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1.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(5): 565-573, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33210481

RESUMO

OBJECTIVE: To explore effects of different delivery and storage conditions on concentrations of amino acids and carnitines in neonatal dried blood spots (DBS), so as to provide evidence for improving accurate and reliable detection by tandem mass spectrometry. METHODS: A total of 1 254 616 newborn DBS samples in Newborn Screening Center of Zhejiang Province were delivered and stored at room temperature (group A, n=338 467), delivered by cold-chain logistics system and stored at low temperature (group B, n=480 021), or delivered by cold-chain logistics system and stored at low temperature and low humidity (group C, n= 436 128), respectively. The concentrations of amino acids and carnitines in DBS were detected by tandem mass spectrometry. Data analysis was performed by SPSS 24.0 to explore the influence of temperature and humidity on the concentrations of amino acids and carnitines. RESULTS: The concentrations of amino acids and carnitines in the three groups were skewed, and the differences in amino acid and carnitine concentrations among groups were statistically significant (all P<0.01). The median concentration of tyrosine was lower in group A than those in group B and group C by 18%and 16%respectively, while there was no significant difference between the last two groups. The median concentrations of methionine were lower in group A and group B than that in group C by 15%and 11%, respectively. The median concentrations of arginine were lower in group A and group B than that in group C by 12%and 25%, respectively. The median concentration of free carnitine (C0) was higher in group A than that in group C by 12%, while there was no significant difference between group A and group B. The median concentrations of acetylcarnitine (C2), propionyl carnitine (C3), C3DC+C4OH, C5DC+C6OH and hexadecanoyl carnitine (C16) were lower in group A than those in group B and group C by 21%-64%. The concentrations of other amino acids and acylcarnitines differed little among three groups. The monthly median coefficients of variation of other amino acids and carnitines in group A were higher than those in group B and group C except for citrulline, C4DC+C5OH and isovalerylcarnitine (C5). CONCLUSIONS: Cold-chain logistics system and storage in low temperature and low humidity can effectively reduce degradation of some amino acids and carnitines in DBS, improve the accuracy and reliability of detection, and thus ensures the quality of screening for neonatal metabolic diseases.


Assuntos
Aminoácidos , Teste em Amostras de Sangue Seco , Triagem Neonatal , Aminoácidos/análise , Carnitina/análise , Teste em Amostras de Sangue Seco/métodos , Teste em Amostras de Sangue Seco/normas , Humanos , Umidade , Recém-Nascido , Reprodutibilidade dos Testes , Manejo de Espécimes/normas , Espectrometria de Massas em Tandem , Temperatura , Fatores de Tempo
2.
PLoS One ; 15(9): e0239506, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976523

RESUMO

BACKGROUND: Low carnitine status may underlie the development of insulin resistance and metabolic inflexibility. Intravenous lipid infusion elevates plasma free fatty acid (FFA) concentration and is a model for simulating insulin resistance and metabolic inflexibility in healthy, insulin sensitive volunteers. Here, we hypothesized that co-infusion of L-carnitine may alleviate lipid-induced insulin resistance and metabolic inflexibility. METHODS: In a randomized crossover trial, eight young healthy volunteers underwent hyperinsulinemic-euglycemic clamps (40mU/m2/min) with simultaneous infusion of saline (CON), Intralipid (20%, 90mL/h) (LIPID), or Intralipid (20%, 90mL/h) combined with L-carnitine infusion (28mg/kg) (LIPID+CAR). Ten volunteers were randomized for the intervention arms (CON, LIPID and LIPID+CAR), but two dropped-out during the study. Therefore, eight volunteers participated in all three intervention arms and were included for analysis. RESULTS: L-carnitine infusion elevated plasma free carnitine availability and resulted in a more pronounced increase in plasma acetylcarnitine, short-, medium-, and long-chain acylcarnitines compared to lipid infusion, however no differences in skeletal muscle free carnitine or acetylcarnitine were found. Peripheral insulin sensitivity and metabolic flexibility were blunted upon lipid infusion compared to CON but L-carnitine infusion did not alleviate this. CONCLUSION: Acute L-carnitine infusion could not alleviated lipid-induced insulin resistance and metabolic inflexibility and did not alter skeletal muscle carnitine availability. Possibly, lipid-induced insulin resistance may also have affected carnitine uptake and may have blunted the insulin-induced carnitine storage in muscle. Future studies are needed to investigate this.


Assuntos
Carnitina/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Resistência à Insulina/fisiologia , Lipídeos/administração & dosagem , Adulto , Carnitina/análogos & derivados , Carnitina/sangue , Estudos Cross-Over , Emulsões/administração & dosagem , Humanos , Bombas de Infusão , Insulina/sangue , Insulina/metabolismo , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Fosfolipídeos/administração & dosagem , Óleo de Soja/administração & dosagem , Adulto Jovem
3.
Int Heart J ; 61(5): 1014-1021, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32879261

