of renal OAT1, OAT3, and ABCG2. Altogether, these results show that CYM.E could inhibit the production and promote reabsorption of UA and its excretion.
Asunto(s)
Modelos Animales de Enfermedad , Flavonoides , Hiperuricemia , Transportadores de Anión Orgánico , Ácido Úrico , Animales , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/inducido químicamente , Ácido Úrico/sangre , Masculino , Flavonoides/farmacología , Flavonoides/análisis , Ratones , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Flores/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Alopurinol/farmacología , Ratones Endogámicos ICRRESUMEN
Uric acid induces radical oxygen species formation, endothelial inflammation, and endothelial dysfunction which contributes to the progression of atherosclerosis. Febuxostat inhibits BCRP- and allopurinol stimulates MRP4-mediated uric acid efflux in human embryonic kidney cells. We hypothesized that endothelial cells express uric acid transporters that regulate intracellular uric acid concentration and that modulation of these transporters by febuxostat and allopurinol contributes to their different impact on cardiovascular mortality. The aim of this study was to explore a potential difference between the effect of febuxostat and allopurinol on uric acid uptake by human umbilical vein endothelial cells. Febuxostat increased intracellular uric acid concentrations compared with control. In contrast, allopurinol did not affect intracellular uric acid concentration. In line with this observation, febuxostat increased mRNA expression of GLUT9 and reduced MRP4 expression, while allopurinol did not affect mRNA expression of these uric acid transporters. These findings provide a possible pathophysiological pathway which could explain the higher cardiovascular mortality for febuxostat compared to allopurinol but should be explored further.
Asunto(s)
Alopurinol , Febuxostat , Proteínas Facilitadoras del Transporte de la Glucosa , Células Endoteliales de la Vena Umbilical Humana , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Ácido Úrico , Humanos , Alopurinol/farmacología , Febuxostat/farmacología , Ácido Úrico/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Transporte Biológico/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
Urate, the physiological form of uric acid and a potent antioxidant in serum, plays a pivotal role in scavenging reactive oxygen species. Yet excessive accumulation of urate, known as hyperuricemia, is the primary risk factor for the development of gout. The high-capacity urate transporter GLUT9 represents a promising target for gout treatment. Here, we present cryo-electron microscopy structures of human GLUT9 in complex with urate or its inhibitor apigenin at overall resolutions of 3.5 Å and 3.3 Å, respectively. In both structures, GLUT9 exhibits an inward open conformation, wherein the substrate binding pocket faces the intracellular side. These structures unveil the molecular basis for GLUT9's substrate preference of urate over glucose, and show that apigenin acts as a competitive inhibitor by occupying the substrate binding site. Our findings provide critical information for the development of specific inhibitors targeting GLUT9 as potential therapeutics for gout and hyperuricemia.
Asunto(s)
Apigenina , Microscopía por Crioelectrón , Proteínas Facilitadoras del Transporte de la Glucosa , Ácido Úrico , Humanos , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/antagonistas & inhibidores , Proteínas Facilitadoras del Transporte de la Glucosa/química , Ácido Úrico/metabolismo , Ácido Úrico/química , Apigenina/farmacología , Apigenina/química , Sitios de Unión , Unión Proteica , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Modelos Moleculares , Gota/tratamiento farmacológico , Gota/metabolismo , Células HEK293RESUMEN
Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Proteínas Facilitadoras del Transporte de la Glucosa , Hiperuricemia , Proteínas de Neoplasias , Transportadores de Anión Orgánico , Ácido Úrico , Xantina Deshidrogenasa , Humanos , Hiperuricemia/etiología , Hiperuricemia/metabolismo , Hiperuricemia/genética , Ácido Úrico/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Xantina Deshidrogenasa/metabolismo , Xantina Deshidrogenasa/genética , Xantina Deshidrogenasa/deficiencia , Animales , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/etiología , Defectos Congénitos del Transporte Tubular Renal/metabolismo , Cálculos Urinarios/etiología , Cálculos Urinarios/metabolismo , Cálculos Urinarios/genética , Errores Innatos del MetabolismoRESUMEN
Epigallocatechin gallate (EGCG), a prominent bioactive compound found in tea, offers numerous health benefits. Previous studies have highlighted its potential in mitigating hyperuricemia. In this study, hyperuricemic mice induced by potassium oxonate (PO) were treated with EGCG or the anti-hyperuricemia medication allopurinol (AP) to investigate the mechanisms underlying their anti-hyperuricemic effects. The results demonstrated that both EGCG and AP significantly reduced serum uric acid (UA) levels. Further analysis revealed that EGCG promoted the expression of UA secretion transporter genes (Oat1 and Oct1) while inhibiting the expression of UA reabsorption transporter genes (Urat1 and Glut9) in the kidney. By 16S rDNA sequencing, EGCG, but not AP, was found to alter the composition of the gut microbiota. Notably, EGCG induced significant changes in the relative abundance of specific bacteria such as Lactobacillus, Faecalibaculum, and Bifidobacterium, which displayed high correlations with serum UA levels and UA-related gene expression. Metabolomic analysis suggested that EGCG-induced modifications in bacterial metabolites might contribute to the alleviation of hyperuricemia. Transcriptomic analysis of the intestinal epithelium identifies 191 differentially expressed genes (DEGs) in EGCG-treated mice, including 8 purine-related genes. This study elucidates the anti-hyperuricemic mechanisms of EGCG, particularly its influence on the gut microbiota and gene expression in the intestinal epithelium.
