Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.081
Filtrar
1.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(9): 940-945, 2024.
Artigo em Chinês | MEDLINE | ID: mdl-39267509

RESUMO

OBJECTIVES: To explore early diagnostic biological markers for Leigh syndrome caused by the m.8993T>G mutation. METHODS: A retrospective analysis was performed on the clinical data of four children diagnosed with m.8993T>G mutation-related mitochondrial disease at the Children's Hospital of Chongqing Medical University from January 2014 to January 2024. Additionally, a literature review was conducted. RESULTS: All four children had plasma amino acid and acylcarnitine analyses that revealed decreased citrulline levels, and one child was initially identified through neonatal genetic metabolic disease screening. According to the literature review, there were 26 children with mitochondrial disease and hypocitrullinemia caused by the m.8993T>G mutation (including the four children in this study). Among these, 12 children exhibited clinical phenotypes of Leigh syndrome or Leigh-like syndrome, while 18 children were identified with hypocitrullinemia and/or elevated levels of 3-hydroxyisovalerylcarnitine (C5-OH) during neonatal genetic metabolic disease screening. CONCLUSIONS: Hypocitrullinemia may serve as a potential biomarker for the early diagnosis of m.8993T>G mutation-associated Leigh syndrome, detectable as early as during neonatal genetic metabolic disease screening.


Assuntos
Citrulina , Doença de Leigh , Mutação , Humanos , Doença de Leigh/genética , Masculino , Feminino , Lactente , Citrulina/sangue , Pré-Escolar , Recém-Nascido , Carnitina/análogos & derivados , Carnitina/sangue , Estudos Retrospectivos
2.
Medicine (Baltimore) ; 103(22): e37825, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-39259062

RESUMO

BACKGROUND: Gut microbial metabolites such as trimethylamine N-oxide (TMAO) and its precursors, namely betaine, L-carnitine, and choline, have been implicated as risk factors for cardiovascular events and mortality development. Therefore, we aim to perform a systematic review and meta-analysis to assess the validity of these associations. METHODS: MEDLINE and Scopus were queried from their inception to August 2023 to identify studies that quantified estimates of the associations of TMAO with the development of major adverse cardiovascular events (MACE) or death. A random-effects meta-analysis was conducted to pool unadjusted or multivariable-adjusted hazard ratios (HR) and their 95% confidence intervals. The primary endpoint was the risk of MACE and all-cause death. RESULTS: 30 prospective observational studies (n = 48 968) were included in the analysis. Elevated TMAO levels were associated with a significantly greater risk of MACE and all-cause death compared to low TMAO levels (HR: 1.41, 95% CI 1.2-1.54, P < .00001, I2 = 43%) and (HR: 1.55, 95% CI 1.37-1.75, P < .00001, I2 = 46%), respectively. Furthermore, high levels of either L-carnitine or choline were found to significantly increase the risk of MACE. However, no significant difference was seen in MACE in either high or low levels of betaine. CONCLUSION: Elevated concentrations of TMAO were associated with increased risks of MACE and all-cause mortality. High levels of L-carnitine/choline were also significantly associated with an increased risk of MACE. However, no significant difference was found between high or low levels of betaine for the outcome of MACE.


Assuntos
Doenças Cardiovasculares , Carnitina , Colina , Microbioma Gastrointestinal , Metilaminas , Humanos , Microbioma Gastrointestinal/fisiologia , Metilaminas/metabolismo , Doenças Cardiovasculares/mortalidade , Colina/metabolismo , Betaína/metabolismo , Fatores de Risco
3.
Reprod Domest Anim ; 59(9): e14720, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39267414

RESUMO

The addition of antioxidants to cryopreservation media reportedly improves sperm post-thaw quality and reproductive performance after artificial insemination. Therefore, the objectives of this study were to evaluate if the addition of L-carnitine and pyruvate to freezing media, or their addition to samples after thawing, improves the post-thaw quality of equine spermatozoa. Thus, in Experiment 1, stallion semen samples were cryopreserved in: (1) EDTA-glucose-based extender with 20% egg yolk and 5% dimethylformamide (EDTA control); (2) skim milk-based extender with 20% egg yolk and 5% dimethylformamide (milk control); (3) Extender 1 supplemented with 50 mM L-carnitine and 10 mM pyruvate (EDTA-carnitine-pyruvate); and (4) Extender 2 supplemented with 50 mM L-carnitine and 10 mM pyruvate (milk-carnitine-pyruvate). In Experiment 2, 50 mM L-carnitine and 10 mM pyruvate were added post-thaw to samples cryopreserved with extenders 1 and 2 (EDTA control and milk control). Sperm kinematic parameters, DNA fragmentation, membrane lipid peroxidation, acrosome status and viability were evaluated after thawing. No significant differences (p > 0.05) were observed for most of the kinematic parameters, DNA fragmentation, membrane lipid peroxidation, acrosome status and viability of spermatozoa, between the samples frozen in the presence or absence of L-carnitine and pyruvate, nor between the samples after the post-thaw addition of these components. A higher (p < 0.05) mean velocity and higher (p < 0.05) amplitude of lateral head displacement were observed in the samples frozen in the milk-based extender with the addition of L-carnitine and pyruvate after thawing. The addition of 50 mM L-carnitine and 10 mM pyruvate, either to the freezing extenders or after thawing, was not deleterious for sperm; however, it did not improve equine sperm motility, viability, acrosome and DNA integrity, nor decrease membrane lipid peroxidation after thawing.


