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1.
DNA Cell Biol ; 39(1): 8-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31825254

RESUMO

Atherosclerosis is a major disease that seriously harms human health and is known as the "number one killer" in developed countries and the leading cause of death worldwide. Glutamine is the most abundant nonessential amino acid in the human blood that has multifaceted effects on the body. Recent studies showed that glutamine is negatively corrected with the progression of atherosclerotic lesions. In this review, we focused on the relationship of glutamine with macrophage polarization, nitrification stress, oxidative stress injury, myocardial ischemia-reperfusion injury, and therapeutic angiogenesis to review its roles in atherosclerotic cardiovascular disease.


Assuntos
Aterosclerose/sangue , Doenças Cardiovasculares/sangue , Glutamina/sangue , Ativação de Macrófagos , Estresse Oxidativo , Animais , Aterosclerose/patologia , Doenças Cardiovasculares/patologia , Progressão da Doença , Humanos , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Neovascularização Patológica/sangue , Neovascularização Patológica/fisiopatologia
2.
Indian J Gastroenterol ; 38(4): 338-347, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31612309

RESUMO

BACKGROUND: In severe acute pancreatitis (AP), intravenous glutamine has been shown to reduce the rate of complications, hospital stay, and mortality. In the present randomized trial, we aimed to evaluate the effect of enteral glutamine supplementation on clinical outcomes, gut permeability, systemic inflammation, oxidative stress, and plasma glutamine levels in patients with severe and predicted severe AP. METHODS: Patients with AP admitted within 72 h of onset of symptoms were included. The primary outcome measure was development of infected pancreatic and peri-pancreatic necrosis and in-hospital mortality. High-sensitivity C-reactive protein (HS-CRP) and interleukin-6 (IL-6) were evaluated as markers of inflammation; plasma thiobarbituric acid reactive substances (TBARS) and activities of serum superoxide dismutase and glutathione peroxidase were determined to evaluate oxidative stress; serum polyethylene glycol (PEG) was tested for intestinal permeability; subjective global assessment (SGA) was used for nutritional assessment, and an improvement in organ function was measured by the Modified Marshall score. Intention-to-treat analysis was used. A p-value of < 0.05 was considered statistically significant. RESULTS: After power calculation, we enrolled 18 patients in the glutamine and 22 in the control arm. There was no significant improvement in the development of infected necrosis and in-hospital mortality between the groups. Improvement in Modified Marshall score was observed in a higher proportion of patients receiving glutamine (15 [83.3%] vs. 12 [54.5%]; p = 0.05). Plasma glutamine levels improved more in glutamine-treated group (432.72 ± 307.83 vs. 618.06 ± 543.29 µM/L; p = 0.004), while it was lower in controls (576.90 ± 477.97 vs. 528.20 ± 410.45 µM/L; p = 0.003). PEG level was lower after glutamine supplementation (39.91 ± 11.97 vs. 32.30 ± 7.39 ng/mL; p = 0.02). Statistically significant reduction in IL-6 concentration was observed in the glutamine group at the end of treatment (87.44 ± 7.1 vs. 63.42 ± 33.7 µM/L; p = 0.02). CONCLUSIONS: Despite absence of improvement in infected necrosis and in-hospital mortality, enteral glutamine supplementation showed improvement in gut permeability, oxidative stress, and a trend towards improvement in organ function as depicted by improvement in the Modified Marshall score. TRIAL REGISTRATION: NCT01503320.


Assuntos
Suplementos Nutricionais , Nutrição Enteral/métodos , Glutamina/farmacocinética , Mucosa Intestinal/metabolismo , Pancreatite/terapia , Doença Aguda , Adulto , Biomarcadores/sangue , Feminino , Glutamina/sangue , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Pancreatite/metabolismo , Permeabilidade/efeitos dos fármacos , Índice de Gravidade de Doença , Resultado do Tratamento
3.
Synapse ; 73(11): e22127, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31403728

RESUMO

The aim of the present study was to explore the role of N-methyl-D-aspartate receptor (NMDAR) related amino acids in drug-naive first episode psychosis (FEP) patients. The medication naïve patients with FEP (n = 40) and healthy volunteers with no family history of schizophrenia (n = 35) were recruited to the study and followed up for 10 weeks. Liquid chromatography-mass spectrometry method was used to measure plasma levels of the amino acids. The plasma glutamine, glutamic acid, proline, serine, asparagine, and hydroxyproline levels were significantly higher in the FEP patients compared to healthy controls (p values < .0001). The glutamine/glutamic acid ratio in FEP patients was not different from the healthy controls (p > .05). After the antipsychotic treatment, plasma glutamic acid, proline, and hydroxyproline levels were significantly increased (p values < .05) while the asparagine level and glutamine/glutamic acid ratio were decreased (p values < .05). The serine and glutamine levels did not show any differences with the treatment (p > .05). The initial plasma glutamine levels were negatively correlated with the initial Scale for the Assessment of Positive Symptoms (SAPS) score (r = -.45, p = .003). The initial plasma proline levels were negatively correlated with the initial and follow-up SAPS scores (r = -.51 and -.39, p values < .05). The initial plasma proline and hydroxyproline levels were both negatively correlated with the initial Brief Psychiatric Rating Scale score (r = -.37, p = .017 and r = -.33, p = .033, respectively). Increase in NMDAR-related amino acid levels during the FEP may be a compensatory response to glutamatergic hypofunction. Their plasma levels were significantly correlated with several psychotic symptoms before and after 10-week treatment. Antipsychotic treatment has differential effects on the plasma levels of these amino acids.