Asunto(s)
Catequina , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Hiperuricemia , Ácido Úrico , Animales , Hiperuricemia/tratamiento farmacológico , Catequina/análogos & derivados , Catequina/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Masculino , Ácido Úrico/sangre , Ácido Úrico/metabolismo , Ratones Endogámicos C57BL , Alopurinol/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Ácido Oxónico , Intestinos/efectos de los fármacos , Intestinos/microbiología , Bacterias/clasificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Proteínas Facilitadoras del Transporte de la GlucosaRESUMEN
A detailed phytochemical investigation has been carried out on the aerial parts of G. foetida leading to the isolation of 29 pure compounds, mainly belonging to the amorfrutin and polyphenol classes. Among them, the new amorfrutin N (5) and exiguaflavone L (21) were isolated and their structures elucidated by means of HR-ESIMS and NMR. All the isolated compounds were investigated for modulation of mitochondrial activity and stimulation of glucose uptake via GLUT transporters, two metabolic processes involved in intracellular glucose homeostasis, which, therefore, correlate with the incidence of metabolic syndrome. These experiments revealed that amorfrutins were active on both targets, with amorfrutin M (17) and decarboxyamorfrutin A (2) emerging as mitochondrial stimulators, and amorfrutin 2 (12) as a glucose uptake promoter. However, members of the rich chalcone/flavonoid fraction also proved to contribute to this activity.
Asunto(s)
Glucosa , Síndrome Metabólico , Componentes Aéreos de las Plantas , Síndrome Metabólico/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Componentes Aéreos de las Plantas/química , Humanos , Glucosa/metabolismo , Glycyrrhiza/química , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Flavonoides/química , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genéticaRESUMEN
Fatty acids have been shown to modulate glucose metabolism in vitro and in vivo. However, there is still a need for substantial evidence and mechanistic understanding in many cell types whether both saturated and unsaturated fatty acids (SFAs and UFAs) pose a similar effect and, if not, what determines the net effect of fatty acid mixes on glucose metabolism. In the present study, we asked these questions by treating granulosa cells (GCs) with the most abundant non-esterified fatty acid species in bovine follicular fluid. Results revealed that oleic and alpha-linolenic acids (UFAs) significantly increased glucose consumption compared to palmitic and stearic acids (SFAs). A significant increase in lactate production, extracellular acidification rate, and decreased mitochondrial activity indicate glucose channeling through aerobic glycolysis in UFA treated GCs. We show that insulin independent glucose transporter GLUT10 is essential for UFA driven glucose consumption, and the induction of AKT and ERK signaling pathways necessary for GLUT10 expression. To mimic the physiological conditions, we co-treated GCs with mixes of SFAs and UFAs. Interestingly, co-treatments abolished the UFA induced glucose uptake and metabolism by inhibiting AKT and ERK phosphorylation and GLUT10 expression. These data suggest that the net effect of fatty acid induced glucose uptake in GCs is determined by SFAs under physiological conditions.
Asunto(s)
Ácidos Grasos Insaturados , Ácidos Grasos , Proteínas Facilitadoras del Transporte de la Glucosa , Glucosa , Glucólisis , Células de la Granulosa , Animales , Bovinos , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Células de la Granulosa/metabolismo , Células de la Granulosa/efectos de los fármacos , Femenino , Ácidos Grasos Insaturados/metabolismo , Ácidos Grasos Insaturados/farmacología , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Ácidos Grasos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células CultivadasRESUMEN
OBJECTIVE: To investigate the potential changes of glucose metabolism and glucose transporter protein (GLUT) in the visual cortex of formally deprived amblyopic rats, as well as the effects of enriched environments on the levels of nerve conduction and glucose metabolism in the visual cortex of amblyopic rats. METHODS: 36 rats were randomly divided into three groups: CON + SE (n = 12), MD + SE (n = 12) and MD + EE (n = 12). The right eyelids of both MD + SE and MD + EE groups were sutured. After successful modelling, the MD + EE group was maintained in an enriched environment, and the other two groups were kept in the same environment. Pattern visual evoked potentials (PVEP) was used to confirm models' effect, glucose metabolism was analyzed by Micro-PET/CT (18F-FDG), and the protein as well as mRNA expression levels of GLUT were detected by Western Blot and quantitative RT-PCR (quantitative Reverse Transcription-Polymerase Chain Reaction) analyses, site of GLUT expression by immunofluorescence (IF). RESULTS: After suture modelling, both the MD + EE and MD + SE groups objective visual nerve conduction function decreased, the glucose metabolism in the visual cortex was markedly lower. After the enriched environment intervention, it recovered in the MD + EE group. The expression levels of GLUT1 and GLUT3 were increased in the MD + EE group in comparison with the MD + SE group. GLUT1 was primarily expressed on astrocytes and endothelial cells, but GLUT3 was mainly expressed on neurons. CONCLUSION: Enrichment of the environment exhibited a therapeutic effect on amblyopia, which could be related to the enhancement of glucose metabolism and GLUT expression in the visual cortex.