Assuntos
Carnitina , Criopreservação , Crioprotetores , Fragmentação do DNA , Peroxidação de Lipídeos , Ácido Pirúvico , Preservação do Sêmen , Espermatozoides , Animais , Masculino , Cavalos , Criopreservação/veterinária , Criopreservação/métodos , Carnitina/farmacologia , Carnitina/administração & dosagem , Preservação do Sêmen/veterinária , Preservação do Sêmen/métodos , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Ácido Pirúvico/farmacologia , Crioprotetores/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Análise do Sêmen/veterinária , Acrossomo/efeitos dos fármacos , Motilidade dos Espermatozoides/efeitos dos fármacos , Antioxidantes/farmacologia
4.
Sci Rep ; 14(1): 21055, 2024 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-39251658

RESUMO

Nutritional status assessment, including amino acids, carnitine, and acylcarnitine profile, is an important component of diabetes care management, influencing growth and metabolic regulation. A designed case-control research included 100 Egyptian participants (50 T1DM and 50 healthy controls) aged 6 to 18 years old. The participants' nutritional status was assessed using the Body Mass Index (BMI) Z-score. Extended metabolic screening (EMS) was performed using a high-performance liquid chromatography-electrospray ionization-mass spectroscopy system to evaluate the levels of 14 amino acids, free carnitine, and 27 carnitine esters. T1DM children had considerably lower anthropometric Z-scores than the control group, with 16% undernutrition and 32% short stature. Total aromatic amino acids, phenylalanine, phenylalanine/tyrosine ratio, proline, arginine, leucine, isoleucine, free carnitine, and carnitine esters levels were considerably lower in the diabetic group, suggesting an altered amino acid and carnitine metabolism in type 1 diabetes. BMI Z-score showed a significant positive correlation with Leucine, Isoleucine, Phenylalanine, Citrulline, Tyrosine, Arginine, Proline, free carnitine, and some carnitine esters (Acetylcarnitine, Hydroxy-Isovalerylcarnitine, Hexanoylcarnitine, Methylglutarylcarnitine, Dodecanoylcarnitine, Tetradecanoylcarnitine, and Hexadecanoylcarnitine). HbA1c% had a significant negative correlation with Total aromatic amino acids, Branched-chain amino acid/Total aromatic amino acids ratio, Glutamic Acid, Citrulline, Tyrosine, Arginine, Proline, and certain carnitine esters (Propionylcarnitine, Methylglutarylcarnitine, Decanoylcarnitine, Octadecanoylcarnitine and Octadecenoylcarnitine), suggest that dysregulated amino acid and carnitine metabolism may be negatively affect the glycaemic control in children with TIDM. In conclusion, regular nutritional assessments including EMS of T1DM patients are critical in terms of diet quality and protein content for improved growth and glycemic management.


Assuntos
Aminoácidos , Carnitina , Diabetes Mellitus Tipo 1 , Estado Nutricional , Humanos , Criança , Masculino , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Adolescente , Egito , Carnitina/análogos & derivados , Carnitina/metabolismo , Carnitina/sangue , Estudos de Casos e Controles , Aminoácidos/metabolismo , Índice de Massa Corporal
5.
Mol Genet Genomic Med ; 12(9): e70003, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39248612

RESUMO

BACKGROUND: Newborn screening (NBS) for primary carnitine deficiency (PCD) has poor performance. This study aimed to evaluate the feasibility of incorporating next-generation sequencing (NGS) as a second-tier PCD test. METHODS: Between March and December 2020, 60,070 newborns were screened for inherited metabolic disorders. Newborns with free carnitine (C0) levels below 8.5 µmol/L were selected for second-tier genetic testing. RESULTS: In total, 130 (0.22%) newborns with low C0 levels underwent second-tier genetic testing, 87 (66.92%) had positive genetic testing results, and 30 (23.08%) carried pathogenic variants of the SLC22A5 gene. Six newborns were diagnosed with PCD. The incidence of PCD was approximately 1 in 1:10,012 newborns. The PPV reached 20% after combining with second-tier NGS. Of the eight variants identified in patients with PCD, the three most common variants were c.760C>T (p.Arg254*), c.51C>G (p.Phe17Leu), and c.1400C>G (p.Ser467Cys). The C0 levels of patients with PCD were significantly lower than those of PCD carriers (p = 0.0026) and PCD-negative individuals (p = 0.0005). CONCLUSIONS: Our results showed that the PPV reached 20% after combining with second-tier NGS. The MS/MS-based NBS and second-tier NGS combination can effectively reduce the false-positive rate and detect PCD in patients.


