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1.
Toxicol Lett ; 319: 204-212, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760061

RESUMO

Doxorubicin has been indicated to be cardiotoxic and nephrotoxic, and thus it is often used as a model drug. Possible molecular mechanisms of this toxicity have been proposed, however, the systematic investigation of time-related metabolic trajectories specific to renal toxicity has rarely been reported. The present study was designed to assess time-dependent changes in doxorubicin-induced nephropathy through urinary metabolomics and to reveal the molecular mechanism based on key pathways. Urinary metabolomics revealed that the 14th day was the critical time point for model construction. Pathway analysis results showed that 5 pathways with impact (>0.1), FDR (<0.1) and p value (<0.05) were important. Furthermore, three pathways, including butanoate metabolism, alanine, aspartate and glutamate metabolism and arginine and proline metabolism, were focused on and validated by partial least squares regression analysis (PLS-RA) and molecular docking techniques. Our findings also showed that robust metabolomics combined with PLS-RA and molecular docking techniques is promising for elucidating time-dependent changes due to doxorubicin toxicity and for clarifying mechanisms, and the results provide a research foundation for the construction of a nephropathy model.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Nefropatias/induzido quimicamente , Nefropatias/urina , Metaboloma/efeitos dos fármacos , Aminoácidos/metabolismo , Animais , Rim/patologia , Nefropatias/patologia , Masculino , Metabolômica , Simulação de Acoplamento Molecular , Proteinúria/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
2.
J Pharm Biomed Anal ; 177: 112837, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31493746

RESUMO

The ambiguity of dose-effect relationship of many traditional Chinese medicines (TCMs) has always influenced their rational use in TCM clinic. Rhubarb, a preferred representative of cathartic TCM, is currently widely used that results in a diversity of its dosage. The aim of this study was to use an integrated metabolomics strategy to simultaneously reveal dose-effect relationship and therapeutic mechanisms of different efficacy of rhubarb in constipation rats. Six doses of rhubarb (0.135, 0.27, 0.81, 1.35, 4.05, and 8.1 g/kg) were examined to elucidate the laxative and fire-purging effects by pathological sections and UPLC-Q-TOF/MSE. The results showed that there existed serious lesions in the stomach and colon of model rats. And conditions were basically improved to some extent in rhubarb-treated groups. Through relative distance calculation based on metabolomics score plots, it suggested that the effective dose threshold (EC20-EC80 range) of rhubarb was from 0.31 to 4.5 g/kg (corresponding to 3.44-50.00 g in the clinic) in rat serum and 0.29-2.1 g/kg (corresponding to 3.22-23.33 g in the clinic) in feces. Then, 33 potential biomarkers were identified in total. Functional pathway analysis revealed that the alterations of these biomarkers were associated with 15 metabolic pathways, mainly including arachidonic acid metabolism, glycerophospholipid metabolism, steroid biosynthesis, primary bile acid biosynthesis and sphingolipid metabolism. Of note, different doses of rhubarb could alleviate endogenous disorders to varying degrees through regulating multiple perturbed pathways to the normal state, which might be in a dose-dependent manner and involved in therapeutic mechanisms. To sum up, integrated serum and fecal metabolomics obtained that rhubarb ranging from 0.31 to 2.1 g/kg is safe and effective for constipation treatment. Also, our findings showed that the robust metabolomics techniques would be promising to be more accurately used in the dose-effect studies of complex TCM, and to clarify syndrome pathogenesis and action mechanisms in Chinese medicine.


Assuntos
Constipação Intestinal/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Laxantes/administração & dosagem , Redes e Vias Metabólicas/efeitos dos fármacos , Rheum/química , Animais , Ácido Araquidônico/análise , Ácido Araquidônico/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Constipação Intestinal/sangue , Constipação Intestinal/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Fezes/química , Glicerofosfolipídeos/análise , Glicerofosfolipídeos/metabolismo , Humanos , Laxantes/isolamento & purificação , Masculino , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Ratos
3.
J Ethnopharmacol ; 247: 112223, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31553926

