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1.
J Pharm Biomed Anal ; 177: 112871, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31539712

RESUMO

Osimertinib is a "third-generation'' oral, irreversible, tyrosine kinase inhibitor. It is used in the treatment of non-small cellular lung carcinoma and spares wild-type EGFR. Due to its reactive nature, osimertinib is, in addition to oxidative routes, metabolized through GSH coupling and subsequent further metabolism of these conjugates. The extent of the non-oxidative metabolism of osimertinib is unknown, and methods to quantify this metabolic route have not been reported yet. To gain insight into this metabolic route, a sensitive bioanalytical assay was developed for osimertinib, the active desmethyl metabolite AZ5104, and the thio-metabolites osimertinibs glutathione, cysteinylglycine, and cysteine conjugates was developed. The ease of synthesis of these metabolites was a key-part in the development of this assay. This was done through simple one-step synthesis and subsequent LC-purification. The compounds were characterized by NMR and high-resolution mass spectrometry. Sample preparation was done by a simple protein crash with acetonitrile containing the stable isotopically labeled internal standards for osimertinib and the thio-metabolites, partial evaporation of solvents, and reconstitution in eluent, followed by UHPLC-MS/MS quantification. The assay was successfully validated in a 2-2000 nM calibration range for all compounds except the glutathione metabolite, where the LLOQ was set at 6 nM due to low accuracy at 2 nM. Limited stability was observed for osimertinib, AZ5104, and the glutathione metabolite. The clinical applicability of the assay was demonstrated in samples of patients treated with 80 mg osimertinib once daily, containing all investigated compounds at detectable and quantifiable levels.


Assuntos
Acrilamidas/farmacocinética , Compostos de Anilina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Acrilamidas/administração & dosagem , Acrilamidas/sangue , Acrilamidas/metabolismo , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Compostos de Anilina/sangue , Compostos de Anilina/metabolismo , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Cromatografia Líquida de Alta Pressão/métodos , Dipeptídeos/sangue , Dipeptídeos/síntese química , Dipeptídeos/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Glutationa/sangue , Glutationa/síntese química , Glutationa/metabolismo , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Sulfidrila/sangue , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/metabolismo , Espectrometria de Massas em Tandem/métodos
2.
Biosci Biotechnol Biochem ; 83(6): 1146-1156, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30739561

RESUMO

Collagen hydrolysate is a well-known nutritional supplement for the improvement of healthy skin. Here, collagen peptide NS (CPNS) from fish scale was prepared, and its physicochemical properties were investigated. Gly-Pro was revealed as a representative low molecular weight peptide of CPNS, by performing prep-HPLC and LC-MS/MS. CPNS treatment attenuated matrix metalloproteinase-1 production and increased the synthesis of type 1 procollagen in HDF cells. After orally administering CPNS to rats, the plasma concentrations of Gly-Pro and Pro-Hyp increased dramatically. To examine the protective effects of CPNS against ultraviolet B (UVB)-induced photoaging in vivo, the dorsal skins of hairless mice were exposed to UVB and supplemented with CPNS for 12 weeks. The CPNS consumption significantly attenuated UVB-induced wrinkle formation, transepidermal water loss, and epidermis thickness, and increased skin hydration. Collectively, these results suggest that bioactive peptides of CPNS, Gly-Pro and Pro-Hyp, exert beneficial effects on skin health.


Assuntos
Colágeno Tipo I/química , Dipeptídeos/farmacologia , Hidroxiprolina/química , Prolina/química , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta , Administração Oral , Animais , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , Colágeno Tipo I/sangue , Dipeptídeos/administração & dosagem , Dipeptídeos/sangue , Dipeptídeos/química , Feminino , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Camundongos Pelados , Peso Molecular , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos
3.
Int J Cancer ; 144(8): 1929-1940, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30346061

RESUMO

Prior epidemiologic findings for plasma folate and B-vitamins and breast cancer risk are inconsistent and have not assessed the influence of folic acid fortification. Therefore, we examined the associations of plasma folate, B12 , pyridoxal 5'-phosphate (PLP), homocysteine, cysteine and cysteinylglycine with breast cancer risk, before and after fortification. We conducted a nested case-control study within the prospective Nurses' Health Study. In 1989-1990 (pre-fortification), 32,826 women donated a blood sample and 18,743 donated an additional blood sample in 2000-2001 (post-fortification). Between the first blood collection and 2006, 1874 incident breast cancer cases with at least one blood sample and 367 with two were 1:1 matched to controls. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) adjusting for breast cancer risk factors. Overall, higher plasma folate, B12 , PLP, homocysteine, cysteine and cysteinylglycine levels were not associated with breast cancer risk. Associations did not vary by in situ/invasive, hormone receptor status, or tumor molecular subtype. Additionally, associations were null before and after fortification. For example, the RR (95% CI) for the highest versus lowest tertile of 1990 (pre-fortification) plasma folate with 1990-2000 follow-up was 0.93 (0.75-1.16) and for the 2000 plasma folate (post-fortification) with 2000-2006 follow-up the RR (95% CI) was 1.17 (0.79-1.74). Plasma folate, B12 , PLP, homocysteine, cysteine and cysteinylglycine were not significantly associated with breast cancer overall, before and after fortification, or with specific tumor molecular subtypes. However, long term associations (>8 years) after the implementation of fortification could not be examined.