Assuntos
Ácido Glutâmico/sangue , Transtornos Psicóticos/sangue , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/sangue , Asparagina/sangue , Cromatografia Líquida , Feminino , Glutamina/sangue , Humanos , Hidroxiprolina/sangue , Masculino , Espectrometria de Massas , Prolina/sangue , Serina/sangue , Adulto Jovem
4.
Nutr Metab Cardiovasc Dis ; 29(10): 1040-1049, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31377179

RESUMO

BACKGROUND AND AIMS: Glutamate, glutamine are involved in energy metabolism, and have been related to cardiometabolic disorders. However, their roles in the development of type-2 diabetes (T2D) remain unclear. The aim of this study was to examine the effects of Mediterranean diet on associations between glutamine, glutamate, glutamine-to-glutamate ratio, and risk of new-onset T2D in a Spanish population at high risk for cardiovascular disease (CVD). METHODS AND RESULTS: The present study was built within the PREDIMED trial using a case-cohort design including 892 participants with 251 incident T2D cases and 641 non-cases. Participants (mean age 66.3 years; female 62.8%) were non diabetic and at high risk for CVD at baseline. Plasma levels of glutamine and glutamate were measured at baseline and after 1-year of intervention. Higher glutamate levels at baseline were associated with increased risk of T2D with a hazard ratio (HR) of 2.78 (95% CI, 1.43-5.41, P for trend = 0.0002). In contrast, baseline levels of glutamine (HR: 0.64, 95% CI, 0.36-1.12; P for trend = 0.04) and glutamine-to-glutamate ratio (HR: 0.31, 95% CI, 0.16-0.57; P for trend = 0.0001) were inversely associated with T2D risk when comparing extreme quartiles. The two Mediterranean diets (MedDiet + EVOO and MedDiet + mixed nuts) did not alter levels of glutamine and glutamate after intervention for 1 year. However, MedDiet mitigated the positive association between higher baseline plasma glutamate and T2D risk (P for interaction = 0.01). CONCLUSION: Higher levels of glutamate and lower levels of glutamine were associated with increased risk of T2D in a Spanish population at high risk for CVD. Mediterranean diet might mitigate the association between the imbalance of glutamine and glutamate and T2D risk. This trial is registered at http://www.controlled-trials.com, ISRCTN35739639.


Assuntos
Doenças Cardiovasculares/sangue , Diabetes Mellitus Tipo 2/sangue , Ácido Glutâmico/sangue , Glutamina/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Dieta Saudável , Dieta Mediterrânea , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevenção Primária/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Espanha/epidemiologia , Fatores de Tempo , Resultado do Tratamento
5.
Nutrients ; 11(7)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31330962

RESUMO

Both glutamine (Gln) and glutamate (Glu) are known to exist in plasma and brain. However, despite the assumed relationship between brain and plasma, no studies have clarified the association between them. Proton magnetic resonance spectroscopy (MRS) was sequentially performed twice, with a 60-min interval, on 10 males and 10 females using a 3T scanner. Blood samples for liquid chromatography-mass spectrometry (LC/MS) to measure Gln and Glu concentrations in plasma were collected during the time interval between the two MRS sessions. MRS voxels of interest were localized at the posterior cingulate cortex (PCC) and cerebellum (Cbll) and measured by the SPECIAL sequence. Spearman's correlation coefficient was used to examine the association between brain and plasma metabolites. The Gln concentrations in PCC (mean of two measurements) were positively correlated with Gln concentrations in plasma (p < 0.01, r = 0.72). However, the Glu concentrations in the two regions were not correlated with those in plasma. Consideration of the different dynamics of Gln and Glu between plasma and brain is crucial when addressing the pathomechanism and therapeutic strategies for brain disorders such as Alzheimer's disease and hepatic encephalopathy.


