Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.170
Filtrar
1.
Nutrients ; 13(2)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567505

RESUMO

Scope: To identify a metabolomic profile related to postprandial satiety sensations involved in appetite control would help for a better understanding of the regulation of food intake. Methods and Results: A cross-sectional analysis of plasma metabolites was conducted over 151 overweight/obese adults from the "Satiety Innovation"-SATIN study, a randomized clinical trial of a 12-week weight-loss maintenance period. Postprandial satiety sensations (3 h-iAUC) were assessed by visual analogue scale (VAS) at the beginning and at the end of the study. Fasting plasma metabolites were profiled using a targeted multiplatform metabolomics approach before each appetite test meal. Associations between 124 metabolites and iAUC-satiety were assessed using elastic net linear regression analyses. The accuracy of the multimetabolite weighted models for iAUC-VAS was evaluated using a 10-fold cross-validation (CV) approach and the Pearson's correlation coefficients were estimated. Five and three metabolites were selected in the first and the second assessments, respectively. Circulating glycine and linoleic acid concentrations were consistently and positively associated with higher iAUC-satiety in both visits. Sucrose and sphingomyelins (C32:2, C38:1) were negatively associated with iAUC-satiety in the first visit. The Pearson correlations coefficients between the metabolomic profiles and iAUC-satiety in the first and the second appetite assessments were 0.37 and 0.27, respectively. Conclusion: Higher glycine and linoleic acid were moderately but consistently associated with higher postprandial satiety in two different appetite assessments in overweight and obese subjects.


Assuntos
Regulação do Apetite/fisiologia , Obesidade/sangue , Sobrepeso/sangue , Período Pós-Prandial/fisiologia , Saciação/fisiologia , Adulto , Idoso , Área Sob a Curva , Estudos Transversais , Método Duplo-Cego , Jejum/sangue , Feminino , Glicina/sangue , Humanos , Modelos Lineares , Ácido Linoleico/sangue , Masculino , Metaboloma , Pessoa de Meia-Idade , Fosfatidilcolinas/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Esfingomielinas/sangue , Sacarose/sangue , Escala Visual Analógica , Adulto Jovem
2.
Am J Physiol Renal Physiol ; 320(3): F351-F358, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33459166

RESUMO

A heterozygous mutation (c.643C.A; p.Q215X) in the creatine transporter SLC16A12 has been proposed to cause a syndrome with juvenile cataracts, microcornea, and glucosuria in humans. To further explore the role of SLC16A12 in renal physiology and decipher the mechanism underlying the phenotype of humans with the SLC16A12 mutation, we studied Slc16a12 knockout (KO) rats. Slc16a12 KO rats had lower plasma levels and increased absolute and fractional urinary excretion of creatine and its precursor guanidinoacetate (GAA). Slc16a12 KO rats displayed lower plasma and urinary creatinine levels, but the glomerular filtration rate was normal. The phenotype of heterozygous rats was indistinguishable from wild-type (WT) rats. Renal artery to vein (RAV) concentration differences in WT rats were negative for GAA and positive for creatinine. However, RAV differences for GAA were similar in Slc16a12 KO rats, indicating incomplete compensation of urinary GAA losses by renal GAA synthesis. Together, our results reveal that Slc16a12 in the basolateral membrane of the proximal tubule is critical for the reabsorption of creatine and GAA. Our data suggest a dominant-negative mechanism underlying the phenotype of humans affected by the heterozygous SLC16A12 mutation. Furthermore, in the absence of Slc16a12, urinary losses of GAA are not adequately compensated by increased tubular synthesis, likely caused by feedback inhibition of the rate-limiting enzyme l-arginine:glycine amidinotransferase by creatine in proximal tubular cells.NEW & NOTEWORTHY SLC16A12 is a recently identified creatine transporter of unknown physiological function. A heterozygous mutation in the human SLC16A12 gene causes juvenile cataracts and reduced plasma guanidinoacetate (GAA) levels with an increased fractional urinary excretion of GAA. Our study with transgenic SLC16A12-deficient rats reveals that SLC16A12 is critical for tubular reabsorption of creatine and GAA in the kidney. Our data furthermore indicate a dominant-negative mechanism underlying the phenotype of humans affected by the heterozygous SLC16A12 mutation.