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Arecae semen has been used as vermifuge and digestant in traditional Chinese medicine (TCM) for more than one thousand years. However, the toxicity effect of areca semen and its underlying mechanism are still unclear. THE AIM OF THE STUDY: This study was aimed to investigate the toxicity of arecae semen and to explore its mechanisms by serum metabolomics. MATERIALS AND METHODS: The male Wistar rats were divided into the control group and treated group (n = 6 in each group), which were given by gavage with distill water or arecae semen aqueous extract (ASAE) once a day for 30 days, respectively. Serum samples were collected from all the rats after treatment of 7-day, 14-day and 30-day for metabolomics analysis. Moreover, biochemistry analysis and histopathological examination were performed at the end of study. RESULTS: The phenomenon of diarrhea, less physical activity, tremors and body curl up were observed in the treated group. Additionally, the body weights of treated rats were significantly decreased compared with control rats from the 8th day after oral administration. Except the level of creatinekinase (CK) in the treated group significantly increased compared with the control group, there were no differences on biochemistry parameters and histopathological test in the two groups. Combined with the methods of principal component analysis (PCA), orthogonal projection to latent structure-discrimination analysis (OPLS-DA) and available databases, the treated and control rats were clearly distinguished from each other and 19 metabolites were identified as the potential biomarkers in the arecae semen treated rats. The identified biomarkers indicated that there were perturbations of the phospholipid metabolism, amino acid metabolism and fat acid metabolism in the treated group. CONCLUSIONS: This indicated that arecae semen possessed certain cardiotoxicity and inhibited the normal growth in Wistar male rats. In addition, the metabolomics approach is a useful tool to study the toxicity in TCM.


Assuntos
Areca/química , Cardiotoxicidade/etiologia , Medicamentos de Ervas Chinesas/toxicidade , Crescimento e Desenvolvimento/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Administração Oral , Aminoácidos/metabolismo , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/isolamento & purificação , Anti-Helmínticos/toxicidade , Biomarcadores/sangue , Biomarcadores/metabolismo , Cardiotoxicidade/sangue , Cardiotoxicidade/diagnóstico , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/isolamento & purificação , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/isolamento & purificação , Fármacos Gastrointestinais/toxicidade , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metabolômica , Ratos , Ratos Wistar , Sementes/química , Testes de Toxicidade , Água/química
4.
Food Chem ; 309: 125692, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31670119

RESUMO

Persimmon tannin (PT) exhibits antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) isolated from retail pork. The involved molecular mechanisms were investigated for the first time using transcriptome and metabolome in this study. Results showed that subinhibitory concentration of PT (0.5 mg/ml) induced significant changes in MRSA at both transcriptional and metabolic levels, as 370 genes and 19 metabolites were differentially expressed. Bioinformatic analysis revealed that the varying genes and metabolites were mainly involved in pathways of membrane transport, amino acids, carbohydrate, and energy metabolism. The highlighted changes were those related to osmotic regulation, intracellular pH regulation, amino acid synthesis and metabolism, glycolysis, TCA cycle and iron metabolism, suggesting the multifaceted effects including cell membrane damage, amino acids limitation, energy metabolism disorder and iron deprivation induced by PT. The results provided insight into the anti-MRSA mechanism of PT, which is useful for PT's development and application in food safety.


Assuntos
Diospyros/química , Metaboloma/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Carne Vermelha/microbiologia , Taninos/farmacologia , Transcriptoma/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Diospyros/metabolismo , Metabolismo Energético/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Metabolômica , Staphylococcus aureus Resistente à Meticilina/genética , Testes de Sensibilidade Microbiana , Suínos
5.
Artigo em Inglês | MEDLINE | ID: mdl-31877430