Assuntos
Carnitina , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Hiperamonemia , Membro 5 da Família 22 de Carreadores de Soluto , Humanos , Carnitina/sangue , Carnitina/deficiência , Membro 5 da Família 22 de Carreadores de Soluto/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Hiperamonemia/genética , Hiperamonemia/diagnóstico , Recém-Nascido , Masculino , Feminino , Testes Genéticos/métodos , Testes Genéticos/normas , Cardiomiopatias/genética , Cardiomiopatias/diagnóstico , Triagem Neonatal/métodos , Triagem Neonatal/normas , Doenças Musculares/genética , Doenças Musculares/diagnóstico , Mutação
6.
Amino Acids ; 56(1): 53, 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39207612

RESUMO

The exposure to modifiable risk factors at young ages have been linked to premature fatal and non-fatal cardiovascular and kidney outcomes. The use of urinary metabolomics has shown strong predictability of kidney function and cardiovascular disease (CVD). We therefore determined the associations between estimated glomerular filtration rate (eGFR) and urinary metabolites in young adults with and without CVD risk factors. Apparently healthy Black and White sexes were included (aged 20-30 years) and categorised by the presence or absence of risk factors, i.e., obesity, physical inactivity, smoking, excessive alcohol intake, masked hypertension, hyperglycemia, dyslipidemia and low socio-economic status, forming the CVD risk group (N = 1036), CVD risk clusters (i.e. presenting with 1 CVD risk factor (N = 344), 2 CVD risk factors (N = 360) and 3 + CVD risk factors (N = 332)) and the control group (N = 166). eGFR was calculated with CKD-EPI equations. A targeted metabolomics approach using liquid chromatography-tandem mass spectrometry was used to measure amino acids and acylcarnitines. Lower cystatin C-based eGFR were indicated in the CVD risk group, 2 and 3 + CVD risk clusters compared to the control group (all P ≤ 0.033). In the CVD risk group, eGFR associated positively with histidine, lysine, asparagine, glycine, serine, glutamine, dimethylglycine, threonine, alanine, creatine, cystine, methionine, tyrosine, pyroglutamic acid, leucine/isoleucine, aspartic acid, tryptophan, glutamic acid, free carnitine, acetylcarnitine, propionylcarnitine, isovalerylcarnitine, octanoylcarnitine and decanoylcarnitine (all P ≤ 0.044), with similar results found in the CVD risk clusters, particularly the 2 CVD risk cluster. eGFR was positively associated with metabolites linked to aromatic amino acid and branched-chain amino acid metabolism, energy metabolism and oxidative stress. These findings may indicate altered reabsorption of these metabolites or altered metabolic regulation to preserve renal health in the setting of CVD risk factors at this young age without established CVD.


Assuntos
Doenças Cardiovasculares , Taxa de Filtração Glomerular , Humanos , Masculino , Adulto , Feminino , Doenças Cardiovasculares/urina , Doenças Cardiovasculares/epidemiologia , Adulto Jovem , Rim/fisiopatologia , Rim/metabolismo , Fatores de Risco , Metabolômica , Carnitina/análogos & derivados , Carnitina/urina , Carnitina/metabolismo , Aminoácidos/urina , Aminoácidos/metabolismo , Cistatina C/urina
7.
Nutrients ; 16(16)2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39203843

RESUMO

Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible. Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake. In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 ratio), with medium-chain triglyceride supplementation at 10-25% of total energy (total MCT+LCT ratio = 20-35%). Trihepatnoin is a new therapeutic option with a good safety and efficacy profile. Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise. In medium- and short-chain deficits, dietary modifications are not advised (except during exacerbations), with MCT contraindicated and slow sugars recommended 20 min before any significant physical exertion. Parents should be alerted to the need to increase the amount and frequency of carbohydrate intake in stressful situations. The main measure in emergency hospital treatment is the administration of IV glucose. The use of carnitine remains controversial and new therapeutic options are under investigation.


Assuntos
Ácidos Graxos , Humanos , Ácidos Graxos/administração & dosagem , Oxirredução , Carboidratos da Dieta/administração & dosagem , Erros Inatos do Metabolismo Lipídico/dietoterapia , Triglicerídeos/sangue , Carnitina/administração & dosagem , Suplementos Nutricionais , Rabdomiólise
8.
Sci Rep ; 14(1): 18972, 2024 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-39152132

