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1.
Life Sci ; 248: 117474, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32112869

RESUMO

BACKGROUND/OBJECTIVES: Nicotinamide N-methyltransferase (NNMT) is a novel regulator of energy homeostasis in adipocytes. NNMT expression in adipose tissue is increased in obesity and diabetes. Knockdown of NNMT prevents mice from developing diet-induced obesity, which is closely linked to insulin resistance. An early sign of systemic insulin resistance is reduced expression of glucose transporter 4 (GLUT4) selectively in adipose tissue. Adipose tissue-specific knockout and overexpression of GLUT4 cause reciprocal changes in NNMT expression. The aim of the current study was to elucidate the mechanism that regulates NNMT expression in adipocytes. METHODS: 3T3-L1 adipocytes were cultured in media with varying glucose concentrations or activators and inhibitors of intracellular pathways. NNMT mRNA and protein levels were measured with quantitative polymerase chain reaction and Western blotting. RESULTS: Glucose deprivation of 3T3-L1 adipocytes induced a 2-fold increase in NNMT mRNA and protein expression. This effect was mimicked by inhibition of glucose transport with phloretin, and by inhibition of glycolysis with the phosphoglucose isomerase inhibitor 2-deoxyglucose. Conversely, inhibition of the pentose phosphate pathway did not affect NNMT expression. Pharmacological activation of the cellular energy sensor AMP-activated protein kinase (AMPK) and inhibition of the mammalian target of rapamycin (mTOR) pathway caused an increase in NNMT levels that was similar to the effect of glucose deprivation. Activation of mTOR with MHY1485 prevented the effect of glucose deprivation on NNMT expression. Furthermore, upregulation of NNMT levels depended on functional autophagy and protein translation. CONCLUSION: Glucose availability regulates NNMT expression via an mTOR-dependent mechanism.


Assuntos
Adipócitos/efeitos dos fármacos , Transportador de Glucose Tipo 4/genética , Glucose/farmacologia , Nicotinamida N-Metiltransferase/genética , Serina-Treonina Quinases TOR/genética , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Transporte Biológico/efeitos dos fármacos , Diferenciação Celular , Desoxiglucose/farmacologia , Metabolismo Energético/genética , Regulação da Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 4/antagonistas & inibidores , Transportador de Glucose Tipo 4/metabolismo , Glucose-6-Fosfato Isomerase/antagonistas & inibidores , Glucose-6-Fosfato Isomerase/genética , Glucose-6-Fosfato Isomerase/metabolismo , Homeostase/genética , Camundongos , Morfolinas/farmacologia , Nicotinamida N-Metiltransferase/antagonistas & inibidores , Nicotinamida N-Metiltransferase/metabolismo , Via de Pentose Fosfato/efeitos dos fármacos , Via de Pentose Fosfato/genética , Floretina/farmacologia , Biossíntese de Proteínas , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Triazinas/farmacologia
2.
Medicine (Baltimore) ; 99(12): e19562, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195965

RESUMO

It has been established that prediabetes can causes significant comorbidities, particularly in the elderly. The deterioration of glucose metabolism are generally considered to be results of the impairment of the 4 factors: first, second insulin secretion (FPIS, SPIS, respectively), glucose effectiveness (GE), and insulin resistance. In this study, we enrolled older women to investigate their relationships with prediabetes.Five thousand four hundred eighty-two nonobese, nondiabetic women were included. They were divided into normal glucose tolerance and prediabetes groups. Receiver operating characteristic curve was performed to investigate the effects on whether to have prediabetes for each factors. Two models were built: Model 1: FPIS + SPIS, and Model 2: model 1 + GE. The area under the receiver operating characteristic (aROC) curve was used to determine the predictive power of these models.The aROC curve of GE was significantly higher than the diagonal line followed by SPIS and FPIS accordingly. The aROC curve of Model 1 (0.611) was not different from GE. However, Model 2 improved significantly up to 0.663. Based on this model, an equation was built (-0.003 × GE - 212.6 × SPIS - 17.9 × insulin resistance + 4.8). If the calculated value is equal or higher than 0 (≥0), then the subject has higher chance to have prediabetes (sensitivity = 0.607, specificity = 0.635).Among the 4 factors, GE is the most important contributor for prediabetes in older women. By building a model composed of FPIS, SPIS, and GE, the aROC curve increased significantly. The equation built from this model could predict prediabetes precisely.