RESUMO

Impaired fatty acid metabolism is associated with heart failure (HF) prognosis. However, specific changes in acylcarnitine profiles and their potential clinical value have not been well explored in patients recovering from acute decompensation.This study recruited 79 HF patients hospitalized because of acute decompensation with a left ventricular ejection fraction (LVEF) of < 40% and 51 normal controls. Patients were dichotomized into two groups, namely, the "improved (IMP) " and the "non-improved (NIMP) " groups, as defined by the changes in LVEF from baseline to 12 months after discharge. Mass spectrometry was used to quantify the acylcarnitine concentrations at baseline and 6 and 12 months after discharge. The IMP and NIMP groups contained 42 and 37 patients, respectively. At baseline, HF patients had higher plasma concentrations of specific long-, medium-, and short-chain acylcarnitines compared to normal controls. From baseline to 12 months post-discharge, the IMP group showed significant decreases in long- and short-chain acylcarnitine concentrations, but significant increases in medium-chain acylcarnitines. In the NIMP group, none of the acylcarnitines significantly decreased, and significant increases were noted in long-, medium-, and short-chain acylcarnitines. Generalized estimating equations demonstrated that nine acylcarnitines could discriminate the IMP group from the NIMP group, including three long-chain (C18:1, C16, and C16:1) and six short-chain acylcarnitines (C5, C5-OH, C4, C4:1-DC, C3, and C2). After adjusting for age, the six short-chain acylcarnitines remained significant. Changes in short-chain acylcarnitine profiles are independently associated with the improvement in cardiac systolic function after acute decompensation.


Assuntos
Carnitina/análogos & derivados , Ácidos Graxos/metabolismo , Insuficiência Cardíaca/metabolismo , Metabolômica , Idoso , Carnitina/metabolismo , Estudos de Casos e Controles , Ésteres/metabolismo , Feminino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Prognóstico , Volume Sistólico , Sístole
4.
Ann Biol Clin (Paris) ; 78(5): 537-546, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32933890

RESUMO

Biochemical diagnosis of hereditary metabolic diseases requires the detection and simultaneous identification of a large number of compounds, hence the interest in metabolic profiles. Acylcarnitine profile allows the identification and quantification of more than thirty compounds. As part of the accreditation process for medical biology examinations according to standard NF EN ISO 15189, the group from SFEIM recommends an approach to accredit acylcarnitine profile. Validation parameters and recommendations are discussed in this specific framework.


Assuntos
Carnitina/análogos & derivados , Serviços de Laboratório Clínico/normas , Testes Diagnósticos de Rotina/normas , Erros Inatos do Metabolismo/diagnóstico , Acreditação , Adulto , Amniocentese/métodos , Amniocentese/normas , Líquido Amniótico/química , Análise Química do Sangue/métodos , Análise Química do Sangue/normas , Coleta de Amostras Sanguíneas/métodos , Coleta de Amostras Sanguíneas/normas , Carnitina/análise , Carnitina/sangue , Carnitina/urina , Criança , Cromatografia em Papel/normas , Feminino , Humanos , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/urina , Triagem Neonatal/métodos , Triagem Neonatal/normas , Fase Pré-Analítica/métodos , Fase Pré-Analítica/normas , Gravidez , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/normas , Urinálise/métodos , Urinálise/normas , Coleta de Urina/métodos , Coleta de Urina/normas
5.
BMC Med Genet ; 21(1): 183, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32957924

RESUMO

BACKGROUND: Disorders of the metabolism and absorption of vitamin B12 can lead to decrease in activity of methionine synthetase and methylmalonate coenzyme A mutase (MMUT), which results in increased levels of methylmalonic acid and homocysteine in blood and urine. Often, combined methylmalonic acidemia (MMA) and homocysteinemia is misdiagnosed due to a lack of specific symptoms. The clinical manifestations are diverse, but proteinuria as the initial presentation is rare. CASE PRESENTATION: Two cases of MMA with homocysteinemia in children are reported. Proteinuria were a primary presenting symptom, followed by anemia and neurologic symptoms (frequent convulsions and unstable walking, respectively). Screening of amino acids and acyl carnitine in serum showed that the propionyl carnitine:acetylcarnitine ratio increased. Profiling of urinary organic acids by gas chromatography-mass spectrometry revealed high levels of methylmalonic acid. Homocysteine content in blood was increased. Comprehensive genetic analyses of peripheral blood-derived DNA demonstrated heterozygous variants of methylmalonic aciduria type C and homocystinuria (MMACHC) and amnionless (AMN) genes in our two patients, respectively. After active treatment, the clinical manifestations in Case 1 were relieved and urinary protein ceased to be observed; Case 2 had persistent proteinuria and was lost to follow-up. CONCLUSIONS: Analyses of the organic acids in blood and urine suggested MMA combined with homocysteinemia. In such diseases, reports of renal damage are uncommon and proteinuria as the initial presentation is rare. Molecular analysis indicated two different genetic causes. Although the pathologic mechanisms were related to vitamin B12, the severity and prognosis of renal lesions were different. Therefore, gene detection provides new insights into inherited metabolic diseases.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Hiper-Homocisteinemia/complicações , Proteinúria/diagnóstico , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/genética , Aminoácidos/sangue , Sequência de Bases , Carnitina/análogos & derivados , Carnitina/sangue , Pré-Escolar , DNA/sangue , DNA/genética , Cromatografia Gasosa-Espectrometria de Massas , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/genética , Masculino , Ácido Metilmalônico/urina , Proteinúria/etiologia
6.
Life Sci ; 258: 118242, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32784056