RESUMO

Postmortem metabolomics holds promise for identifying crucial biological markers relevant to death investigations and clinical scenarios. We aimed to assess its applicability in diagnosing hypothermia, a condition lacking definitive biomarkers. Our retrospective analysis involved 1095 postmortem femoral blood samples, including 150 hypothermia cases, 278 matched controls, and 667 randomly selected test cases, analyzed using UHPLC-QTOF mass spectrometry. The model demonstrated robustness with an R2 and Q2 value of 0.73 and 0.68, achieving 94% classification accuracy, 92% sensitivity, and 96% specificity. Discriminative metabolite patterns, including acylcarnitines, stress hormones, and NAD metabolites, along with identified pathways, suggest that metabolomics analysis can be helpful to diagnose fatal hypothermia. Exposure to cold seems to trigger a stress response in the body, increasing cortisol production to maintain core temperature, possibly explaining the observed upregulation of cortisol levels and alterations in metabolic markers related to renal function. In addition, thermogenesis seems to increase metabolism in brown adipose tissue, contributing to changes in nicotinamide metabolism and elevated levels of ketone bodies and acylcarnitines, these findings highlight the effectiveness of UHPLC-QTOF mass spectrometry, multivariate analysis, and pathway identification of postmortem samples in identifying metabolite markers with forensic and clinical significance. The discovered patterns may offer valuable clinical insights and diagnostic markers, emphasizing the broader potential of postmortem metabolomics in understanding critical states or diseases.


Assuntos
Biomarcadores , Hipotermia , Metabolômica , Humanos , Metabolômica/métodos , Biomarcadores/sangue , Masculino , Hipotermia/metabolismo , Hipotermia/diagnóstico , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Autopsia , Estudos Retrospectivos , Carnitina/análogos & derivados , Carnitina/metabolismo , Carnitina/sangue , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas/métodos
9.
EBioMedicine ; 106: 105267, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39098109

RESUMO

BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event characterized by new pulmonary infiltrates in cancer patients receiving immune checkpoint inhibitor therapy. This study aims to explore the interplay between lung microbiota, dysregulated metabolites, and host immunity in CIP. METHODS: We recruited thirteen hospitalized CIP patients, eleven idiopathic pulmonary fibrosis (IPF) patients, and ten new-onset non-small cell lung cancer patients. Bronchoalveolar lavage fluid samples were collected for 16S rRNA gene sequencing. The percentages of immune cells were determined using manual counting and flow cytometry. Interactions among microbiota, metabolites, and lymphocytes were analyzed using cultured mouse splenocytes and human T cells. FINDINGS: Proteobacteria emerged as the dominant phylum, notably abundant in both the CIP and IPF groups. Vibrio, Halomonas, Mangrovibacter, and Salinivibrio were the predominant microbiota because of their discriminative abundance patterns. Vibrio (r = 0.72, P-adj = 0.007) and Halomonas (r = 0.65, P-adj = 0.023) demonstrated strong correlations with lymphocytes. Vibrio metschnikovii and Mangrovibacter plantisponsors were more abundant in the CIP group than in the IPF group. Lauroylcarnitine, a key intermediary metabolite co-occurring with the predominant microbiota, exhibited a potent effect on cytokine secretion by mouse and human T cells, notably enhancing IFN-γ and TNF-α production from CD4 and CD8 cells in vitro. INTERPRETATION: Lauroylcarnitine, co-occurring with the predominant lung microbiota in CIP, could activate T cells in vitro. These findings suggest potential involvement of lung microbiota and acylcarnitine metabolism dysregulation in the pathogenesis of CIP. FUNDING: This work was supported by Peking University People's Hospital Scientific Research Development Funds (RDJ2022-15) and Provincial Key Clinical Specialty Capacity Building Project 2020 (Department of the Respiratory Medicine).


Assuntos
Inibidores de Checkpoint Imunológico , Pulmão , Ativação Linfocitária , Microbiota , Pneumonia , Linfócitos T , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Animais , Camundongos , Microbiota/efeitos dos fármacos , Masculino , Feminino , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Idoso , Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pneumonia/microbiologia , Pneumonia/etiologia , Pneumonia/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pessoa de Meia-Idade , Carnitina/análogos & derivados , Carnitina/metabolismo , RNA Ribossômico 16S/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Citocinas/metabolismo
10.
Meat Sci ; 217: 109621, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39116534

RESUMO

The objective of this exploratory study was to assess the changes on lipidome and metabolome profiling of Longissimus lumborum bull muscle with different ultimate pH (pHu) and aging periods. The bull muscles classified as normal, intermediate, or high pHu were collected from a Brazilian commercial slaughterhouse, cut into steaks, individually vacuum-packaged, and aged for 3 days (3-d) or 21 days (21-d) at 2 °C. Muscle extracts were analyzed for the profiles of both lipids, by mass spectrometry (via direct flow-injection), and metabolites, by nuclear magnetic resonance, with downstream multivariate data analysis. As major results, pairwise comparisons identified C12:0 and C14:0 acylcarnitines as potential biomarkers of the intermediate pHu-muscle, which are related to lipid catabolism for alternative energy metabolism and indicate less protein breakage postmortem. Interestingly, the concentration of arginine at early postmortem aging (3-d) may influence the previously reported improved tenderness in normal and high pHu-muscles. Moreover, upregulation of fumarate, formate, and acetate with increased pHu muscle at 21-d aging indicate more intense tricarboxylic acid cycle, amino acid degradation, and pyruvate oxidation by reactive oxygen species, respectively. These three compounds (fumarate, formate, and acetate) discriminated statistically the muscle with high pHu at 21-d aging. The normal pHu-muscle showed higher concentrations of glycogenolysis and glycolysis metabolites, including glucose, mannose, and pyruvate. Hence, our results enhance knowledge of postmortem biochemical changes of beef within different pHu groups aged up to 21 days, which is essential to understand the mechanisms underpinning bull meat quality changes.