Assuntos
Creatinina/urina , Glicina/análogos & derivados , Túbulos Renais Proximais/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Reabsorção Renal , Animais , Creatinina/sangue , Técnicas de Inativação de Genes , Genótipo , Glicina/sangue , Glicina/urina , Fígado/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Fenótipo , Ratos Endogâmicos F344 , Ratos Transgênicos
3.
Nutrients ; 12(12)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352682

RESUMO

Circulating levels of branched-chain amino acids, glycine, or aromatic amino acids have been associated with risk of type 2 diabetes. However, whether those associations reflect causal relationships or are rather driven by early processes of disease development is unclear. We selected diabetes-related amino acid ratios based on metabolic network structures and investigated causal effects of these ratios and single amino acids on the risk of type 2 diabetes in two-sample Mendelian randomization studies. Selection of genetic instruments for amino acid traits relied on genome-wide association studies in a representative sub-cohort (up to 2265 participants) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study and public data from genome-wide association studies on single amino acids. For the selected instruments, outcome associations were drawn from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis, 74,124 cases and 824,006 controls) consortium. Mendelian randomization results indicate an inverse association for a per standard deviation increase in ln-transformed tyrosine/methionine ratio with type 2 diabetes (OR = 0.87 (0.81-0.93)). Multivariable Mendelian randomization revealed inverse association for higher log10-transformed tyrosine levels with type 2 diabetes (OR = 0.19 (0.04-0.88)), independent of other amino acids. Tyrosine might be a causal trait for type 2 diabetes independent of other diabetes-associated amino acids.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Tirosina/sangue , Adulto , Aminoácidos Aromáticos/sangue , Aminoácidos de Cadeia Ramificada/sangue , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Glicina/sangue , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos
4.
J Anim Sci ; 98(5)2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32283549

RESUMO

Body temperature maintenance is one of the most important physiological processes initiated after birth. Brown adipose tissue (BAT) is an essential mediator of thermogenesis in many species and is responsible for 50% of the heat generated in the newborn lamb. To determine if maternal arginine supplementation could enhance thermogenesis in the neonate, we randomly assigned 31 multiparous Suffolk ewes, gestating singletons or twins, to receive intravenous injections of either l-arginine (27 mg/kg body weight; n = 17) or sterile saline (n = 14) three times daily from day 75 to 125 of gestation (term = 147). Following parturition, lambs were removed from their mothers and subjected to 0 °C cold challenges at 4 and 22 h of age. Rectal temperatures were higher for the duration of the cold challenges in lambs from arginine-treated ewes compared with lambs from saline-treated ewes (P < 0.05). Elevated rectal temperatures were associated with increased (P < 0.05) circulating glycine and serine concentrations in lambs. The mRNA expression of genes related to BAT function changed over time, but not between lambs from arginine-treated vs. saline-treated ewes. Results indicate that maternal arginine treatment increases neonatal thermogenesis after birth. Although the underlying mechanisms remain to be elucidated, these data are a first step in improving neonatal survival in response to cold.


Assuntos
Arginina/administração & dosagem , Suplementos Nutricionais/análise , Ovinos/fisiologia , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/fisiologia , Administração Intravenosa/veterinária , Animais , Animais Recém-Nascidos , Temperatura Corporal , Temperatura Baixa , Feminino , Glicina/sangue , Parto , Gravidez , Serina/sangue , Ovinos/sangue
5.
J Nutr ; 150(4): 722-729, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31773161

RESUMO

BACKGROUND: Cys is limiting for reduced glutathione (GSH) synthesis and can be synthesized from Met. We hypothesized that the dietary Met hydroxyl analogue dl-2-hydroxy-4-methylthiobutyric acid (dl-HMTBA) affects Cys and GSH metabolism and oxidative stress defense differently than Met. OBJECTIVE: The objective was to elucidate whether dl-HMTBA supplementation of a Met-deficient diet affects Cys flux, GSH fractional synthetic rate (FSR), and the basal oxidative stress level relative to Met supplementation in pigs. METHODS: Twenty-nine male German Landrace piglets aged 28 d were allocated to 3 dietary groups: a basal diet limiting in Met (69% of Met plus Cys requirement) supplemented with either 0.15% l-Met (LMET; n = 9), 0.15% dl-Met (DLMET; n = 11), or 0.17% dl-HMTBA (DLHMTBA; n = 9) on an equimolar basis. At age 54 d the pigs received a continuous infusion of [1-13C]-Cys to calculate Cys flux and Cys oxidation. After 3 d, GSH FSR was determined by [2,2-2H2]-glycine infusion, and RBC GSH and oxidized GSH concentrations were measured. At age 62 d the animals were killed to determine hepatic mRNA abundances of enzymes involved in GSH metabolism, GSH concentrations, and plasma oxidative stress defense markers. RESULTS: The Cys oxidation was 21-39% and Cys flux 5-15% higher in the fed relative to the feed-deprived state (P < 0.001). On average, GSH FSR was 49% lower (P < 0.01), and RBC GSH and total GSH concentrations were 12% and 9% lower, respectively, in DLHMTBA and DLMET relative to LMET pigs (P < 0.05). In the feed-deprived state, Gly flux, the GSH:oxidized glutathione (GSSG) ratio, RBC GSSG concentrations, plasma oxidative stress markers, and the hepatic GSH content did not differ between groups. CONCLUSIONS: Although GSH FSR was higher in LMET compared with DLMET or DLHMTBA feed-deprived pigs, these differences were not reflected by lower oxidative stress markers and antioxidant defense enzymes in LMET pigs.