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Glucose/metabolismo , Resistência à Insulina/fisiologia , Secreção de Insulina/fisiologia , Estado Pré-Diabético/epidemiologia , Idoso , Índice de Massa Corporal , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Teste de Tolerância a Glucose/métodos , Humanos , Pessoa de Meia-Idade , Estado Pré-Diabético/fisiopatologia , Prevalência , Sensibilidade e Especificidade , Taiwan/epidemiologia
3.
Science ; 367(6482): 1147-1151, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32139546

RESUMO

Mycobacterium tuberculosis has an unusual outer membrane that lacks canonical porin proteins for the transport of small solutes to the periplasm. We discovered that 3,3-bis-di(methylsulfonyl)propionamide (3bMP1) inhibits the growth of M. tuberculosis, and resistance to this compound is conferred by mutation within a member of the proline-proline-glutamate (PPE) family, PPE51. Deletion of PPE51 rendered M. tuberculosis cells unable to replicate on propionamide, glucose, or glycerol. Growth was restored upon loss of the mycobacterial cell wall component phthiocerol dimycocerosate. Mutants in other proline-glutamate (PE)/PPE clusters, responsive to magnesium and phosphate, also showed a phthiocerol dimycocerosate-dependent growth compromise upon limitation of the corresponding substrate. Phthiocerol dimycocerosate determined the low permeability of the mycobacterial outer membrane, and the PE/PPE proteins apparently act as solute-specific channels.


Assuntos
Amidas/metabolismo , Proteínas de Bactérias/metabolismo , Membrana Celular/metabolismo , Glucose/metabolismo , Glicerol/metabolismo , Mycobacterium tuberculosis/metabolismo , Proteínas de Bactérias/genética , Transporte Biológico , Permeabilidade da Membrana Celular , Farmacorresistência Bacteriana/genética , Deleção de Genes , Lipídeos/química , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia
4.
Drug Discov Ther ; 14(1): 8-13, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32147629

RESUMO

Natto is a well-known traditional Japanese food produced by fermenting soybeans with Bacillus subtilis var natto. Here we found that the water-soluble viscous fraction of natto inhibits sucrose- or glucose-induced hyperglycemia in silkworms. The water-soluble viscous fraction treated with DNase I, RNase A, and proteinase K, followed by phenol extraction also suppressed sucrose-induced hyperglycemia in silkworms. The enzyme-treated polysaccharide fraction of natto inhibits glucose uptake by Caco-2 cells, human intestinal epithelial cells. These findings suggest that the polysaccharide components of natto selected on the basis of their suppressive effects on sucrose-induced hyperglycemia in silkworms inhibit glucose uptake by human intestinal cells.


Assuntos
Bacillus subtilis , Glucose/metabolismo , Hiperglicemia , Mucosa Intestinal/metabolismo , Polissacarídeos/farmacologia , Animais , Bombyx , Células CACO-2 , Humanos , Hiperglicemia/terapia , Polissacarídeos/metabolismo , Alimentos de Soja , Sacarose
5.
World J Microbiol Biotechnol ; 36(3): 46, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32140791

RESUMO

Azotobacter vinelandii is a microorganism with biotechnological potential because its ability to produce alginate and polyhydroxybutyrate. Large-scale biotechnological processes are oriented to sustainable production by using biomass hydrolysates that are mainly composed by glucose and xylose. In the present study, it was observed that A. vinelandii was unable to consume xylose as the sole carbon source and that glucose assimilation in the presence of xylose was negatively affected. Adaptive Laboratory Evolution (ALE) was used as a metabolic engineering tool in A. vinelandii, to improve both carbohydrate assimilation. As a result of ALE process, the CT387 strain was obtained. The evolved strain (CT387) grown in shaken flask cultivations with xylose (8 g L-1) and glucose (2 g L-1), showed an increase of its specific growth rate (µ), as well as of its glucose and xylose uptake rates of 2, 6.45 and 3.57-fold, respectively, as compared with the parental strain. At bioreactor level, the µ, the glucose consumption rate and the relative expression of gluP that codes for the glucose permease in the evolved strain were also higher than in the native strain (1.53, 1.29 and 18-fold, respectively). Therefore, in the present study, we demonstrated the potential of ALE as a metabolic engineering tool for improving glucose and xylose consumption in A. vinelandii.