Assuntos
Metaboloma , Músculo Esquelético , Carne Vermelha , Animais , Bovinos , Carne Vermelha/análise , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Concentração de Íons de Hidrogênio , Masculino , Lipidômica/métodos , Mudanças Depois da Morte , Brasil , Manipulação de Alimentos/métodos , Formiatos , Carnitina/análogos & derivados , Carnitina/metabolismo , Carnitina/análise
11.
Eur J Pharmacol ; 982: 176879, 2024 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-39128806

RESUMO

Alzheimer's disease (AD), the most common cause of dementia, leads to neurodegeneration and cognitive decline. We investigated the therapeutic effects of L-carnitine on cognitive performance and anxiety-like behavior in a rat model of AD induced by unilateral intracerebroventricular injection of ß-amyloid1-42 (Aß1-42). L-carnitine (100 mg/kg/day) was administered intraperitoneally for 28 consecutive days. Following this, the open-field test, novel object recognition test, elevated plus-maze test, Barnes maze test, and passive avoidance learning test were used to assess locomotor activity, recognition memory, anxiety-like behavior, spatial memory, and passive avoidance memory, respectively. Plasma and hippocampal oxidative stress markers, including total oxidant status (TOS) and total antioxidant capacity (TAC), were examined. In addition, histological investigations were performed in the dentate gyrus of the hippocampus using Congo red staining and hematoxylin and eosin staining. The injection of Aß1-42 resulted in cognitive deficits and increased anxiety-like behavior. These changes were associated with an imbalance of oxidants and antioxidants in plasma and the hippocampus. Also, neuronal death and Aß plaque accumulation were increased in the hippocampal dentate gyrus region. However, injection of L-carnitine improved recognition memory, spatial memory, and passive avoidance memory in AD rats. These findings provide evidence that L-carnitine may alleviate anxiety-like behavior and cognitive deficits induced by Aß1-42 through modulating oxidative-antioxidant status and preventing Aß plaque accumulation and neuronal death.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Ansiedade , Carnitina , Modelos Animais de Doenças , Transtornos da Memória , Estresse Oxidativo , Ratos Wistar , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ansiedade/tratamento farmacológico , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/prevenção & controle , Ratos , Carnitina/farmacologia , Carnitina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Fragmentos de Peptídeos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Memória Espacial/efeitos dos fármacos
12.
Mol Metab ; 88: 102016, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39182842

RESUMO

OBJECTIVE: A prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial ß-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells. METHODS: HTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer. RESULTS: This work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model. CONCLUSIONS: This preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps.


Assuntos
Carnitina , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Membro 5 da Família 22 de Carreadores de Soluto , Carnitina/metabolismo , Carnitina/farmacologia , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/efeitos adversos , Animais , Humanos , Camundongos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Masculino , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos
13.
J Proteome Res ; 23(9): 3746-3753, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39162688

RESUMO

A comprehensive understanding of the exact influence of type 2 diabetes mellitus (T2DM) on the metabolic status of non-small cell lung cancer (NSCLC) is still lacking. This study explores metabolic alterations in tumor tissues among patients with coexisting NSCLC and T2DM in comparison with NSCLC patients. A combined approach of clinical analysis and metabolomics was employed, including 20 NSCLC patients and 20 NSCLC+T2DM patients. Targeted metabolomics analysis was performed on tumor tissues using the liquid chromatography-mass spectrometry (LC-MS) approach. A clear segregation was observed between NSCLC+T2DM and matched NSCLC tissue samples in Orthogonal Partial Least Squares Discrimination Analysis (OPLS-DA). Furthermore, the levels of 7 metabolites are found to be significantly different between diabetes/nondiabetes tumor tissue samples. The related pathways included arginine biosynthesis, glutathione metabolism, arginine and proline metabolism, purine metabolism, biotin metabolism, and histidine metabolism. 3-Phenyllactic acid, carnitine-C5, carnitine-C12, and serotonin showed a positive linear correlation with fasting blood glucose levels in NSCLC patients. Uridine, pipecolic acid, cytosine, and fasting blood glucose levels were found to have a negative correlation. Our results suggest that NSCLC patients with concurrent T2DM exhibit distinct metabolic shifts in tumor tissues compared to those of solely NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Diabetes Mellitus Tipo 2 , Neoplasias Pulmonares , Metabolômica , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicações , Masculino , Metabolômica/métodos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Feminino , Idoso , Cromatografia Líquida , Metaboloma , Espectrometria de Massas , Glicemia/metabolismo , Carnitina/metabolismo , Carnitina/análogos & derivados , Arginina/metabolismo
14.
Circ Heart Fail ; 17(8): e011569, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39119698