Assuntos
Neoplasias da Mama/epidemiologia , Ácido Fólico/sangue , Fosfato de Piridoxal/sangue , Vitamina B 12/sangue , Adulto , Neoplasias da Mama/sangue , Carbono/metabolismo , Estudos de Casos e Controles , Cisteína/sangue , Dipeptídeos/sangue , Feminino , Ácido Fólico/administração & dosagem , Seguimentos , Homocisteína/sangue , Humanos , Incidência , Pessoa de Meia-Idade , Estudos Prospectivos , Estados Unidos/epidemiologia
4.
Mol Nutr Food Res ; 63(5): e1801094, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30521147

RESUMO

SCOPE: Peptide transporter 1 (PEPT1) function is well understood, yet little is known about its contribution toward the absorption of dietary amino acids in the form of di- and tripeptides. In the present human study, changes in plasma concentrations of a representative oligopeptide panel are investigated after meat intake. METHODS AND RESULTS: Based on a method for quantitative analysis of a panel of selected di- and tripeptides in biological samples, the kinetics of plasma changes of peptides derived from a widely accessible dietary protein source are described. The findings demonstrate postprandial changes of a whole spectrum of dipeptides of different size, charge, and polarity in peripheral blood in a dose-dependent manner after consumption of chicken breast in healthy human volunteers. Although the substrate specificity of PEPT1 is well known, the spectrum of peptides appearing in blood cannot be matched to the affinity to PEPT1. Stability against hydrolysis by exo- and endopeptidases appears to be another factor influencing their presence in blood. In addition, the study shows that dipeptides, including gamma-glutamyl-peptides, as well as tripeptides are common components present in human plasma. CONCLUSION: Besides amino acids, human peripheral blood contains numerous di- and tripeptides. The dietary source determines their abundance and composition.


Assuntos
Proteínas na Dieta/farmacocinética , Transportador 1 de Peptídeos/metabolismo , Peptídeos/sangue , Adulto , Aminoácidos/sangue , Animais , Anserina/sangue , Biomarcadores/sangue , Carnosina/sangue , Galinhas , Estudos Cross-Over , Proteínas na Dieta/administração & dosagem , Dipeptídeos/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Oryza , Período Pós-Prandial , Especificidade por Substrato , Espectrometria de Massas em Tandem
5.
J Pharm Biomed Anal ; 164: 442-451, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30447532

RESUMO

An ultra-high performance hydrophilic interaction liquid chromatography - triple quadrupole tandem mass spectrometry method was developed for the determination of biologically important thiols, namely cysteine, homocysteine, cysteinyl-glycine, glutathione, in rat plasma. The sample preparation procedure as well as the analytical method were comprehensively optimized and subsequently validated. An optimum sample preparation protocol was based on the simple and fast derivatization of the thiols with new derivatization reagent, N-phenylmaleimide, enabling highly selective and sensitive quantification in plasma matrices. The method, characterized by favourable performance parameters and meeting the FDA criteria for biomedical analysis, was successfully applied for monitoring the concentration levels of the selected thiols in the samples from transgenic rat model for tauopathy. The study revealed significant changes in homocysteine and glutathione levels related to tauopathy while other thiols did not indicate such relationship. Indeed, these findings could play an important role in further understanding of tauopathy process in the brain. Moreover, the proposed highly effective, reliable and robust analytical protocol can be easily adapted for other thiol compounds, spreading its application range in this biomedical field.


