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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1067-1072, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703127

RESUMO

OBJECTIVE: To determine the incidence and mutational types of fatty acid oxidation disorders (FAOD) in central-northern region of Guangxi. METHODS: A total of 62 953 neonates were screened for FAOD during December 2012 and December 2017. Acyl-carnitine profiling of neonatal blood sample was performed by tandem mass spectrometry using dry blood spots on a filter paper. The diagnosis of FAOD was confirmed by organic acid profiling of urea and genetic testing. RESULTS: Eighteen cases of FAOD were diagnosed among the 62 953 neonates. Among these, primary carnitine deficiency (PCD) was the most common type (n=13), which was followed by short-chain acyl-CoA dehydrogenase deficiency (SCADD) (n=2), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) (n=1), multiple acyl-CoA dehydrogenase deficiency (MADD) (n=1), and carnitine palmitoyltransferase II deficiency (CPT II D) (n=1). Genetic testing has revealed two previously unreported variants, i.e., c.337G to A (p.Gly113Arg) of ACADS gene and c.737G TO T (p.Gly246Val) of ETFA gene. CONCLUSION: PCD is the most common FAOD in central-northern Guangxi. Tandem mass spectrometry combined with genetic testing may facilitate early diagnosis of FAOD.


Assuntos
Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Carnitina/sangue , Carnitina O-Palmitoiltransferase/deficiência , China , Flavoproteínas Transferidoras de Elétrons/genética , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/diagnóstico , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Triagem Neonatal , Espectrometria de Massas em Tandem
2.
Zhonghua Er Ke Za Zhi ; 57(10): 797-801, 2019 Oct 02.
Artigo em Chinês | MEDLINE | ID: mdl-31594068

RESUMO

Objective: To investigate the profiles of blood amino acid and acylcarnitine in early neonates with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and the sensitivity of newborn screening, and to explore potential biochemical metabolic markers for newborn screening program. Methods: Amino acid and acylcarnitine profiles in dried blood spots of newborn screening program were analyzed by tandem mass spectrometry (MS/MS). A total of 158 651 neonates born in Guangzhou from January 1, 2015 to June 30, 2019 were enrolled in this newborn screening program, and additionally 55 patients with NICCD confirmed by SLC25A13 gene analysis in Guangzhou Women and Children Medical Center were included in this study. NICCD screen-positive was defined as the cutoff value of citrulline (Cit) ≥ 30 µmol/L. The values of blood sampling time of the true positive group and those of the false negative group were compared by t-test. The levels of amino acid and acylcarnitine among different groups, including true positive group (Cit≥30 µmol/L), false negative group (Cit 21-<30 µmol/L and Cit<21 µmol/L) and the normal control group, were analyzed by F test, respectively. Results: Among 158 651 neonates, 39 neonates were positive for NICCD screening. Three of them were confirmed NICCD and 4 cases were found to be false negatives. The positive predictive value was 7.7% and the sensitivity was about 43.0%. Among 55 patients with NICCD, 18 cases (18/55, 32.7%) were true positives and 37 cases (37/55, 67.3%) were false negatives based on the cutoff value of citrulline in the dried blood spots for newborn screening. The blood sampling time was significantly different between true positive group and false negative group ((4.28±1.6) vs. (2.98±0.74) d, t=4.06, P<0.01). The increased levels of tyrosine((176.0±98.4) µmol/L), methionine ((37.0±26.9) µmol/L) and phenylalanine ((133.0±80.9)µmol/L) in Cit≥30 µmol/L group (n=18) were significantly different as compared with those in the other three groups, respectively (F=117.0, 58.5, 135.0, P<0.01). The levels of arginine ( (10.0±9.2) , (11.0±9.3) , (9.0±17.8) µmol/L), valine ( (119.0±29.8) , (107.6±14.1) , (102±68) µmol/L) and leucine ( (167.0±37.1) , (161.0±37.7) , (163.5±180.6) µmol/L) were not statistically significant among groups of Cit≥30 µmol/L(n=18), Cit21-<30 µmol/L(n=7) and Cit<21µmol/L(n=30,P>0.05), but they were significantly higher than those of the normal control group ((4±3), (78±21), (114.0±31.5) µmol/L, n=1 000), respectively(F=30.1, 23.0, 29.8, P<0.01). Alanine (Ala) ( (150±50) , (156.0±30.2), (168±105), (152±52) µmol/L) levels showed no significant difference (F=0.86, P>0.05) but the ratios of Ala/Cit (1.52±1.44, 6.82±1.56, 12.06±7.71, 19.42±6.27) decreased significantly among the four groups (F=69.0, P<0.05). The acylcarnitine levels showed no statistically significant results among the different groups (P>0.05). With Cit≥30 µmol/L and Ala/Cit<7.5 as cutoff values, the number of screen-positive cases reduced from 39 to 22 cases with no additional false negative case. With Cit≥21 µmol/L and Ala/Cit<7.5 as cutoff values the number of screen-positive cases increased to 117 cases with 1 additional true positive. Conclusions: The profiles of blood amino acid in early neonates with NICCD present the increased levels of multiple amino acids including citrulline, tyrosine, methionine and phenylalanine, and decreased ratio of Ala/Cit. Taking citrulline and ratio of Ala/Cit as screening markers can improve the positive predictive value appropriately. The limited sensitivity of NICCD newborn screening may be related to early blood sampling time.