RESUMO

BACKGROUND: Growing evidence indicates that trimethylamine N-oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine N-oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine) affect incident heart failure (HF). METHODS: We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors. RESULTS: In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine N-oxide (hazard ratio, 1.15 [95% CI, 1.09-1.20]; P<0.001), choline (hazard ratio, 1.44 [95% CI, 1.26-1.64]; P<0.001), and crotonobetaine (hazard ratio, 1.24 [95% CI, 1.16-1.32]; P<0.001) were associated with increased risk for incident HF. After further adjustment for renal function (potential confounder or mediator), these associations did not reach Bonferroni-corrected statistical significance (P=0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF (P<0.05). In exploratory analyses, results were similar for subtypes of HF based on left ventricular ejection fraction, and associations appeared generally stronger among Black and Hispanic/Latino versus White adults, although there were no interactions for any metabolites with race. CONCLUSIONS: In this pooled analysis of 2 well-phenotyped, diverse, community-based cohorts, circulating concentrations of gut microbe-derived metabolites such as trimethylamine N-oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF. REGISTRATION: URL: https://www.clinicaltrials.gov/; Unique identifiers: NCT00005133 and NCT00005487.


Assuntos
Betaína , Carnitina , Colina , Microbioma Gastrointestinal , Insuficiência Cardíaca , Metilaminas , Humanos , Metilaminas/sangue , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etnologia , Insuficiência Cardíaca/sangue , Microbioma Gastrointestinal/fisiologia , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Incidência , Colina/sangue , Carnitina/análogos & derivados , Carnitina/sangue , Betaína/sangue , Betaína/análogos & derivados , Estados Unidos/epidemiologia , Fatores de Risco , Biomarcadores/sangue , Idoso de 80 Anos ou mais
15.
Food Chem Toxicol ; 192: 114949, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39182635

RESUMO

Acute kidney injury (AKI) is a worldwide public health problem with high morbidity and mortality. Cisplatin is a widely used chemotherapeutic agent for treating solid tumors, but the induction of AKI restricts its clinical application. In this study, the effect of cisplatin on the expression of organic ion transporters was investigated through in vivo and in vitro experiments. Targeted metabolomics techniques were used to measure the levels of selected endogenous substances in serum. Transmission electron microscopy was used to observe the microstructure of renal tubular epithelial cells. Our results show that the toxicity of cisplatin on HK-2 cells or HEK-293 cells was time- and dose-dependent. Administration of cisplatin decreased the expression of OAT1/3 and OCT2 and increased the expression of MRP2/4. Mitochondrial damage induced by cisplatin lead to renal tubular epithelial cell injury. In addition, administration of cisplatin resulted in significant changes in endogenous substance levels in serum, including amino acids, carnitine, and fatty acids. These serum amino acids and metabolites (α-aminobutyric acid, proline, and alanine), carnitines (tradecanoylcarnitine, hexanylcarnitine, octanoylcarnitine, 2-methylbutyroylcarnitine, palmitoylcarnitine, and linoleylcarnitine) and fatty acids (9E-tetradecenoic acid) represent endogenous substances with diagnostic potential for cisplatin-induced AKI.


Assuntos
Injúria Renal Aguda , Cisplatino , Cisplatino/toxicidade , Humanos , Animais , Células HEK293 , Masculino , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Antineoplásicos/toxicidade , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportador 2 de Cátion Orgânico/metabolismo , Transportador 2 de Cátion Orgânico/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Carnitina/análogos & derivados , Carnitina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo
16.
Exp Dermatol ; 33(9): e15170, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39207113

RESUMO

Prurigo nodularis (PN) is a chronic and debilitating skin disease with severe itching that negatively impacts patients' quality of life and mental state. However, the treatment options for PN remain limited. Global metabolomics analysis can offer effective information on energy metabolism, pathogenesis and potential diagnostic biomarkers. No study on metabolomic analysis of PN has been reported. To further understand the mechanisms of PN and analyse the plasma metabolite profiles in patients with PN. Targeted-metabolome analysis of 306 metabolites in plasma from 18 patients with PN and 19 healthy controls was performed using Liquid Chromatography-tandem Mass Spectrometer analysis. We identified 31 differential metabolites. Most acylcarnitines, long-chain fatty acids, alpha-aminobutyric acid, hydroxybutyric acid and lactic acid among these metabolites were up-regulated in patients with PN; in contrast, glucaric acid, suberic acid, bile acid derivatives and most amino acids were down-regulated. Positive correlations exist between glucaric acid and itching severity and acylcarnitines and insomnia. Suberic acid and the Investigator's Global Assessment (IGA) scores correlate negatively. Metabolite variation reflects the dysregulation of energy metabolism and chronic systematic inflammation in PN. Several metabolites, such as glucaric acid, suberic acid and acylcarnitines, merit further study as potential biomarkers of disease severity in PN.