Assuntos
Aminoácidos Sulfúricos/administração & dosagem , Dieta/veterinária , Glutationa/biossíntese , Metionina/análogos & derivados , Sus scrofa/metabolismo , Aminoácidos/sangue , Animais , Antioxidantes/análise , Biomarcadores/sangue , Cisteína/sangue , Suplementos Nutricionais , Eritrócitos/química , Glutationa/análise , Glutationa/sangue , Glicina/sangue , Fígado/química , Masculino , Metionina/administração & dosagem , Estresse Oxidativo/fisiologia , Desmame
6.
Ann Pharmacother ; 54(1): 29-35, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31416331

RESUMO

Background: High-dose methotrexate (HD-MTX) therapy is widely implemented for leukemia, osteosarcoma, and lymphoma. Although various measures have been taken to avoid toxicity from high serum MTX concentrations, there are many cases of delayed elimination of MTX. Objective: We suspected that delayed elimination of serum MTX was caused by unknown interactions between MTX and concomitant drugs. Methods: Concerning concomitant drugs in the case of delayed elimination of MTX, we performed screening tests in 35 patients who had undergone HD-MTX therapy. We then investigated the risk factors for delayed MTX elimination in 94 patients with leukemia, lymphoma, or osteosarcoma retrospectively. Results: The percentages of concomitant use of Stronger Neo-Minophagen C (SNMC), a glycyrrhizin preparation, and vincristine were higher in the delayed group. The percentage of delayed MTX elimination in patients receiving HD-MTX therapy was 41%. Multiple logistic regression analysis revealed that the concomitant use of SNMC solely was a significant risk factor for delayed MTX (odds ratio = 12.20; 95% CI = 1.06-139.84). Conclusion and Relevance: Concomitant use of SNMC was shown to be related to delayed elimination of serum MTX, and our results suggested a previously unknown drug-drug interaction between MTX and SNMC.


Assuntos
Monitoramento de Medicamentos/métodos , Metotrexato/administração & dosagem , Metotrexato/sangue , Cisteína/administração & dosagem , Cisteína/sangue , Cisteína/uso terapêutico , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Glicina/administração & dosagem , Glicina/sangue , Glicina/uso terapêutico , Ácido Glicirretínico/administração & dosagem , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/sangue , Ácido Glicirretínico/uso terapêutico , Humanos , Leucemia/sangue , Leucemia/tratamento farmacológico , Modelos Logísticos , Linfoma/sangue , Linfoma/tratamento farmacológico , Masculino , Taxa de Depuração Metabólica , Metotrexato/uso terapêutico , Osteossarcoma/sangue , Osteossarcoma/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco , Vincristina/administração & dosagem , Vincristina/sangue , Vincristina/uso terapêutico
7.
J Nutr ; 150(3): 443-449, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31687740