Assuntos
Azotobacter vinelandii/metabolismo , Glucose/metabolismo , Engenharia Metabólica/métodos , Xilose/metabolismo , Azotobacter vinelandii/genética , Azotobacter vinelandii/crescimento & desenvolvimento , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biomassa , Reatores Biológicos , Meios de Cultura/química , Fermentação , Regulação Bacteriana da Expressão Gênica , RNA Bacteriano/genética , RNA Bacteriano/isolamento & purificação
6.
Gen Physiol Biophys ; 39(1): 79-87, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039827

RESUMO

Glucose triggers glucagon-like peptide (GLP)-1 secretion from L cells involving several glucose sensors including sodium-glucose transporter (SGLT)1, glucose transporter (GLUT)2, and sweet taste receptors (STRs). This study investigated the effects of different glucose concentrations on GLP-1 secretion, intracellular concentrations of Ca2+ and cAMP, glucose uptake, and protein levels of SGLT1, GLUT2, and STRs in STC-1 cells. Low glucose (5.6 mM) increased GLP-1 secretion, intracellular Ca2+ concentration, and SGLT1 protein level compared with glucose-free group. GLP-1 secretion and intracellular Ca2+ concentration triggered by low glucose were inhibited by the SGLT1 inhibitor. GLP-1 secretion or intracellular Ca2+ concentration in high-glucose (25, 100, 200 mM) groups was significantly higher than that of low-glucose group. Elevation of cAMP level was observed in concentration-dependent manner, and decreased glucose uptake was observed in 100 or 200 mM glucose group. High glucose increased protein levels of STRs and GLUT2 in comparison to low-glucose group. GLP-1 secretion and intracellular levels of Ca2+ and cAMP triggered by high glucose were inhibited in the presence of the GLUT2 or STR inhibitor. These results suggest that SGLT1 is dominantly responsible for GLP-1 secretion triggered by low glucose, and that STRs and GLUT2 are involved in GLP-1 secretion induced by high glucose.


Assuntos
Células Enteroendócrinas , Linhagem Celular , Peptídeo 1 Semelhante ao Glucagon , Glucose
7.
Gen Physiol Biophys ; 39(1): 99-106, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039829

RESUMO

A reduction in glucose consumption has been shown in both patients with acquired epilepsy and in animal epilepsy models. However, the question remains whether the disturbance of glucose metabolism is the driving force of epileptogenesis. We have recently reported that a chronic partial inhibition of brain glycolysis by the non-metabolizable glucose analogue 2-deoxy-D-glucose (2-DG) triggers epileptogenesis in initially healthy rats. In this study, we further investigated whether chronic 2-DG treatment caused a cellular loss in the dorsal hippocampus and mossy fiber sprouting in the dentate gyrus. We found that prolonged (four weeks) treatment with 2-DG induced a neuronal loss in the CA1 field and the dentate hilus. We also found mossy fibers reorganization in the 2-DG group. In addition, we showed that pentylenetetrazole-induced convulsions were considerably strengthened and prolonged in 2-DG-treated rats. Our results demonstrate that the chronically impaired brain glucose metabolism likely leads to a structural remodeling resembling epileptogenesis and has a proconvulsive effect.


Assuntos
Fibras Musgosas Hipocampais , Animais , Giro Denteado , Desoxiglucose , Glucose , Ratos
8.
Medicine (Baltimore) ; 99(8): e19242, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080127