Assuntos
Química Encefálica , Ácido Glutâmico/análise , Glutamina/análise , Espectroscopia de Prótons por Ressonância Magnética , Adulto , Cerebelo/química , Cromatografia Líquida , Feminino , Ácido Glutâmico/sangue , Glutamina/sangue , Giro do Cíngulo/química , Humanos , Masculino , Espectrometria de Massas , Reprodutibilidade dos Testes , Adulto Jovem
6.
J Pediatr Endocrinol Metab ; 32(8): 803-809, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31246579

RESUMO

Background Arginine family amino acids (AFAAs) include glutamine (Gln) plus glutamate (Glu), ornithine (Orn), proline (Pro), citrulline (Cit) and arginine (Arg). We aimed to quantitate these amino acids in the blood of full-term infants in relation to their birth weight (BW) perinatally. Methods Breastfeeding full-term infants (n = 2000, 1000 males, 1000 females) with a BW of 2000-4000 g were divided into four equal groups: group A, 2000-2500 g; B, 2500-3000 g; C, 3000-3500 g and D, 3500-4000 g. Blood samples as dried blood spots (DBS) were collected on the third day of life and analyzed via a liquid chromatography tandem mass spectrometry (LC-MS/MS) protocol. Results Gln plus Glu mean values were found to be statistically significantly different between males and females in all studied groups. The highest values of these amino acids were detected in both males and females in group D. Orn mean values were found to be statistically significantly different between males and females of the same BW in all groups except the last one. The lower mean value was determined in group A, whereas the highest was determined in group D. Cit and Arg mean values were determined to be almost similar in all studied groups. Conclusions Gln plus Glu and Orn blood concentrations were directly related to infants' BW. Conversely, Cit and Arg did not vary significantly in all groups.


Assuntos
Arginina/sangue , Peso ao Nascer/fisiologia , Citrulina/sangue , Ácido Glutâmico/sangue , Glutamina/sangue , Ornitina/sangue , Prolina/sangue , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Recém-Nascido , Masculino , Prognóstico
7.
Artigo em Inglês | MEDLINE | ID: mdl-31216744

RESUMO

Excessive manganese (Mn) exposure may adversely affect the central nervous system, and cause an extrapyramidal disorder known as manganism. The glutamine (Gln)/glutamate (Glu)-γ-aminobutyric acid (GABA) cycle and thyroid hormone system may be involved in Mn-induced neurotoxicity. However, the effect of Mn on the Gln/Glu-GABA cycle in the serum has not been reported. Herein, the present study aimed to investigate the effects of sub-acute Mn exposure on the Gln/Glu-GABA cycle and thyroid hormones levels in the serum of rats, as well as their relationship. The results showed that sub-acute Mn exposure increased serum Mn levels with a correlation coefficient of 0.733. Furthermore, interruption of the Glu/Gln-GABA cycle in serum was found in Mn-exposed rats, as well as thyroid hormone disorder in the serum via increasing serum Glu levels, and decreasing serum Gln, GABA, triiodothyronine (T3) and thyroxine (T4) levels. Additionally, results of partial correlation showed that there was a close relationship between serum Mn levels and the detected indicators accompanied with a positive association between GABA and T3 levels, as well as Gln and T4 levels in the serum of Mn-exposed rats. Unexpectedly, there was no significant correlation between serum Glu and the serum T3 and T4 levels. In conclusion, the results demonstrated that both the Glu/Gln-GABA cycle and thyroid hormone system in the serum may play a potential role in Mn-induced neurotoxicity in rats. Thyroid hormone levels, T3 and T4, have a closer relationship with GABA and Gln levels, respectively, in the serum of rats.


Assuntos
Glutamina/sangue , Manganês/toxicidade , Hormônios Tireóideos/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Ácido gama-Aminobutírico/sangue , Animais , Masculino , Manganês/sangue , Ratos Sprague-Dawley
8.
Endocrinology ; 160(7): 1731-1742, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125048

RESUMO

Most patients with pancreatic cancer present with advanced disease and die within the first year after diagnosis. Predictive biomarkers that signal the presence of pancreatic cancer in an early stage are desperately needed. We aimed to identify new and validate previously found plasma metabolomic biomarkers associated with early stages of pancreatic cancer. Prediagnostic blood samples from individuals who were to receive a diagnosis of pancreatic cancer between 1 month and 17 years after sampling (N = 356) and age- and sex-matched controls (N = 887) were collected from five large population cohorts (HUNT2, HUNT3, FINRISK, Estonian Biobank, Rotterdam Study). We applied proton nuclear magnetic resonance-based metabolomics on the Nightingale platform. Logistic regression identified two interesting hits: glutamine (P = 0.011) and histidine (P = 0.012), with Westfall-Young family-wise error rate adjusted P values of 0.43 for both. Stratification in quintiles showed a 1.5-fold elevated risk for the lowest 20% of glutamine and a 2.2-fold increased risk for the lowest 20% of histidine. Stratification by time to diagnosis suggested glutamine to be involved in an earlier process (2 to 5 years before diagnosis), and histidine in a process closer to the actual onset (<2 years). Our data did not support the branched-chain amino acids identified earlier in several US cohorts as potential biomarkers for pancreatic cancer. Thus, although we identified glutamine and histidine as potential biomarkers of biological interest, our results imply that a study at this scale does not yield metabolomic biomarkers with sufficient predictive value to be clinically useful per se as prognostic biomarkers.