Assuntos
Fracionamento Químico/métodos , Glutationa/sangue , Homocisteína/sangue , Tauopatias/sangue , Animais , Fracionamento Químico/instrumentação , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Cisteína/sangue , Cisteína/química , Dipeptídeos/sangue , Dipeptídeos/química , Modelos Animais de Doenças , Glutationa/química , Homocisteína/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Maleimidas/química , Ratos , Ratos Endogâmicos SHR , Ratos Transgênicos , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos , Tauopatias/diagnóstico , Tauopatias/genética , Tauopatias/patologia , Proteínas tau/genética
6.
Sci Rep ; 8(1): 15976, 2018 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-30374076

RESUMO

Anxiety-related disorders, including fearfulness are common and leading welfare problems among the worldwide dog population. The etiology of anxieties is complex and affected by genetic and environmental factors. Thus, there is a need for more comprehensive approaches, such as metabolomics, to understand the causes of anxiety and to identify anxiety-related biomarkers for more efficient diagnostic and treatment options. To study metabolic alterations related to canine fearfulness, a non-targeted plasma metabolite profiling was performed in a cohort of 20 fearful and 21 non-fearful dogs. The results showed that nine metabolic features were significantly associated with fearfulness. The most prominent change included increased plasma glutamine and γ-glutamyl glutamine (γ-Glu Gln) in fearful dogs across breeds. Alterations in glutamine metabolism have previously been associated with several psychiatric disorders, indicating the relevance of this finding also in dogs. In addition, we describe a novel breed-specific association between renal biomarker symmetric dimethylarginine (SDMA) and canine fearfulness. These observed metabolic alterations may result from high levels of prolonged psychological stress in fearful dogs.


Assuntos
Dipeptídeos/sangue , Cães/sangue , Medo/fisiologia , Glutamina/sangue , Animais , Ansiedade/sangue , Arginina/análogos & derivados , Arginina/sangue , Comportamento Animal , Biomarcadores , Cruzamento , Cães/classificação , Cães/psicologia , Feminino , Masculino , Metaboloma , Especificidade da Espécie
7.
Nutrients ; 10(10)2018 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-30248982

RESUMO

Levels of short linear hydroxyproline (Hyp)-containing peptides, such as prolyl-hydroxyproline (Pro-Hyp), increase in human blood after the ingestion of collagen hydrolysate, which has been associated with beneficial effects for human skin and joints. The present study demonstrates the presence of a novel food-derived collagen peptide, cyclic Pro-Hyp, in human blood after the ingestion of collagen hydrolysate. The cyclic Pro-Hyp levels in plasma samples were estimated by liquid chromatography mass spectrometry (LC-MS). Cyclic Pro-Hyp levels significantly increased in the plasma after ingestion of collagen hydrolysate, reaching a maximum level after 2 h and then decreasing. The maximum level of cyclic Pro-Hyp in plasma ranged from 0.1413 to 0.3443 nmol/mL, representing approximately 5% of linear Pro-Hyp in plasma after ingestion of collagen hydrolysate. Addition of cyclic Pro-Hyp in medium at 7 nmol/mL significantly enhanced the growth rate of mouse skin fibroblasts on collagen gel more extensively compared to linear Pro-Hyp.


Assuntos
Colágeno/farmacologia , Dipeptídeos/sangue , Hidroxiprolina/sangue , Peptídeos/sangue , Hidrolisados de Proteína/farmacologia , Pele , Adulto , Animais , Colágeno/administração & dosagem , Colágeno/sangue , Ingestão de Alimentos , Feminino , Fibroblastos/efeitos dos fármacos , Gelatina , Humanos , Camundongos , Pessoa de Meia-Idade , Peptídeos/administração & dosagem , Peptídeos/farmacologia , Projetos Piloto , Hidrolisados de Proteína/administração & dosagem , Hidrolisados de Proteína/sangue , Sus scrofa , Espectrometria de Massas em Tandem
8.
Toxicol Lett ; 299: 11-20, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30165092

RESUMO

A method is described allowing forensic analysis of plasma samples to prove human poisoning with the organophosphorus pesticides omethoate (OM) and dimethoate (DIM). Upon incubation of human serum albumin (HSA) with both pesticides tyrosine residues were phosphorylated. In addition, a novel disulfide-adduct between the identical thiol-containing leaving group of OM and DIM (2-mercapto-N-methylacetamide, MNMA) and the only free cysteine residue in HSA (Cys34) was formed. Following pronase-catalyzed proteolysis either O,O-dimethyl phosphotyrosine (Tyr-dmp) or O,O-dimethyl thiophosphotyrosine (Tyr-dmsp) as well as the cysteine-proline dipeptide disulfide-adduct (MNMA-CysPro) were produced. All biomarkers were simultaneously detected using modern microbore liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (µLC-ESI MS/HR MS). Corresponding limits of identification (LOI) for tyrosine-adducts (LOIOM: 30 µM, LOIDIM: 120 µM) and disulfide-adducts (LOIOM: 1.2 µM, LOIDIM: 30 µM) demonstrated that MNMA-CysPro allowed a considerably more sensitive detection. Finally, this novel method was applied to a plasma sample of an 87-year-old man, who had unintentionally ingested the pesticide Roxion® containing DIM as active ingredient. Unambiguous proof of poisoning demonstrated suitability of the novel biomarkers for sensitive verification analysis.