RESUMO

The gestational diabetes mellitus (GDM) diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Group (IADPSG) were established based on the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study and have been the most commonly used criteria for determining GDM worldwide. Although individuals from mainland China were not included in the HAPO study, the IADPSG criteria have been used in China since 2011. However, the appropriateness of the criteria for evaluating maternal postpartum outcomes in mainland China are unknown. We conducted this study to determine whether the IADPSG criteria are appropriate for Chinese patients for evaluating long-term maternal postpartum outcomes.Eighty-four patients who were diagnosed with hyperglycemia during pregnancy and had delivery in Peking University First Hospital from February 2007 to December 2009 were enrolled in the study. For patients in Group A, GDM was diagnosed using both the National Diabetes Data Group (NDDG) and the IADPSG criteria, while patients in Group B, gestational impaired glucose tolerance (GIGT) was diagnosed using the NDDG criteria while GDM was diagnosed based on the IADPSG criteria. Anthropometric data, glucose metabolism, lipid profiles, ß cell function, and insulin resistance index were evaluated and compared to baseline after 5- to 6-year postpartum period.Patients in group A had significantly higher oral glucose tolerance test (OGTT) fasting, 2-hour and 3-hour plasma glucose levels compared to patients in group B at 24 to 28 weeks of gestation (P < .05). No significant differences were observed between the groups for anthropometric data, postpartum abnormal glucose metabolism (50.91% vs 44.83%, P = .596), type 2 diabetes mellitus (T2DM) (16.36% vs 3.45%, P = .167), lipid profiles, ß cell function (homeostasis model assessment ß-cell function index (HOMA-ß) 1.04 vs 0.99, P = .935) and insulin resistance (homeostasis model assessment insulin resistance index (HOMA-IR) 2.01 vs 1.69, P = .583).Patients diagnosed with GDM using either the NDDG or IADPSG criteria had abnormal glucose levels and lipid metabolism after delivery. Patients with mild hyperglycemia had similar postpartum ß-cell functional impairment and insulin resistance to those with moderate hyperglycemia during pregnancy. Hence, with respect to maternal long-term postpartum outcomes, the IADPSG diagnostic criteria for GDM could be appropriate for patients in mainland China.


Assuntos
Diabetes Gestacional/fisiopatologia , Período Pós-Parto/fisiologia , Adulto , Pesos e Medidas Corporais , China , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Lipídeos/sangue , Gravidez
9.
Chem Biol Interact ; 318: 108978, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32044341

RESUMO

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) accumulates in human body, probably influencing adipocyte differentiation and causing various toxic effects, including wasting syndrome. Recently, orientin, a phenolic compound abundant in natural health products, has been shown to have antioxidant properties. We investigated the protective effects of orientin against TCDD-induced adipocyte dysfunction and its underlying mechanisms. In this study, orientin suppressed TCDD-induced loss of lipid accumulation. Orientin inhibited TCDD-driven decreases in the levels of peroxisome proliferator-activated receptor γ and adiponectin. Orientin also reduced TCDD-induced prostaglandin E2, and cytosolic phospholipase A2α levels, and increased TCDD-inhibited peroxisome proliferator-activated receptor gamma coactivator 1-alpha levels in 3T3-L1 adipocytes. TCDD reduced the levels of insulin receptor substrate 1 and glucose transporter 4, and decreased insulin-stimulated glucose uptake activity; however, orientin diminished these TCDD-induced effects. These results suggest that orientin may have beneficial effects on the prevention of TCDD-induced wasting syndrome and type II diabetes mellitus accompanied by insulin resistance.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Flavonoides/farmacologia , Glucosídeos/farmacologia , Insulina/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Células 3T3-L1 , Animais , Dinoprostona , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Camundongos
10.
Gene ; 735: 144404, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32018013

RESUMO

Glucose uptake in adipocytes is crucial for regulating systemic metabolism. Long noncoding RNAs (lncRNAs), defined as being transcripts with lengths exceeding 200 nucleotides that are not translated, are recently identified regulators of cellular functions. Previously, we have shown that an lncRNA, "down-regulated expression by hepatitis B virus X" (dreh), is involved in glucose transport in skeletal muscle cells. Here, we aimed to examine the involvement of dreh in glucose transport in 3T3-L1 adipocytes. Expression analysis showed that dreh was expressed in 3T3-L1 fibroblasts and adipocytes. Knockdown of dreh expression using its specific siRNAs lowered the glucose concentration of the medium and facilitated [3H]-2-deoxyglucose transport in adipocytes. Additionally, dreh silencing enhanced the protein expression of glucose transporter (GLUT4) in the plasma membrane of adipocytes. Treatment with siRNA against vimentin attenuated the glucose-lowering effect of dreh depletion. These results suggest that the repression of dreh facilitates glucose transport via increased GLUT4 expression in the plasma membrane through the involvement of vimentin in 3T3-L1 adipocytes. In conclusion, dreh is the first observed lncRNA that regulates glucose transport in adipocytes and could serve as a novel therapeutic target for diabetes by modulating adipocyte function. Considering the new function of dreh, we propose that dreh be renamed "down-regulated expression-related hexose/glucose transport enhancer."