RESUMO

AIMS: As the spermatogenesis process is targeted by cisplatin (Cis) that changes testicular morphology, alters sperm quality, and hence causes male infertility. This study investigated the possible therapeutic effects of l-carnitine (LC) on Cis impaired spermatogenesis's establishment during the prepubertal phase. MATERIALS AND METHODS: Ninety-six prepubertal Sprague Dawley male rats were divided into four groups. CONTROL GROUP: rats were injected with 0.9% saline solution intraperitoneally (i.p.). LC group: animals were injected for eight weeks, with 250 mg/kg/wk. LC (i.p.). Cis group: animals were injected with a single dose of 5 mg/kg Cis (i.p.). LC + Cis group: animals were pre-injected with LC 250 mg/kg 2 h before Cis injection. The rats were sacrificed at 37, 60, and 90 days old, and their testes were taken for biochemical, molecular, and histopathological studies. The motility, viability, morphology, and DNA fragmentation of sperm in adult rats were also measured. KEY FINDINGS: Group treated with LC and Cis showed an increase in antioxidant and hormonal activity compared to the Cis treated group in the pre and post-pubertal period. Moreover, there was an increase in sperm survival, motility, and DNA integrity. Furthermore, LC showed an increase in the anti-apoptotic and chromatin remodeling genes and a decrease in the pro-inflammatory genes. SIGNIFICANCE: LC could enhance the spermatogenesis process after exposure to Cis during the prepubertal phase by restoring the balance between reactive oxygen species and antioxidant activity, improving hormonal activity, sperm quality and DNA integrity, promoting protamination and blood-testis barrier integrity, and maintaining the testicular architecture.


Assuntos
Carnitina/farmacologia , Cisplatino/toxicidade , Infertilidade Masculina/prevenção & controle , Infertilidade Masculina/fisiopatologia , Maturidade Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Animais , Antineoplásicos/toxicidade , Carnitina/uso terapêutico , Infertilidade Masculina/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologia , Motilidade Espermática/efeitos dos fármacos , Motilidade Espermática/fisiologia , Espermatogênese/fisiologia
7.
Zhonghua Shao Shang Za Zhi ; 36(7): 553-559, 2020 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-32842402

RESUMO

Objective: To explore the effects of early exogenous L-carnitine supplementation on renal function in severely scalded rats. Methods: According to the random number table, sixty-six adult female Sprague-Dawly rats were divided into healthy control group (n=6), scald alone group (n=30), and scald+ carnitine group (n=30). In the latter two groups, the rats were inflicted with full-thickness scald of 30% total body surface area on the back, and the lactated Ringer's solution was injected through the tail vein for resuscitation immediately after scald. At post injury hour (PIH) 1, rats in scald+ carnitine group were intraperitoneally injected with 100 mg/mL L-carnitine solution 400 mg/kg, while rats in scald alone group were intraperitoneally injected with the same volume of normal saline. Rats in these two groups were injected once every 24 hours thereafter. Six rats were taken from each of scald alone group and scald+ carnitine group to collect the renal tissue and abdominal aorta blood at PIH 6, 12, 24, 48, and 72, respectively. The serum content of total protein, albumin, urea nitrogen, creatinine, and cystatin C were determined by the automatic biochemical analyzer. Renal tissue was stained with hematoxylin-eosin to observe histopathological changes. Rats in healthy control group did not undergo any treatment, and their renal tissue and blood sample were extracted and analyzed in the same way as those of severely scalded rats. Data were statistically analyzed with one-way analysis of variance and Bonferroni method. Results: (1) The serum content of total protein and albumin of rats in scald alone group at each time point after injury was significantly lower than that in healthy control group (P<0.05). The serum content of total protein of rats in scald+ carnitine group was significantly higher than that in scald alone group at PIH 12 and 24 (P<0.05), and the serum content of albumin of rats in scald+ carnitine group was significantly higher than that in scald alone group at PIH 12 (P<0.05). The serum content of total protein and albumin of rats in scald alone group and scald+ carnitine group showed a trend of decrease followed by an increase, with the lowest value at PIH 24. (2) The serum content of urea nitrogen and creatinine of rats in scald alone group at each time point after injury was significantly higher than that of healthy control group (P<0.05). The serum content of urea nitrogen of rats in scald+ carnitine group was significantly lower than that in scald alone group at PIH 6, 48, and 72 (P<0.05). The serum content of creatinine of rats in scald+ carnitine group was significantly lower than that in scald alone group at PIH 12, 24, 48, and 72 (P<0.05). The serum content of urea nitrogen and creatinine of rats in scald alone group and scald+ carnitine group showed a trend of increase followed by a decrease, with the peak value at PIH 12. (3) The serum content of cystatin C of rats in scald alone group at PIH 6, 12, 24, 48, and 72 was (0.250±0.030), (0.330±0.070), (0.300±0.060), (0.240±0.060), and (0.190±0.030) mg/L, and the content at the first 4 time points were significantly higher than (0.170±0.020) mg/L of healthy control group (P<0.05). At PIH 24, the serum content of cystatin C of rats in scald+ carnitine group was (0.210±0.040) mg/L, which was significantly lower than that of scald alone group (P<0.05). The serum content of cystatin C of rats in scald alone group and scald+ carnitine group showed a trend of increase followed by a decrease, with the peak value at PIH 12. (4) The renal tissue of rats in healthy control group was almost normal, and the degree of renal tissue injury of rats in scald+ carnitine group was lighter than that in scald alone group at each time point after injury. At PIH 24, the renal tissue of rats in scald alone group showed extensive swelling of the renal tubular epithelial cells, vacuolar degeneration and necrosis, loss of brush borders, and nuclear shrinkage; more than 2/3 of the renal tubular cell nuclei disappeared, the tubular lumen was narrowed, necrotic exfoliated cells could be seen in the lumen, and edema and inflammatory cell infiltration could be seen in the renal interstitial. Compared with those of scald alone group, significantly reduced severity of edema and necrosis of renal tubular epithelial cells, as well as less inflammatory cell infiltration were observed in the renal tissue of rats in scald+ carnitine group. Conclusions: Early supplement of L-carnitine in severely scalded rats can reduce the damage of renal cells, accelerate the restoration of the content of total protein, albumin, urea nitrogen, creatinine, and cystatin C, thereby maintaining the stability of renal function metabolism level.