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Ambliopía , Ambiente , Glucosa , Ratas Sprague-Dawley , Corteza Visual , Animales , Corteza Visual/metabolismo , Ambliopía/metabolismo , Ambliopía/terapia , Ambliopía/fisiopatología , Glucosa/metabolismo , Ratas , Potenciales Evocados Visuales/fisiología , Masculino , Modelos Animales de Enfermedad , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Conducción Nerviosa/fisiología , Transportador de Glucosa de Tipo 1/metabolismoRESUMEN
Different multifactorial pathophysiological processes are involved in the development of heart failure (HF), including neurohormonal dysfunction, the hypertrophy of cardiomyocytes, interstitial fibrosis, microvascular endothelial inflammation, pro-thrombotic states, oxidative stress, decreased nitric oxide (NO) bioavailability, energetic dysfunction, epicardial coronary artery lesions, coronary microvascular rarefaction and, finally, cardiac remodeling. While different pharmacological strategies have shown significant cardiovascular benefits in HF with reduced ejection fraction (HFrEF), there is a residual unmet need to fill the gap in terms of knowledge of mechanisms and efficacy in the outcomes of neurohormonal agents in HF with preserved ejection fraction (HFpEF). Recently, type-2 sodium-glucose transporter inhibitors (SGLT2i) have been shown to contribute to a significant reduction in the composite outcome of HF hospitalizations and cardiovascular mortality across the entire spectrum of ejection fraction. Moreover, glucagon-like peptide-1 receptor agonists (GLP1-RA) have demonstrated significant benefits in patients with high cardiovascular risk, excess body weight or obesity and HF, in particular HFpEF. In this review, we will discuss the biological pathways potentially involved in the action of SGLT2i and GLP1-RA, which may explain their effective roles in the treatment of HF, as well as the potential implications of the use of these agents, also in combination therapies with neurohormonal agents, in the clinical practice.
Asunto(s)
Insuficiencia Cardíaca , Humanos , Agonistas Receptor de Péptidos Similares al Glucagón , Volumen Sistólico , Miocitos Cardíacos , Proteínas Facilitadoras del Transporte de la Glucosa , SodioRESUMEN
Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2-fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC50 = 2.01 µM) and glucose transporter 9 (GLUT9, IC50 = 18.21 µM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.
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Gota , Hiperuricemia , Transportadores de Anión Orgánico , Tioglicolatos , Triazoles , Humanos , Ácido Úrico/uso terapéutico , Gota/tratamiento farmacológico , Hiperuricemia/tratamiento farmacológico , Uricosúricos/uso terapéutico , Pirimidinas/toxicidad , Pirimidinas/uso terapéutico , Proteínas Facilitadoras del Transporte de la Glucosa , Proteínas de Transporte de Catión OrgánicoRESUMEN
Opisthorchis viverrini infection and the subsequent bile duct cancer it induces remains a significant public health problem in Southeast Asia. Opisthorchiasis has been reported to cause reduced plasma glucose levels among infected patients. The underlying mechanism for this phenomenon is unclear. In the present study, evidence is presented to support the hypothesis that O. viverrini exploits host cholangiocyte glucose transporters (GLUTs) in a similar manner to that of rodent intestinal nematodes, to feed on unabsorbed glucose in the bile for survival. GLUT levels in a cholangiocyte H69 cell line co-cultured with excretory-secretory products of O. viverrini were examined using qPCR and immunoblotting. GLUT 8 mRNA and expressed proteins were found to be downregulated in H69 cells in the presence of O. viverrini. This suggests that O. viverrini alters glucose metabolism in cells within its vicinity by limiting transporter expression resulting in increased bile glucose that it can utilize and potentially explains the previously reported anti-insulin effect of opisthorchiasis.