Assuntos
Adipócitos/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , RNA Longo não Codificante/genética , Vimentina/metabolismo , Animais , Linhagem Celular , Fibroblastos/metabolismo , Camundongos , RNA Longo não Codificante/metabolismo
11.
World J Microbiol Biotechnol ; 36(2): 28, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32002680

RESUMO

In Saccharomyces cerevisiae, los1 encodes a nuclear tRNA exporter. Despite the non-essentiality, the deletion of los1 has been shown to extend replicative life span in yeast. Here, we characterized AfuXpot, the los1 homologue in human pathogen Aspergillus fumigatus and found that it is continuously expressed during fungal growth. Microscopic examination of an AfuXpot-GFP-expressing transformant confirmed the nuclear localization of the fusion protein. The targeted gene deletion affirmed the non-essential role of AfuXpot in hyphal growth and sporulation. However, the growth of the deletion mutant was affected by amino acid, but not glucose, deprivation. The susceptibility of the deletant strain to protein and DNA/RNA synthesis inhibitors was also altered. Using bioinformatics tools, some transcription factor binding sites were predicted in AfuXpot promoter. Expression analyses of potential AfuXpot-interacting genes showed a marked down-regulation of sfp1 and mtr10 homologues in ΔAfuXpot strain. Our data demonstrates some conserved aspects of AfuXpot as a tRNA exporter in A. fumigatus.


Assuntos
Aminoácidos/metabolismo , Aspergillus fumigatus/crescimento & desenvolvimento , Aspergillus fumigatus/genética , Proteínas Fúngicas/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , RNA Fúngico/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Aminoácidos/deficiência , Aspergillus fumigatus/metabolismo , Clonagem Molecular , DNA Fúngico/genética , DNA Fúngico/isolamento & purificação , Farmacorresistência Fúngica , Proteínas Fúngicas/genética , Deleção de Genes , Regulação Fúngica da Expressão Gênica , Glucose/metabolismo , Hifas/crescimento & desenvolvimento , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Regiões Promotoras Genéticas , RNA Fúngico/isolamento & purificação , RNA de Transferência/genética , RNA de Transferência/isolamento & purificação , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
12.
Crit Care Resusc ; 22(1): 80-82, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32102646

RESUMO

BACKGROUND: Due to the lack of double-blind randomised controlled trials, the true effect of intravenous sodium bicarbonate therapy in ICU patients with metabolic acidosis remains unclear. METHODS: We diluted 100 mL 8.4% sodium bicarbonate in 150 mL 5% dextrose (D5W) within a 250 mL polyolefin bag after removing 100 mL. We asked ICU clinicians to inspect a 250 mL bag containing sodium bicarbonate or a 250 mL bag where 100 mL of D5W had been removed and then returned. The bags were attached to intravenous giving sets. We asked participants to identify the contents of the bags. RESULTS: Among 60 participants (39 nursing staff [65%], 20 medical staff [33.3%] and one pharmacist), 36 (60%) answered correctly. The Cohen κ for agreement between test bag content and participants' answers was 0.20 (95% CI, -0.05 to 0.45; P = 0.12), implying the answers were correct by chance. In the group of 28 participants who indicated they used a clue to help them decide their answer, 15 (53.6%) answered correctly, whereas in the remainder (n = 32), 21 (65.6%) answered correctly (P = 0.49). CONCLUSION: When 100 mL of 8.4% sodium bicarbonate were diluted in 150 mL of D5W within a 250 mL polyolefin bag, clinicians were unable to correctly identify the contents of the bags. Our findings imply that sodium bicarbonate therapy can be successfully blinded.


Assuntos
Acidose/tratamento farmacológico , Glucose/uso terapêutico , Bicarbonato de Sódio/uso terapêutico , Administração Intravenosa , Método Duplo-Cego , Eletrólitos , Glucose/administração & dosagem , Humanos , Injeções Intravenosas , Sódio/sangue , Bicarbonato de Sódio/administração & dosagem , Resultado do Tratamento
13.
J Assoc Physicians India ; 68(2): 43-47, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32009362