Assuntos
Queimaduras , Lesões dos Tecidos Moles , Animais , Carnitina , Suplementos Nutricionais , Ensaio de Imunoadsorção Enzimática , Ratos , Ratos Sprague-Dawley
8.
PLoS One ; 15(8): e0237097, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810864

RESUMO

Neurofibromatosis type 1 (NF1) is a genetic disorder that affects a range of tissue systems, however the associated muscle weakness and fatigability can have a profound impact on quality of life. Prior studies using the limb-specific Nf1 knockout mouse (Nf1Prx1-/-) revealed an accumulation of intramyocellular lipid (IMCL) that could be rescued by a diet supplemented with L-carnitine and enriched for medium-chain fatty acids (MCFAs). In this study we used the Nf1Prx1-/- mouse to model a range of dietary interventions designed to reduce IMCL accumulation, and analyze using other modalities including in situ muscle physiology and lipid mass spectrometry. Histological IMCL accumulation was significantly reduced by a range of treatments including L-carnitine and high MCFAs alone. A low-fat diet did not affect IMCL, but did provide improvements to muscle strength. Supplementation yielded rapid improvements in IMCL within 4 weeks, but were lost once treatment was discontinued. In situ muscle measurements were highly variable in Nf1Prx1-/- mice, attributable to the severe phenotype present in this model, with fusion of the hips and an overall small hind limb muscle size. Lipidome analysis enabled segregation of the normal and modified chow diets, and fatty acid data suggested increased muscle lipolysis with the intervention. Acylcarnitines were also affected, suggestive of a mitochondrial fatty acid oxidation disorder. These data support the theory that NF1 is a lipid storage disease that can be treated by dietary intervention, and encourages future human trials.


Assuntos
Metabolismo dos Lipídeos , Força Muscular , Músculo Esquelético/metabolismo , Neurofibromatose 1/dietoterapia , Animais , Carnitina/administração & dosagem , Carnitina/uso terapêutico , Suplementos Nutricionais , Ácidos Graxos/administração & dosagem , Ácidos Graxos/uso terapêutico , Feminino , Camundongos , Músculo Esquelético/fisiopatologia , Neurofibromatose 1/genética , Neurofibromina 1/genética
9.
Nutr Metab Cardiovasc Dis ; 30(10): 1662-1672, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32684363

RESUMO

BACKGROUND AND AIMS: Current epidemiologic data suggest beneficial cardiovascular effects of fermented dairy products (FDP). However, the relationship between FDP consumption and angiographic coronary status has not been previously studied. Furthermore, the role of novel metabolomic biomarkers of cardiovascular risk in this context is unclear. We hypothesize that short-chain acylcarnitines (SCA) reflect the link between FDP intake and angiographic extent of stable coronary artery disease (CAD). METHODS AND RESULTS: We recruited 1185 patients admitted for suspected CAD [median age 62 years (interquartile range: 54-69); 714 men (60.3%)]. Prior to coronary angiography, each patient completed a validated Food Frequency Questionnaire. In addition, venous blood was collected from each patient for whole blood metabolomic analysis, using targeted mass-spectrometry. CAD was defined by the presence of ≥1 coronary stenosis ≥50%. Patients with CAD (n = 441) reported lower median FDP intake [86.8 g/day (IQR: 53.4-127.6)] than patients without CAD [n = 744; 103.9 g/day (IQR: 62.9-152.7); p < 0.001]. Upon adjustment for relevant confounders, increased circulating SCA, particularly level of acetylcarnitine (C2) associated with both higher CAD probability [SCA:ß(SE) = 0.584 (0.235), p = 0.013; C2:ß(SE) = 0.575 (0.242), p = 0.017] and decreased FDP consumption [SCA:ß/100 g FDP-increment/day (SE) = -0.785 (0.242), p = 0.001; C2:ß(SE) = -0.560 (0.230), p = 0.015]. By mediation analysis, neither SCA nor C2 showed relevant mediator effect linking FDP consumption to the risk of CAD. CONCLUSION: Increased consumption of fermented milk was associated with lower prevalence of CAD and correlated inversely with circulating SCA, in particular with acetylcarnitine. No substantial mediator effect of SCA linking fermented milk intake with risk of CAD was found. CLINICAL TRIAL REGISTRY: NCT00497887.


