RESUMEN
2', 3', 5'-Tri-O-acetyl-N6-(3-hydroxylaniline)adenosine (WS070117) is a derivative compound of natural product cordycepin. It has significant lipids regulating activity and low toxicity which has been proved by in vitro and in vivo experiments. In this study, 1H NMR-based metabolomics was used to investigate the dose-related effects of WS070117 on hyperlipidemia of high-fat-fed hamsters. The hyperlipidemic hamsters were administrated with six different doses of WS070117, including 3, 12, 50, 100, 200 and 400 mg x kg(-1) x d(-1). 1H NMR spectra of hamster serum were visually and statistically analyzed using two multivariate analyses: principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). As a result, WS070117-treated groups showed dose-related regulation of metabolites associated with lipid metabolism, choline metabolism and glucose metabolism. The dose of 3 mg x kg(-1) x d(-1) of WS070117 only exhibited a little lipids regulating activity. However, the doses of 12 and 50 mg x kg(-1) x d(-1) of WS070117 both regulated the contents of metabolites to reverse significantly toward normal levels. When the dose of WS070117 reached 100 mg x kg(-1) x d(-1), it was more effective than positive control drugs. The work suggested that NMR-based metabolomics might be a valuable approach to evaluate dose-related effects of lipids regulating compounds.
Asunto(s)
Adenosina/análogos & derivados , Metabolismo de los Lípidos/efectos de los fármacos , Metabolómica , Adenosina/farmacología , Animales , Cricetinae , Hiperlipidemias/metabolismo , Análisis de los Mínimos Cuadrados , Espectroscopía de Resonancia Magnética , Análisis Multivariante , Análisis de Componente PrincipalRESUMEN
The application of HPLC-NMR-MS hyphenated technique in the structural identification of trace substances from complex mixtures and the identification of endogenous and exogenous substances in the establishment process of metabolic profiling have become effective analytical tools in pharmaceutical chemistry, pharmacological and pharmacokinetic studies of active substances from natural products. Metabolomics method based on NMR technology can accurately portray metabolic phenotypes with the characteristics of diseases and a variety of disease-related pathways, and it can greatly enrich and supplement the traditional disease evaluation methods. So it can be used for pharmacological studies of active substances from natural products, such as toxicological studies, the dose optimization, active substances screening and pharmacodynamic evaluation. Hyphenated technique associated with metabolomics method based on NMR technology will accelerate the speed of the discovery of active substances from natural products, and improve the efficiency of their pharmacological evaluation.
Asunto(s)
Productos Biológicos/química , Espectroscopía de Resonancia Magnética , Metabolómica/métodos , Productos Biológicos/farmacología , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Técnicas Químicas Combinatorias , Espectrometría de Masas , Estructura MolecularRESUMEN
To obtain a better understanding of the progression of atherosclerosis and identify potential biomarkers, proton nuclear magnetic resonance spectroscopy (1H NMR)-based metabonomics was used to study the metabolic changes in the plasma of hamster fed with a high-fat/cholesterol diet. Plasma samples were collected at different time points during the progression of atherosclerosis and individual proton NMR spectra were visually and statistically assessed using multivariate analyses. NMR results for all samples showed a time-dependent development from physiological to pathophysiological status during atherosclerosis. Analysis of the identified biomarkers of atherosclerosis suggests that lipid and amino acid metabolisms are significantly disturbed, together with inflammation, oxidative stress, following cholesterol overloading. The results enriched our understanding of the mechanism of atherosclerosis and demonstrated the effectiveness of the NMR-based metabonomics approach to study such a complex disease.
Asunto(s)
Biomarcadores/metabolismo , Enfermedad de la Arteria Coronaria/metabolismo , Metaboloma , Metabolómica , Aminoácidos/sangre , Animales , Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Lípidos/sangre , Espectroscopía de Resonancia Magnética , Masculino , Mesocricetus , Estrés Oxidativo/efectos de los fármacos , Análisis de Componente Principal , Distribución AleatoriaRESUMEN
The hamster has been previously found to be a suitable model to study the changes associated with diet-induced hyperlipidemia in humans. Traditionally, studies of hyperlipidemia utilize serum- or plasma-based biochemical assays and histopathological evaluation. However, unbiased metabonomic technologies have the potential to identify novel biomarkers of disease. Thus, to obtain a better understanding of the progression of hyperlipidemia and discover potential biomarkers, we have used a proton nuclear magnetic resonance spectroscopy ((1)H-NMR)-based metabonomics approach to study the metabolic changes occurring in the plasma, urine and liver extracts of hamsters fed a high-fat/high-cholesterol diet. Samples were collected at different time points during the progression of hyperlipidemia, and individual proton NMR spectra were visually and statistically assessed using two multivariate analyses (MVA): principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). Using the commercial software package Chenomx NMR suite, 40 endogenous metabolites in the plasma, 80 in the urine and 60 in the water-soluble fraction of liver extracts were quantified. NMR analysis of all samples showed a time-dependent transition from a physiological to a pathophysiological state during the progression of hyperlipidemia. Analysis of the identified biomarkers of hyperlipidemia suggests that significant perturbations of lipid and amino acid metabolism, as well as inflammation, oxidative stress and changes in gut microbiota metabolites, occurred following cholesterol overloading. The results of this study substantially broaden the metabonomic coverage of hyperlipidemia, enhance our understanding of the mechanism of hyperlipidemia and demonstrate the effectiveness of the NMR-based metabonomics approach to study a complex disease.