Assuntos
Dimetoato/análogos & derivados , Dipeptídeos/sangue , Dissulfetos/sangue , Intoxicação por Organofosfatos/sangue , Praguicidas/toxicidade , Albumina Sérica Humana/metabolismo , Tirosina/sangue , Biomarcadores/sangue , Dimetoato/toxicidade , Toxicologia Forense/métodos , Humanos , Fosforilação , Ligação Proteica , Estabilidade Proteica , Proteólise
9.
Bioorg Med Chem Lett ; 28(14): 2446-2450, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29929882

RESUMO

The dipeptide amide H-Phe-Phe-NH2 (1) that previously was identified as a ligand for the substance P 1-7 (SP1-7) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH2 peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED50) of 4 was superior as compared to gabapentin and morphine that are used in clinic.


Assuntos
Amidas/farmacologia , Dipeptídeos/farmacologia , Hiperalgesia/tratamento farmacológico , Imidazóis/farmacologia , Peptidomiméticos/farmacologia , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/lesões , Amidas/sangue , Amidas/química , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dipeptídeos/sangue , Dipeptídeos/química , Relação Dose-Resposta a Droga , Imidazóis/sangue , Imidazóis/química , Injeções Intraperitoneais , Camundongos , Estrutura Molecular , Peptidomiméticos/sangue , Peptidomiméticos/química , Ratos
10.
Clin Biochem ; 56: 33-40, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29655960

RESUMO

BACKGROUND: Oxidative stress is evident from an early stage in chronic kidney disease (CKD). Therefore, we investigated redox biomarkers in polycystic kidney disease (ADPKD) and IgA nephropathy (IGAN). METHODS: This is a case-control study with three groups: ADPKD (n = 54), IGAN (n = 58) and healthy controls (n = 86). The major plasma aminothiols with their redox species were examined: homocysteine (Hcy), cysteinglycine (CG), cysteine (Cys) and glutathione (GSH). The redox ratio was the ratio of reduced free and oxidized aminothiols in plasma. We investigated malonedialdehyde (MDA) and advanced oxidation protein products (AOPP), and ten single nucleotide polymorphisms of antioxidant enzymes. RESULTS: Patients had elevated oxidized free Hcy and Cys with associated low redox ratios - most pronounced in IGAN. Patients with IGAN had elevated AOPP and possibly MDA. Oxidized free Hcy and Cys with redox ratios were correlated to AOPP, MDA and proteinuria. Furthermore, there was an independent relationship to parathyroid hormone (PTH). IGAN had an elevated frequency of Val16Ala SNP rs4880, which influence the function of mitochondrial superoxide dismutase 2 (p = 0.03). CONCLUSIONS: Patients with ADPKD and IGAN have evidence of oxidative stress from stage 1 to 4 - most pronounced in IGAN. In patients, aminothiol redox biomarkers were correlated to AOPP, proteinuria and PTH, which are known prognostic markers in CKD. It may be possible that oxidative stress influences PTH dysregulation in CKD. The association between IGAN and the redox related variant allele rs4880(C) might indicate a new susceptibility locus for IGAN, but this needs verification.


Assuntos
Glomerulonefrite por IGA/diagnóstico , Peroxidação de Lipídeos , Estresse Oxidativo , Rim Policístico Autossômico Dominante/diagnóstico , Adulto , Produtos da Oxidação Avançada de Proteínas/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Dipeptídeos/sangue , Dipeptídeos/química , Progressão da Doença , Feminino , Estudos de Associação Genética , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/epidemiologia , Glomerulonefrite por IGA/fisiopatologia , Homocisteína/sangue , Homocisteína/química , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Oxirredutases/sangue , Oxirredutases/genética , Oxirredutases/metabolismo , Rim Policístico Autossômico Dominante/sangue , Rim Policístico Autossômico Dominante/epidemiologia , Rim Policístico Autossômico Dominante/fisiopatologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Risco , Superóxido Dismutase/sangue , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
11.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1081-1082: 109-117, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29518719