Assuntos
Carnitina/análogos & derivados , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Produtos Fermentados do Leite , Idoso , Biomarcadores/sangue , Carnitina/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/prevenção & controle , Estenose Coronária/sangue , Estenose Coronária/epidemiologia , Estenose Coronária/prevenção & controle , Estudos Transversais , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Fatores de Proteção , Fatores de Risco , Índice de Gravidade de Doença
10.
Medicine (Baltimore) ; 99(28): e21061, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664122

RESUMO

Sarcopenia has a negative impact on the prognosis of patients with liver cirrhosis (LC). We investigated the significance of skeletal muscle volume and its changes in LC patients taking levocarnitine (L-carnitine).We retrospectively analyzed 51 LC patients taking L-carnitine from December 2012 to March 2019. Skeletal mass index was calculated as the left-right sum of the major × minor axis of psoas muscle at the third lumbar vertebra, divided by height squared (psoas muscle index [PMI]). Patients were classified into 2 groups (low and normal PMI) depending on PMI < 6.0 and < 3.4 cm/m for men and women, respectively. Changes in PMI per month during L-carnitine administration (ΔPMI/m) were calculated, and we classified the patients into 2 groups (severe and mild muscle atrophy) depending on ΔPMI/m below the lower quartile. We assessed overall survival (OS).At the start of L-carnitine administration, there were no significant differences in OS between groups with low and normal PMI. Multivariate analysis showed that ΔPMI/m (hazard ratio [HR], 0.007; P = .005) and L-carnitine administration period (HR, 0.956; P = .021) were significantly associated with OS. Patients with severe muscle atrophy had a significantly lower OS than those with mild muscle atrophy. There was the positive correlation relationship between ΔPMI/m and L-carnitine administration period.Among LC patients taking L-carnitine, progressive muscle volume loss was a predictor of poor prognosis. L-carnitine administration for longer may be able to prevent muscle volume loss and lead to a better prognosis in LC patients.


Assuntos
Carnitina/uso terapêutico , Cirrose Hepática/epidemiologia , Sarcopenia/tratamento farmacológico , Sarcopenia/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Amônia/sangue , Feminino , Humanos , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Músculos Psoas , Estudos Retrospectivos , Sarcopenia/fisiopatologia , Índice de Gravidade de Doença , Fatores Sexuais
11.
Anticancer Res ; 40(7): 4173-4182, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620667

RESUMO

BACKGROUND/AIM: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of cancers. Sorafenib, an oral multi-target TKI, improves the median overall survival time in patients with hepatocellular carcinoma (HCC). It also inhibits the absorption of carnitine by down-regulating the human organic cationic transporter OCTN2 located largely in the small intestinal mucosa and skeletal muscle. The aim of the study was to determine, by assessing carnitine metabolism, whether sarcopenia is induced in patients with HCC who are receiving sorafenib. PATIENTS AND METHODS: This retrospective study included 110 adult Japanese patients with liver cirrhosis and HCC who received sorafenib. Sorafenib was administered at a dose of 200-800 mg/day for 4 weeks. Blood samples were collected before and after treatment, and serum carnitine fraction and myostatin levels were measured. Cross-sectional areas (cm2) of the skeletal muscles at the third lumbar vertebra level were determined by manually outlining computed tomography images before and after treatment. The cross-sectional areas were normalized for height [skeletal muscle index (SMI), cm2/m2]. RESULTS: Patients were allocated to two groups according to Child-Pugh (CP) class; 81 had CP-A liver function, and 29 had CP-B. SMI after treatment was significantly lower than that before treatment in both groups. Serum levels of total carnitine and free carnitine after treatment were significantly lower than those before treatment in both groups. There were no differences in serum levels of myostatin before and after treatment in either group. CONCLUSION: Sorafenib might decrease serum levels of carnitine by inhibiting carnitine absorption. Decreasing of serum levels of carnitine might lead to presarcopenia.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carnitina/sangue , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Sarcopenia/induzido quimicamente , Sorafenibe/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/sangue , Carnitina/metabolismo , Feminino , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/sangue , Masculino , Pessoa de Meia-Idade
12.
J Food Sci ; 85(7): 2207-2215, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32572979

