RESUMO
Datura metel L. (D. metel) is one well-known folk medical herb with wide application and also the most abused plants all over the world, mainly for spiritual or religious purpose, over-dosing of which often produces poisonous effects. In this study, mice were orally administered with the extract of D. metel once a day at doses for 10 mg/kg and 40 mg/kg for consecutive 4 days, 1H NMR based metabolomics approach aided with histopathological inspection and biochemical assays were used for the first time to study the psychoactive and toxic effects of D. metel. Histopathological inspection revealed obvious hypertrophy of hepatocytes, karyolysis and karyorrhexis in livers as well as distinct nerve cell edema, chromatolysis and lower nuclear density in brains. The increased tissue level of methane dicarboxylic aldehyde (MDA) and superoxide dismutase (SOD), decreased tissue level of glutathione (GSH) along with increased serum level of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) suggested brain and liver injury induced by D. metel. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles supplemented with correlation network analysis revealed significant altered metabolites and related pathway that contributed to oxidative stress, energy metabolism disturbances, neurotransmitter imbalance and amino acid metabolism disorders.
Assuntos
Encéfalo/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Datura metel/toxicidade , Fígado/efeitos dos fármacos , Extratos Vegetais/toxicidade , Animais , Encéfalo/metabolismo , Metabolismo Energético/efeitos dos fármacos , Glutationa/metabolismo , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Metabolômica , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
Imidazolium cations are promising candidates for preparing anion-exchange membranes because of their good alkaline stability. Substitution of imidazolium cations is an efficient way to improve their alkaline stability. By combining density functional theory calculations with experimental results, it is found that the LUMO energy correlates with the alkaline stability of imidazolium cations. The results indicate that alkyl groups are the most suitable substituents for the N3 position of imidazolium cations, and the LUMO energies of alkyl-substituted imidazolium cations depend on the electron-donating effect and the hyperconjugation effect. Comparing 1,2-dimethylimidazolium cations (1,2-DMIm+) and 1,3-dimethylimidazolium cations (1,3-DMIm+) with the same substituents reveals that the hyperconjugation effect is more significant in influencing the LUMO energy of 1,3-DMIms. This investigation reveals that LUMO energy is a helpful aid in predicting the alkaline stability of imidazolium cations.
Assuntos
Álcalis/química , Imidazóis/química , Cátions , Solventes/químicaRESUMO
Ginkgolic acid (15:1) is a major toxic component in extracts obtained from Ginkgo biloba (EGb) that has allergic and genotoxic effects. This study is the first to explore the hepatotoxicity of ginkgolic acid (15:1) using a NMR (nuclear magnetic resonance)-based metabolomics approach in combination with biochemistry assays. Mice were orally administered two doses of ginkgolic acid (15:1), and mouse livers and serum were then collected for NMR recordings and biochemical assays. The levels of activity of alanine aminotransferase (ALT) and glutamic aspartate transaminase (AST) observed in the ginkgolic acid (15:1)-treated mice suggested that it had induced severe liver damage. An orthogonal signal correction partial least-squares discriminant analysis (OSC-PLSDA) performed to determine the metabolomic profile of mouse liver tissues indicated that many metabolic disturbances, especially oxidative stress and purine metabolism, were induced by ginkgolic acid (15:1). A correlation network analysis combined with information related to structural similarities further confirmed that purine metabolism was disturbed by ginkgolic acid (15:1). This mechanism might represent the link between the antitumour activity and the liver injury-inducing effect of ginkgolic acid (15:1). A SUS (Shared and Unique Structure) plot suggested that a two-dose treatment of ginkgolic acid (15:1) had generally the same effect on metabolic variations but that its effects were dose-dependent, revealing some of the common features of ginkgolic acid (15:1) dosing. This integrated metabolomics approach helped us to characterise ginkgolic acid (15:1)-induced liver damage in mice.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fígado/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Metabolômica , Salicilatos/toxicidade , Administração Oral , Animais , Doença Hepática Induzida por Substâncias e Drogas/sangue , Relação Dose-Resposta a Droga , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos Endogâmicos ICR , Ressonância Magnética Nuclear BiomolecularRESUMO
Pyrazinamide (PZA) is a well-known first line anti-tuberculosis drug used in combination with other drugs such as isoniazid and rifampicin. Unfortunately, PZA suffered from a high rate of hepatotoxicity and hyperuricemia, which has not been clearly elucidated, hindering its wide application for therapeutic purposes. The purpose of this investigation was to develop a model of rat sub-acute hepatotoxicity induced by PZA and to explore the affected metabolic pathways by a 1H NMR-based metabolomics approach complemented with histopathological analysis and clinical chemistry. Rats of both genders were administered with PZA by gavage at doses of 1.0 and 2.0 g kg-1 for 4 weeks. PZA decreased the weights of dosed rats and induced liver injury dose-dependently. The female rats were more sensitive to PZA induced damage. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of the rat liver and serum revealed that PZA produced a status of oxidative stress and disturbances in purine metabolism, energy metabolism and NAD+ metabolism in a gender-specific and dose-dependent manner. These findings could be helpful to clarify the mechanism of PZA-induced hepatotoxicity and hyperuricemia. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organisms, providing a powerful and feasible tool to probe drug induced toxicity or side effects.
RESUMO
Imidazolium cations with butyl groups at various substitution positions (N1-, C2-, and N3-), 1-butyl-2,3-dimethylimidazolium ([N1-BDMIm](+)), 2-butyl-1,3-dimethylimidazolium ([C2-BDMIm](+)), and 3-butyl-1,2-dimethylimidazolium ([N3-BDMIm](+)), were synthesized. Quantitative (1)H NMR spectra and density functional theory calculation were applied to investigate the chemical stability of the imidazolium cations in alkaline solutions. The results suggested that the alkaline stability of the imidazolium cations was drastically affected by the C2-substitution groups. The alkaline stability of imidazolium cations with various substitution groups at the C2-position, including 2-ethyl-1-butyl-3-methylimidazolium ([C2-EBMIm](+)), 1,2-dibutyl-3-methylimidazolium ([C2-BBMIm](+)), and 2-hydroxymethyl-1-butyl-3-methylimidazolium ([C2-HMBMIm](+)), was further studied. The butyl group substituted imidazolium cation ([C2-BBMIm](+)) exhibited the highest alkaline stability at the elevated temperatures. The synthesized anion-exchange membranes based on the [C2-BBMIm](+) cation showed promising alkaline stability. These observations should pave the way to the practical application of imidazolium-based anion exchange membrane fuel cells.