Assuntos
Aminoácidos/sangue , Carnitina/análogos & derivados , Citrulinemia/diagnóstico , Triagem Neonatal/métodos , Carnitina/sangue , Criança , Citrulinemia/sangue , Feminino , Humanos , Recém-Nascido , Proteínas de Transporte da Membrana Mitocondrial , Espectrometria de Massas em Tandem
3.
Amino Acids ; 51(9): 1259-1271, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31388851

RESUMO

Cardiovascular disease (CVD) and chronic kidney disease (CKD) constitute substantial burdens for public health. The identification and validation of risk markers for CVD and CKD in epidemiological studies requires frequent adaption of existing analytical methods as well as development of new methods. In this study, an analytical procedure to simultaneously quantify ten endogenous biomarkers for CVD and CKD is described. An easy-to-handle sample preparation requiring only 20 µL of human plasma is followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The method was successfully validated according to established guidelines meeting required criteria for accuracy, precision, recovery, linearity, selectivity, and limits of quantification. The scalability of the method for application in larger cohorts was assessed using a set of plasma samples from healthy volunteers (n = 391) providing first reference values for the recently established biomarker Nɛ-acetyllysine (Nɛ-AcLys). Other biomarkers analyzed were creatinine, ß-aminoisobutyric acid (ß-AIB), carnitine, 1-methylnicotinamide (1-MNA), citrulline, symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA), homoarginine (hArg), and ornithine. All obtained results are within reference values specified elsewhere. Overall, these results demonstrate the suitability of the method for simultaneous quantification of ten endogenous biomarkers for CVD and CKD in plasma samples from larger cohorts and allow validation of Nɛ-AcLys as a biomarker in large cohorts.


Assuntos
Cromatografia Líquida/métodos , Lisina/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Arginina/análogos & derivados , Arginina/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Carnitina/sangue , Citrulina/sangue , Creatinina/sangue , Feminino , Homoarginina/sangue , Humanos , Lisina/sangue , Lisina/normas , Masculino , Pessoa de Meia-Idade , Ornitina/sangue , Valores de Referência , Insuficiência Renal Crônica/sangue , Adulto Jovem
4.
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
5.
Nutrients ; 11(9)2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31450550

RESUMO

l-carnitine is an important co-factor in fatty-acid metabolism, and its deficiency is associated with insulin resistance, which is independently associated with arterial stiffness. This study evaluated the relationship between serum l-carnitine level and peripheral arterial stiffness (PAS) in kidney transplantation (KT). Fasting blood samples were collected from 65 patients who underwent KT. We measured the brachial-ankle pulse wave velocity, and 36 patients (55.4%) had PAS. Patients with PAS had a significantly higher percentage of diabetes (p = 0.001), hypertension (p = 0.033), and metabolic syndrome (p = 0.044); higher waist circumference (p = 0.010), systolic blood pressure (p = 0.002), serum triglyceride level (p = 0.040), insulin level (p = 0.002), and homeostasis model assessment of insulin resistance (p = 0.002); lower high-density lipoprotein cholesterol (p = 0.036) and serum l-carnitine levels (p < 0.001); older age (p = 0.041); and a longer KT duration (p = 0.025) than those without PAS. Statistical analysis revealed an independent association between PAS in KT and KT duration (95% confidence interval (CI): 1.003-1.054, p = 0.029) and serum l-carnitine levels (95% CI: 0.842-0.998, p = 0.044). The area under the receiver operating characteristic curve indicated that the diagnostic power of l-carnitine to predict PAS was 0.789 (95% CI: 0.670-0.881, p < 0.001). Serum-free l-carnitine level is negatively associated with PAS in patients who undergo KT.


