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1.
Sheng Wu Gong Cheng Xue Bao ; 40(7): 1997-2009, 2024 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-39044571

RESUMO

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.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose , Linfócitos , Linfócitos/imunologia , Linfócitos/metabolismo , Humanos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Glucose/metabolismo , Animais , Transportador de Glucose Tipo 3/metabolismo , Transportador de Glucose Tipo 3/genética , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 1/genética
2.
PLoS Negl Trop Dis ; 18(7): e0012315, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38968307

RESUMO

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.


Assuntos
Clonorchis sinensis , Proteínas Facilitadoras de Transporte de Glucose , Glucose , Proteínas de Transporte de Sódio-Glucose , Animais , Clonorchis sinensis/metabolismo , Clonorchis sinensis/genética , Glucose/metabolismo , Proteínas de Transporte de Sódio-Glucose/metabolismo , Proteínas de Transporte de Sódio-Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Clonorquíase/parasitologia , Transporte Biológico
3.
PLoS One ; 19(6): e0305906, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38905201

RESUMO

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.


Assuntos
Alopurinol , Febuxostat , Proteínas Facilitadoras de Transporte de Glucose , Células Endoteliais da Veia Umbilical Humana , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Ácido Úrico , Humanos , Alopurinol/farmacologia , Febuxostat/farmacologia , Ácido Úrico/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Transporte Biológico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos
4.
Yakugaku Zasshi ; 144(6): 659-674, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38825475

RESUMO

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.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Proteínas Facilitadoras de Transporte de Glucose , Hiperuricemia , Proteínas de Neoplasias , Transportadores de Ânions Orgânicos , Ácido Úrico , Xantina Desidrogenase , Humanos , Hiperuricemia/etiologia , Hiperuricemia/metabolismo , Hiperuricemia/genética , Ácido Úrico/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Xantina Desidrogenase/metabolismo , Xantina Desidrogenase/genética , Xantina Desidrogenase/deficiência , Animais , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Erros Inatos do Transporte Tubular Renal/genética , Erros Inatos do Transporte Tubular Renal/etiologia , Erros Inatos do Transporte Tubular Renal/metabolismo , Cálculos Urinários/etiologia , Cálculos Urinários/metabolismo , Cálculos Urinários/genética , Erros Inatos do Metabolismo
5.
J Ethnopharmacol ; 333: 118488, 2024 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-38925319

RESUMO

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.


Assuntos
Modelos Animais de Doenças , Flavonoides , Hiperuricemia , Transportadores de Ânions Orgânicos , Ácido Úrico , Animais , Hiperuricemia/tratamento farmacológico , Hiperuricemia/induzido quimicamente , Ácido Úrico/sangue , Masculino , Flavonoides/farmacologia , Flavonoides/análise , Camundongos , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/genética , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Flores/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Alopurinol/farmacologia , Camundongos Endogâmicos ICR
6.
Biomolecules ; 14(4)2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38672484

RESUMO

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.


Assuntos
Glucose , Síndrome Metabólica , Componentes Aéreos da Planta , Síndrome Metabólica/metabolismo , Síndrome Metabólica/tratamento farmacológico , Componentes Aéreos da Planta/química , Humanos , Glucose/metabolismo , Glycyrrhiza/química , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/isolamento & purificação , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética
7.
Biochem Biophys Res Commun ; 696: 149494, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38219491

RESUMO

Skeletal muscle is the largest metabolic tissue responsible for systemic glucose handling. Glucose uptake into skeletal tissue is highly dynamic and delicately regulated, in part through the controlled expression and subcellular trafficking of multiple types of glucose transporters. Although the roles of GLUT4 in skeletal muscle metabolism are well established, the physiological significance of other, seemingly redundant, glucose transporters remain incompletely understood. Nonetheless, recent studies have shed light on the roles of several glucose transporters, such as GLUT1 and GLUT10, in skeletal muscle. Mice experiments suggest that GLUT10 could be a novel player in skeletal muscle metabolism in the context of mechanical overload, which is in line with the meta-analytical results of gene expression changes after resistance exercise in humans. Herein we discuss the knowns, unknowns, and implications of these recent findings.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose , Proteínas de Transporte de Monossacarídeos , Animais , Humanos , Camundongos , Transporte Biológico , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Insulina/metabolismo , Proteínas de Transporte de Monossacarídeos/genética , Músculo Esquelético/metabolismo
8.
Nutrients ; 16(2)2024 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-38257088