RESUMO

Trimethylamine-N-oxide (TMAO) is considered to have negative effect on human health. Different precursors of TMAO, such as choline, betaine, and L-carnitine, are commonly found in daily foods. The aim of the present study was to compare the ability of different precursors to be metabolized into TMAO, as well as the possible effect of chronic administration with TMAO precursors on TMAO production. The rate of TMAO generation after single gavage with different precursors was L-carnitine > choline >betaine. Moreover, the serum TMAO level of mice increased more than twofold after administration with choline for 3 weeks compared with L-carnitine and betaine groups, which was accompanied by the change of intestinal flora. After the gavage of choline chloride, the production for TMAO was 2.8 and 1.6 times higher in chronic choline-treated group compared with L-carnitine and betaine groups, respectively. In addition, administration with choline increased the lowest TMAO level after intraperitoneal injection of trimethylamine (TMA) hydrochloride among the three treated groups. These findings indicated that different TMAO precursors had different ability to form TMAO in vivo, and long-term dietary intervention would affect the metabolism of precursors to generate TMA and the TMA oxidation to form TMAO, suggesting that TMAO levels in vivo could be regulated by dietary intervention. PRACTICAL APPLICATION: Diverse TMAO precursors exhibited different ability to be converted into TMAO in vivo. The ability of choline to produce TMAO was stronger than that of betaine and L-carnitine. Long-term dietary intervention would affect the metabolism of precursors to generate TMA and the TMA oxidation to form TMAO, suggesting that TMAO levels in vivo could be regulated by adjustment of dietary structure.


Assuntos
Betaína/metabolismo , Carnitina/metabolismo , Colina/metabolismo , Metilaminas/sangue , Animais , Feminino , Microbioma Gastrointestinal , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
13.
Saudi Med J ; 41(6): 590-596, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32518924

RESUMO

OBJECTIVES: To describe the clinical and molecular characteristics of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.   Methods: A retrospective observational cross-sectional analysis was conducted on all patients with VLCAD deficiency at  (Genetic/Metabolic Section), Prince Sultan Military Medical City (PSMMC), Riyadh, Saudi Arabia from 2000 to 2019. Demographic, clinical, and laboratory data were abstracted from the electronic hospital records using a case report form. Results: A total of 14 children were analyzed. Six presented with hypoglycemia, 4 with cardiomyopathy, and 10 had rhabdomyolysis. Five patients had early onset severe phenotype, while 9 had mild form. The molecular study revealed homozygous mutations in ACADVL in all 14 patients. Three variants were not reported before. All patients were treated with medium-chain triglyceride and carnitine. Ten patients are alive and have normal development, while 4 died. Conclusion: Most of the patients in this cohort presented in the neonatal period either by newborn screening or clinically with hypoglycemia, cardiomyopathy, and rhabdomyolysis. The new molecular variants detected in this study broaden the genetic spectrum of VLCAD deficiency in Saudi Arabia.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea , Erros Inatos do Metabolismo Lipídico , Doenças Mitocondriais , Doenças Musculares , Acil-CoA Desidrogenase de Cadeia Longa/genética , Cardiomiopatias/etiologia , Carnitina/uso terapêutico , Estudos de Coortes , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/tratamento farmacológico , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Estudos Transversais , Homozigoto , Humanos , Hipoglicemia/etiologia , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/tratamento farmacológico , Doenças Musculares/genética , Mutação , Triagem Neonatal , Rabdomiólise/etiologia , Arábia Saudita , Triglicerídeos/uso terapêutico
14.
Zhonghua Er Ke Za Zhi ; 58(6): 476-481, 2020 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-32521959

RESUMO

Objective: To evaluate and improve the performance of the newborn screening program for primary carnitine deficiency (PCD) based on tandem mass spectrometry and to investigate the incidence of PCD and molecular characteristics of SLC22A5 gene in Guangzhou. Methods: A total of 200 180 neonates born in Guangzhou from 2015 to 2019 were enrolled into the newborn screening program for PCD by tandem mass spectrometry at Guangzhou Newborn Screening Center. The positive results of screening for PCD was defined as free carnitine (C0) less than 10 µmol/L with decreased acylcarnitine species in dried blood spots of three to seven days after birth. Screen-positive newborns and their mothers were recalled for another blood spot sample. The diagnosis was confirmed based on decreased levels of C0 and acylcarnitine species in recalled blood spots and genetic analysis in SLC22A5 gene sequencing. The utility of using the sum of propionylcarnitine and palmitoylcarnitine (C3+C16) as a biomarker for acylcarnitine species in newborn screening was retrospectively evaluated. The levels of C0 and (C3+C16) at first screening were compared between newborns with PCD and newborns born to mothers with PCD by independent t test. The variant spectrum and known pathogenic variants carrier rate of SLC22A5 in 2 395 healthy children in Guangzhou Women and Children's Medical Center through whole exon sequencing were analyzed. Results: Among 200 180 neonates, 239 (0.12%) cases were screen-positive for PCD. A total of 37 patients including 15 newborns and 22 mothers had confirmed PCD. The incidence of PCD was 1/13 345 in newborns and 1/9 099 in mothers, respectively. The positive predictive value of this program was 15.5%. Taking cutoff values of C0<8.5 µmol/L or C0 8.5~9.9 µmol/L with (C3+C16)<2 µmol/L, the number of screen-positive cases would be reduced from 810 to 224 without additional false negative case, when compared with cutoff value C0<10 µmol/L only. Both levels of C0 and (C3+C16) at first screening were not significant difference between newborns with PCD and newborns born to mothers with PCD ((6.2±2.4) vs. (5.0±1.8) µmol/L, (1.4±0.4) vs. (1.2±0.5) µmol/L, t=3.826, 0.326; P=0.058, 0.572). Seven PCD mothers experienced moderate fatigue and dizziness in the morning. One of them presented with cardiomyopathy in pregnancy. Genetic analysis of the SLC22A5 gene showed that p.S467C, p.F17L, p.R254X were the three most common variants in newborns with PCD. In PCD mothers and healthy children, the p.S467C, p.F17L and R399W were the three most common whereas the severe variant p.R254X was rare. The population carrier rate for pathogenic variants was 1 in 65 and the estimated incidence of PCD was about 1/16 500. Conclusions: Newborn screening can detect PCD both in newborns and mothers. Adding a quantitative biomarker (C3+C16) <2 µmol/L into the newborn screening program can improve the PCD screen performance. The severe variant p.R253X was common in PCD newborns but rare in PCD mothers and healthy children, indicating that the current screening program maybe failed to detect all PCD newborns and under-estimated the incidence rate of PCD in Guangzhou.