Assuntos
Nefropatias/cirurgia , Transplante de Rim , Doença Arterial Periférica/diagnóstico , Rigidez Vascular , Adulto , Índice Tornozelo-Braço , Biomarcadores/sangue , Carnitina/sangue , Estudos Transversais , Regulação para Baixo , Feminino , Humanos , Nefropatias/sangue , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/fisiopatologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
6.
Invest Ophthalmol Vis Sci ; 60(8): 3119-3126, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323682

RESUMO

Purpose: To determine plasma metabolite and metabolic pathway differences between patients with type 2 diabetes with diabetic retinopathy (DR) and without retinopathy (diabetic controls), and between patients with proliferative DR (PDR) and nonproliferative DR (NPDR). Methods: Using high-resolution mass spectrometry with liquid chromatography, untargeted metabolomics was performed on plasma samples from 83 DR patients and 90 diabetic controls. Discriminatory metabolic features were identified through partial least squares discriminant analysis, and linear regression was used to adjust for age, sex, diabetes duration, and hemoglobin A1c. Pathway analysis was performed using Mummichog 2.0. Results: In the adjusted analysis, 126 metabolic features differed significantly between DR patients and diabetic controls. Pathway analysis revealed alterations in the metabolism of amino acids, leukotrienes, niacin, pyrimidine, and purine. Arginine, citrulline, glutamic γ-semialdehyde, and dehydroxycarnitine were key contributors to these pathway differences. A total of 151 features distinguished PDR patients from NPDR patients, and pathway analysis revealed alterations in the ß-oxidation of saturated fatty acids, fatty acid metabolism, and vitamin D3 metabolism. Carnitine was a major contributor to the pathway differences. Conclusions: This study demonstrates that arginine and citrulline-related pathways are dysregulated in DR, and fatty acid metabolism is altered in PDR patients compared with NPDR patients.


Assuntos
Arginina/sangue , Carnitina/sangue , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida , Diabetes Mellitus Tipo 2/sangue , Retinopatia Diabética/etiologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Acuidade Visual
7.
Int J Mol Sci ; 20(15)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349613

RESUMO

Treatment with all-trans retinoic acid (ATRA), the carboxylic form of vitamin A, lowers body weight in rodents by promoting oxidative metabolism in multiple tissues including white and brown adipose tissues. We aimed to identify novel markers of the metabolic impact of ATRA through targeted blood metabolomics analyses, with a focus on acylcarnitines and amino acids. Blood was obtained from mice treated with a high ATRA dose (50 mg/kg body weight/day, subcutaneous injection) or placebo (controls) during the 4 days preceding collection. LC-MS/MS analyses with a focus on acylcarnitines and amino acids were conducted on plasma and PBMC. Main results showed that, relative to controls, ATRA-treated mice had in plasma: increased levels of carnitine, acetylcarnitine, and longer acylcarnitine species; decreased levels of citrulline, and increased global arginine bioavailability ratio for nitric oxide synthesis; increased levels of creatine, taurine and docosahexaenoic acid; and a decreased n-6/n-3 polyunsaturated fatty acids ratio. While some of these features likely reflect the stimulation of lipid mobilization and oxidation promoted by ATRA treatment systemically, other may also play a causal role underlying ATRA actions. The results connect ATRA to specific nutrition-modulated biochemical pathways, and suggest novel mechanisms of action of vitamin A-derived retinoic acid on metabolic health.


Assuntos
Aminoácidos/sangue , Carnitina/análogos & derivados , Metaboloma/efeitos dos fármacos , Metabolômica , Tretinoína/farmacologia , Tecido Adiposo , Animais , Carnitina/sangue , Perfilação da Expressão Gênica , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Metabolômica/métodos , Camundongos , Modelos Biológicos , Oxirredução/efeitos dos fármacos
8.
Intern Med ; 58(19): 2891-2894, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31243204

RESUMO

Pivoxil-containing cephalosporins can result in symptomatic hypocarnitinemia in children. We herein report a case of an 85-year-old man at risk of carnitine deficiency who developed relapsing symptomatic hypoglycemia after treatment with cefcapene pivoxil for urinary tract infection. On admission, laboratory tests showed low blood carnitine concentrations with low normal blood ketone levels. The patient was successfully treated by the oral administration of levocarnitine and dietary modification, including aggressive consumption of meat and dairy products, and remained symptom-free for nine months after the correction of carnitine concentrations. Healthcare providers should be cautious when prescribing pivoxil-containing antimicrobials to patients at high risk of hypocarnitinemia.