RESUMO

A simple, sensitive and specific hydrophilic interaction liquid chromatography coupled to electrospray ionization mass spectrometric (HILIC-MS) method was developed and validated to determine the plasma concentrations of metformin, saxagliptin and 5-hydroxy saxagliptin simultaneously in clinical studies. Plasma samples were first acidified and then protein precipitated with acetonitrile. Chromatographic separation was achieved on a HILIC Chrom Matrix HP amide column (5 µm, 3.0 × 100 mm I.D.). The mobile phase consisted of acetonitrile and 5 mM ammonium formate buffer containing 0.1% formic acid. Multiple reaction monitoring transitions were performed on triple quadrupole mass spectrometric detection in positive-ion mode with an electrospray ionization source. The calibration curves showed good linearity (r ≥ 0.999) over the established concentration range of 1.0-1000 ng/mL for metformin and 0.1-100 ng/mL for saxagliptin and its active metabolite 5-hydroxy saxagliptin. The extraction recovery for all of the analytes was >92% and the matrix effect ranged from 91.0 to 110.0%. After validation, the method was successfully applied to a bioequivalence study with a single-pill combination (SPC) consisting of 5 mg saxagliptin and 500 mg metformin in 10 healthy Chinese subjects.


Assuntos
Adamantano/análogos & derivados , Cromatografia Líquida/métodos , Dipeptídeos/sangue , Metformina/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Adamantano/sangue , Adamantano/química , Adamantano/farmacocinética , Dipeptídeos/química , Dipeptídeos/farmacocinética , Combinação de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Lineares , Metformina/química , Metformina/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Equivalência Terapêutica
12.
J Nutr ; 148(1): 13-21, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29378040

RESUMO

Background: It remains unknown whether sustained daily feeding-fasting patterns modify the acute response to specific feedings on a given day. Objective: We conducted a randomized controlled trial to establish if daily breakfast consumption or fasting until noon modifies the acute metabolic and appetitive responses to a fixed breakfast and ad libitum lunch. Methods: With the use of a parallel group design, we randomly assigned 31 healthy, lean men and women (22-56 y) to 6 wk of either consuming ≥700 kcal of self-selected items before 1100 or fasting (0 kcal) until 1200 daily. Following 48 h of diet and physical activity standardization, we examined metabolic and appetite responses to a standardized breakfast and ad libitum lunch before and after the intervention. Data were analyzed using 3- and 2-way ANCOVA. Results: Systemic concentrations of energy balance regulatory hormones total and acylated ghrelin, leptin, and peptide tyrosine-tyrosine) responded similarly to breakfast and lunch before and after 6 wk of either morning fasting or regular breakfast, with the exception of a tendency for increased glucagon-like peptide-1 concentrations from baseline to follow-up in the Breakfast Group compared with a decrease over that period in the Fasting Group [P = 0.06, partial eta squared value (ƞ2) = 0.16]. Subjective appetite sensations also did not differ over the course of the day, and ad libitum energy intake at lunch was not systematically affected by either intervention, decreasing by 27 kcal (95% CI: -203, 149 kcal) with fasting and by 77 kcal (95% CI: -210, 56 kcal) with breakfast. Similarly, glycemic, insulinemic, lipemic, and thermogenic responses to breakfast and lunch were very stable at baseline and follow-up and, thus, did not differ between treatment groups. Conclusions: Our results indicate that a sustained period of either extended morning fasting or eating a daily breakfast has minimal effect upon acute metabolic and appetite responses in lean adults. This trial was registered at www.isrctn.org as ISRCTN31521726.


Assuntos
Apetite , Desjejum , Metabolismo , Período Pós-Prandial , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Estudos Cross-Over , Dipeptídeos/sangue , Metabolismo Energético , Exercício Físico , Jejum , Feminino , Seguimentos , Grelina/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Insulina/sangue , Leptina/sangue , Almoço , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Nutrients ; 10(2)2018 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-29370091

RESUMO

Recent evidence suggests that increased brain serotonin synthesis impairs performance in high-intensity intermittent exercise and specific amino acids may modulate this condition, delaying fatigue. This study investigated the effects of glutamine and alanine supplementation on central fatigue markers in rats submitted to resistance training (RT). Wistar rats were distributed in: sedentary (SED), trained (CON), trained and supplemented with alanine (ALA), glutamine and alanine in their free form (G + A), or as dipeptide (DIP). Trained groups underwent a ladder-climbing exercise for eight weeks, with progressive loads. In the last 21 days, supplementations were offered in water with a 4% concentration. Albeit without statistically significance difference, RT decreased liver glycogen, and enhanced the concentrations of plasma glucose, free fatty acids (FFA), hypothalamic serotonin, and ammonia in muscle and the liver. Amino acids affected fatigue parameters depending on the supplementation form. G + A prevented the muscle ammonia increase by RT, whereas ALA and DIP augmented ammonia and glycogen concentrations in muscle. DIP also increased liver ammonia. ALA and G + A reduced plasma FFA, whereas DIP increased this parameter, free tryptophan/total tryptophan ratio, hypothalamic serotonin, and the serotonin/dopamine ratio. The supplementations did not affect physical performance. In conclusion, glutamine and alanine may improve or impair central fatigue markers depending on their supplementation form.


