RESUMEN
It has been assumed that exercise intensity variation throughout a cycling time trial (TT) occurs in alignment of various metabolic changes to prevent premature task failure. However, this assumption is based on target metabolite responses, which limits our understanding of the complex interconnection of metabolic responses during exercise. The current study characterized the metabolomic profile, an untargeted metabolic analysis, after specific phases of a cycling 4-km TT. Eleven male cyclists performed three separated TTs in a crossover counterbalanced design, which were interrupted at the end of the fast-start (FS, 600 ± 205 m), even-pace (EP, 3600 ± 190 m), or end-spurt (ES, 4000 m) phases. Blood samples were taken before any exercise and 5 min after exercise cessation, and the metabolomic profile characterization was performed using Nuclear Magnetic Resonance metabolomics. Power output (PO) was also continually recorded. There were higher PO values during the FS and ES compared to the EP (all p < 0.05), which were accompanied by distinct metabolomic profiles. FS showed high metabolite expression in TCA cycle and its related pathways (e.g., glutamate, citric acid, and valine metabolism); whereas, the EP elicited changes associated with antioxidant effects and oxygen delivery adjustment. Finally, ES was related to pathways involved in NAD turnover and serotonin metabolism. These findings suggest that the specific phases of a cycling TT are accompanied by distinct metabolomic profiles, providing novel insights regarding the relevance of specific metabolic pathways on the process of exercise intensity regulation.
Asunto(s)
Ciclismo , Estudios Cruzados , Metaboloma , Humanos , Masculino , Metaboloma/fisiología , Adulto , Ciclismo/fisiología , Ciclo del Ácido Cítrico , Serotonina/sangre , NAD/sangre , NAD/metabolismo , Adulto Joven , Ácido Glutámico/sangre , Ácido Glutámico/metabolismo , Metabolómica , Valina/sangre , Ácido Cítrico/sangreRESUMEN
BACKGROUND: Breast cancer is a heterogeneous and complex etiological disease. Understanding perturbations of circulating metabolites could improve prognosis. METHODS: We recruited breast cancer patients from Kaohsiung Medical University (KMU) to perform untargeted (case-control design) and targeted (patient cohort) metabolomics analyses in the discovery and validation phases to evaluate interaction effects between clinical factors and plasma metabolites using multivariable Cox proportional hazards model. RESULTS: In the discovery phase, partial least squares-discriminant analysis (PLS-DA) showed that plasma metabolites were significantly different between recurrent and non-recurrent breast cancer patients. Metabolite set enrichment analysis (MSEA) and metabolomic pathway analysis (MetPA) showed that valine, leucine, and isoleucine degradation was the significant pathway, and volcano plot showed significant ten upregulated and two downregulated metabolites between recurrent and non-recurrent cases. Combined with receiver operating characteristic (ROC) curve and biological significance, creatine, valine, methionine, and mannose were selected for the validation phase. In this patient cohort with 41 new-recurrent vs. 248 non-recurrent breast cancer cases, followed for 720.49 person-years, compared with low level of valine, high valine level was significantly negatively associated with recurrent breast cancer (aHR: 0.36, 95% CI: 0.18-0.72, P = 0.004), especially in ER-negative and PR-negative status. There were interaction effects between valine and ER (Pinteraction = 0.006) as well as PR (Pinteraction = 0.002) on recurrent breast cancer. After Bonferroni correction, stratification effects between valine and hormone receptors were still significant. CONCLUSION: Our study revealed that plasma metabolites were significantly different between recurrent and non-recurrent patients, proposing therapeutic insights for breast cancer prognosis.
Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama , Metabolómica , Recurrencia Local de Neoplasia , Humanos , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Femenino , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Persona de Mediana Edad , Metabolómica/métodos , Estudios de Casos y Controles , Biomarcadores de Tumor/sangre , Adulto , Receptores de Estrógenos/metabolismo , Pronóstico , Receptores de Progesterona/metabolismo , Anciano , Valina/sangre , Receptor ErbB-2/metabolismo , Receptor ErbB-2/sangre , Isoleucina/sangre , Curva ROC , MetabolomaRESUMEN
Globin adducts of various chemicals, persisting in organism over the whole lifetime of erythrocytes, have been used as biomarkers of cumulative exposures to parent compounds. After removal of aged erythrocytes from the bloodstream, cleavage products of these adducts are excreted with urine as alternative, non-invasively accessible biomarkers. In our biomonitoring studies on workers exposed to ethylene oxide, its adduct with globin, N-(2-hydroxyethyl)valine, and the related urinary cleavage product N-(2-hydroxyethyl)-L-valyl-L-leucine have been determined. To describe a toxicokinetic relationship between the above types of biomarkers, a general compartmental model for simulation of formation and removal of globin adducts has been constructed in the form of code in R statistical computing environment. The essential input variables include lifetime of erythrocytes, extent of adduct formation following a single defined exposure, and parameters of exposure scenario, while other possible variables are optional. It was shown that both biomarkers reflect the past exposures differently as the adduct level in globin is a mean value of adduct levels across all compartments (subpopulations of erythrocytes of the same age) while excretion of cleavage products reflects the adduct level in the oldest compartment. Application of the model to various scenarios of continuous exposure demonstrated its usefulness for human biomonitoring data interpretation.
Asunto(s)
Monitoreo Biológico , Biomarcadores , Eritrocitos , Exposición Profesional , Humanos , Biomarcadores/orina , Biomarcadores/sangre , Eritrocitos/metabolismo , Eritrocitos/efectos de los fármacos , Modelos Biológicos , Óxido de Etileno/toxicidad , Óxido de Etileno/farmacocinética , Óxido de Etileno/orina , Toxicocinética , Globinas/metabolismo , Valina/análogos & derivados , Valina/farmacocinética , Valina/orina , Valina/sangre , Simulación por ComputadorRESUMEN
Las enfermedades metabólicas pueden presentarse con síntomas, signos y laboratorios inespecíficos, que si no se consideran entre los diagnósticos diferenciales pueden retrasar el diagnóstico de estos pacientes, lo que lleva a un alto grado de secuelas neurológicas o muerte en etapas tempranas. La enfermedad de Orina a Jarabe de Arce es una enfermedad metabólica de baja incidencia caracterizada por la acumulación de niveles tóxicos de valina, isoleucina y principalmente leucina. Se presenta un paciente sin antecedentes que a los 11 días de vida comienza con mala actitud alimentaria, letargia y fontanela tensa. Descartadas las causas infectológicas se realizó un screening para enfermedades metabólicas. Se diagnosticó Leucinosis (Enfermedad de orina con olor a Jarabe de Arce) y se inició el tratamiento con restricción de leucina, valina e isoleucina en la dieta. A los pocos días del tratamiento el paciente mostró evidencias de mejoría clínica y en los parámetros de laboratorio.
Clinical signs, symptoms and lab tests of neonatal metabolic diseases may be unspecific and a high grade of suspicion is necessary to include them among the differential diagnosis avoiding a significant delay in recognizing this condition and consequent risk of neurologic handicap or early dead. Maple syrup urine disease is a congenital metabolic disorder with a low rate of prevalence and characterized by a toxic accumulation of the amino acids valine, isoleucine and mainly leucine. In this report we describe the history of a patient apparently healthy that on the 11th day after birth initiates symptoms like poor feeding, lethargy and tense fontanel. Excluded sepsis a work up for metabolic disease was performed, being diagnosed a leucinosis (Maple syrup urine disease). A dietary treatment with leucine, valine and isoleucine restriction was immediately initiated and a few days after the patient showed significant clinical and lab improvement. A short description and discussion of this disease is presented.