Assuntos
Cardiomiopatias/induzido quimicamente , Carnitina/deficiência , Cefalosporinas/efeitos adversos , Hiperamonemia/induzido quimicamente , Hipoglicemia/induzido quimicamente , Doenças Musculares/induzido quimicamente , Administração Oral , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Cardiomiopatias/sangue , Cardiomiopatias/complicações , Carnitina/sangue , Cefalosporinas/administração & dosagem , Humanos , Hiperamonemia/sangue , Hiperamonemia/complicações , Hipoglicemia/sangue , Hipoglicemia/complicações , Masculino , Doenças Musculares/sangue , Doenças Musculares/complicações , Recidiva , Infecções Urinárias/tratamento farmacológico
9.
Pediatr Int ; 61(6): 551-557, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31033143

RESUMO

BACKGROUND: Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is a rare autosomal recessive disorder that affects the degradation of medium-chain fatty acids. Few cases of MCADD have been documented to date in mainland China. METHODS: Medium-chain acyl-coenzyme A dehydrogenase deficiency was diagnosed in six patients (three girls and three boys) from six unrelated Chinese families at ages ranging from 10 days to 3 years old. The diagnosis was confirmed by the identification of a primary biomarker of serum octanoyl-carnitine (C8) and genetic pathogenic mutations. RESULTS: Only two patients were admitted because of vomiting, diarrhea, myasthenia, and coma; the other four patients were diagnosed via the newborn screening process. Six mutations were found in acyl-CoA dehydrogenase medium chain (ACADM). One mutation (c.727C>T) was novel and the others (c.158G>A, c.387+1delG, c.449_452del, c.1045C>T, and c.1085G>A) have been previously reported. CONCLUSIONS: Six Chinese cases of MCADD were identified. One novel mutation was found. c.449_452del and c.1085G>A were common mutations in this study.


Assuntos
Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Acil-CoA Desidrogenase/sangue , Biomarcadores/sangue , Carnitina/análogos & derivados , Carnitina/sangue , Pré-Escolar , China , Feminino , Marcadores Genéticos , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Mutação , Triagem Neonatal
10.
Mol Genet Metab ; 127(1): 64-73, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31031081

RESUMO

BACKGROUND: Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is a disorder of fatty acid oxidation included in the recommended uniform newborn screening (NBS) panel in the USA. It can have variable clinical severity and there is limited information on the natural history of this condition, clinical presentation according to genotype and effectiveness of newborn screening. METHODS: Retrospective data (growth parameters, morbidity, biochemical and genetic testing results) were collected from patients with VLCAD deficiency, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate continuous variables. RESULTS: VLCAD deficiency (screened by measuring elevated levels of C14:1-carnitine in blood spots) was more frequent in Utah than the national average (1:27,617 versus 1:63,481) in the first ten years of screening. Twenty-six patients had a confirmed diagnosis of VLCAD deficiency using DNA testing or functional studies. The c.848T>C (p.V283A) variant in the ACADVL gene was the most frequent in our population. Novel variants (c.623-21A>G (IVS7-21A>G); c.1052C>T (p.T351I); c.1183-7A>G (IVS11-7A>G); c.1281G>C (p.W427C); c.1923G>C (p.L641F); c.1924G>A (p.V642M)) were identified in this study, with their pathogenicity remaining unclear in most cases. C14:1-carnitine levels decreased with age and significantly correlated with CK levels as index of muscle involvement. There were no cases of HELLP syndrome nor liver disease during pregnancies in the mothers of VLCAD patients. None of our patients developed cardiac involvement after birth and all patients had normal growth parameters while on treatment. Clinical manifestations were related to concomitant infections and altered biochemical parameters. DISCUSSION: VLCAD deficiency can be identified by neonatal screening. Most patients compliant with therapy normalized biochemical parameters and had no major clinical manifestations. Complications were completely prevented with a relatively low number of pre-emptive ER visits or hospital admissions. It remains unclear whether neonatal screening is now identifying less severely affected patient or if complications will arise as subjects become older. Observation beyond puberty is necessary to fully understand the impact of VLCAD deficiency on morbidity in patients with VLCAD deficiency.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Variação Genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Triagem Neonatal , Acil-CoA Desidrogenase de Cadeia Longa/genética , Adolescente , Carnitina/sangue , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/terapia , Masculino , Doenças Mitocondriais/terapia , Morbidade , Doenças Musculares/terapia , Estudos Retrospectivos , Resultado do Tratamento , Utah , Adulto Jovem
11.
Nutrients ; 11(4)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013835

RESUMO

It has been established that OMEGA-3 polyunsaturated fatty acids (PUFAs) may improve lipid and glucose homeostasis and prevent the "low-grade" state of inflammation in animals. Little is known about the effect of PUFAs on adipocytokines expression and biologically active lipids accumulation under the influence of high-fat diet-induced obesity. The aim of the study was to examine the effect of fish oil supplementation on adipocytokines expression and ceramide (Cer) and diacylglycerols (DAG) content in visceral and subcutaneous adipose tissue of high-fat fed animals. The experiments were carried out on Wistar rats divided into three groups: standard diet-control (SD), high-fat diet (HFD), and high-fat diet + fish oil (HFD+FO). The fasting plasma glucose and insulin concentrations were examined. Expression of carnitine palmitoyltransferase 1 (CPT1) protein was determined using the Western blot method. Plasma adipocytokines concentration was measured using ELISA kits and mRNA expression was determined by qRT-PCR reaction. Cer, DAG, and acyl-carnitine (A-CAR) content was analyzed by UHPLC/MS/MS. The fish oil supplementation significantly decreased plasma insulin concentration and Homeostatic Model Assesment for Insulin Resistance (HOMA-IR) index and reduced content of adipose tissue biologically active lipids in comparison with HFD-fed subjects. The expression of CPT1 protein in HFD+FO in both adipose tissues was elevated, whereas the content of A-CAR was lower in both HFD groups. There was an increase of adiponectin concentration and expression in HFD+FO as compared to HFD group. OMEGA-3 fatty acids supplementation improved insulin sensitivity and decreased content of Cer and DAG in both fat depots. Our results also demonstrate that PUFAs may prevent the development of insulin resistance in response to high-fat feeding and may regulate the expression and secretion of adipocytokines in this animal model.