RESUMO

The aim of this study was to investigate the synergistic effect and underlying mechanism of compatibility of Aconiti Lateralis Radix Praeparata water-soluble alkaloids (FWA) and Ginseng Radix et Rhizoma total ginsenosides (RTG) on propafenone hydrochloride induced acute heart failure (AHF) rats. Firstly, hemodynamics and serum biochemical indexes were measured to observe the therapeutic effect of FWA, RTG and their compatibility on AHF rats. Non-target serum metabolomics and multicomponent pharmacokinetic experiments were then performed to reveal the mechanism from the two aspects of body reaction and drug behavior in vivo. Data showed the haemodynamics indexes (maximum change rate of left ventricular pressure, heart rate) and neuroendocrine cytokines (TNF-α and Nt-proBNP) levels in rats treated by compatibility of FWA and RTG were improved more significantly than that treated by single drug. Through metabolomics analysis, six metabolites, including L-pipecolic acid, L-arginine, uric acid, N-benzoylglycine, sphingosine-1-phosphate and phosphatidylinositol lyso 16:0, were selected and identified as the potential biomarkers of the synergistic effect. Furthermore, lysine degradation, arginine and proline metabolism, purine metabolism, sphingolipid metabolism, etc. were the differential pathways involved. The results of pharmacokinetics showed Cmax, AUClast and t1/2 of the four components (uracil, salsolinol, guanosine, higenamine) of FWA in compatibility group were obviously higher than that in single drug group, which indicated the absorption and bioavailability of these alkaloids were increased, and the residence time was prolonged after FWA combined with RTG. In conclusion, the therapeutic effect of FWA-RTG on AHF rats was enhanced and that might because the compatibility of FWA-RTG affected the process of some metabolites in AHF rats, and pharmacokinetic behavior of components in FWA was obviously influenced after co-administered with RTG.


Assuntos
Aconitum/química , Alcaloides , Ginsenosídeos , Insuficiência Cardíaca/metabolismo , Panax/química , Alcaloides/farmacocinética , Alcaloides/farmacologia , Animais , Sinergismo Farmacológico , Ginsenosídeos/farmacocinética , Ginsenosídeos/farmacologia , Coração/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Metabolômica , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley
6.
Artigo em Inglês | MEDLINE | ID: mdl-31877432

RESUMO

Gandou Decoction (GDD), a well-known traditional Chinese medicine prescription, has been widely used for decades in clinical practice to treat Wilson's disease (WD) in China. However, due to lack of in vivo metabolism research, the absorbed components and metabolites of GDD have not been fully elucidated. In this study, a rapid and high-throughput ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MSE) was applied to rapidly identify prototypes and metabolites after oral administration of GDD. On this basis, the possible metabolic pathways of the main prototypes were proposed between normal and copper-laden rats. As a result, a total of 89 GDD-related xenobiotics were detected in normal dosed rats, including 83 (36 prototypes and 47 metabolites) in plasma and 52 (21 prototypes and 31 metabolites) in liver; a total of 77 GDD-related xenobiotics were detected in copper-laden dosed rats, including 68 (31 prototypes and 37 metabolites) in plasma and 42 (19 prototypes and 23 metabolites) in liver. Our findings showed that anthraquinones, alkaloids and protostane triterpenoids as well as a few saponins, flavonoids, tannins and curcuminoids were the main absorbed chemical components of GDD in rat plasma; anthraquinones, protostane triterpenoids and curcuminoids were the major components in rat liver. Glucuronidation and sulfation were deduced to be the predominant metabolic pathways of GDD. Methylation, acetylation, reduction, hydroxylation, demethylation and deglycosylation were often occurred in the metabolic process. Furthermore, the holistic metabolic profile of GDD revealed that copper-laden rats and normal rats had certain differences in drug absorption and metabolism. This study offered a solid basis for ascertaining bioactive components and action mechanism of GDD.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas , Fígado , Espectrometria de Massas em Tandem/métodos , Alcaloides/análise , Alcaloides/farmacocinética , Animais , Antraquinonas/análise , Antraquinonas/farmacocinética , Cobre/administração & dosagem , Cobre/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metaboloma/efeitos dos fármacos , Metabolômica , Ratos , Triterpenos/análise , Triterpenos/farmacocinética
7.
Aquat Toxicol ; 217: 105349, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31734626

RESUMO

Ocean acidification, due to increased levels of anthropogenic carbon dioxide, is known to affect the physiology and growth of marine phytoplankton, especially in polar regions. However, the effect of acidification or carbonation on cellular metabolism in polar marine phytoplankton still remains an open question. There is some evidence that small chlorophytes may benefit more than other taxa of phytoplankton. To understand further how green polar picoplankton could acclimate to high oceanic CO2, studies were conducted on an Antarctic Chlorella sp. Chlorella sp. maintained its growth rate (∼0.180 d-1), photosynthetic quantum yield (Fv/Fm = ∼0.69) and chlorophyll a (0.145 fg cell-1) and carotenoid (0.06 fg cell-1) contents under high CO2, while maximum rates of electron transport decreased and non-photochemical quenching increased under elevated CO2. GCMS-based metabolomic analysis reveal that this polar Chlorella strain modulated the levels of metabolites associated with energy, amino acid, fatty acid and carbohydrate production, which could favour its survival in an increasingly acidified ocean.