RESUMO

BACKGROUND: Arginine:glycine amidinotransferase, necessary for the conversion of arginine (Arg) to guanidinoacetic acid (GAA), is expressed mainly in kidney and pancreas. The methylation of GAA to creatine (Cre) primarily occurs in the liver. The role of the gut in Cre homeostasis has not been characterized. OBJECTIVE: We aimed to quantify the contribution of kidney, pancreas, and gut as sources of GAA for Cre synthesis. METHODS: Sow-reared, feed-deprived Yucatan miniature piglets (17-21 d old) were randomly assigned to acute intravenous treatments (expressed in µmol/kg/min) of: 1) Arg (4.8) + methionine (1.4) (Arg/Met), 2) Cre (0.6) with Arg/Met (Cre/Arg/Met), 3) citrulline (4.8) + methionine (1.4) (Cit/Met), or 4) alanine (6.2) (Ala). Suckling piglets were also studied. RESULTS: Renal GAA release was higher during Cit/Met compared with all other treatments (53-360% higher; P < 0.01), suggesting that Cit is a better precursor than Arg for renal GAA synthesis. Kidneys contributed higher (P < 0.01) proportions of the total GAA with Cit/Met (89%) and Arg/Met (68%) treatments compared with pancreas and gut. In the suckling pigs, kidneys contributed 88% of the GAA, with the remainder released by pancreas. None of the treatments resulted in a net flux of Cre across the kidney or pancreas. In the gut, Arg/Met and Cre/Arg/Met, but not Cit/Met, resulted in a net release of Cre. Cre/Arg/Met resulted in a higher net GAA release from the gut (P < 0.0001) and pancreas (P < 0.001) (68% of total GAA produced) compared with all other treatments (<19% from both organs), perhaps because GAA not needed for creatine synthesis was subsequently released. CONCLUSIONS: Cit is a better precursor than Arg for renal GAA synthesis, and kidney is the major source of GAA for Cre synthesis in neonatal piglets, but the gut also has the capacity to synthesize GAA and Cre when Arg and Met are available.


Assuntos
Creatina/biossíntese , Glicina/análogos & derivados , Mucosa Intestinal/metabolismo , Rim/metabolismo , Fígado/metabolismo , Pâncreas/metabolismo , Aminoácidos/metabolismo , Animais , Creatina/sangue , Feminino , Glicina/sangue , Glicina/metabolismo , Metilação , Suínos , Porco Miniatura
8.
Nutrients ; 12(1)2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31878000

RESUMO

Bile acids play an active role in fat metabolism and, in high-fat diets, elevated concentrations of fecal bile acids may be related to an increased risk of colorectal cancer. This study investigated concentrations of fecal and serum bile acids in 36 vegans and 36 omnivores. The reduced rank regression was used to identify dietary patterns associated with fecal bile acids. Dietary patterns were derived with secondary and conjugated fecal bile acids as response variables and 53 food groups as predictors. Vegans had higher fiber (p < 0.01) and lower fat (p = 0.0024) intake than omnivores. In serum, primary and glycine-conjugated bile acids were higher in vegans than in omnivores (p ≤ 0.01). All fecal bile acids were significantly lower in vegans compared to omnivores (p < 0.01). Processed meat, fried potatoes, fish, margarine, and coffee contributed most positively, whereas muesli most negatively to a dietary pattern that was directly associated with all fecal bile acids. According to the pattern, fat intake was positively and fiber intake was inversely correlated with bile acids. The findings contribute to the evidence that, in particular, animal products and fat may play a part in higher levels of fecal bile acids.


Assuntos
Ácidos e Sais Biliares/análise , Ácidos e Sais Biliares/sangue , Dieta Vegana , Dieta , Fezes/química , Adulto , Animais , Café , Estudos Transversais , Fibras na Dieta/administração & dosagem , Peixes , Glicina/sangue , Humanos , Masculino , Margarina , Carne , Pessoa de Meia-Idade , Fatores de Transcrição/administração & dosagem , Veganos
9.
Respir Res ; 20(1): 254, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718676

RESUMO

BACKGROUND: Pulmonary and systemic inflammation are central features of chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated relationships between biologically active extracellular matrix components, or matrikines, and COPD pathogenesis. We studied the relationships between the matrikine acetyl-proline-glycine-proline (AcPGP) in sputum and plasma and clinical features of COPD. METHODS: Sputum and plasma samples were obtained from COPD participants in the SPIROMICS cohort at enrollment. AcPGP was isolated using solid phase extraction and measured by mass spectrometry. Demographics, spirometry, quality of life questionnaires, and quantitative computed tomography (CT) imaging with parametric response mapping (PRM) were obtained at baseline. Severe COPD exacerbations were recorded at 1-year of prospective follow-up. We used linear and logistic regression models to measure associations between AcPGP and features of COPD, and Kaplan-Meier analyses to measure time-to-first severe exacerbation. RESULTS: The 182 COPD participants in the analysis were 66 ± 8 years old, 62% male, 84% White race, and 39% were current smokers. AcPGP concentrations were 0.61 ± 1.89 ng/mL (mean ± SD) in sputum and 0.60 ± 1.13 ng/mL in plasma. In adjusted linear regression models, sputum AcPGP was associated with FEV1/FVC, spirometric GOLD stage, PRM-small airways disease, and PRM-emphysema. Sputum AcPGP also correlated with severe AECOPD, and elevated sputum AcPGP was associated with shorter time-to-first severe COPD exacerbation. In contrast, plasma AcPGP was not associated with symptoms, pulmonary function, or severe exacerbation risk. CONCLUSIONS: In COPD, sputum but not plasma AcPGP concentrations are associated with the severity of airflow limitation, small airways disease, emphysema, and risk for severe AECOPD at 1-year of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01969344 (SPIROMICS).