RESUMO

Sucrose is a disaccharide that is degraded into fructose and glucose in the small intestine. High-sucrose and high-fructose diets have been reported, using two-dimensional imaging, to alter the intestinal morphology and the expression of genes associated with sugar transport, such as sodium glucose co-transporter 1 (SGLT1), glucose transporter 2 (GLUT2), and glucose transporter 5 (GLUT5). However, it remains unclear how high-fructose and high-sucrose diets affect the expression of sugar transporters and the intestinal morphology in the whole intestine. We investigate the influence of a chronic high-sucrose diet on the expression of the genes associated with sugar transport as well as its effects on the intestinal morphology using 3D imaging. High sucrose was found to increase GLUT2 and GLUT5 mRNA levels without significant changes in the intestinal morphology using 3D imaging. On the other hand, the delay in sucrose absorption by an α-glucosidase inhibitor significantly improved the intestinal morphology and the expression levels of SGLT1, GLUT2, and GLUT5 mRNA in the distal small intestine to levels similar to those in the proximal small intestine, thereby improving glycemic control after both glucose and sucrose loading. These results reveal the effects of chronic high-sugar exposure on glucose absorption and changes in the intestinal morphology.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose , Sacarose , Proteínas Facilitadoras de Transporte de Glucose/genética , Intestinos , Glucose , Frutose , RNA Mensageiro/genética , Expressão Gênica
9.
Pathol Res Pract ; 253: 154966, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38043192

RESUMO

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms. Additionally, glucose transporter 2 (GLUT2) is associated with insulin production and is essential for glucose transport to normal pancreatic ß-cells. Neoplastic cell GLUT2 expression may also influence insulin production by using this transporter. GLUT2 expression and its clinical significance remain unclear in PanNETs. This study aimed to provide GLUT2 expression profiles and evidence of correlation with insulin in PanNETs. METHODS: Clinical data were retrieved from 113 surgically resected paraffin-embedded PanNET tissue samples fixed with 10% formalin. PanNETs are categorized as insulinoma, non-functional (NF)-PanNET, or PanNET-not otherwise specified (NOS). A GLUT2 score was used to evaluate cytoplasmic GLUT2 immunoreactivity. The immunoreactive score (IRS) was used to determine membranous GLUT2, cytoplasmic insulin, and proinsulin immunoreactivities. A commercially available in situ hybridization (ISH) kit detected human SLC2A2 (GLUT2) mRNA on tissues in all seven positive- and 20 negative-GLUT2 IRS cases. RESULTS: GLUT2 and IRSs significantly differed among insulinoma, NF-PanNET, and PanNET-NOS. Insulinomas exhibited significantly higher GLUT2 scores and IRSs than did NF-PanNETs. GLUT2 IRS positive cases demonstrated significantly higher insulin and proinsulin IRSs than did negative cases. Additionally, GLUT2 ISH-positive cases demonstrated positive GLUT2 scores and IRSs, with significantly higher GLUT2 IRSs than did negative cases. PanNET histological grade categories did not significantly affect GLUT2 scores and IRSs. CONCLUSION: The first evidence of a correlation between GLUT2 expressions and insulin in PanNETs is shown in this study.


Assuntos
Insulinoma , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Insulina , Tumores Neuroendócrinos/patologia , Proinsulina/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Facilitadoras de Transporte de Glucose/genética
10.
Mol Diagn Ther ; 28(1): 87-99, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37971623

RESUMO

BACKGROUND: Renal hypouricemia (RHUC), a rare inherited disorder characterized by impaired uric acid reabsorption and subsequent profound hypouricemia, occurs mainly due to variants in SLC22A12 or SLC2A9. Only anecdotal cases and one small-scale RHUC screening study have been reported in the Chinese population. METHODS: A total of 19 patients with RHUC from 17 unrelated families were recruited from our center. The medical history, clinical manifestations, biochemical exam, and clinical outcomes were collected. Next-generation sequencing-based targeted gene sequencing or whole exon sequencing was performed. RESULTS: A total of 22 variants in SLC22A12 or SLC2A9 were found in 19 patients. The variant c.944G>A (p.W315X) in SLC2A9 was identified in three patients. Three variants c.165C>A (p.D55E), c.1549_1555delGAGACCC (p.E517Rfs*17), and c.1483T>C (p.W495R) in SLC22A12 and three variants c.1215+1G>A (splicing variant), c.643A>C (p.T215P), and c.227C>A (p.S76X) in SLC2A9 were novel. A proportion of 10 out of 19 patients presented with exercise-induced acute kidney injury (EIAKI). The renal outcome was favorable. Five patients had nephrolithiasis, in whom three had hypercalciuria. CONCLUSION: The current study reported six novel variants in SLC22A12 and SLC2A9 genes of Chinese patients with RHUC. The variant c.944G>A (p.W315X) in SLC2A9 may be common in Chinese patients. EIAKI is the main clinical phenotype associated with RHUC in our cohort, with a favorable outcome. Hypercalciuria presented in some RHUC patients is a new finding.