Assuntos
Biomarcadores Tumorais/sangue , Glutamina/sangue , Histidina/sangue , Neoplasias Pancreáticas/diagnóstico , Idoso , Bancos de Espécimes Biológicos , Estudos de Casos e Controles , Diagnóstico Precoce , Europa (Continente) , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Metabolômica , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue
9.
Pharm Biol ; 57(1): 280-286, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30990732

RESUMO

CONTEXT: Currently, there is no cure or early preclinical diagnostic assay available for depression. Recently, depression has been observed in association with metabolic abnormalities of the glutamate (Glu)-glutamine (Gln) cycling, which is regulated by Glu, Gln and γ-aminobutyric acid (GABA) amino acids. OBJECTIVE: The purpose of this study is to determine the changes of Glu, Gln and GABA in blood and brain of chronic unpredictable mild stress (CUMS) induced mice and to clarify the depression biomarkers in the Glu-Gln cycling. MATERIALS AND METHODS: Male Kunming mice were divided into model group and control group randomly (n = 12). The depression model of mice was established by CUMS stimulation for 56 days. The liquid chromatography-fluorescence method was used for simultaneous determination of Glu, Gln and GABA in the plasma and brain of mice. o-Phthalaldehyde and ß-mercaptoethanol were used as pre-column derivatization reagents. Neurotransmitters were analysed on high performance liquid chromatography (HPLC) on an HPH C18 column in combination with a fluorescence detector. RESULTS: The method was simple, highly sensitive and showed excellent linearity with regression coefficients higher than 0.999, good accuracy (95-108%) and good inter-day precision (RSD <15%) for all analytes. Limit of quantification (LOQ) values were established as 0.01, 0.01 and 0.005 µg/mL for Glu, Gln and GABA. The GABA in the CUMS mouse brain (p < 0.01) was significantly increased and Gln in plasma (p < 0.01) and brain (p < 0.01) were both decreased. CONCLUSIONS: Our study demonstrates that the Gln in plasma can be used as a biological marker of depression.


Assuntos
Comportamento Animal , Encéfalo/metabolismo , Depressão/metabolismo , Ácido Glutâmico/sangue , Glutamina/sangue , Estresse Psicológico/metabolismo , Animais , Depressão/sangue , Depressão/psicologia , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Masculino , Camundongos Endogâmicos
10.
Nutrients ; 11(4)2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31010101

RESUMO

Limited studies have assessed the associations of pretreatment serum glutamine level with clinicopathological characteristics and prognosis of colorectal cancer (CRC) patients. This study focuses on clarifying the clinical significance of baseline serum glutamine level in CRC patients. We retrospectively examine 123 patients with newly diagnosed CRC between 2009 and 2011. The associations of pretreatment serum glutamine level with clinicopathological characteristics, proinflammatory cytokines, overall survival (OS), and progression-free survival (PFS) were analyzed. We executed univariate and multivariate analyses to assess the associations between serum glutamine level and clinicopathological variables able to predict survival. Low glutamine levels were associated with older age, advanced stage, decreased albumin levels, elevated carcinoembryonic antigen levels, higher C-reactive protein levels, higher modified Glasgow prognostic scores, and higher proinflammatory cytokine levels. Furthermore, patients with low glutamine levels had poorer OS and PFS than those with high glutamine levels (p < 0.001 for both). In multivariate analysis, pretreatment glutamine level independently predicted OS (p = 0.016) and PFS (p = 0.037) in CRC patients. Pretreatment serum glutamine level constitutes an independent prognostic marker to predict survival and progression in CRC patients.


Assuntos
Neoplasias Colorretais/sangue , Glutamina/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/metabolismo , Biomarcadores Tumorais , Proteína C-Reativa/metabolismo , Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Citocinas/sangue , Progressão da Doença , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
11.
Acta Diabetol ; 56(5): 569-579, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30888539