Assuntos
Glicina/sangue , Prolina/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Espirometria/métodos , Escarro/metabolismo , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escarro/química
10.
PLoS One ; 14(11): e0224274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31697702

RESUMO

Glycated hemoglobin (HbA1c) is an indicator of the average blood glucose concentration. Failing to control HbA1c levels can accelerate the development of complications in patients with diabetes. Although metabolite profiles associated with HbA1c level in diabetes patients have been characterized using different platforms, more studies using high-throughput technology will be helpful to identify additional metabolites related to diabetes. Type 2 diabetes (T2D) patients were divided into two groups based on the HbA1c level: normal (HbA1c ≤6%) and high (HbA1c ≥9%) in both discovery and replication sets. A targeted metabolomics approach was used to quantify serum metabolites and multivariate logistic regression was used to identify significant differences between groups. The concentrations of 22 metabolites differed significantly between the two groups in the discovery set. In the replication set, the levels of 21 metabolites, including 16 metabolites identified in the discovery set, differed between groups. Among these, concentrations of eleven amino acids and one phosphatidylcholine (PC), lysoPC a C16:1, were higher and four metabolites, including three PCs (PC ae C36:1, PC aa C26:0, PC aa C34:2) and hexose, were lower in the group with normal HbA1c group than in the group with high HbA1c. Metabolites with high concentrations in the normal HbA1c group, such as glycine, valine, and PCs, may contribute to reducing HbA1c levels in patients with T2D. The metabolite signatures identified in this study provide insight into the mechanisms underlying changes in HbA1c levels in T2D.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Metabolômica , Idoso , Aminoácidos/sangue , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Glicina/sangue , Hexoses/sangue , Humanos , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Fosfatidilcolinas/sangue , Valina/sangue
11.
Physiol Res ; 68(6): 1033-1036, 2019 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-31647299

RESUMO

Guanidinoacetic acid (GAA) is a fundamental intermediate in cellular bioenergetics, with circulating levels of GAA often reflects disturbances in its conversion due to many intrinsic and extrinsic factors, including gender or age. Here, we evaluated serum GAA in 172 healthy women aged 18 to 65 years, with age found to significantly predict serum GAA concentrations (r=0.29; P=0.03). This perhaps nominates serum GAA as a novel gender-specific proxy of impaired bioenergetics with aging.


Assuntos
Envelhecimento/sangue , Metabolismo Energético/fisiologia , Exercício Físico/fisiologia , Glicina/análogos & derivados , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Feminino , Glicina/sangue , Humanos , Vida Independente/tendências , Pessoa de Meia-Idade , Adulto Jovem
12.
Anal Biochem ; 587: 113447, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31562850

RESUMO

Glycine analysis is important in research fields such as physiology and healthcare because the concentration of glycine in human plasma has been reported to change with various disorders. Glycine oxidase from Bacillus subtilis (GlyOX) is useful for quantitative analysis of glycine. However, GlyOX is not sufficiently stable for use in physiology-based research or clinical settings. In this report, site-directed mutagenesis was used to engineer a GlyOX mutant suitable for glycine analysis. The GlyOX triple-mutant (T42 A/C245 S/L301V) retained most of its enzymatic activity during storage for over a year at 4 °C. A colorimetric enzyme analysis protocol was established using the GlyOX triple-mutant to determine glycine concentrations in human plasma. The analysis showed high accuracy (-5.4 to 3.5% relative errors when compared with the results from an amino acid analyzer, and 96.0-98.7% recoveries) and high precision (<4% between-run variation). Sample pretreatments of deproteinization and derivatization were not required. Therefore, this novel enzymatic analysis offers an effective and useful method for determining glycine concentrations in physiology related research and the healthcare field.