Assuntos
Chlorella/metabolismo , Metaboloma/efeitos dos fármacos , Microalgas/metabolismo , Água do Mar/química , Aclimatação/efeitos dos fármacos , Aminoácidos/biossíntese , Regiões Antárticas , Dióxido de Carbono/análise , Dióxido de Carbono/toxicidade , Chlorella/efeitos dos fármacos , Clorofila A/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Ácidos Graxos/biossíntese , Concentração de Íons de Hidrogênio , Metabolômica , Microalgas/efeitos dos fármacos , Oceanos e Mares , Fotossíntese/efeitos dos fármacos , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
8.
Artigo em Inglês | MEDLINE | ID: mdl-31756623

RESUMO

Inflammatory bowel disease (IBD) is often accompanied by metabolic imbalance and Berberine can relieve the symptoms of IBD, but the mechanism is still unclear. To explore the relationship between IBD, metabolism and Berberine, dextran sulfate sodium-induced ulcerative colitis (UC) model was built and urine and feces samples were analyzed with ultra-performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry, followed by multivariate statistical analyses. Targeted metabolomics was applied to verify and supplement the result of amino acids tested by non-targeted metabolomics. The study found that Berberine could ameliorate UC and improve metabolic disorders. The level of 4 metabolites increased and 35 decreased in urine and these metabolites mainly belong to amino acid, glucide, organic acid and purine. Besides, Berberine could reduce the level of 5 metabolites and raise the level of 7 metabolites in feces, which mainly belong to amino acid and lipid. Additionally, these altered metabolites were mainly related to amino acids metabolism, purine metabolism, vitamin metabolism, lipid metabolism and citrate cycle pathways. Furthermore, microbiome metabolism may be regulated by Berberine in UC. In general, this study provides a useful approach for exploring the mechanism of Berberine in the treatment of UC from the perspective of metabolomics.


Assuntos
Berberina/farmacologia , Cromatografia Líquida/métodos , Colite Ulcerativa/metabolismo , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Aminoácidos/metabolismo , Animais , Colite Ulcerativa/urina , Modelos Animais de Doenças , Fezes/química , Distribuição Aleatória , Ratos , Espectrometria de Massas em Tandem/métodos
9.
Life Sci ; 237: 116914, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31622606

RESUMO

AIMS: The aim of the presente study was to examine the effects of oral gallic acid (GA) administration on the brown adipose tissue of obese mice fed with high-fat diet. New mechanisms and interactions pathways in thermogenesis were accessed through bioinformatics analyses. MAIN METHODS: Swiss male mice were divided into four groups and fed during 60 days with: standard diet, standard diet combined with gallic acid, high-fat diet and high-fat diet combined with gallic acid. Body weight, food intake, and blood parameters (glucose tolerance test, total-cholesterol, high-density low-c, triglyceride and glucose levels) were evaluated. Brown and subcutaneous white adipose tissue histological analysis were performed. SIRT1 and PGC1-α mRNA expression in the brown adipose tissue were assessed. KEY FINDINGS: Our main findings showed that the gallic acid improved glucose tolerance and metabolic parameters. These results were accompanied by bioinformatics analyses that evidenced SIRT1 as main target in the thermogenesis process, confirmed as increased SIRT1 mRNA expression was evidenced in the brown adipose tissue. SIGNIFICANCE: Together, the data suggest that the gallic acid effect in brown adipose tissue may improve body metabolism, glucose homeostasis and increase thermogenesis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Biologia Computacional/métodos , Dieta Hiperlipídica/efeitos adversos , Ácido Gálico/farmacologia , Metaboloma/efeitos dos fármacos , Obesidade/metabolismo , Sirtuína 1/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/patologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/etiologia , Sirtuína 1/genética , Termogênese/efeitos dos fármacos
10.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505804