Assuntos
Injúria Renal Aguda , Transportadores de Ânions Orgânicos , Erros Inatos do Transporte Tubular Renal , Cálculos Urinários , Humanos , Hipercalciúria , Proteínas Facilitadoras de Transporte de Glucose/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Genótipo , Fenótipo , China
11.
Biochimie ; 219: 55-62, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37967737

RESUMO

Glucose transporters (GLUTs) are crucial in maintaining glucose homeostasis and supporting energy production in various tissues, including the testes. This review article delves into the distribution and function of GLUTs in distinct testicular cell types, namely Leydig cells, Sertoli cells, germ cells, and spermatozoa, shedding light on their significance in the context of male reproductive health-an issue of mounting global concern. Furthermore, this article examines the implications of GLUT dysregulation in testicular dysfunction. Altered GLUT expression has been associated with impaired steroidogenesis, spermatogenesis, sperm count, and motility in various animal models. Lastly, the article underscores the potential therapeutic implications of targeting GLUTs concerning testicular toxicity. Insights gleaned from studies in diabetes and cancer suggest that modulating GLUT expression and translocation could present novel strategies for mitigating testicular dysfunction and safeguarding male fertility. In summary, the intricate interplay between GLUTs, glucose metabolism, and testicular health underscores the significance of sustaining testicular glucose homeostasis for male reproductive health. Manipulating GLUTs presents an innovative avenue to address testicular dysfunction, potentially revolutionizing therapeutic strategies to restore male fertility and overall reproductive well-being. Future research in this field holds great promise for advancing male fertility treatments and reproductive health interventions.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose , Testículo , Animais , Masculino , Testículo/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Sêmen/metabolismo , Espermatozoides/metabolismo , Glucose/metabolismo
12.
Neuromuscul Disord ; 34: 49-53, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38150892

RESUMO

Acute rhabdomyolysis (AR) leading to acute kidney injury has many underlying etiologies, however, when the primary trigger is exercise, the most usual underlying cause is either a genetic muscle disorder or unaccustomed intense exercise in a healthy individual. Three adult men presented with a history of exercise intolerance and episodes of acute renal impairment following intense exercise, thought to be due to AR in the case of two, and dehydration in one. The baseline serum CK was mildly raised between attacks in all three patients and acutely raised during attacks in two of the three patients. Following referral to a specialized neuromuscular centre, further investigation identified very low serum urate (<12 umol/L). In all three men, genetic studies confirmed homozygous mutations in SLC2A9, which encodes for facilitated glucose transporter member 9 (GLUT9), a major regulator of urate homeostasis. Hereditary hypouricaemia should be considered in people presenting with acute kidney injury related to intense exercise. Serum urate evaluation is a useful screening test best undertaken after recovery.


Assuntos
Injúria Renal Aguda , Erros Inatos do Transporte Tubular Renal , Rabdomiólise , Cálculos Urinários , Masculino , Adulto , Humanos , Ácido Úrico , Cálculos Urinários/genética , Cálculos Urinários/complicações , Cálculos Urinários/diagnóstico , Erros Inatos do Transporte Tubular Renal/genética , Erros Inatos do Transporte Tubular Renal/complicações , Erros Inatos do Transporte Tubular Renal/diagnóstico , Proteínas Facilitadoras de Transporte de Glucose/genética , Injúria Renal Aguda/genética , Mutação , Rabdomiólise/genética , Rabdomiólise/complicações
13.
PLoS One ; 18(12): e0295038, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38060535