Assuntos
Adiponectina/sangue , Tecido Adiposo/efeitos dos fármacos , Suplementos Nutricionais , Ácidos Graxos Ômega-3/farmacologia , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/sangue , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Carnitina/análogos & derivados , Carnitina/sangue , Carnitina O-Palmitoiltransferase/sangue , Ceramidas/metabolismo , Dieta Hiperlipídica , Diglicerídeos/metabolismo , Ensaio de Imunoadsorção Enzimática , Óleos de Peixe/farmacologia , Insulina/sangue , Gordura Intra-Abdominal/metabolismo , Masculino , Obesidade/etiologia , Reação em Cadeia da Polimerase , Distribuição Aleatória , Ratos Wistar , Gordura Subcutânea/metabolismo
12.
Contrib Nephrol ; 198: 73-77, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30991404

RESUMO

BACKGROUND: Carnitine deficiency is a common condition in hemodialysis patients. Therefore, abnormalities in fatty acid metabolism and organic acid metabolism are also common in dialysis patients. Tandem mass spectrometry is a standard technique in pediatric and neonatal medicine. However, it could be a new powerful tool in other fields for estimating the state of intracellular fatty acid metabolism. SUMMARY: Tandem mass spectrometry has recently revealed the relationships between carnitine profile and dialysis patients' anemia, reduced physical function, and survival rate. Fatty acid and organic acid metabolism, which could previously only be evaluated qualitatively, can now be quantitatively assessed. Key Message: The applications of tandem mass spectrometry are expected to expand not only in the field of dialysis but also in clinical medicine in general.


Assuntos
Cardiomiopatias/diagnóstico , Carnitina/deficiência , Hiperamonemia/diagnóstico , Doenças Musculares/diagnóstico , Diálise Renal/efeitos adversos , Espectrometria de Massas em Tandem/métodos , Ácidos Carboxílicos/metabolismo , Cardiomiopatias/etiologia , Carnitina/sangue , Ácidos Graxos/metabolismo , Humanos , Hiperamonemia/etiologia , Doenças Musculares/etiologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-30999273

RESUMO

Changes in metabolites composition can reflect currently present pathological processes in a living organism and constitute a basis for diagnosis and treatment improvements. Thus, the multiplatform metabolomics approach was applied for the investigation of molecular mechanisms of chronic kidney disease (CKD) progression. The high-performance liquid chromatography coupled with time-of-flight mass spectrometry (HPLC-TOF-MS) and gas chromatography coupled with triple quadrupole mass spectrometry (GC-QqQ/MS) serum metabolic fingerprinting followed by uni- and multivariate statistical analysis was carried out to determine metabolic pattern differentiating CKD patients and healthy controls. Furthermore, metabolites changes between stage 3 and 4 of the disease, as well as health status were investigated. The progression of the disease was found to be related to alterations in acylcarnitine, amino acid, lysophospholipid and carbohydrate metabolism. Elevated levels of serum acylcarnitines, sugar alcohols, and organic acids, as well as decreased levels of lysophospholipids, and amino acids, were found to be statistically significant for CKD progression. The obtained results confirm the utility of metabolomics approach as a tool for an explanation of molecular processes underlying CKD development.