Assuntos
Alanina/farmacologia , Fadiga/tratamento farmacológico , Glutamina/farmacologia , Condicionamento Físico Animal , Amônia/metabolismo , Animais , Glicemia/metabolismo , Suplementos Nutricionais , Dipeptídeos/sangue , Dopamina/sangue , Fadiga/sangue , Ácidos Graxos não Esterificados/sangue , Glicogênio/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Wistar , Serotonina/sangue
14.
Biochem Biophys Res Commun ; 496(2): 267-273, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29294327

RESUMO

Migraine is a highly disabling primary headache associated with a high socioeconomic burden and a generally high prevalence. The clinical management of migraine remains a challenge. This study was undertaken to identify potential serum biomarkers of migraine. Using Liquid Chromatography coupled to Mass Spectrometry (LC-MS), the metabolomic profile of migraine was compared with healthy individuals. Principal component analysis (PCA) and Orthogonal partial least squares-discriminant analysis (orthoPLS-DA) showed the metabolomic profile of migraine is distinguishable from controls. Volcano plot analysis identified 10 serum metabolites significantly decreased during migraine. One of these was serotonin, and the other 9 were amino acids. Pathway analysis and enrichment analysis showed tryptophan metabolism (serotonin metabolism), arginine and proline metabolism, and aminoacyl-tRNA biosynthesis are the three most prominently altered pathways in migraine. ROC curve analysis indicated Glycyl-l-proline, N-Methyl-dl-Alanine and l-Methionine are potential sensitive and specific biomarkers for migraine. Our results show Glycyl-l-proline, N-Methyl-dl-Alanine and l-Methionine may be as specific or more specific for migraine than serotonin which is the traditional biomarker of migraine. We propose that therapeutic manipulation of these metabolites or metabolic pathways may be helpful in the prevention and treatment of migraine.


Assuntos
Alanina/análogos & derivados , Dipeptídeos/sangue , Metionina/sangue , Transtornos de Enxaqueca/diagnóstico , Serotonina/sangue , Adulto , Alanina/sangue , Arginina/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão/métodos , Análise Discriminante , Feminino , Humanos , Masculino , Metaboloma , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/fisiopatologia , Análise de Componente Principal , Prolina/sangue , Aminoacil-RNA de Transferência/sangue , Curva ROC , Triptofano/sangue
15.
J Pharm Biomed Anal ; 150: 287-293, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29258048

RESUMO

A rapid and highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the determination of a novel anti-HBV compound Y101 and its metabolites M8 and M9 in human plasma. The plasma samples were deproteinated with acetonitrile after addition of Peramivir (internal standard, IS) and separated on a 40 °C ACQUITY UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm). The mobile phase consisted of water (containing 5 mM ammonium acetate and 0.1% formic acid) and acetonitrile (74:26, v/v) at a flow rate of 0.3 mL/min. The detection was performed on a Triple Quad 5500 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive mode. Quantification was conducted by multiple reaction monitoring (MRM) of the transitions of m/z 490.1 → 339.0 for Y101, m/z 357.2 → 105.2 for metabolite M8, m/z 373.1 → 105.1 for metabolite M9 and m/z 329.1 → 270.2 for IS, respectively. The method was validated over the calibration curve range of 1.000-1000 ng/mL for Y101, 2.000-2000 ng/mL for metabolite M8 and 0.3000-300.0 ng/mL for metabolite M9, using linear regression and 1/x2 weighting. No matrix effect and carryover effect was observed. The intra- and inter-batch precision and accuracy of Y101, metabolite M8 and M9 were all within the acceptable criteria. This method allows a rapid and simple determination of Y101 and its metabolites M8 and M9 in human plasma. It was successfully applied in a pharmacokinetic study in human for the first time.


Assuntos
Antivirais/sangue , Antivirais/farmacocinética , Benzamidas/sangue , Benzamidas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Dipeptídeos/sangue , Dipeptídeos/farmacocinética , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Administração Oral , Antivirais/administração & dosagem , Benzamidas/administração & dosagem , Biotransformação , Calibragem , China , Cromatografia Líquida de Alta Pressão/normas , Dipeptídeos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Limite de Detecção , Masculino , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/normas , Espectrometria de Massas em Tandem/normas
16.
ANZ J Surg ; 88(1-2): 20-25, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28593706

RESUMO

Bariatric surgery is currently the most effective strategy for treating morbid obesity. Weight regain following significant weight loss, however, remains a problem, with the outcome proportional to the period of follow-up. This review revisits a well-established physiological neurohormonally-mediated feedback loop, the so called ileal brake mechanism, with a special emphasis on the gut hormone peptide tyrosine tyrosine. The manuscript not only highlights the potential role of the ileal brake mechanism in weight loss and weight maintenance thereafter following obesity surgery, it also provides a compelling argument for using this appetite suppressing feedback loop to enable sustained long-term weight loss in patients undergoing surgery for morbid obesity.