Assuntos
Cardiomiopatias/genética , Carnitina/sangue , Carnitina/deficiência , Hiperamonemia/diagnóstico , Doenças Musculares/diagnóstico , Triagem Neonatal/métodos , Membro 5 da Família 22 de Carreadores de Soluto/genética , Cardiomiopatias/diagnóstico , Cardiomiopatias/metabolismo , Carnitina/genética , Criança , Feminino , Predisposição Genética para Doença , Humanos , Hiperamonemia/genética , Recém-Nascido , Doenças Musculares/genética , Gravidez , Estudos Retrospectivos , Espectrometria de Massas em Tandem
15.
Environ Toxicol ; 35(10): 1033-1042, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32478940

RESUMO

Widespread occupational and environmental exposure to benzene is unavoidable and poses a public health threat. Studies of potential interventions to prevent or relieve benzene toxicity are, thus, essential. Research has shown l-carnitine (LC) has beneficial effects against various pathological processes and diseases. LC possesses antioxidant activities and participates in fatty acid oxidation (FAO). In this study, we investigated whether 1,4-benzoquinone (1,4-BQ) affects LC levels and the FAO pathway, as well as analyzed the influence of LC on the cytotoxic effects of 1,4-BQ. We found that 1,4-BQ significantly decreased LC levels and downregulated Cpt1a, Cpt2, Crat, Hadha, Acaa2, and Acadvl mRNA expression in K562 cells. Subsequent assays confirmed that 1,4-BQ decreased cell viability and increased apoptosis and caspase-3, -8, and -9 activities. It also induced obvious oxidative stress and DNA damage, including an increase in the levels of reactive oxygen species and malondialdehyde, tail DNA%, and olive tail moment. Additionally, the mitochondrial membrane potential was significantly reduced. Cotreatment with LC (500 µmol/L) relieved these alterations by reducing oxidative stress and increasing the protein expression levels of Cpt1a and Hadha, particularly in the 20 µmol/L 1,4-BQ group. Thus, our results demonstrate that 1,4-BQ causes cytotoxicity, reduces LC levels, and downregulates the FAO genes. In contrast, LC exhibits protective effects against 1,4-BQ-induced apoptosis and DNA damage by decreasing oxidative stress and promoting the FAO pathway.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Benzoquinonas/toxicidade , Carnitina/farmacologia , Dano ao DNA/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Carnitina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Células K562 , Metabolismo dos Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
16.
Am J Clin Nutr ; 112(2): 381-388, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32492168

RESUMO

BACKGROUND: Acylcarnitines (ACs) play a major role in fatty acid metabolism and are potential markers of metabolic dysfunction with higher blood concentrations reported in obese and diabetic individuals. Diet, and in particular red and processed meat intake, has been shown to influence AC concentrations but data on the effect of meat consumption on AC concentrations is limited. OBJECTIVES: To investigate the effect of red and processed meat intake on AC concentrations in plasma and urine using a randomized controlled trial with replication in an observational cohort. METHODS: In the randomized crossover trial, 12 volunteers successively consumed 2 different diets containing either pork or tofu for 3 d each. A panel of 44 ACs including several oxidized ACs was analyzed by LC-MS in plasma and urine samples collected after the 3-d period. ACs that were associated with pork intake were then measured in urine (n = 474) and serum samples (n = 451) from the European Prospective Investigation into Cancer and nutrition (EPIC) study and tested for associations with habitual red and processed meat intake derived from dietary questionnaires. RESULTS: In urine samples from the intervention study, pork intake was positively associated with concentrations of 18 short- and medium-chain ACs. Eleven of these were also positively associated with habitual red and processed meat intake in the EPIC cross-sectional study. In blood, C18:0 was positively associated with red meat intake in both the intervention study (q = 0.004, Student's t-test) and the cross-sectional study (q = 0.033, linear regression). CONCLUSIONS: AC concentrations in urine and blood were associated with red meat intake in both a highly controlled intervention study and in subjects of a cross-sectional study. Our data on the role of meat intake on this important pathway of fatty acid and energy metabolism may help understanding the role of red meat consumption in the etiology of some chronic diseases. This trial was registered at Clinicaltrials.gov as NCT03354130.