RESUMO

AIMS: To investigate the interactions among fecal and plasma glutamate levels, insulin resistance cognition and gut microbiota composition in obese and non-obese subjects. METHODS: Gut microbiota composition (shotgun) and plasma and fecal glutamate, glutamine and acetate (NMR) were analyzed in a pilot study of obese and non-obese subjects (n = 35). Neuropsychological tests [Trail making test A (TMT-A) and Trail making test B (TMT-B)] scores measured cognitive information about processing speed, mental flexibility and executive function. RESULTS: Trail-making test score was significantly altered in obese compared with non-obese subjects. Fecal glutamate and glutamate/glutamine ratio tended to be lower among obese subjects while fecal glutamate/acetate ratio was negatively associated with BMI and TMT-A scores. Plasma glutamate/acetate ratio was negatively associated with TMT-B. The relative abundance (RA) of some bacterial families influenced glutamate levels, given the positive association of fecal glutamate/glutamine ratio with Corynebacteriaceae, Coriobacteriaceae and Burkholderiaceae RA. In contrast, Streptococaceae RA, that was significantly higher in obese subjects, negatively correlated with fecal glutamate/glutamine ratio. To close the circle, Coriobacteriaceae/Streptococaceae ratio and Corynebacteriaceae/Streptococaceae ratio were associated both with TMT-A scores and fecal glutamate/glutamine ratio. CONCLUSIONS: Gut microbiota composition is associated with processing speed and mental flexibility in part through changes in fecal and plasma glutamate metabolism.


Assuntos
Cognição/fisiologia , Fezes/química , Microbioma Gastrointestinal/fisiologia , Ácido Glutâmico/análise , Resistência à Insulina , Obesidade/fisiopatologia , Ácido Acético/análise , Ácido Acético/sangue , Bactérias/isolamento & purificação , Feminino , Ácido Glutâmico/sangue , Glutamina/análise , Glutamina/sangue , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Obesidade/complicações , Obesidade/microbiologia , Projetos Piloto , Teste de Sequência Alfanumérica
12.
Infect Immun ; 87(4)2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718287

RESUMO

The low bioavailability of nitric oxide (NO) and its precursor, arginine, contributes to the microvascular pathophysiology of severe falciparum malaria. To better characterize the mechanisms underlying hypoargininemia in severe malaria, we measured the plasma concentrations of amino acids involved in de novo arginine synthesis in children with uncomplicated falciparum malaria (UM; n = 61), children with cerebral falciparum malaria (CM; n = 45), and healthy children (HC; n = 109). We also administered primed infusions of l-arginine uniformly labeled with 13C6 and 15N4 to 8 children with severe falciparum malaria (SM; age range, 4 to 9 years) and 7 healthy children (HC; age range, 4 to 8 years) to measure the metabolic flux of arginine, hypothesizing that arginine flux is increased in SM. Using two different tandem mass spectrometric methods, we measured the isotopic enrichment of arginine in plasma obtained at 0, 60, 90, 120, 150, and 180 min during the infusion. The plasma concentrations of glutamine, glutamate, proline, ornithine, citrulline, and arginine were significantly lower in UM and CM than in HC (P ≤ 0.04 for all pairwise comparisons). Of these, glutamine concentrations were the most markedly decreased: median, 457 µM (interquartile range [IQR], 400 to 508 µM) in HC, 300 µM (IQR, 256 to 365 µM) in UM, and 257 µM (IQR, 195 to 320 µM) in CM. Arginine flux during steady state was not significantly different in SM than in HC by the respective mass spectrometric methods: 93.2 µmol/h/kg of body weight (IQR, 84.4 to 129.3 µmol/h/kg) versus 88.0 µmol/h/kg (IQR, 73.0 to 102.2 µmol/h/kg) (P = 0.247) by the two mass spectrometric methods in SM and 93.7 µmol/h/kg (IQR, 79.1 to 117.8 µmol/h/kg) versus 81.0 µmol/h/kg (IQR, 75.9 to 88.6 µmol/h/kg) (P = 0.165) by the two mass spectrometric methods in HC. A limited supply of amino acid precursors for arginine synthesis likely contributes to the hypoargininemia and NO insufficiency in falciparum malaria in children.


Assuntos
Arginina/sangue , Malária Falciparum/sangue , Plasmodium falciparum/fisiologia , Arginina/química , Criança , Pré-Escolar , Estudos Transversais , Feminino , Glutamina/sangue , Glutamina/química , Humanos , Lactente , Malária Falciparum/parasitologia , Masculino
13.
Anal Bioanal Chem ; 411(10): 2045-2055, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30739195

RESUMO

Glutaminolysis is the metabolic pathway that lyses glutamine to glutamate, alanine, citrate, aspartate, and so on. As partially recruiting reaction steps from the tricarboxylic acid (TCA) cycle and the malate-aspartate shuttle, glutaminolysis takes essential place in physiological and pathological situations. We herein developed a sensitive, rapid, and reproducible liquid chromatography-tandem mass spectrometry method to determine the perturbation of glutaminolysis in human plasma by quantifying 13 involved metabolites in a single 20-min run. A pHILIC column with a gradient elution system consisting of acetonitrile-5 mM ammonium acetate was used for separation, while an electrospray ionization source (ESI) operated in negative mode with multiple reaction monitoring was employed for detection. The method was fully validated according to FDA's guidelines, and it generally provided good results in terms of linearity (the correlation coefficient no less than 0.9911 within the range of 0.05-800 µg/mL), intra- and inter-day precision (less than 18.38%) and accuracy (relative standard deviation between 89.24 and 113.4%), with lower limits of quantification between 0.05 and 10 µg/mL. The new analytical approach was successfully applied to analyze the plasma samples from 38 healthy volunteers and 34 patients with type 2 diabetes (T2D). Based on the great sensitivity and comprehensive capacity, the targeted analysis revealed the imperceptible abnormalities in the concentrations of key intermediates, such as iso-citrate and cis-aconitate, thus allowing us to obtain a thorough understanding of glutaminolysis disorder during T2D. Graphical abstract ᅟ.