RESUMO

Gout-a very painful inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints-is influenced by several factors. We identified the association of single- nucleotide polymorphisms (SNPs) that link gout with health-related lifestyle factors using genomic data from the Korean Genome and Epidemiology Study. We conducted a genome-wide association study (GWAS) on 18,927 samples of 438 Korean patients with gout and 18,489 controls for the discovery stage. For the replication stage, another batch containing samples of 326 patients with gout and 2,737 controls were analyzed. Lastly, a meta-analysis was performed using these two cohorts. We analyzed the effects of health-related lifestyle factors, including eating habits, physical activity, drinking behavior, and smoking behavior, on gout. After identifying the association between GWAS-derived SNPs and health-related lifestyle factors, we confirmed the interaction between the polygenic risk score (PRS) and health-related lifestyle factors. We identified 15 SNPs related to gout, among which rs1481012 of ABCG2 located on chromosome 4 has been newly discovered (P = 2.46e-11). On examining the interaction between SNPs and health-related lifestyles, rs3109823-located in ABCG2-was found to be associated with smoking status. In addition, rs11936395-located in SLC2A9-was significantly associated with the average momentum of exercise per session, whereas rs11066325 located in PTPN11, showed a significant association with the number of exercise sessions per week, smoking status, drinking status, and amount of soju drink per session. rs9421589-located in FAM35A-was significantly associated with the duration of smoking. In addition, we verified that the association between PRS and duration of smoking affects gout. Thus, in this study, we identified novel SNPs that link gout with health-related lifestyle factors in the Korean population.


Assuntos
Gota , Polimorfismo de Nucleotídeo Único , Humanos , Estudo de Associação Genômica Ampla , Ácido Úrico , Gota/epidemiologia , Gota/genética , Estilo de Vida , República da Coreia/epidemiologia , Predisposição Genética para Doença , Fatores de Risco , Proteínas Facilitadoras de Transporte de Glucose/genética
14.
BMC Nephrol ; 24(1): 384, 2023 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-38129773

RESUMO

BACKGROUND: Hereditary renal hypouricemia (RHUC) is a heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA. RHUC is an important cause of exercise-induced acute kidney injury (EIAKI), nephrolithiasis and posterior reversible encephalopathy syndrome (PRES). We present here an unusual case of a patient with RHUC who presented with recurrent EIAKI and had two heterozygous mutations in the SLC2A9 gene. CASE PRESENTATION: A 43-year old man was admitted to our clinic because of bilateral loin pain, nausea and sleeplessness for 3 days after strenuous exercise. The laboratory results revealed increased levels of blood urea nitrogen (BUN) (15 mmol/l) and serum creatinine (Scr) (450 µmol/l), while the UA level was extremely low at 0.54 mg/dl, and his fractional excretion of urate (FE-UA) was 108%. The patient had an episode of acute kidney injury after playing soccer approximately 20 years ago, and on routine physical examination, his UA was less than 0.50 mg/dl. In view of the marked hypouricemia and high FE-UA, a diagnosis of RHUC was suspected, which led us to perform mutational screening of the SLC22A12 and SLC2A9 genes. DNA sequencing revealed no mutation in SLC22A12 gene, but two heterozygous mutations in the SLC2A9 gene. CONCLUSIONS: This is a rare report of a patient with RHUC2 due to the mutation of SLC2A9. And this unique symptom of EIAKI and decreased or normal serum concentrations of UA warrant more attention as an early cue of RHUC.


Assuntos
Injúria Renal Aguda , Transportadores de Ânions Orgânicos , Síndrome da Leucoencefalopatia Posterior , Masculino , Humanos , Adulto , Síndrome da Leucoencefalopatia Posterior/complicações , Síndrome da Leucoencefalopatia Posterior/diagnóstico , Síndrome da Leucoencefalopatia Posterior/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/complicações , Heterozigoto , Mutação , Ácido Úrico , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética
15.
Exp Cell Res ; 433(2): 113851, 2023 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-37940066