RESUMO

Bacterial meningitis remains a disease with devastating attack rates and growing drug resistance among causative bacteria. Early diagnosis and timely management has an implication on the prognosis and outcome. However, lack of laboratory facilities, travel time for the sample to reach the laboratory and the laborious laboratory methods may result in deferment in precise treatment resulting in avoidable morbidity and mortality. Such delays can be avoided by determining CSF sugar in the emergency room using bedside glucometers, which can assist in crucial decision-making on the use of antibiotics in suspected patients. We aimed to test the accuracy of CSF glucose estimation using glucometers in detecting bacterial meningitis. This single-centred, prospective, comparative study was conducted in 50 consecutive patients suspected with CNS infections. Lumbar puncture for CSF collection was performed to test for glucose by boththe laboratory evaluation and a glucometer. Logistic regression analysis was performed to understand the relationship between culture-proven bacterial meningitis with established independent variables. The mean CSF glucose value using the conventional laboratory technique was 98.97 ± 61.10 mg/dL, and with glucometer was 109.59 ± 67.85 mg/dL. There was no significant difference (p=0.4613) among the mean glucose levels by the two methods. A statistically significant association was noted between bacterial meningitis and CSF glucose using the conventional technique (OR, 0.976; 95% CI, 0.957-0.993; p=0.0165), and CSF glucose using the glucometer (OR, 0.975; 95% CI, 0.956-0.996; p=0.0066). Bedside glucose testing from CSF fluid may be an alternative to laboratory plasma glucose measurement.


Assuntos
Glucose/metabolismo , Meningites Bacterianas/diagnóstico , Bactérias , Testes Hematológicos , Humanos , Índia , Estudos Prospectivos
14.
J Agric Food Chem ; 68(9): 2702-2710, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32054270

RESUMO

d-Xylose is the most abundant hemicellulosic monomer on earth, but wild-type Saccharomyces cerevisiae has very limited d-xylose uptake capacity. We conducted bioprospecting for new sugar transporters from the d-xylose-consuming filamentous fungus Trichoderma reesei and identified three candidates belonging to the major facilitator superfamily. When they were expressed in yeast and assayed for d-xylose uptake, one of them, Xltr1p, had d-xylose transport activity that was more efficient than that of Gal2p, an endogenous yeast transporter. Site-directed mutagenesis was used to examine the functional contributions of 13 amino acid residues for the uptake of d-xylose, and these experiments identified particular amino acids that function distinctly in d-xylose vs glucose transport (e.g., F300). Excitingly, the yeast strain expressing the N326FXltr1p variant was able to carry a "high efficiency" transport for d-xylose but was nearly unable to utilize glucose; in contrast, the strain with the F300AXltr1p variant grew on glucose but lost d-xylose transport activity.


Assuntos
Proteínas Fúngicas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Saccharomyces cerevisiae/genética , Trichoderma/metabolismo , Xilose/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Transporte Biológico , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Expressão Gênica , Glucose/metabolismo , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/genética , Saccharomyces cerevisiae/metabolismo , Alinhamento de Sequência , Trichoderma/genética
15.
Life Sci ; 248: 117459, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32092332

RESUMO

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus that affects approximately half of patients with diabetes. Current treatment regimens cannot treat DPN effectively. Schwann cells (SCs) are very sensitive to glucose concentration and insulin, and closely associated with the occurrence and development of type 1 diabetic mellitus (T1DM) and DPN. Apoptosis of SCs is induced by hyperglycemia and is involved in the pathogenesis of DPN. This review considers the pathological processes of SCs apoptosis under high glucose, which include the following: oxidative stress, inflammatory reactions, endoplasmic reticulum stress, autophagy, nitrification and signaling pathways (PI3K/AKT, ERK, PERK/Nrf2, and Wnt/ß-catenin). The clarification of mechanisms underlying SCs apoptosis induced by high glucose will help us to understand and identify more effective strategies for the treatment of T1DM DPN.