Assuntos
Cromatografia Líquida/métodos , Ciclo do Ácido Cítrico , Glutamina/sangue , Glutamina/metabolismo , Espectrometria de Massas em Tandem/métodos , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos
14.
Clin Chem ; 65(3): 406-418, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30647123

RESUMO

BACKGROUND: Clinical practice guidelines recommend estimation of glomerular filtration rate (eGFR) using validated equations based on serum creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys). However, when compared with the measured GFR (mGFR), only eGFRcr-cys meets recommended performance standards. Our goal was to develop a more accurate eGFR method using a panel of metabolites without creatinine, cystatin C, or demographic variables. METHODS: An ultra-performance liquid chromatography-tandem mass spectrometry assay for acetylthreonine, phenylacetylglutamine, pseudouridine, and tryptophan was developed, and a 20-day, multiinstrument analytical validation was conducted. The assay was tested in 2424 participants with mGFR data from 4 independent research studies. A new GFR equation (eGFRmet) was developed in a random subset (n = 1615) and evaluated in the remaining participants (n = 809). Performance was assessed as the frequency of large errors [estimates that differed from mGFR by at least 30% (1 - P30); goal <10%]. RESULTS: The assay had a mean imprecision (≤10% intraassay, ≤6.9% interassay), linearity over the quantitative range (r 2 > 0.98), and analyte recovery (98.5%-113%). There was no carryover, no interferences observed, and analyte stability was established. In addition, 1 - P30 in the validation set for eGFRmet (10.0%) was more accurate than eGFRcr (13.1%) and eGFRcys (12.0%) but not eGFRcr-cys (8.7%). Combining metabolites, creatinine, cystatin C, and demographics led to the most accurate equation (7.0%). Neither equation had substantial variation among population subgroups. CONCLUSIONS: The new eGFRmet equation could serve as a confirmatory test for GFR estimation.


Assuntos
Cromatografia Líquida/métodos , Taxa de Filtração Glomerular , Espectrometria de Massas em Tandem/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Glutamina/análogos & derivados , Glutamina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Pseudouridina/sangue , Reprodutibilidade dos Testes , Treonina/análogos & derivados , Treonina/sangue , Triptofano/sangue
15.
Mitochondrion ; 44: 65-74, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29337141

RESUMO

We evaluated plasma glutamine levels and basal mitochondrial oxygen consumption rate (mOCRB) and basal extracellular acidification rate (ECARB) of peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients and healthy controls (HCs). Lower plasma glutamine levels correlated with higher SLE disease activity indexes (p=0.025). Incubated in DMEM containing 100mg/dL glucose, SLE-PBMCs displayed lower mOCRB (p=0.018) but similar ECARB (p=0.467) to those of HC-PBMCs, and their mOCRB got elevated (p<0.001) without altering ECARB (p=0.239) by supplementation with 2 or 4mM glutamine. We conclude that impaired mitochondrial respiration of SLE-PBMCs could be improved by glutamine under euglycemic condition.


Assuntos
Glutamina/sangue , Leucócitos Mononucleares/química , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Mitocôndrias/metabolismo , Consumo de Oxigênio , Plasma/química , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Gastroenterology ; 156(4): 1098-1111, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30452920