Assuntos
Cirurgia Bariátrica/efeitos adversos , Dipeptídeos/metabolismo , Íleo/metabolismo , Perda de Peso/fisiologia , Apetite/fisiologia , Cirurgia Bariátrica/métodos , Cirurgia Bariátrica/tendências , Densidade Óssea/fisiologia , Dipeptídeos/sangue , Hormônios Gastrointestinais/metabolismo , Humanos , Obesidade Mórbida/cirurgia
17.
Radiat Environ Biophys ; 57(1): 55-61, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29149420

RESUMO

The main target of this work is to examine blood clearance and external exposure for 177Lu-DOTATATE compared with new emerging 177Lu-PSMA therapy. Blood clearance and radiation exposure of 31 patients treated with 5.5 ± 1.1 GBq 177Lu-DOTATATE were compared to those of 23 patients treated with 7.4 GBq 177Lu-PSMA. Dose rates were measured at several distances and time points up to 120 h after treatment. Blood samples were collected conjunctively after infusion. Caregiver's cumulative dose was measured by means of an OSL (optically stimulated luminescence) dosimeter for 4-5 days and medical staff's dose was also estimated using electronic personal dosimeters. Finger dose was determined via ring TLD (Thermoluminescence Dosimeter) for radiopharmacists and nurses. Dose rates due to 177Lu-DOTATATE at a distance of 1 m, 4 h and 6 h after infusion, were 3.0 ± 2.8 and 2 ± 1.9 µSv/(h GBq), respectively, while those due to 177Lu-PSMA were 3.1 ± 0.8 and 2.2 ± 0.9 µSv/(h GBq). Total effective dose of 17 caregivers was 100-200 µSv for 177Lu-DOTATATE therapy. Mean effective doses to nurses and radiopharmacists were 5 and 4 µSv per patient, respectively, while those for physicists and physicians were 2 µSv per patient. For 177Lu-DOTATATE, effective half-life in blood and early elimination phase were 0.31 ± 0.13 and 4.5 ± 1 h, while they were found as 0.4 ± 0.1 and 5 ± 1 h, respectively, for 177Lu-PSMA. The first micturition time following 177Lu-DOTATATE infusion was noted after 36 ± 14 min, while the second and third voiding times were after 74 ± 9 and 128 ± 41 min, respectively. It is concluded that blood clearance and radiation exposure for 177Lu-DOTATATE are very similar to those for 177Lu-PSMA, and both treatment modalities are reasonably reliable for outpatient treatment, since the mean dose rate [2.1 µSv/(h GBq)] decreased below the dose rate that allows release of the patient from the hospital (20 µSv/h) after 6 h at 1 m distance.


Assuntos
Dipeptídeos/sangue , Dipeptídeos/farmacocinética , Compostos Heterocíclicos com 1 Anel/sangue , Compostos Heterocíclicos com 1 Anel/farmacocinética , Octreotida/análogos & derivados , Compostos Organometálicos/sangue , Compostos Organometálicos/farmacocinética , Dipeptídeos/uso terapêutico , Pessoal de Saúde , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Humanos , Exposição Ocupacional , Octreotida/sangue , Octreotida/farmacocinética , Octreotida/uso terapêutico , Compostos Organometálicos/uso terapêutico , Distribuição Tecidual
18.
Eur J Clin Nutr ; 71(8): 995-1001, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28378853

RESUMO

BACKGROUND/OBJECTIVES: Fatty liver disease (FLD) is an important intermediate trait along the cardiometabolic disease spectrum and strongly associates with type 2 diabetes. Knowledge of biological pathways implicated in FLD is limited. An untargeted metabolomic approach might unravel novel pathways related to FLD. SUBJECTS/METHODS: In a population-based sample (n=555) from Northern Germany, liver fat content was quantified as liver signal intensity using magnetic resonance imaging. Serum metabolites were determined using a non-targeted approach. Partial least squares regression was applied to derive a metabolomic score, explaining variation in serum metabolites and liver signal intensity. Associations of the metabolomic score with liver signal intensity and FLD were investigated in multivariable-adjusted robust linear and logistic regression models, respectively. Metabolites with a variable importance in the projection >1 were entered in in silico overrepresentation and pathway analyses. RESULTS: In univariate analysis, the metabolomics score explained 23.9% variation in liver signal intensity. A 1-unit increment in the metabolomic score was positively associated with FLD (n=219; odds ratio: 1.36; 95% confidence interval: 1.27-1.45) adjusting for age, sex, education, smoking and physical activity. A simplified score based on the 15 metabolites with highest variable importance in the projection statistic showed similar associations. Overrepresentation and pathway analyses highlighted branched-chain amino acids and derived gamma-glutamyl dipeptides as significant correlates of FLD. CONCLUSIONS: A serum metabolomic profile was associated with FLD and liver fat content. We identified a simplified metabolomics score, which should be evaluated in prospective studies.