RESUMO

BACKGROUND: Ovarian cancer has been a worldwide health burden for women and its progression is highly hypoxia-independent. Here, we investigated the exact mechanisms by which hypoxia contributes to the malignant progression of ovarian cancer. METHOD: MTT, transwell, colony formation, and scratch wound healing assays were carried out for cellular functions. The underlying mechanism by which hypoxia functions was explored by RNA-seq, enrichment analysis, western blotting, qRT-PCR, flow cytometry, ChIP, luciferase reporter, and ELISA. Finally, animal experiments including the xenograft model and tumor metastasis model were constructed to validate the role of SLC2A12 in vivo. RESULTS: Hypoxia treatment promoted the cell proliferation, mobility, and colony growth abilities of the two ovarian cancer cell lines HO-8910 and A2780. RNA-seq and enrichment analysis showed that SLC2A12 was hyper-expressed under hypoxia condition and it may be related to glutathione and lipid metabolism. Besides, the expression of SLC2A12 was negatively correlated with overall survival. Hypoxia suppressed ferroptosis by SLC2A12 because silencing SLC2A12 declined the cell viability of HO-8910 and A2780 cells under hypoxia conditions, while the ferroptosis inhibitor ferrostatin-1 (Fer-1) breached that result and upregulated the expression of glutathione peroxidase 4 (GPX4). Moreover, hypoxia increased the expression of hypoxia inducible factor 1 A (HIF-1A), and the accumulated HIF-1A binds to hypoxia inducible factor 1 B (HIF1B) to form HIF-1 complex, then promoted the binding of hypoxic response elements (HRE) to SLC2A12 promoter by HIF-1/HRE signal. Subsequently, SLC2A12 regulated glutathione metabolism and in turn inhibited ferroptosis. The animal experiments indicated that silencing SLC2A12 could significantly inhibit tumor growth and metastasis in vivo. CONCLUSION: Hypoxia promoted ovarian cancer progression by upregulating SLC2A12 and then regulating glutathione metabolism to inhibit ferroptosis.


Assuntos
Ferroptose , Proteínas Facilitadoras de Transporte de Glucose , Neoplasias Ovarianas , Animais , Feminino , Humanos , Linhagem Celular Tumoral , Ferroptose/genética , Glutationa , Hipóxia , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Ovarianas/patologia , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo
16.
Asian Pac J Cancer Prev ; 24(11): 3917-3924, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-38019251

RESUMO

OBJECTIVE: Fructose and glucose are types of sugars commonly found in the diet that have been linked to cancer development. Glucose transporters (GLUTs) are facilitating the uptake of these hexoses. Expression of GLUT5 is higher in cancer cells than in healthy tissue. GLUT7 and GLUT11 facilitate the transport of glucose and fructose; however, their expression in breast cancer has not been extensively studied. The Bcl-2 family has been known as a regulator of the cell's survival and death. Here, we investigated the effect of the fructose-glucose combination in MCF-7 breast cancer cells on the viability, migration, and expression of GLUT5, GLUT7, GLUT11, and Bcl-2/Bax ratio. METHODS: Breast cancer cells MCF-7 were treated with fructose, glucose, and combinations of fructose:glucose (75%:25%, 50%:50%, 25%:75%). Cell viability was assessed using an MTT test. Cell migration was examined with a wound-healing assay. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to evaluate the mRNA expression of GLUT5, GLUT7, GLUT11, and Bcl-2/Bax. RESULTS: The viability and migration of MCF-7 breast cancer cells elevated when treated with a combination of fructose and glucose, and glucose alone, compared to fructose alone. The expression levels of GLUT5 and GLUT7 were highest in combination of fructose:glucose (75%:25%). Conversely, the expression of GLUT11 was consistently low across all treated media. The highest Bcl-2/Bax ratio was shown in fructose:glucose combination (25%:75%). CONCLUSION: The viability, migration, and Bcl-2/Bax ratio are enhanced in the combination media with higher glucose. In contrast, when the fructose composition was higher in the media, expression of GLUT5 and GLUT7 increased.


Assuntos
Neoplasias da Mama , Frutose , Proteínas Facilitadoras de Transporte de Glucose , Glucose , Feminino , Humanos , Proteína X Associada a bcl-2/genética , Neoplasias da Mama/tratamento farmacológico , Frutose/farmacologia , Glucose/farmacologia , Células MCF-7 , Proteínas Facilitadoras de Transporte de Glucose/genética
17.
Biochim Biophys Acta Gen Subj ; 1867(12): 130490, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37844739

RESUMO

BACKGROUND: The yeast S. cerevisiae preferably metabolizes glucose through aerobic glycolysis. Glucose transport is facilitated by multiple hexose transporters (Hxts), and their expression and activity are tightly regulated by multiple mechanisms. However, detailed structural and functional analyses of Hxts remain limited, largely due to the lack of crystal structure. METHODS: Homology modeling was used to build a 3D structural model for the yeast glucose transporter Hxt1 and investigate the effects of site directed mutations on Hxt1 stability and glucose transport activity. RESULTS: The conserved salt bridge-forming residues observed in the human Glut4 and the yeast glucose receptor Rgt2 were identified within and between the two 6-transmembrane spanning segments of Hxt1. Most of the RGT2 mutations that disrupt the salt bridge networks were known to cause constitutive signal generation, whereas the corresponding substitutions in HXT1 were shown to decrease Hxt1 stability. While substitutions of the two residues in the salt bridge 2 in Glut4-E329Q and E393D-were reported to abolish glucose transport, the equivalent substitutions in Hxt1 (D382Q and E454D) did not affect Hxt1 glucose transport activity. CONCLUSIONS: Substitutions of equivalent salt bridge-forming residues in Hxt1, Rgt2, and Glut4 are predicted to lock them in an inward-facing conformation but lead to different functional consequences. GENERAL SIGNIFICANCE: The salt bridge networks in yeast and human glucose transporters and yeast glucose receptors may play different roles in maintaining their structural and functional integrity.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Humanos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte de Monossacarídeos/genética , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glucose/metabolismo
18.
Nat Metab ; 5(11): 1969-1985, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37884694