Assuntos
Apoptose/efeitos dos fármacos , Neuropatias Diabéticas/genética , Glucose/farmacologia , Hiperglicemia/genética , Células de Schwann/efeitos dos fármacos , Animais , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Insulina/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células de Schwann/metabolismo , Células de Schwann/patologia , Transdução de Sinais , beta Catenina/genética , beta Catenina/metabolismo
16.
J Agric Food Chem ; 68(10): 2973-3005, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32105058

RESUMO

Leaf teas are widely used as a purported treatment for dysregulated glucose homeostasis. The objective of this study was to systematically evaluate the clinical and cellular-metabolic evidence, published between January 2013 and May 2019, and indexed on PubMed, ScienceDirect, and Web of Science, supporting the use of leaf teas for this purpose. Fourteen randomized controlled trials (RCTs) (13 on Camellia sinensis teas) were included, with mixed results, and providing scant mechanistic information. In contrast, 74 animal and cell culture studies focusing on the pancreas, liver, muscle, and adipose tissue yielded mostly positive results and highlighted enhanced insulin signaling as a recurring target associated with the effects of teas on glucose metabolism. We conclude that more studies, including RCTs and pre-clinical studies examining teas from a wider variety of species beyond C. sinensis, are required to establish a stronger evidence base on the use of leaf teas to normalize glucose metabolism.


Assuntos
Camellia sinensis/química , Glucose/metabolismo , Extratos Vegetais/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Humanos , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculos/efeitos dos fármacos , Músculos/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Extratos Vegetais/química , Folhas de Planta/química , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Life Sci ; 245: 117367, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32001265

RESUMO

AIMS: The present study determines the effect of administration of novel antioxidant astaxanthin-s-allyl cysteine biconjugate (AST-SAC) against streptozotocin-induced diabetes mellitus (DM) in rats. MAIN METHODS: AST-SAC (1 mg/kg/day) was treated against DM in rats for 45 days. The oxidative stress, antioxidants level, insulin secretion, activities of various carbohydrate metabolizing enzymes were studied. The glucose uptake in L6 myotubes was studied. In addition, in silico analysis of interaction of AST-SAC with proteins such as insulin receptor (IR) and 5'-adenosine monophosphate-activated protein kinase (AMPK) were carried out. KEY FINDINGS: Administration of AST-SAC in DM rats has protected the mitochondrial function (decreased oxidative stress and normalized oxidative phosphorylation activities) and antioxidant capacity of the pancreas which has resulted in beta cells rejuvenation and insulin secretion restoration. AST-SAC decreased the alpha-glucosidases activities to bring glycemic control in DM rats. Due to these effects the glycoprotein components and lipids were restored to near normalcy in DM rats. AST-SAC protected the antioxidant status of liver, kidney and plasma; and curbed the progression of secondary complications of DM. AST-SAC treatment stimulated glucose uptake in L6 myotubes in in vitro. To support this observation, AST-SAC interacted with proteins such as IR and AMPK in silico. SIGNIFICANCE: AST-SAC can be considered as "multi-target-directed ligand", that is, through these manifold effects, AST-SAC has been able to prevail over DM in rats.


Assuntos
Antioxidantes/uso terapêutico , Cisteína/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Colesterol/metabolismo , Cisteína/farmacologia , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Masculino , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Triglicerídeos/metabolismo
18.
Life Sci ; 245: 117361, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32001268

RESUMO

AIMS: Evaluation of the anti-diabetic effect of superparamagnetic iron oxide nanoparticles (SPIONs) on Type 2 diabetic rats and compared their effect to metformin treatment. MAIN METHODS: Diabetic rats were treated with different doses of nanoparticles one time per week for 4 weeks. Fasting blood glucose level was determined for studied groups during the experimental period (30 days). At the end of the experiment, oral glucose tolerance test was carried out, serum samples were collected for biochemical assays. Then animals were sacrificed to obtain tissues for assessment of glucose transporters, insulin receptors and insulin signaling proteins. KEY FINDING: SPIONs treatment normalized fasting blood glucose and lowering insulin level in diabetic rats compared to untreated diabetic rats. SPIONs significantly ameliorate the glucose sensing and the active components of insulin signaling pathway. The anti-diabetic effects of SPIONs may be mediated through its effect on (i) hepatic peroxisome proliferator-activated receptor gamma coactivator 1-alpha content, which induced by SPIONs treatment in a dose-dependent manner, (ii) adipocytokines as SPIONs treated diabetic rats showed significantly higher levels of adiponectin and lower retinol binding protein 4 compared to untreated diabetic rats, (iii) lipid profile as SPIONs treatment significantly corrected the lipid profile in a dose-dependent manner and to a similar extent as metformin or even better. SIGNIFICANCE: To our knowledge, this is the first study that explores the anti-diabetic effects of SPIONs on diabetic model.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Compostos Férricos/uso terapêutico , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Nanopartículas de Magnetita/uso terapêutico , Animais , Glicemia/análise , Teste de Tolerância a Glucose , Masculino , Metformina/uso terapêutico , Ratos , Ratos Sprague-Dawley
19.
Life Sci ; 246: 117382, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32004509