Assuntos
Aminoácido Oxirredutases/genética , Análise Química do Sangue , Colorimetria , Glicina/sangue , Aminoácido Oxirredutases/metabolismo , Engenharia Genética , Humanos , Mutação
13.
Amino Acids ; 51(10-12): 1485-1499, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31535220

RESUMO

L-Arginine:glycine amidinotransferase (AGAT) is the main producer of the creatine precursor, guanidinoacetate (GAA), and L-homoarginine (hArg). We and others previously reported lower levels of circulating and urinary hArg in renal transplant recipients (RTR) compared to healthy subjects. In adults, hArg emerged as a novel risk factor for renal and cardiovascular adverse outcome. Urinary GAA was found to be lower in children and adolescents with kidney transplants compared to healthy controls. Whether GAA is also a risk factor in the renal and cardiovascular systems of adults, is not yet known. In the present study, we aimed to investigate the significance of circulating GAA and the GAA-to-hArg molar ratio (GAA/hArg) in adult RTR. We hypothesized that GAA/hArg represents a measure of the balanced state of the AGAT activity in the kidneys, and would prospectively allow assessing a potential association between GAA/hArg and long-term outcome in RTR. The median follow-up period was 5.4 years. Confounders and potential mediators of GAA/hArg associations were evaluated with multivariate linear regression analyses, and the association with all-cause and cardiovascular mortality or death-censored graft loss was studied with Cox regression analyses. The study cohort consisted of 686 stable RTR and 140 healthy kidney donors. Median plasma GAA concentration was significantly lower in the RTR compared to the kidney donors before kidney donation: 2.19 [1.77-2.70] µM vs. 2.78 [2.89-3.35] µM (P < 0.001). In cross-sectional multivariable analyses in RTR, HDL cholesterol showed the strongest association with GAA/hArg. In prospective analyses in RTR, GAA/hArg was associated with a higher risk for all-cause mortality (hazard ratio (HR): 1.35 [95% CI 1.19-1.53]) and cardiovascular mortality (HR: 1.46 [95% CI 1.24-1.73]), independent of potential confounders. GAA but not GAA/hArg was associated with death-censored graft loss in crude survival and Cox regression analyses. The association of GAA and death-censored graft loss was lost after adjustment for eGFR. Our study suggests that in the kidneys of RTR, the AGAT-catalyzed biosynthesis of GAA is decreased. That high GAA/hArg is associated with a higher risk for all-cause and cardiovascular mortality may suggest that low plasma hArg is a stronger contributor to these adverse outcomes in RTR than GAA.


Assuntos
Doenças Cardiovasculares/mortalidade , Glicina/análogos & derivados , Homoarginina/sangue , Transplante de Rim/mortalidade , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Causas de Morte , Estudos Transversais , Feminino , Seguimentos , Glicina/sangue , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Fatores de Risco
14.
Clin Chim Acta ; 498: 116-121, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442447

RESUMO

BACKGROUND: Isovaleric acidemia (IVA), a rare autosomal recessive disorder in leucine metabolism caused by defected IVD gene, is characterized by episodes of acute metabolic crisis and psychomotor development retardation. This study aimed to determine the clinical, biochemical, and mutation spectrum of patients with IVA from mainland China. METHODS: Eight patients (three boys and five girls) from eight unrelated families were collected, IVD gene mutations and phenotypes were examined. RESULTS: The patients were admitted because of vomiting, feeding difficulty, psychomotor retardation and "dirty sock" odor. Elevated blood isovaleryl (C5)-carnitine and urine isovalerylglycine were detected from all our patients. Fourteen mutations of the IVD gene were detected, eight of them are novel, c.145C>T (p.Q49Ter), c.359G>A (p.R120Q), c.424C>T (p.R142C), c.458T>C (p.L153P), c.466-1G>T, c.676_677insA (p.T226Nfs*13), c.1039G>A (p.A347T) and c.1076A>G (p.D359G). With this study, a total of 34 alleles were studied in the Chinese population. c.1208A>G (p.Y403C), the common mutation in Taiwan, accounts for 9/34 alleles (7 in previous reports and 2 in this study). CONCLUSIONS: We described eight novel mutations detected from eight unrelated Chinese patients and provided evidence to support that the p.Y403C is the hotspot mutation in this population.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Grupo com Ancestrais do Continente Asiático/genética , Isovaleril-CoA Desidrogenase/deficiência , Mutação , Alelos , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Carnitina/sangue , China/epidemiologia , Feminino , Glicina/sangue , Humanos , Recém-Nascido , Isovaleril-CoA Desidrogenase/genética , Masculino , Fenótipo
15.
Biomed Chromatogr ; 33(11): e4658, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325170