RESUMO

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose , Glucose , Camundongos , Humanos , Animais , Glucose/metabolismo , Transporte Biológico/fisiologia , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Diferenciação Celular , Linfócitos T CD8-Positivos/metabolismo
19.
Genes (Basel) ; 14(9)2023 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-37761963

RESUMO

Renal hypouricemia (RHUC) is a rare hereditary disorder caused by loss-of-function mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, encoding urate transporters URAT1 and GLUT9, respectively, that reabsorb urate in the renal proximal tubule. The characteristics of this disorder are low serum urate levels, high renal fractional excretion of urate, and occasional severe complications such as nephrolithiasis and exercise-induced acute renal failure. In this study, we report two Spanish (Caucasian) siblings and a Pakistani boy with clinical characteristics compatible with RHUC. Whole-exome sequencing (WES) analysis identified two homozygous variants: a novel pathogenic SLC22A12 variant, c.1523G>A; p.(S508N), in the two Caucasian siblings and a previously reported SLC2A9 variant, c.646G>A; p.(G216R), in the Pakistani boy. Our findings suggest that these two mutations cause RHUC through loss of urate reabsorption and extend the SLC22A12 mutation spectrum. In addition, this work further emphasizes the importance of WES analysis in clinical settings.


Assuntos
Transportadores de Ânions Orgânicos , Erros Inatos do Transporte Tubular Renal , Masculino , Humanos , Sequenciamento do Exoma , Ácido Úrico , Erros Inatos do Transporte Tubular Renal/genética , Biologia Computacional , Doenças Raras , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas Facilitadoras de Transporte de Glucose/genética
20.
Thorac Cancer ; 14(27): 2761-2769, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37549925

RESUMO

BACKGROUND: Glucose transporters (GLUTs) are highly expressed in various cancers. However, the implications of these variable expression patterns are unclear. This study aimed to clarify the correlation between class I GLUT expression patterns and clinical outcomes in non-small cell lung cancer (NSCLC), including their potential role in inflammatory signaling. METHODS: Biopsy tissues from 132 patients with NSCLC (92 adenocarcinomas [ADC] and 40 squamous cell carcinomas [SQCC]) were analyzed. mRNA expression levels of class I GLUTs (solute carrier 2A [SLC2A]1, SLC2A2, SLC2A3, and SLC2A4) and inflammation-related molecules (toll-like receptors TLR4, RelA/p65, and interleukins IL8 and IL6) were measured. Cellular localization of GLUT3 and GLUT4 was investigated using immunofluorescence. RESULTS: Single, combined, and negative GLUT (SLC2A) expression were observed in 27/92 (29.3%), 27/92 (29.3%), and 38/92 (41.3%, p < 0.001) of ADC and 8/40 (20.0%), 29/40 (72.5%, p < 0.001), and 3/40 (7.5%) of SQCC, respectively. In ADC, the single SLC2A3-expressed group had a significantly poorer prognosis, whereas the single SLC2A4-expressed group had a significantly better prognosis. The combined expression groups showed no significant difference. SLC2A expression was not correlated with SQCC prognosis. SLC2A4 expression correlated with lower IL8 expression. GLUT3 and GLUT4 expressions were localized in the tumor cytoplasm. CONCLUSIONS: In lung ADC, single SLC2A3 expression correlated with poor prognosis, whereas single SLC2A4 expression correlated with better prognosis and lower IL8 expression. GLUT3 expression, which is increased by IL8 overexpression, may be suppressed by increasing the expression of GLUT4 through decreased IL8 expression.


Assuntos
Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 3/genética , Interleucina-8/genética , Interleucina-8/metabolismo , Neoplasias Pulmonares/genética
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