RESUMO

Our preliminary research revealed that metformin, a classic anti-diabetic drug, could rescue Parkin protein expression and mitophagy in high glucose-challenged human renal epithelial cells in vitro, but the molecular mechanism remains to be explored. In the study, Human Renal Cortical Epithelial Cells (HRCEpiC) and Human Renal Proximal Tubular Epithelial Cells (HRPTEpic) were challenged with high glucose with or without metformin pre-treatment to monitor Parkin mRNA and protein expression level change. PRKN gene knockdown was performed by lentiviral-based shRNA delivery. Cell viability, apoptosis and mitophagy were monitored after treatment. Mitochondrial damage was evaluated by analyzing mitochondrial permeability transition pore opening, membrane potential change, mitochondrial superoxide accumulation and cytochrome C release. Protein levels of activating transcription factor 4 (ATF4), p53 phospho-Ser15, IκBα phosphor-Ser32, IKKα phosphor-Ser176/180 in whole cell lysate and nuclear entry of p50/p65 were assessed by western blot. Okadaic acid was used to inhibit protein phosphatase 2A (PP2A). The data suggested high glucose challenge significantly reduced PRKN gene expression, mitophagy, mitochondria integrity and cell viability in vitro, which was rescued by metformin co-treatment. The effects of metformin were crippled by PRKN gene knockdown. Metformin increased PRKN gene transcription while reducednuclear factor kappa B (NF-κB) activation but not that of p53 or ATF4. Inhibiting PP2A weakened NF-κB inhibition and PRKN induction by metformin in high glucose-challenged cells, reducing its mitochondrial protective and cytoprotective effect. So, we concluded thatmetformin protects human renal epithelial cells from high glucose-induced apoptosis by restoring Parkin protein expression and mitophagy via PP2A activation and NF-κB inhibition.


Assuntos
Células Epiteliais/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Metformina/farmacologia , NF-kappa B/metabolismo , Proteína Fosfatase 2/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Western Blotting , Nefropatias Diabéticas/tratamento farmacológico , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/metabolismo , Glucose/farmacologia , Humanos , Rim/citologia , Rim/metabolismo , Mitocôndrias/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real
20.
N Engl J Med ; 382(6): 534-544, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32023373

RESUMO

BACKGROUND: Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment. METHODS: In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of <36 mg per deciliter [2.0 mmol per liter]) would be noninferior to a traditional threshold (treatment at a glucose concentration of <47 mg per deciliter [2.6 mmol per liter]) with respect to psychomotor development at 18 months, assessed with the Bayley Scales of Infant and Toddler Development, third edition, Dutch version (Bayley-III-NL; scores range from 50 to 150 [mean {±SD}, 100±15]), with higher scores indicating more advanced development and 7.5 points (one half the SD) representing a clinically important difference). The lower threshold would be considered noninferior if scores were less than 7.5 points lower than scores in the traditional-threshold group. RESULTS: Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed. The mean glucose concentration was 57±0.4 mg per deciliter (3.2±0.02 mmol per liter) in the lower-threshold group and 61±0.5 mg per deciliter (3.4±0.03 mmol per liter) in the traditional-threshold group. Fewer and less severe hypoglycemic episodes occurred in the traditional-threshold group, but that group had more invasive diagnostic and treatment interventions. Serious adverse events in the lower-threshold group included convulsions (during normoglycemia) in one newborn and one death. CONCLUSIONS: In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold (36 mg per deciliter) was noninferior to a traditional threshold (47 mg per deciliter) with regard to psychomotor development at 18 months. (Funded by the Netherlands Organization for Health Research and Development; HypoEXIT Current Controlled Trials number, ISRCTN79705768.).


Assuntos
Glicemia/análise , Glucose/administração & dosagem , Hipoglicemia/terapia , Doenças do Recém-Nascido/terapia , Transtornos Psicomotores/prevenção & controle , Desenvolvimento Infantil/efeitos dos fármacos , Nutrição Enteral , Humanos , Hipoglicemia/sangue , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Doenças do Recém-Nascido/sangue , Infusões Intravenosas , Valores de Referência
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