RESUMO

The screening of drug metabolites in biological matrixes and structural characterization based on product ion spectra is among the most important, but also the most challenging due to the significant interferences from endogenous species. Traditionally, metabolite detection is accomplished primarily on the basis of predicted molecular masses or fragmentation patterns of prototype drug metabolites using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). Although classical techniques are well-suited for achieving the partial characterization of prototype drug metabolites, there is a pressing need for a strategy to enable comprehensive drug metabolism depiction. Therefore, we present drug metabolite clusters (DMCs), different from, but complementary to, traditional approaches for mining the information regarding drugs and their metabolites on the basis of raw, processed, or identified tandem mass spectrometry (MS/MS) data. In this paper, we describe a DMC-based data-mining method for the metabolite identification of 5-hydroxy-6,7,3',4'-tetramethoxyflavone (HTF), a typical hydroxylated-polymethoxyflavonoid (OH-PMF), which addressed the challenge of creating a thorough metabolic profile. Consequently, eight primary metabolism clusters, sixteen secondary metabolism clusters, and five tertiary metabolism clusters were proposed and 106 metabolites (19 potential metabolites included) were detected and identified positively and tentatively. These metabolites were presumed to generate through oxidation (mono-oxidation, di-oxidation), methylation, demethylation, methoxylation, glucuronidation, sulfation, ring cleavage, and their composite reactions. In conclusion, our study expounded drug metabolites in rats and provided a reference for further research on therapeutic material basis and the mechanism of drugs.


Assuntos
Mineração de Dados , Flavonas/metabolismo , Metaboloma/efeitos dos fármacos , Animais , Cromatografia Líquida de Alta Pressão , Desmetilação/efeitos dos fármacos , Flavonas/farmacologia , Humanos , Hidroxilação/efeitos dos fármacos , Hidroxilação/genética , Metaboloma/genética , Metilação/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Ratos , Espectrometria de Massas em Tandem
11.
Pharm Res ; 36(11): 158, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31512001

RESUMO

PURPOSE: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are xenobiotic transporters which pump out variety types of compounds, but information on their interaction with endogenous substrates in the skin is limited. The purpose of the present study was to clarify possible association of these transporters in dermal accumulation of inflammatory mediators. METHODS: Dermatitis model was constructed by repeated topical application of oxazolone in wild-type, and P-gp and BCRP gene triple knockout (Mdr1a/1b/Bcrp-/-) mice to observe difference in phenotype. Target metabolome analysis of 583 metabolites was performed using skin and plasma. RESULTS: Dermatitis and scratching behavior in dermatitis model of Mdr1a/1b/Bcrp-/- mice were more severe than wild-type mice, suggesting protective roles of these transporters. This hypothesis was supported by the metabolome analysis which revealed that concentration of histamine and other dermatitis-associated metabolites like urate and serotonin in the dermatitis skin, but not normal skin, of Mdr1a/1b/Bcrp-/- mice was higher than that of wild-type mice. Gene expression of P-gp and BCRP was reduced in oxazolone-treated skin and the skin of patients with atopic dermatitis or psoriasis. CONCLUSIONS: These results suggest possible association of these efflux transporters with dermal inflammatory mediators, and such association could be observed in the dermatitis skin.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Dermatite/metabolismo , Histamina/metabolismo , Metaboloma/efeitos dos fármacos , Proteínas de Neoplasias/genética , Pele/metabolismo , Animais , Deleção de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout
12.
Environ Sci Process Impacts ; 21(11): 1980-1990, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553340

RESUMO

Per- and polyfluoroalkyl substances (PFASs) are frequently detected in aquatic environments. Longer chained perfluoroalkyl acids (PFAAs), in particular, have been found to bioaccumulate in a broad range of aquatic biota. PFAAs have a physiochemical similarity to naturally occurring fatty acids and could potentially disrupt metabolic processes, however, there has been limited study in this area, especially in aquatic species. In this study, the associations between PFAAs and metabolite profiles were investigated in crustaceans. Eastern School Prawn (Metapenaeus macleayi) were obtained from three different locations (n = 15 per location) with similar environmental conditions but different levels of PFAA contamination. The concentrations of PFAAs, fatty acids and amino acids were analysed and differences in PFAA and metabolite profiles were evaluated. Different PFAA profiles were mirrored by significant differences in the composition of both fatty acid and amino acid profiles, indicating a potential association between PFAA concentration and the composition of metabolites in prawns. These results highlight a need for further research investigating the impacts of PFAA exposure, with the current study providing a foundation for further investigation of the relationship between PFAA bioaccumulation and organism metabolism.