Asunto(s)
Humanos , Masculino , Recién Nacido , Aminoácidos de Cadena Ramificada/metabolismo , Aminoácidos de Cadena Ramificada/sangre , Enfermedad de la Orina de Jarabe de Arce/diagnóstico , Enfermedad de la Orina de Jarabe de Arce/dietoterapia , Argentina , Diagnóstico Precoz , Enfermedades Metabólicas/diagnóstico , Isoleucina/metabolismo , Isoleucina/sangre , Leucina/metabolismo , Leucina/sangre , Tamizaje Neonatal , Proteínas en la Dieta/administración & dosificación , Valina/metabolismo , Valina/sangreRESUMEN
Introducción La enfermedad de la orina con olor a jarabe de arce (MSUD) es un raro trastorno de herencia autosómica recesiva en el que, debido a la deficiencia enzimática en el complejo deshidrogenasa de los α-cetoácidos de cadena ramificada, se produce acumulación de los aminoácidos leucina, isoleucina, valina y aloisoleucina y sus productos metabólicos en células y líquidos biológicos, lo que conduce a una disfunción cerebral grave. Pacientes y método Presentamos los tres casos de MSUD diagnosticados desde el año 2000 en Galicia, a partir de la puesta en marcha del Programa de Cribado Neonatal por espectrometría de masas en tándem (MS/MS) en muestra de sangre impregnada en papel. Se trata de dos formas clásicas y una intermedia de MSUD, una diagnosticada por el inicio clínico precoz y dos a través del cribado neonatal. Todos los casos fueron confirmados mediante estudio enzimático y genético. Se expone la situación clínica y bioquímica al diagnóstico y durante el seguimiento posterior. Los tres mantuvieron un adecuado control metabólico con concentraciones medias de leucina a lo largo del tiempo cercanos al rango normal (220, 177 y 252 μmol/l, respectivamente). Presentaron descompensaciones moderadas y sólo superaron de forma aislada, un día en dos de los pacientes, los 1.000 μmol/l de leucina. Los cocientes de desarrollo en los tres casos están en rango normal. Resultados A la vista de nuestros resultados, consideramos clave para mejorar el pronóstico de los pacientes con MSUD: la inclusión de esta enfermedad dentro de los programas de cribado neonatal con toma de muestra precoz, a los dos o tres días de vida; un tratamiento agresivo en la fase inicial y en las crisis por descompensación metabólica; un control evolutivo estricto con el fin de prevenir descompensaciones, y la monitorización de aminoácidos ramificados de forma cómoda para el paciente (sobre muestra de sangre en papel) manteniendo concentraciones de leucina inferiores a 300 μmol/l
Introduction Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder caused by an inherited deficiency of branched chain α-ketoacid dehydrogenase activity. Accumulation of the amino acids leucine, isoleucine, valine and alloisoleucine and their metabolic products in cells and biological fluids results in severe brain dysfunction. Patients and methods We present three cases of MSUD diagnosed in Galicia since 2000, the year in which the Extended Newborn Screening Program by tandem mass spectrometry was started in this region. One of the patients was diagnosed on the basis of early clinical presentation and the others by neonatal screening. Enzymatic and molecular studies confirmed two classic cases of MSUD and an intermediate variant. We describe the clinical and biochemical details at confirmation of diagnosis and the long-term outcome of the three patients. Throughout follow-up, all the patients maintained adequate leucine levels, which were near the normal range (mean levels: 220, 177 and 252 μmol/L, respectively). Several moderate metabolic decompensations were observed but leucine levels only occasionally exceeded 1000 μmol/L (one day in two patients). IQ tests were performed in all patients and scores were within the normal range. In view of our results, we believe the following measures are essential to improve the prognosis of MSUD: inclusion of this disease in Expanded Neonatal Screening Programs with early samples (at 2-3 days of life); aggressive treatment in the initial phase and during acute decompensations; strict metabolic control to prevent crises, monitoring of branched-chain amino acids (dried blood spot sample), and maintenance of long term plasma leucine levels below 300 μmol/L
Asunto(s)
Masculino , Femenino , Recién Nacido , Humanos , Enfermedad de la Orina de Jarabe de Arce/diagnóstico , Enfermedad de la Orina de Jarabe de Arce/terapia , Aminoácidos de Cadena Ramificada/sangre , Complejos Multienzimáticos/sangre , Complejos Multienzimáticos/genética , Enfermedad de la Orina de Jarabe de Arce/sangre , Aminoácidos de Cadena Ramificada/metabolismo , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida) , Alanina/sangre , Estudios de Seguimiento , Furosemida/uso terapéutico , Isoleucina/sangre , Cetona Oxidorreductasas/sangre , Cetona Oxidorreductasas/genética , Leucina/sangre , Manitol/uso terapéutico , Mutación , Tamizaje Neonatal , Concentración Osmolar , Reacción en Cadena de la Polimerasa , Solución Salina Hipertónica/uso terapéutico , Valina/sangreRESUMEN
Apresentaçäo de um caso de leucinose em recém-nascido do sexo feminino, diagnóstico no 26§ dia de vida. O quadro neurológico se caracteriza por alteraçöes do tono muscular, convulsöes, letargia e dificuldade respiratória. A demosntraçäo do aumento de aminoácidos de cadeia ramificada através do aminoacidograma constituiu o teste diagnóstico mais importante e o tratamento com MSUD resultou na boa evoluçäo da paciente