Assuntos
Metaboloma/fisiologia , Metabolômica/métodos , Insuficiência Renal Crônica , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Carnitina/análogos & derivados , Carnitina/sangue , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão/métodos , Análise por Conglomerados , Progressão da Doença , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/metabolismo
14.
Medicine (Baltimore) ; 98(15): e15221, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985723

RESUMO

Optimal prognostic markers evaluating early neuroprotective interventions in neonatal hypoxic-ischemic encephalopathy (HIE) are lacking. This study was designed to assess the prognostic value of acylcarnitines in neonatal HIE.An observational cohort study was conducted over 10 years in 67 HIE. Variables analyzed included sex, blood cord pH, Apgar score, hypothermia treatment (yes/no), neuron-specific enolase (NSE) levels, and clinical outcome (neurological examination, brain magnetic resonance imaging [MRI], and electroencephalogram) before discharge and at 6 months. Acylcarnitine profiles were analyzed by tandem-mass spectrometry on dried-blood spots collected on day 3 for newborn screening. A cohort of healthy newborns was used as control group.HIE patients had significantly increased C4, C5, C5:1, C6, C6-OH, C8 levels (all P < .01) and decreased long-chain acylcarnitine levels (P < .03). Hypothermia treatment was associated with a decrease in C4 levels (p = 0.005) and an increase in most long-chain acylcarnitine levels (P < .01). A significant association was found between C4 levels and NSE on day 1 of hypothermia treatment (P = .002) and abnormal brain magnetic resonance imaging (MRI) at discharge (P = .037). In the hypothermia group, C4 levels decreased in patients with favorable outcomes but remained high in those who progressed unfavorably.C4 appears to be a good prognostic marker in HIE, as blood levels correlated with NSE levels and abnormal MRI findings. Furthermore, hypothermia did not lead to decreased levels in patients with adverse outcomes.


Assuntos
Carnitina/análogos & derivados , Hipóxia-Isquemia Encefálica/sangue , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Carnitina/sangue , Feminino , Humanos , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Recém-Nascido , Masculino , Fosfopiruvato Hidratase/sangue , Prognóstico , Estudos Retrospectivos
15.
Lipids Health Dis ; 18(1): 94, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967146

RESUMO

BACKGROUND: Obesity, widely recognized as a serious health concern, is characterized by profoundly altered metabolism. However, the intermediate metabolites involved in this change remain largely unknown. OBJECTIVE: We conducted targeted metabolomics profiling to identify moieties associated with adult obesity. METHODS: In this case-control study of Iranian adults, 200 obese patients were compared with 100 controls based on 104 metabolites profiled by a targeted metabolomic approach using liquid chromatography coupled to triple quadrupole mass spectrometry (LC-MS/MS). The analysis comprised acylcarnitines, diacyl-phosphatidylcholines (PCaa), acyl-alkyl-phosphatidylcholines (PCae), sphingomyelins (SM), lyso-phospholipids (LPC) and amino acids. We performed multivariable linear regression to identify metabolites associated with obesity, adjusting for age, sex, total energy intake, total physical activity, smoking, and alcohol consumption. The Bonferroni correction was used to adjust for multiple testing. RESULTS: A pattern of 19 metabolites was significantly associated with obesity. Branched chain amino acids, alanine, glutamic acid, proline, tyrosine LPCa C16:1, PCaa C32:1, PCaa C32:2 and PCaa C38:3 were positively, while serine, asparagine, LPCa C18:1, LPCa C18:2, LPCe C18:0, PCae C34:3, PCae C38:4 and PCae C40:6 were negatively associated with obesity (all p < 0.00048). CONCLUSIONS: A metabolomic profile containing 9 amino acids and 10 polar lipids may serve as a potential biomarker of adult obesity. Further studies are warranted to replicate these findings as well as investigate potential changes in this profile after weight reduction.


Assuntos
Aminoácidos/sangue , Carnitina/análogos & derivados , Lisofosfolipídeos/sangue , Obesidade/sangue , Fosfatidilcolinas/sangue , Esfingomielinas/sangue , Adulto , Consumo de Bebidas Alcoólicas/fisiopatologia , Aminoácidos/classificação , Biomarcadores/sangue , Índice de Massa Corporal , Carnitina/sangue , Estudos de Casos e Controles , Cromatografia Líquida , Exercício , Feminino , Humanos , Irã (Geográfico) , Modelos Lineares , Lisofosfolipídeos/classificação , Masculino , Metaboloma , Metabolômica/métodos , Obesidade/diagnóstico , Obesidade/fisiopatologia , Fosfatidilcolinas/classificação , Fumar/fisiopatologia , Esfingomielinas/classificação , Espectrometria de Massas em Tandem
16.
Blood Purif ; 47 Suppl 2: 38-44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943487

RESUMO

BACKGROUND: Patients on hemodialysis (HD) are known to be at risk of carnitine deficiency. The aims of this study were to investigate the prevalence of carnitine deficiency in patients on dialysis and to compare the likelihood of a reduction in the serum carnitine level on HD with that on hemodiafiltration (HDF). METHODS: The prevalence of carnitine deficiency, defined as a serum free carnitine level < 20 µmol/L, and that of carnitine insufficiency, defined as an acyl/free carnitine ratio > 0.4, was investigated in 150 patients on dialysis. The reduction rate of serum carnitine was then compared between HD and HDF. RESULTS: The prevalence of carnitine deficiency and that of carnitine insufficiency was 25.3 and 86.7%, respectively. Patients at high risk of carnitine deficiency accounted for 64.7%. Multivariate regression identified an association of duration of dialysis with the free serum carnitine level. The reduction rates of serum free carnitine in HD and HDF were 64 ± 4 and 75 ± 7%, respectively (p < 0.0001). CONCLUSION: The prevalence rates of carnitine deficiency and carnitine insufficiency were high in patients on dialysis. The serum carnitine reduction rate was greater with HDF than with HD.