RESUMO

BACKGROUND & AIMS: Activating transcription factor 4 (ATF4) regulates genes involved in the inflammatory response, amino acid metabolism, autophagy, and endoplasmic reticulum stress. We investigated whether its activity is altered in patients with inflammatory bowel diseases (IBDs) and mice with enterocolitis. METHODS: We obtained biopsy samples during endoscopy from inflamed and/or uninflamed regions of the colon from 21 patients with active Crohn's disease (CD), 22 patients with active ulcerative colitis (UC), and 38 control individuals without IBD and of the ileum from 19 patients with active CD and 8 individuals without IBD in China. Mice with disruption of Atf4 specifically in intestinal epithelial cells (Atf4ΔIEC mice) and Atf4-floxed mice (controls) were given dextran sodium sulfate (DSS) to induce colitis. Some mice were given injections of recombinant defensin α1 (DEFA1) and supplementation of l-alanyl-glutamine or glutamine in drinking water. Human and mouse ileal and colon tissues were analyzed by quantitative real-time polymerase chain reaction, immunoblots, and immunohistochemistry. Serum and intestinal epithelial cell (IEC) amino acids were measured by high-performance liquid chromatography-tandem mass spectrometry. Levels of ATF4 were knocked down in IEC-18 cells with small interfering RNAs. Microbiomes were analyzed in ileal feces from mice by using 16S ribosomal DNA sequencing. RESULTS: Levels of ATF4 were significantly decreased in inflamed intestinal mucosa from patients with active CD or active UC compared with those from uninflamed regions or intestinal mucosa from control individuals. ATF4 was also decreased in colonic epithelia from mice with colitis vs mice without colitis. Atf4ΔIEC mice developed spontaneous enterocolitis and colitis of greater severity than control mice after administration of DSS. Atf4ΔIEC mice had decreased serum levels of glutamine and reduced levels of antimicrobial peptides, such as Defa1, Defa4, Defa5, Camp, and Lyz1, in ileal Paneth cells. Atf4ΔIEC mice had alterations in ileal microbiomes compared with control mice; these changes were reversed by administration of glutamine. Injections of DEFA1 reduced the severity of spontaneous enteritis and DSS-induced colitis in Atf4ΔIEC mice. We found that expression of solute carrier family 1 member 5 (SLC1A5), a glutamine transporter, was directly regulated by ATF4 in cell lines. Overexpression of SLC1A5 in IEC-18 or primary IEC cells increased glutamine uptake and expression of antimicrobial peptides. Knockdown of ATF4 in IEC-18 cells increased expression of inflammatory cytokines, whereas overexpression of SLC1A5 in the knockdown cells reduced cytokine expression. Levels of SLC1A5 were decreased in inflamed intestinal mucosa of patients with CD and UC and correlated with levels of ATF4. CONCLUSIONS: Levels of ATF4 are decreased in inflamed intestinal mucosa from patients with active CD or UC. In mice, ATF4 deficiency reduces glutamine uptake by intestinal epithelial cells and expression of antimicrobial peptides by decreasing transcription of Slc1a5. ATF4 might therefore be a target for the treatment of IBD.


Assuntos
Fator 4 Ativador da Transcrição/deficiência , Peptídeos Catiônicos Antimicrobianos/metabolismo , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Glutamina/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Adolescente , Adulto , Sistema ASC de Transporte de Aminoácidos/genética , Sistema ASC de Transporte de Aminoácidos/metabolismo , Animais , Estudos de Casos e Controles , Linhagem Celular , Colite/induzido quimicamente , Colite/metabolismo , Colite Ulcerativa/sangue , Colite Ulcerativa/patologia , Colo/citologia , Colo/metabolismo , Doença de Crohn/sangue , Doença de Crohn/patologia , Células Epiteliais , Feminino , Técnicas de Silenciamento de Genes , Glutamina/sangue , Glutamina/farmacologia , Humanos , Íleo/citologia , Íleo/metabolismo , Íleo/microbiologia , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Microbiota/efeitos dos fármacos , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Celulas de Paneth/metabolismo , Adulto Jovem
17.
Biol Psychiatry ; 85(4): 345-354, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30446206

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BCAAs) may contribute to the behavioral characteristics of ASD, we tested whether dysregulation of amino acids (AAs) was a pervasive phenomenon in individuals with ASD. This is the first article to report results from the Children's Autism Metabolome Project (CAMP), a large-scale effort to define autism biomarkers based on metabolomic analyses of blood samples from young children. METHODS: Dysregulation of AA metabolism was identified by comparing plasma metabolites from 516 children with ASD with those from 164 age-matched typically developing children recruited into the CAMP. ASD subjects were stratified into subpopulations based on shared metabolic phenotypes associated with BCAA dysregulation. RESULTS: We identified groups of AAs with positive correlations that were, as a group, negatively correlated with BCAA levels in ASD. Imbalances between these two groups of AAs identified three ASD-associated amino acid dysregulation metabotypes. The combination of glutamine, glycine, and ornithine amino acid dysregulation metabotypes identified a dysregulation in AA/BCAA metabolism that is present in 16.7% of the CAMP subjects with ASD and is detectable with a specificity of 96.3% and a positive predictive value of 93.5% within the ASD subject cohort. CONCLUSIONS: Identification and utilization of metabotypes of ASD can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions.