Assuntos
Organismos Aquáticos/química , Crustáceos/química , Monitoramento Ambiental/métodos , Fluorcarbonetos/toxicidade , Metaboloma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Aminoácidos/metabolismo , Animais , Organismos Aquáticos/metabolismo , Crustáceos/metabolismo , Ácidos Graxos/metabolismo , Fluorcarbonetos/análise , Metabolômica , New South Wales , Poluentes Químicos da Água/análise
13.
Molecules ; 24(19)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554153

RESUMO

Alpinetin, a bioactive flavonoid, has been known to have a diverse therapeutic effect, with namely anti-inflammatory, anticancer and antioxidant effects with low systemic toxicity. This study aimed to obtain metabolic profiles of alpinetin in orally administrated rats. The metabolites of alpinetin were systematically analyzed and identified by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The chromatographic separation was achieved on a High Strength Silica (HSS) T3 (1.8 µm, 2.1 × 100 mm) column with the mobile phase consisting of water containing 0.1% formic acid and acetonitrile with 0.1% formic acid via gradient elution. An extracted ion chromatogram strategy based on multiple prototype/metabolite intermediate templates and 71 typical metabolic reactions was proposed to comprehensively profile the metabolites of alpinetin. With the metabolite profiling strategy, altogether 15 compounds were recognized from urine, plasma, bile and feces of rats after intragastric administration of alpinetin for the first time. The prototype, glucuronide conjugates and phenolic acids metabolites were the probable predominant form of alpinetin in rats. This work showed a comprehensive study of the probable metabolic pathways of alpinetin in vivo, which could provide meaningful information for future pharmacological studies.


Assuntos
Flavanonas/administração & dosagem , Metaboloma/efeitos dos fármacos , Metabolômica , Administração Oral , Animais , Bile/química , Líquidos Corporais/química , Cromatografia Líquida de Alta Pressão , Fezes/química , Masculino , Redes e Vias Metabólicas , Metabolômica/métodos , Estrutura Molecular , Plasma/química , Ratos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
14.
Nat Commun ; 10(1): 4358, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554818

RESUMO

Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-myc/genética , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Progressão da Doença , Humanos , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética
15.
Ecotoxicol Environ Saf ; 184: 109602, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31493589

RESUMO

Given the wide applications of engineered nanomaterials (ENMs) in various fields, the ecotoxicology of ENMs has attracted much attention. The traditional plant physiological activity (e.g., reactive oxygen species and antioxidant enzymes) are limited in that they probe one specific process of nanotoxicity, which may result in the loss of understanding of other important biological reactions. Metabolites, which are downstream of gene and protein expression, are directly related to biological phenomena. Metabolomics is an easily performed and efficient tool for solving the aforementioned problems because it involves the comprehensive exploration of metabolic profiles. To understand the roles of metabolomics in phytotoxicity, the analytical methods for metabolomics should be organized and discussed. Moreover, the dominant metabolites and metabolic pathways are similar in different plants, which determines the universal applicability of metabolomics analysis. The analysis of regulated metabolism will globally and scientifically help determine the ecotoxicology that is induced by ENMs. In the past several years, great developments in nanotoxicology have been achieved using metabolomics. However, many knowledge gaps remain, such as the relationships between biological responses that are induced by ENMs and the regulation of metabolism (e.g., carbohydrate, energy, amino acid, lipid and secondary metabolism). The phytotoxicity that is induced by ENMs has been explored by metabolomics, which is still in its infancy. The detrimental and defence mechanisms of plants in their response to ENMs at the level of metabolomics also deserve much attention. In addition, owing to the regulation of metabolism in plants by ENMs affected by multiple factors, it is meaningful to uniformly identify the key influencing factor.