Assuntos
Biomarcadores , Metaboloma , Prurigo , Humanos , Biomarcadores/sangue , Prurigo/sangue , Prurigo/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Metabolômica/métodos , Estudos de Casos e Controles , Carnitina/análogos & derivados , Carnitina/sangue , Espectrometria de Massas em Tandem , Idoso , Cromatografia Líquida , Metabolismo Energético
17.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(8): 845-851, 2024 Aug 15.
Artigo em Chinês | MEDLINE | ID: mdl-39148390

RESUMO

OBJECTIVES: To investigate the clinical and genetic features of children with 3-methylcrotonyl-coenzyme A carboxylase deficiency (MCCD). METHODS: A retrospective analysis was conducted on the clinical manifestations and genetic testing results of six children with MCCD who attended Children's Hospital Affiliated to Zhengzhou University from January 2018 to October 2023. RESULTS: Among the six children with MCCD, there were 4 boys and 2 girls, with a mean age of 7 days at the time of attending the hospital and 45 days at the time of confirmed diagnosis. Of all children, one had abnormal urine odor and five had no clinical symptoms. All six children had increases in blood 3-hydroxyisovaleryl carnitine and urinary 3-hydroxyisovaleric acid and 3-methylcrotonoylglycine, and five of them had a reduction in free carnitine. A total of six mutations were identified in the MCCC1 gene, i.e., c.1630del(p.R544Dfs*2), c.269A>G(p.D90G), c.1609T>A(p.F537I), c.639+2T>A, c.761+1G>T, and c.1331G>A(p.R444H), and three mutations were identified in the MCCC2 gene, i.e., c.838G>T(p.D280Y), c.592C>T(p.Q198*,366), and c.1342G>A(p.G448A). Among these mutations, c.269A>G(p.D90G) and c.1609T>A(p.F537I) had not been previously reported in the literature. There was one case of maternal MCCD, and the child carried a heterozygous mutation from her mother. Five children with a reduction in free carnitine were given supplementation of L-carnitine, and free carnitine was restored to the normal level at the last follow-up visit. CONCLUSIONS: This study identifies two new mutations, c.269A>G(p.D90G) and c.1609T>A(p.F537I), thereby expanding the mutation spectrum of the MCCC1 gene. A combination of blood amino acid and acylcarnitine profiles, urine organic acid analysis, and genetic testing can facilitate early diagnosis and treatment of MCCD, and provide essential data for genetic counseling.


Assuntos
Carnitina , Mutação , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Carbono-Carbono Ligases/genética , Carbono-Carbono Ligases/deficiência , Carboxiliases/genética , Carboxiliases/deficiência , Carnitina/análogos & derivados , Carnitina/sangue , Estudos Retrospectivos , Distúrbios Congênitos do Ciclo da Ureia/genética , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico
18.
Exp Dermatol ; 33(8): e15159, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39166459

RESUMO

Psoriasis is a chronic inflammatory skin disorder with various subtypes, including psoriasis vulgaris (PV) and palmoplantar pustulosis (PPP). Metabolomics studies have provided insights into psoriasis pathogenesis. However, research on metabolomic alterations in PV and PPP patients is limited. We aimed to explore and compare the metabolic profiles of patients with PV and PPP to those of healthy volunteers (HVs). A single-centre retrospective cohort was constructed, comprising Korean patients with psoriasis and HVs matched by age and sex. Clinical information including demographics, disease severity, and comorbidities were collected. Plasma samples were subjected to targeted metabolic analysis using an Absolute IDQ®p180 kit, which quantified 188 metabolites, including amino acids and carnitines. Statistical significance was assessed using an independent t-test and chi-square test, with p-values adjusted by the Benjamini-Hochberg procedure. Pathway analyses were employed to gain a comprehensive understanding of the metabolite profile. This study included 93 patients (73 PV and 20 PPP) and an equal number of HVs. PV patients showed increased levels of sarcosine, serotonin, propionylcarnitine, proline, aspartic acid, tyrosine, taurine, spermine and ornithine, but exhibited a decreased level of acetylcarnitine than matched HVs. Notably, sarcosine levels were significantly elevated in PPP patients. Furthermore, the sarcosine/glycine ratio was significantly higher in both PV and PPP patients than in HVs. Pathway analysis showed significant increases in metabolites involved in amino acid metabolism and the urea cycle in PV patients. In conclusion, this study demonstrated distinct metabolic profiles in PV and PPP patients compared to HVs, suggesting sarcosine as a potential biomarker for psoriasis.