RESUMO

Isocitrate dehydrogenase (IDH) inhibitors comprise a novel class of anticancer drugs, which are approved to treat acute myeloid leukemia patients having mutations on IDH1/2. We report the development and validation of a high-performance liquid chromatography (HPLC) method for the simultaneous quantitation of IDH inhibitors, namely enasidenib (EDB), ivosidenib (IDB) and vorasidenib (VDB), in mouse plasma as per the US Food and Drug Administration regulatory guidelines. The method involves extraction of EDB, IDB and VDB along with internal standard (IS; phenacetin) from mouse plasma (100 µl) using a simple protein precipitation process. The chromatographic analysis was performed on an HPLC system using a gradient mobile phase (comprising 10 mm ammonium acetate and acetonitrile in a flow-gradient) and an X-Terra Phenyl column. The UV detection wave length was set at λmax 265 nm. EDB, IDB, VDB and the IS eluted at 7.36, 8.60, 9.50 and 5.12 min, respectively, with a total run time of 10 min. The calibration curve was linear over a concentration range of 0.20-12.5 µg/ml for EDB and 0.50-12.5 µg/ml for IDB and VDB (r2  = ≥0.998 for all of the analytes). Validation results met the acceptance criteria. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.


Assuntos
Aminopiridinas/sangue , Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/sangue , Triazinas/sangue , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Estabilidade de Medicamentos , Glicina/sangue , Glicina/química , Glicina/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Piridinas/química , Piridinas/farmacocinética , Reprodutibilidade dos Testes , Triazinas/química , Triazinas/farmacocinética
16.
Sci Rep ; 9(1): 10319, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311965

RESUMO

Low-dose CT has shown promise in detecting early stage lung cancer. However, concerns about the adverse health effects of radiation and high cost prevent its use as a population-wide screening tool. Effective and feasible screening methods to triage suspicious patients to CT are needed. We investigated human lung cancer metabolomics from 93 paired tissue-serum samples with magnetic resonance spectroscopy and identified tissue and serum metabolomic markers that can differentiate cancer types and stages. Most interestingly, we identified serum metabolomic profiles that can predict patient overall survival for all cases (p = 0.0076), and more importantly for Stage I cases alone (n = 58, p = 0.0100), a prediction which is significant for treatment strategies but currently cannot be achieved by any clinical method. Prolonged survival is associated with relative overexpression of glutamine, valine, and glycine, and relative suppression of glutamate and lipids in serum.


Assuntos
Biomarcadores/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Metabolômica/métodos , Idoso , Feminino , Glutamina/sangue , Glicina/sangue , Humanos , Neoplasias Pulmonares/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Valina/sangue
17.
J Pharm Biomed Anal ; 174: 175-181, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31170631

RESUMO

Glufosinate and glyphosate, which are non-selective herbicides that include an amino acid moiety in their structures, are frequently used worldwide to control unwanted vegetation. Unfortunately, these readily available herbicides are also used by people to commit suicide, and thus represent important chemicals of interest in the fields of clinical medicine and forensics. Because of the high water solubility of these herbicides, most analytical methods for their detection require a derivatization step, which results in longer analysis times. Therefore, derivatization-based methods do not currently contribute to judgements on treatment decisions in emergency medicine. In this study, we addressed this limiting factor by developing an ultra-rapid and simple analytical technique using a combination of probe electrospray ionization (PESI) and tandem mass spectrometry (MS/MS), which gives quantitative results within 0.3 min. Herbicide standards were added to human serum that was then subjected to analysis (N = 5 per concentration). The analysis was repeated daily over eight consecutive days. The limit of detection (LOD) was 0.59 µg/mL for glufosinate and 0.20 µg/mL for glyphosate. The limit of quantitation (LOQ), i.e., the lowest point on the calibration curves, was 1.56 µg/mL for both the herbicides. The matrix effects were observed at three different concentrations (between 95.7%-104% for glufosinate, and between 90.7%-95.7% for glyphosate). When applied to samples taken from actual poisoning cases (six samples for each herbicide), the present method gave almost the same quantitative values as those obtained by conventional high-performance liquid chromatography with fluorescence detection. Thus, we believe that PESI-MS/MS could emerge as a rapid diagnosis method in the clinical emergency field.


Assuntos
Aminobutiratos/sangue , Glicina/análogos & derivados , Herbicidas/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Aminobutiratos/envenenamento , Calibragem , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Glicina/sangue , Glicina/envenenamento , Herbicidas/envenenamento , Humanos , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Extração em Fase Sólida
18.
Metab Brain Dis ; 34(5): 1467-1472, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31230217