Assuntos
Metaboloma/efeitos dos fármacos , Nanoestruturas/toxicidade , Plantas/efeitos dos fármacos , Plantas/metabolismo , Antioxidantes/metabolismo , Ecotoxicologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Nanoestruturas/química , Espécies Reativas de Oxigênio/metabolismo
16.
J Agric Food Chem ; 67(38): 10667-10677, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31483636

RESUMO

This study investigated the modulatory effects of Decaisnea insignis seed oil (DISO), which was rich in palmitoleic acid (55.25%), palmitic acid (12.25%), and oleic acid (28.74%), on alcohol-induced metabolism disorder in mice. Fifty mice were orally administered with 38% alcohol (0.4 mL/day) and without or with DISO (3, 6, and 12 g/kg) for consecutive 12 weeks. DISO inhibited the alcohol-induced weight loss and liver function abnormality (p < 0.01) and shifted the profiles of cecal microbiome: elevating the abundance of Lactobacillus, Ruminoccoceae_UCG_004 (p < 0.05) and decreasing abundance of Parabacteroides (p < 0.05). This treatment also regulated metabolome response of amino acid and lipid metabolism in cecal content: upregulating 5-hydroxyindole-3-acetic acid (p < 0.05), 6-hydroxynicotinic acid, 5-methoxytryptamine, nicotinamide, and nicotinic acid (p < 0.1) and downregulating androsterone, tryptophan, and indole-3-acetamide (p < 0.05). DISO protected against alcoholic liver injury and gut microbiota dysbiosis by enriching the relative abundance of Lactobacillus, which was positively associated with the improvement of intestinal permeability and tryptophan metabolism.


Assuntos
Álcoois/efeitos adversos , Disbiose/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/prevenção & controle , Magnoliopsida/química , Óleos Vegetais/administração & dosagem , Consumo de Bebidas Alcoólicas/efeitos adversos , Aminoácidos/metabolismo , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Ceco/efeitos dos fármacos , Ceco/microbiologia , Disbiose/metabolismo , Disbiose/microbiologia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Metaboloma/efeitos dos fármacos , Camundongos , Microbiota/efeitos dos fármacos , Sementes/química
17.
Ecotoxicol Environ Saf ; 185: 109664, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31536914

RESUMO

Effects of sewage sludge biochars (SSBCs) on the growth of wheat and the specific toxicological mechanisms were investigated from a metabolic perspective for better ecological risk assessment. We observed that conversion of sludge to biochar remarkably changed the properties, and also caused a significant (p < 0.05) reduction of the toxicity towards wheat. Wheat growth under exposure to SSBCs was influenced by the pyrolysis temperature (300 °C, 500 °C and 700 °C), with root length being promoted by SSBCs prepared at higher temperatures (500 °C and 700 °C). In addition to the contaminants, including polycyclic aromatic hydrocarbons (PAHs) and potentially toxic elements (PTEs) detected in SSBCs, the morphological characteristics of biochars contributed substantially to the wheat growth. Metabolomics analysis revealed the remarkable differences in the metabolic profiles among the control (CK), SS300- and SS700-treated samples. The toxicological mechanisms involved were found to be associated with the regulation of metabolisms pathways of protein, fatty acids and carbohydrates, among which protein metabolism was most affected by SSBCs. This work presents an innovative concept that SSBCs produced at a proper temperature may minimize the toxic effects on plant growth by regulating the metabolic fluxes in vivo.


Assuntos
Carvão Vegetal/toxicidade , Temperatura Alta , Metaboloma/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Esgotos/química , Triticum/efeitos dos fármacos , Metabolômica , Pirólise , Triticum/crescimento & desenvolvimento , Triticum/metabolismo
18.
Life Sci ; 234: 116751, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415771