Assuntos
Fígado Gorduroso Alcoólico/sangue , Metabolismo dos Lipídeos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Bancos de Espécimes Biológicos , Biomarcadores/sangue , Estudos de Coortes , Biologia Computacional , Estudos Transversais , Dipeptídeos/sangue , Sistemas Especialistas , Fígado Gorduroso Alcoólico/diagnóstico por imagem , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/fisiopatologia , Feminino , Ácido Glutâmico/análogos & derivados , Ácido Glutâmico/sangue , Humanos , Fígado/diagnóstico por imagem , Fígado/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/metabolismo , Autorrelato , Índice de Gravidade de Doença
19.
J Agric Food Chem ; 65(11): 2315-2322, 2017 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-28244315

RESUMO

Collagen hydrolysate is a well-known dietary supplement for the treatment of skin aging; however, its mode of action remains unknown. Previous studies have shown that the oral ingestion of collagen hydrolysate leads to elevated levels of collagen-derived peptides in the blood, but whether these peptides reach the skin remains unclear. Here, we analyzed the plasma concentration of collagen-derived peptides after ingestion of high tripeptide containing collagen hydrolysate in humans. We identified 17 types of collagen-derived peptides transiently, with a particular enrichment in Gly-Pro-Hyp. This was also observed using an in vivo mouse model in the plasma and skin, albeit with a higher enrichment of Pro-Hyp in the skin. Interestingly, this Pro-Hyp enrichment in the skin was derived from Gly-Pro-Hyp hydrolysis, as the administration of pure Gly-Pro-Hyp peptide led to similar results. Therefore, we propose that functional peptides can be transferred to the skin by dietary supplements of collagen.


Assuntos
Colágeno/química , Colágeno/metabolismo , Dipeptídeos/metabolismo , Oligopeptídeos/metabolismo , Hidrolisados de Proteína/metabolismo , Pele/metabolismo , Adulto , Animais , Dipeptídeos/sangue , Ingestão de Alimentos , Feminino , Humanos , Hidrólise , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/sangue , Hidrolisados de Proteína/química , Adulto Jovem
20.
Neurol Res ; 39(5): 381-386, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28222651

RESUMO

INTRODUCTION: Homocysteine increase and glutathione derivative cysteinyl-glycine fall are indirect biomarkers for oxidative stress, for instance due to dopamine D1 receptor stimulation. OBJECTIVES: To investigate the influence of the D1 receptor agonists levodopa and rotigotine compared with placebo on homocysteine and cysteinyl-glycine in plasma of patients with Parkinson's disease. METHODS: Patients received 100 mg levodopa, 4 mg rotigotine or placebo. Cysteinyl-glycine and homocysteine were measured every 30 min over three hours. RESULTS: Homocysteine rose during levodopa- and placebo administration. Rotigotine had no effect. Cysteine-glycine only increased after placebo- but not after levodopa- or rotigotine. DISCUSSION: Homocysteine elevation results from hepatic and gastrointestinal methylation processes. Transdermal rotigotine circumvents these methylation locations. Turnover of segregated alkyl residuals from rotigotine serves as methyl group donors, which counteract homocysteine increment. The placebo-related cysteinyl-glycine increase results from reduced free radical exposure. Low levodopa dosing and antioxidants in the rotigotine patch matrix prevented cysteinyl-glycine fall.


Assuntos
Dipeptídeos/sangue , Dopaminérgicos/administração & dosagem , Homocisteína/sangue , Levodopa/administração & dosagem , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem , Idoso , Análise de Variância , Cromatografia Líquida de Alta Pressão , Di-Hidroxifenilalanina/análogos & derivados , Di-Hidroxifenilalanina/sangue , Dopaminérgicos/sangue , Técnicas Eletroquímicas , Feminino , Humanos , Levodopa/sangue , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/sangue , Doença de Parkinson/tratamento farmacológico , Tetra-Hidronaftalenos/sangue , Tiofenos/sangue , Fatores de Tempo , Tirosina/análogos & derivados
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