Assuntos
Transtorno do Espectro Autista/sangue , Glutamina/sangue , Glicina/sangue , Ornitina/sangue , Transtorno do Espectro Autista/classificação , Transtorno do Espectro Autista/diagnóstico , Biomarcadores/sangue , Estudos de Casos e Controles , Pré-Escolar , Biologia Computacional , Feminino , Humanos , Lactente , Masculino , Metabolômica , Valor Preditivo dos Testes , Sensibilidade e Especificidade
18.
JAMA Neurol ; 76(3): 342-350, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30575854

RESUMO

Importance: The identification and understanding of the monogenic causes of neurodevelopmental disorders are of high importance for personalized treatment and genetic counseling. Objective: To identify and characterize novel genes for a specific neurodevelopmental disorder characterized by refractory seizures, respiratory failure, brain abnormalities, and death in the neonatal period; describe the outcome of glutaminase deficiency in humans; and understand the underlying pathological mechanisms. Design, Setting, and Participants: We performed exome sequencing of cases of neurodevelopmental disorders without a clear genetic diagnosis, followed by genetic and bioinformatic evaluation of candidate variants and genes. Establishing pathogenicity of the variants was achieved by measuring metabolites in dried blood spots by a hydrophilic interaction liquid chromatography method coupled with tandem mass spectrometry. The participants are 2 families with a total of 4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse volume loss of the brain, and cerebral edema. Data analysis occurred from October 2017 to June 2018. Main Outcomes and Measures: Early neonatal epileptic encephalopathy with glutaminase deficiency and lethal outcome. Results: A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included. We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family. The GLS gene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system. All 3 variants probably lead to a loss of function and thus glutaminase deficiency. Indeed, glutamine was increased in affected children (available z scores, 3.2 and 11.7). We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system. Conclusions and Relevance: We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy. This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Glutaminase/deficiência , Mutação/genética , Encéfalo/metabolismo , Encefalopatias/diagnóstico , Epilepsia/diagnóstico , Feminino , Glutamina/sangue , Humanos , Lactente , Recém-Nascido , Masculino , Convulsões/diagnóstico , Convulsões/genética
19.
Sci Rep ; 8(1): 15976, 2018 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-30374076

RESUMO

Anxiety-related disorders, including fearfulness are common and leading welfare problems among the worldwide dog population. The etiology of anxieties is complex and affected by genetic and environmental factors. Thus, there is a need for more comprehensive approaches, such as metabolomics, to understand the causes of anxiety and to identify anxiety-related biomarkers for more efficient diagnostic and treatment options. To study metabolic alterations related to canine fearfulness, a non-targeted plasma metabolite profiling was performed in a cohort of 20 fearful and 21 non-fearful dogs. The results showed that nine metabolic features were significantly associated with fearfulness. The most prominent change included increased plasma glutamine and γ-glutamyl glutamine (γ-Glu Gln) in fearful dogs across breeds. Alterations in glutamine metabolism have previously been associated with several psychiatric disorders, indicating the relevance of this finding also in dogs. In addition, we describe a novel breed-specific association between renal biomarker symmetric dimethylarginine (SDMA) and canine fearfulness. These observed metabolic alterations may result from high levels of prolonged psychological stress in fearful dogs.


Assuntos
Dipeptídeos/sangue , Cães/sangue , Medo/fisiologia , Glutamina/sangue , Animais , Ansiedade/sangue , Arginina/análogos & derivados , Arginina/sangue , Comportamento Animal , Biomarcadores , Cruzamento , Cães/classificação , Cães/psicologia , Feminino , Masculino , Metaboloma , Especificidade da Espécie
20.
J Proteome Res ; 17(10): 3517-3525, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30207476

RESUMO

To identify and screen serum biomarkers to determine pediatric patients with congenital heart diseases (PCH) from healthy control children (NC), a total of 614 clinically diagnosed subjects from three hospitals, including 491 PCH and 234 NC, were enrolled for nontargeted proton nuclear magnetic resonance spectroscopy (1H NMR)-based and targeted ultra-high-performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS)-based metabolomics studies. Nineteen serum metabolites distinguishing PCH from NC were identified by 1H NMR-based metabolomic analysis. The amino acid and choline metabolic pathways were considered to be closely related to PCH. The serum levels of 13 metabolites in these two pathways were further determined by UPLC-MS/MS and observed to be altered significantly in PCH. Taurine, glutamine, and glutamate presented considerable diagnostic value for the diagnosis of PCH (AUROC > 0.80). Logistic regression analysis showed that a combination of four variables, namely, betaine, taurine, glutamine, and phenylalanine, yields a high diagnostic value (AUROC = 0.949) and prediction accuracy (89.1%) for differentiating PCH from the NC, and the sensitivity and specificity were 93.9 and 95.2%, respectively. Further double-blind sample prediction showed that the accuracy of the model was 83.8% for 80 unknown samples. Our results showed that the serum amino acid and choline metabolite levels in PCH were changed considerably. The combination of four metabolites, namely, betaine, taurine, glutamine, and phenylalanine, can be used as potential serum biomarkers in PCH diagnosis, which contributes to the early PCH screening.


Assuntos
Biomarcadores/metabolismo , Cardiopatias Congênitas/metabolismo , Metaboloma , Metabolômica/métodos , Betaína/sangue , Biomarcadores/sangue , Criança , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Glutamina/sangue , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/diagnóstico , Humanos , Modelos Logísticos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Fenilalanina/sangue , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos , Taurina/sangue
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