RESUMO

AIMS: The present study aims to investigate the impacts of olfactory bulbectomy (OBX) on urinary metabolic profile and tryptophan metabolites in prefrontal cortex (PFC) of rats, and to explore the regulation effects of fluoxetine. MAIN METHODS: OBX model was developed by aspiration of olfactory bulbs. After fluoxetine treatment (10 mg/kg) for 14 days, urine samples were collected and behavior tests were applied. Tryptophan (TRP) metabolites and neurotransmitters in PFC were determined by prominence ultrafast liquid chromatography-QTRAP-mass spectrometry, and tryptophan hydroxylase 2 (TPH2) and indoleamine-2,3-dioxygenase 1 (IDO1) were evaluated by western blot. Urinary metabolites were analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry-based metabonomics strategy. KEY FINDING: OBX rats showed hyperlocomotion in open field, hyperactivity in open arm and despair status, and fluoxetine reserved these behavioral abnormalities. The levels of TRP, 5-HIAA, 5-HIAA/5-HT ratio and DA increased, while kynurenine and 5-HT decreased in PFC of OBX rats. The activities of TPH2 and IDO1were inhibited after OBX. Twenty-six altered metabolites were identified as potential biomarkers in OBX rats involved in tryptophan metabolism, gut microbiota metabolism, energy metabolism, purine metabolism, ascorbate and aldarate metabolism, and tyrosine metabolism. Among them, 15 abnormal metabolites were corrected by fluoxetine to some extent. SIGNIFICANCE: Our results revealed that urinary metabolic profile changed greatly in OBX rats, and identified biomarkers might be helpful for the diagnosis of agitated depression. The regulation effects of fluoxetine on urinary metabolic profile and tryptophan metabolites in PFC might contribute to its antidepressant action in OBX rats.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Depressão/tratamento farmacológico , Depressão/metabolismo , Fluoxetina/uso terapêutico , Metaboloma/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/farmacologia , Depressão/urina , Modelos Animais de Doenças , Fluoxetina/farmacologia , Masculino , Bulbo Olfatório/cirurgia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos Sprague-Dawley , Triptofano/metabolismo
19.
Nat Commun ; 10(1): 3666, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413301

RESUMO

Generating effective and durable T cell immunity is a critical prerequisite for vaccination against dengue virus (DENV) and other viral diseases. However, understanding the molecular mechanisms of vaccine-elicited T cell immunity remains a critical knowledge gap in vaccinology. In this study, we utilize single-cell RNA sequencing (scRNAseq) and longitudinal TCR clonotype analysis to identify a unique transcriptional signature present in acutely activated and clonally-expanded T cells that become committed to the memory repertoire. This effector/memory-associated transcriptional signature is dominated by a robust metabolic transcriptional program. Based on this transcriptional signature, we are able to define a set of markers that identify the most durable vaccine-reactive memory-precursor CD8+ T cells. This study illustrates the power of scRNAseq as an analytical tool to assess the molecular mechanisms of host control and vaccine modality in determining the magnitude, diversity and persistence of vaccine-elicited cell-mediated immunity.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Vacinas contra Dengue/farmacologia , Imunidade Celular/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Perfilação da Expressão Gênica , Humanos , Imunidade Celular/genética , Imunidade Celular/imunologia , Imunogenicidade da Vacina/genética , Imunogenicidade da Vacina/imunologia , Memória Imunológica/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/genética , Análise de Sequência de RNA , Análise de Célula Única , Vacinas Atenuadas
20.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1126-1127: 121739, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31430683

RESUMO

The promising effect of Xanthoceras sorbifolia Bunge husks against Alzheimer's disease has attracted more and more attention; however, its therapeutic mechanism has been unclear. A metabolomics study of the husks on rat serum and brain was carried out. Cognitive impairment of rats was induced by D-galactose and amyloid ß, and the result was evaluated by Morris water maze test and brain histological analysis. The metabolite profiling was performed through ultra-high-performance liquid chromatography time-of-flight mass spectrometry. Twelve potential biomarkers were identified in the rat serum and nineteen in the brain. All the biomarkers could be classified as amino acids, lipids, purines and bile acids. Both the husk extract and control drug, huperzine A, showed protective effect against the cognitive disorder induced by amyloid ß, however, the husk extract exhibited significant effect on more targets, which included arachidonic acid, cholic acid, uric acid and citric acid etc., indicating the regulation of the husks of more pathways including neuroinflammation, energy metabolism and antioxidant ability. Triterpenoid saponins and polyphenols in the husks may contribute to the regulation of these pathways. This comprehensive study revealed the underlying therapeutic mechanism of the husks against Alzheimer's disease; some potential biomarkers for its clinical diagnosis were also provided.


Assuntos
Doença de Alzheimer/metabolismo , Metaboloma , Metabolômica/métodos , Extratos Vegetais/farmacologia , Sapindaceae , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Masculino , Espectrometria de Massas , Aprendizagem em Labirinto/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Metaboloma/fisiologia , Ratos , Ratos Sprague-Dawley
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