Assuntos
Carnitina/análogos & derivados , Produtos da Carne/análise , Adulto , Animais , Carnitina/sangue , Carnitina/química , Carnitina/urina , Estudos Transversais , Feminino , Humanos , Masculino , Metabolômica , Estudos Prospectivos , Suínos
17.
Int J Clin Pharmacol Ther ; 58(9): 482-490, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32469304

RESUMO

OBJECTIVES: To evaluate the effect of L-carnitine and piracetam on the muscle injury induced by simvastatin in healthy male subjects during the therapy with oral doses of 10 mL of a solution containing L-carnitine 100 mg/mL + piracetam 80 mg/mL (test group) or placebo (control group) and 40 mg simvastatin once a day during 35 consecutive days. The effect of L-carnitine and piracetam in the reduction of myopathic symptomatology caused by exercise, as well as safety and tolerability were also evaluated. MATERIALS AND METHODS: This study was performed on two different occasions, of which 42 subjects were investigated on occasion 1 and 19 on occasion 2. Discomfort or pain was evaluated according to modified Borg scale. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (γ-GT), creatine kinase (CK), and lactic dehydrogenase (LDH) were evaluated on the 4th, 11th, 18th, 25th, and 32nd day after therapy, and before and until 4 hours after an exercise test performed on a treadmill on day 36. RESULTS: A higher incidence of pain or discomfort was observed in the control group than in the test group, mainly in occasion 1 (29% vs. 62% experienced pain or discomfort in any period, p = 0.0295). The serum levels of AST, ALT, and LDH were statistically different, with lower values in the test group compared to the control group. CONCLUSION: Concomitant use of L-carnitine and piracetam might have a muscle-protective effect and protection against simvastatin-induced myalgia. Furthermore, the formulation was safe and well tolerated by the subjects investigated in this trial.


Assuntos
Carnitina/farmacologia , Piracetam/farmacologia , Alanina Transaminase , Aspartato Aminotransferases , Humanos , Masculino , Sinvastatina/efeitos adversos
18.
Gan To Kagaku Ryoho ; 47(3): 490-492, 2020 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-32381925

RESUMO

AIM: Low serum carnitine levels have been reported in patients with cancer receiving chemotherapy and are considered one of the factors causing fatigue associated with chemotherapy. We evaluated the effectiveness of L-carnitine in the treatment of fatigue associated with chemotherapy in patients with gastric cancer(GC). MATERIALS AND METHODS: We performed a randomized controlled trial between December 2013 and December 2018. Untreated patients with advanced GC were included in the study; 1 patient developed an allergy after receiving the first chemotherapy and was excluded from the study. The primary endpoint was brief fatigue inventory(BFI). Patients were categorized into 2 groups: those who received L-carnitine oral supplements(group C)and those who did not receive L-carnitine oral supplements(group N). RESULTS: The serum carnitine levels were improved significantly in group C compared with group N. BFIwas more aggravated in group N than group C; however, the difference was not significant. CONCLUSION: We could not demonstrate the effectiveness of L-carnitine in the treatment of fatigue associated with chemotherapy in patients with GC.


Assuntos
Antineoplásicos/efeitos adversos , Fadiga/induzido quimicamente , Neoplasias Gástricas , Carnitina , Humanos , Neoplasias Gástricas/tratamento farmacológico
20.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R43-R49, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432915

RESUMO

γ-Butyrobetaine hydroxylase (γ-BBH) is the last limiting enzyme of the l-carnitine biosynthesis pathway and plays an important role in catalyzing the hydroxylation of γ-butyrobetaine (γ-BB) to l-carnitine. To study the developmental effect of substrate concentration on the enzyme's specific activity, kinetics of γ-BBH were measured in liver and kidney from newborn and 1-, 7-, 21-, 35-, 56-, and 210-day-old domestic pigs. Fresh tissue homogenates were assayed under nine concentrations of γ-BB from 0 to 1.5 mM. Substrate inhibition associated with age was observed at ≥0.6 mM of γ-BB. Hepatic activity was low at birth but increased after 1 day. By 21 days, the activity rose by 6.6-fold (P < 0.05) and remained constant after 56 days. Renal activity was higher than in liver at birth but remained constant through 35 days. By 56 days, the velocity increased by 44% over the activity at birth (P < 0.05). The apparent Km for γ-BB at birth on average was 2.8-fold higher than at 1 day. The Km value was 60% higher in kidney than liver during development but showed no difference in adult pigs. The total organ enzyme activity increased by 130-fold for liver and 18-fold for kidney as organ weight increased from birth to 56 days. In conclusion, age and substrate affect γ-BBH specific activity and Km for γ-BB in liver and kidney. Whereas the predominant organ for carnitine synthesis is likely the kidney at birth, the liver appears to predominate after the pig exceeds 7 days of age.


Assuntos
Carnitina/biossíntese , gama-Butirobetaína Dioxigenase/metabolismo , Envelhecimento/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal , Inibidores Enzimáticos/farmacologia , Rim/enzimologia , Rim/crescimento & desenvolvimento , Rim/metabolismo , Cinética , Fígado/enzimologia , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Tamanho do Órgão , Sus scrofa , Suínos , gama-Butirobetaína Dioxigenase/antagonistas & inibidores
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