RESUMO

Nonketotic hyperglycinemia (NKH) is a neuro-metabolic disorder caused by a deficiency in the glycine cleavage system (GCS) and glycine transporter 1 (GlyT1). A case of atypical late onset of NKH has been reported in a colony of captive-bred Vervet monkeys. The purpose of this study was to evaluate the effect of sodium benzoate and dextromethorphan in reducing glycine levels in hyperglycinemic monkeys. Twelve captive-bred Vervet monkeys were assigned into three groups consisting of four animals (control, valproate induced and cataract with spontaneous hyperglycinemia). Valproate was used to elevate glycine levels and the induced group was then treated with sodium benzoate and dextromethorphan together with group three to normalise glycine levels in cerebrospinal fluid (CSF) and plasma. Valproate induction elicited changes in phosphate, alkaline phosphatase and platelet count, however, no significant changes in the glycine levels were observed, and this might be due to the individual variability within the group. The treatment intervention was only obtained in the spontaneous group whereby the glycine levels were normalised in CSF and plasma. Therefore, it can be concluded that sodium benzoate and dextromethorphan treatment was effective and beneficial to the hyperglycinemic group.


Assuntos
Dextrometorfano/uso terapêutico , Glicina/sangue , Hiperglicinemia não Cetótica/tratamento farmacológico , Benzoato de Sódio/uso terapêutico , Animais , Chlorocebus aethiops , Hiperglicinemia não Cetótica/sangue , Resultado do Tratamento
19.
J Am Heart Assoc ; 8(10): e011922, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31070104

RESUMO

Background Recent studies have revealed sexually dimorphic associations between the carbamoyl-phosphate synthase 1 locus, intermediates of the metabolic pathway leading from choline to urea, and risk of coronary artery disease ( CAD ) in women. Based on evidence from the literature, the atheroprotective association with carbamoyl-phosphate synthase 1 could be mediated by the strong genetic effect of this locus on increased circulating glycine levels. Methods and Results We sought to identify additional genetic determinants of circulating glycine levels by carrying out a meta-analysis of genome-wide association study data in up to 30 118 subjects of European ancestry. Mendelian randomization and other analytical approaches were used to determine whether glycine-associated variants were associated with CAD and traditional risk factors. Twelve loci were significantly associated with circulating glycine levels, 7 of which were not previously known to be involved in glycine metabolism ( ACADM , PHGDH , COX 18- ADAMTS 3, PSPH , TRIB 1, PTPRD , and ABO ). Glycine-raising alleles at several loci individually exhibited directionally consistent associations with decreased risk of CAD . However, these effects could not be attributed directly to glycine because of associations with other CAD -related traits. By comparison, genetic models that only included the 2 variants directly involved in glycine degradation and for which there were no other pleiotropic associations were not associated with risk of CAD or blood pressure, lipid levels, and obesity-related traits. Conclusions These results provide additional insight into the genetic architecture of glycine metabolism, but do not yield conclusive evidence for a causal relationship between circulating levels of this amino acid and risk of CAD in humans.


Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Loci Gênicos , Glicina/sangue , Polimorfismo de Nucleotídeo Único , Biomarcadores/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Fenótipo , Medição de Risco , Fatores de Risco
20.
J Pharm Biomed Anal ; 173: 1-17, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31100508

RESUMO

An ultrahigh performance liquid chromatography tandem mass spectrometry method (UHPLC-MS/MS) was developed for the determination of 41 target and 8 additional bile acids isomers (BAs) in biological fluids. BAs were analysed by solid-phase extraction on 50 µL biofluid-aliquots, followed by a properly optimised 27 min-chromatographic run. The method provided high sensitivity (limits of detection 0.0002-0.03 µM, limits of quantitation 0.0007-0.11 µM), linearity (R2>0.99) and precision (relative standard deviations ≤16%). A strategy of scheduled/ unscheduled injections of real samples together with neutral loss (80 Da and 176 Da) scans allowed us to find additional bile acid isomers not a priori included in the method, while high resolution full scan and MS/MS fragmentation analysis confirmed their structural adherence to the bile acid family. Moreover this is the first study quantifying four sulfate glycine conjugated-dihydroxy bile acid isomers, independently of the diet and postprandial time. Application to a dietary intervention kinetic study confirmed the existence of possible metabotypes amongst the study population (n = 20). A trend differentiating males from females was observed suggesting that serum samples from women contained smaller amounts of certain bile acids.


Assuntos
Ácidos e Sais Biliares/sangue , Glucuronídeos/sangue , Glicina/sangue , Técnica de Diluição de Radioisótopos , Ácidos e Sais Biliares/química , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão/métodos , Jejum/sangue , Feminino , Glucuronídeos/química , Glicina/química , Humanos , Limite de Detecção , Masculino , Período Pós-Prandial , Reprodutibilidade dos Testes , Fatores Sexuais , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...