Assuntos
Carnitina/sangue , Carnitina/deficiência , Hemodiafiltração , Falência Renal Crônica/sangue , Diálise Renal , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Hemodiafiltração/efeitos adversos , Humanos , Japão/epidemiologia , Falência Renal Crônica/complicações , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Prevalência , Diálise Renal/efeitos adversos
17.
Am Heart J ; 211: 54-59, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30889527

RESUMO

BACKGROUND: Peripheral blood metabolite profiles have yielded mechanistic insights into various cardiovascular disease states. We hypothesized that peripheral blood metabolite profiles would be associated with new onset atrial fibrillation (AF). METHODS AND RESULTS: The study population comprised 1892 patients without AF at baseline, who, as part the MURDOCK Cardiovascular Disease Study molecular profiling cohort (n = 2023), had previously had determination of levels of 69 metabolites from frozen, fasting plasma specimens obtained during coronary angiography. We used Cox proportional hazards models to examine the association of 13 uncorrelated metabolite factors created from these data using principal components analysis (PCA) with new occurrences of AF during a median follow up of 2.8 (0.1-4.9) years. A total of 233 patients developed new AF (12.3%) during follow up. Patients with new onset AF were older (median 67 vs. 60 years); more often white (82 vs. 71%) and male (68 vs. 60%), and had more comorbidities than those who did not develop AF. After adjustment, PCA factor 1 (medium chain acylcarnitines; hazard ratio [HR]: 1.11 [1.01-1.22]), factor 2 (short chain dicarboxylacylcarnitines; HR: 1.21 [1.09-1.34]) and factor 5 (long chain acylcarnitines; HR: 1.19 [1.06-1.34]) were associated with new onset AF. CONCLUSION: Metabolite profiles were associated with new onset AF among patients referred for coronary angiography. Validation of these observations in broader patient populations may provide better mechanistic insight into the development of AF, and may provide new opportunities for prevention and treatment.


Assuntos
Fibrilação Atrial/sangue , Biomarcadores/sangue , Idoso , Aminoácidos/sangue , Fibrilação Atrial/diagnóstico por imagem , Carboidratos/sangue , Carnitina/análogos & derivados , Carnitina/sangue , Angiografia Coronária , Ácidos Graxos/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/metabolismo , Análise de Componente Principal , Modelos de Riscos Proporcionais , Fatores de Risco
18.
BMC Vet Res ; 15(1): 96, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894172

RESUMO

BACKGROUND: Obesity in dogs is an increasing problem associated with morbidity, shortened life span and poor life quality. Overweight dogs exhibit postprandial hyperlipidaemia, highlighting the need to identify potential dysregulations in lipid metabolism. This study investigated metabolites related to lipid metabolism (i.e. acylcarnitines and taurine) and phospholipids in a feed-challenge test and aimed to identify metabolic variations in spontaneously overweight dogs. Twenty-eight healthy male Labrador Retriever dogs were included, 12 of which were classified as lean (body condition score (BCS) 4-5 on a 9-point scale) and 16 as overweight (BCS 6-8). After overnight fasting (14-17 h), fasting blood samples were collected and dogs were fed a high-fat meal followed by postprandial blood sample collection hourly for 4 h. Liquid chromatography-time of flight mass spectrometry (LC-TOFMS) was used to identify plasma metabolites and phospholipids. Multivariate models, mixed model repeated measures and linear regression analyses were used for data interpretation. RESULTS: In all dogs, propionylcarnitine, stearoylcarnitine and nine phospholipids increased in response to food intake, while vaccenylcarnitine decreased (P ≤ 0.005 for all). Overall, carnitine and acetylcarnitine signal areas in the feed-challenge test were lower in overweight dogs (P ≤ 0.004). Notably, fasting plasma acetylcarnitine was lower in overweight dogs than in lean dogs (P = 0.001) and it did not change in response to feeding. The latter finding was in contrast to the decreased acetylcarnitine signal area found in lean dogs at one hour postprandially (P < 0.0001). One fasting phosphatidylcholine (PCaa C38:4) was higher in prominently overweight dogs (BCS > 6) than in lean dogs (P < 0.05). CONCLUSIONS: Plasma carnitine status was overall lower in spontaneously overweight dogs than in lean dogs in this cohort of healthy Labrador Retriever dogs, indicating a potential carnitine insufficiency in the overweight group. The acetylcarnitine response in overweight dogs indicated decreased fatty acid oxidation at fasting and metabolic inflexibility to food intake. Further studies on metabolic inflexibility and its potential role in the metabolism of overweight dogs are warranted.


Assuntos
Doenças do Cão/metabolismo , Ingestão de Alimentos , Sobrepeso/veterinária , Animais , Carnitina/análogos & derivados , Carnitina/sangue , Doenças do Cão/etiologia , Cães , Ingestão de Alimentos/fisiologia , Metabolismo dos Lipídeos , Masculino , Sobrepeso/etiologia , Sobrepeso/metabolismo , Fosfolipídeos/sangue
19.
Drug Metab Dispos ; 47(6): 582-591, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30918014

RESUMO

l-Carnitine (l-Car) plays a crucial role in fatty acid ß-oxidation. However, the plasma l-Car concentration in women markedly declines during pregnancy, but the underlying mechanism and its consequences on maternal hepatic ß-oxidation have not yet been clarified. Our results showed that the plasma l-Car level in mice at gestation day (GD) 18 was significantly lower than that in nonpregnant mice, and the mean fetal-to-maternal plasma l-Car ratio in GD 18 mice was 3.0. Carnitine/organic cation transporter 2 (OCTN2) was highly expressed in mouse and human placenta and upregulated as gestation proceeds in human placenta, whereas expressions of carnitine transporter (CT) 1, CT2, and amino acid transporter B0,+ were extremely low. Further study revealed that renal peroxisome proliferator-activated receptor α (PPARα) and OCTN2 were downregulated and the renal l-Car level was reduced, whereas the urinary excretion of l-Car was lower in late pregnant mice than in nonpregnant mice. Meanwhile, progesterone (pregnancy-related hormone) downregulated the expression of renal OCTN2 via PPARα-mediated pathway, and inhibited the activity of OCTN2, but estradiol, corticosterone, and cortisol did not. Unexpectedly, the maternal hepatic level of l-Car and ß-hydroxybutyrate (an indicator of mitochondrial ß-oxidation), and mRNA levels of several enzymes involved in fatty acid ß-oxidation in GD 18 mice were higher than that in nonpregnant mice. In conclusion, OCTN2 mediated l-Car transfer across the placenta played a major role in maternal plasma l-Car reduction during pregnancy, which did not subsequently result in maternal hepatic fatty acid ß-oxidation decrease.


Assuntos
Carnitina/sangue , Ácidos Graxos/metabolismo , Fígado/metabolismo , Placenta/metabolismo , Plasma/metabolismo , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Animais , Transporte Biológico/fisiologia , Linhagem Celular , Cães , Feminino , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos ICR , Oxirredução , Gravidez
20.
Epilepsy Res ; 153: 7-13, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30925397

RESUMO

BACKGROUND AND AIMS: The relationship between anti-epileptic usage and oxidative damage has not yet been clearly understood. In our study, we investigated oxidative stress parameters, carnitine levels, liver function tests (LFT) and their relationship in epileptic children treated with valproic acid or levetiracetam. METHOD: LFTs, serum free carnitine and oxidative damage markers and their relations with each other were determined in patients who are on valproic acid or levetiracetam treatment at least for 6 months. 25 patients on therapeutic doses of valproic acid, 26 patients on therapeutic doses of levetiracetam and 26 healthy volunteers as controls were included. LFTs, ammonia, carnitine, lipid peroxidation biomarker malondialdehyde (MDA) and a sensitive marker of DNA damage, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were measured. Results of patients are compared to healthy controls. The data is evaluated with IBM SPSS Statistics 22.0. RESULTS: Ammonia and MDA levels were elevated in patients using levetiracetam; 8-OHdG levels were elevated in both patient groups. Carnitine levels were significantly low in patients under valproic acid therapy, however they were not found to be correlated with MDA, 8-OHdG or LFTs. MDA showed positive correlation with ammonia and 8-OHdG in the levetiracetam group. CONCLUSION: We did not observe hepatotoxicity in patients under therapeutic doses of valproic acid. However, epileptic children under therapeutic doses of levetiracetam showed significantly elevated levels of MDA and 8-OHdG, which is supportive for oxidative damage under levetiracetam therapy. This result was observed for the first time in childhood epilepsies and further studies are needed to understand its mechanism.


Assuntos
Carnitina/sangue , Epilepsia/tratamento farmacológico , Levetiracetam/efeitos adversos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Ácido Valproico/efeitos adversos , Anticonvulsivantes , Criança , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Epilepsia/sangue , Feminino , Humanos , Testes de Função Hepática , Masculino , Malondialdeído/metabolismo , Estudos Retrospectivos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
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