Assuntos
Psoríase , Humanos , Psoríase/sangue , Psoríase/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Metabolômica , Idoso , Estudos de Casos e Controles , Metaboloma , Sarcosina/sangue , Carnitina/sangue , Carnitina/análogos & derivados , Carnitina/metabolismo , Aminoácidos/sangue , Aminoácidos/metabolismo , Índice de Gravidade de Doença
19.
PLoS One ; 19(8): e0307802, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39178212

RESUMO

Prolonged consumption of diet rich in fats is regarded as the major factor leading to the insulin resistance (IR) and type 2 diabetes (T2D). Emerging evidence link excessive accumulation of bioactive lipids such as diacylglycerol (DAG) and ceramide (Cer), with impairment of insulin signaling in skeletal muscle. Until recently, little has been known about the involvement of long-chain acyl-CoAs synthetases in the above mechanism. To examine possible role of long-chain acyl-coenzyme A synthetase 1 (Acsl1) (a major muscular ACSL isoform) in mediating HFD-induced IR we locally silenced Acsl1 in gastrocnemius of high-fat diet (HFD)-fed C57BL/6J mice through electroporation-delivered shRNA and compared it to non-silenced tissue within the same animal. Acsl1 down-regulation decreased the content of muscular long-chain acyl-CoA (LCACoA) and both the Cer (C18:1-Cer and C24:1-Cer) and DAG (C16:0/18:0-DAG, C16:0/18:2-DAG, C18:0/18:0-DAG) and simultaneously improved insulin sensitivity and glucose uptake as compared with non-silenced tissue. Acsl1 down-regulation decreased expression of mitochondrial ß-oxidation enzymes, and the content of both the short-chain acylcarnitine (SCA-Car) and short-chain acyl-CoA (SCACoA) in muscle, pointing towards reduction of mitochondrial FA oxidation. The results indicate, that beneficial effects of Acsl1 partial ablation on muscular insulin sensitivity are connected with inhibition of Cer and DAG accumulation, and outweigh detrimental impact of decreased mitochondrial fatty acids metabolism in skeletal muscle of obese HFD-fed mice.


Assuntos
Coenzima A Ligases , Dieta Hiperlipídica , Diglicerídeos , Regulação para Baixo , Resistência à Insulina , Camundongos Endogâmicos C57BL , Músculo Esquelético , Obesidade , RNA Interferente Pequeno , Animais , Músculo Esquelético/metabolismo , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Camundongos , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Obesidade/genética , Diglicerídeos/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Masculino , Ceramidas/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Insulina/metabolismo , Camundongos Obesos
20.
Metabolomics ; 20(5): 92, 2024 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-39096437

RESUMO

INTRODUCTION: The human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection presents significant challenges due to the complex interplay between these diseases, leading to exacerbated metabolic disturbances. Understanding these metabolic profiles is crucial for improving diagnostic and therapeutic approaches. OBJECTIVE: This study aimed to characterise the urinary acylcarnitine and amino acid profiles, including 5-hydroxyindoleacetic acid (5-HIAA), in patients co-infected with HIV and TB using targeted liquid chromatography mass spectrometry (LC-MS) metabolomics. METHODS: Urine samples, categorised into HIV, TB, HIV/TB co-infected, and healthy controls, were analysed using HPLC-MS/MS. Statistical analyses included one-way ANOVA and a Kruskal-Wallis test to determine significant differences in the acylcarnitine and amino acid profiles between groups. RESULTS: The study revealed significant metabolic alterations, especially in TB and co-infected groups. Elevated levels of medium-chain acylcarnitines indicated increased fatty acid oxidation, commonly associated with cachexia in TB. Altered amino acid profiles suggested disruptions in protein and glucose metabolism, indicating a shift towards diabetes-like metabolic states. Notably, TB was identified as a primary driver of these changes, affecting protein turnover, and impacting energy metabolism in co-infected patients. CONCLUSION: The metabolic profiling of HIV/TB co-infection highlights the profound impact of TB on metabolic pathways, which may exacerbate the clinical complexities of co-infection. Understanding these metabolic disruptions can guide the development of targeted treatments and improve management strategies, ultimately enhancing the clinical outcomes for these patients. Further research is required to validate these findings and explore their implications in larger, diverse populations.


Assuntos
Aminoácidos , Carnitina , Coinfecção , Infecções por HIV , Metabolômica , Tuberculose , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aminoácidos/urina , Aminoácidos/metabolismo , Carnitina/análogos & derivados , Carnitina/urina , Carnitina/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Coinfecção/urina , Coinfecção/metabolismo , Infecções por HIV/complicações , Infecções por HIV/urina , Infecções por HIV/metabolismo , Espectrometria de Massa com Cromatografia Líquida/métodos , Metabolômica/métodos , Espectrometria de Massas em Tandem/métodos , Tuberculose/urina , Tuberculose/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA