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1.
Medicine (Baltimore) ; 100(8): e24581, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663067

RESUMO

ABSTRACT: Major depressive disorder (MDD) is a common disease with both affective and cognitive disorders. Alterations in metabolic systems of MDD patients have been reported, but the underlying mechanisms still remains unclear. We sought to identify abnormal metabolites in MDD by metabolomics and to explore the association between differential metabolites and neurocognitive dysfunction.Plasma samples from 53 MDD patients and 83 sex-, gender-, BMI-matched healthy controls (HCs) were collected. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) system was then used to detect metabolites in those samples. Two different algorithms were applied to identify differential metabolites in 2 groups. Of the 136 participants, 35 MDD patients and 48 HCs had completed spatial working memory test. Spearman rank correlation coefficient was applied to explore the relationship between differential metabolites and working memory in these 2 groups.The top 5 metabolites which were found in sparse partial least squares-discriminant analysis (sPLS-DA) model and random forest (RF) model were the same, and significant difference was found in 3 metabolites between MDD and HCs, namely, gamma-glutamyl leucine, leucine-enkephalin, and valeric acid. In addition, MDD patients had higher scores in spatial working memory (SWM) between errors and total errors than HCs. Valeric acid was positively correlated with working memory in MDD group.Gamma-glutamyl leucine, leucine-enkephalin, and valeric acid were preliminarily proven to be decreased in MDD patients. In addition, MDD patients performed worse in working memory than HCs. Dysfunction in working memory of MDD individuals was associated with valeric acid.


Assuntos
Transtorno Depressivo Maior/sangue , Memória de Curto Prazo/fisiologia , Navegação Espacial/fisiologia , Adolescente , Adulto , Fatores Etários , Algoritmos , Índice de Massa Corporal , Cromatografia Líquida , Transtorno Depressivo Maior/fisiopatologia , Dipeptídeos/sangue , Encefalina Leucina/sangue , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Ácidos Pentanoicos/sangue , Escalas de Graduação Psiquiátrica , Fatores Sexuais , Espectrometria de Massas em Tandem , Adulto Jovem
2.
Nutrients ; 13(1)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429977

RESUMO

Sugar consumption is associated with a whole range of negative health effects and should be reduced and the natural sweetener xylitol might be helpful in achieving this goal. The present study was conducted as a randomized, placebo-controlled, double-blind, cross-over trial. Twelve healthy, lean volunteers received intragastric solutions with 7, 17 or 35 g xylitol or tap water on four separate days. We examined effects on: gut hormones, glucose, insulin, glucagon, uric acid, lipid profile, as well as gastric emptying rates, appetite-related sensations and gastrointestinal symptoms. We found: (i) a dose-dependent stimulation of cholecystokinin (CCK), active glucagon-like peptide-1 (aGLP-1), peptide tyrosine tyrosine (PYY)-release, and decelerated gastric emptying rates, (ii) a dose-dependent increase in blood glucose and insulin, (iii) no effect on motilin, glucagon, or glucose-dependent insulinotropic peptide (GIP)-release, (iv) no effect on blood lipids, but a rise in uric acid, and (v) increased bowel sounds as only side effects. In conclusion, low doses of xylitol stimulate the secretion of gut hormones and induce a deceleration in gastric emptying rates. There is no effect on blood lipids and only little effect on plasma glucose and insulin. This combination of properties (low-glycemic sweetener which stimulates satiation hormone release) makes xylitol an attractive candidate for sugar replacement.


Assuntos
Esvaziamento Gástrico/efeitos dos fármacos , Hormônios Gastrointestinais/metabolismo , Edulcorantes/farmacologia , Xilitol/farmacologia , Adulto , Glicemia/metabolismo , Colecistocinina/sangue , Estudos Cross-Over , Dipeptídeos/sangue , Método Duplo-Cego , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Hormônios Gastrointestinais/sangue , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Insulina/sangue , Lipídeos/sangue , Masculino , Edulcorantes/administração & dosagem , Ácido Úrico/sangue , Xilitol/administração & dosagem , Adulto Jovem
3.
Med Sci Monit ; 26: e927029, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33377476

RESUMO

BACKGROUND The relative efficacy of carotid endarterectomy (CEA)/thromboendarterectomy (TEA) and carotid artery stenting (CAS) already has been compared in randomized controlled trials and a meta-analysis, but only limited data exist describing the status of cerebral metabolism before and after these interventions. The aim of the present study was to compare metabolic changes before and after treatment of carotid stenosis and assess their potential clinical implications.   MATERIAL AND METHODS Patients with asymptomatic unilateral critical internal CAS were imaged with proton 3T magnetic resonance spectroscopy (H-MRS) because the technique is more sensitive than regular magnetic resonance imaging for detection of the early signs of ischemic events. Abnormal metabolite ratios detected with H-MRS may precede actual morphological changes associated with hypoperfusion as well as reperfusion changes. Ipsilateral and contralateral middle cerebral artery vascular territories were both evaluated before and after vascular intervention. H-MRS was performed within 24 h before and after surgery. Correlations in the metabolic data from H-MRS for N-acetylaspartic acid (NAA)+N-acetylaspartylglutamate, creatinine (Cr)+phosphocreatinine, and phosphocholine+glycerophosphocholine (Cho) were sought. RESULTS H-MRS voxels from 11 subjects were analyzed. Values for dCho/CrI, dCho/CrC and Cho/Naal (P<0.001) were significantly higher ipsilaterally than contralaterally. Ratios for dNaa/ChoC and Cho/NaaC were significantly higher on the non-operated side (P<0.001). CONCLUSIONS H-MRS may be helpful for assessment of patients with CAS, particularly because unlike other modalities, it reveals postoperative changes in metabolic brain status. Initial results indicate the important role of perioperative neuroprotective treatment.


Assuntos
Encéfalo/metabolismo , Artéria Carótida Interna/metabolismo , Estenose das Carótidas/sangue , Metaboloma , Artéria Cerebral Média/metabolismo , Idoso , Idoso de 80 Anos ou mais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/sangue , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/patologia , Artéria Carótida Interna/cirurgia , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/patologia , Estenose das Carótidas/cirurgia , Creatinina/sangue , Dipeptídeos/sangue , Endarterectomia das Carótidas/métodos , Feminino , Glicerilfosforilcolina/sangue , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/patologia , Artéria Cerebral Média/cirurgia , Fosfocreatina/análogos & derivados , Fosfocreatina/sangue , Fosforilcolina/sangue , Estudos Prospectivos , Stents
4.
Nat Commun ; 11(1): 4571, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917871

RESUMO

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aß) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/metabolismo , Serpinas/metabolismo , Proteínas Virais/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal , Disfunção Cognitiva/tratamento farmacológico , Citocinas/metabolismo , Dipeptídeos/sangue , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Encefalite/metabolismo , Encefalite/patologia , Feminino , Humanos , Inflamação/metabolismo , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Serpinas/sangue , Serpinas/farmacologia , Memória Espacial/fisiologia , Proteínas Virais/sangue , Proteínas Virais/farmacologia , para-Aminobenzoatos/sangue , para-Aminobenzoatos/farmacologia
5.
Br J Nutr ; 124(4): 407-417, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32248846

RESUMO

This study investigated metabolic, endocrine, appetite and mood responses to a maximal eating occasion in fourteen men (mean: age 28 (sd 5) years, body mass 77·2 (sd 6·6) kg and BMI 24·2 (sd 2·2) kg/m2) who completed two trials in a randomised crossover design. On each occasion, participants ate a homogenous mixed-macronutrient meal (pizza). On one occasion, they ate until 'comfortably full' (ad libitum) and on the other, until they 'could not eat another bite' (maximal). Mean energy intake was double in the maximal (13 024 (95 % CI 10 964, 15 084) kJ; 3113 (95 % CI 2620, 3605) kcal) compared with the ad libitum trial (6627 (95 % CI 5708, 7547) kJ; 1584 (95 % CI 1364, 1804) kcal). Serum insulin incremental AUC (iAUC) increased approximately 1·5-fold in the maximal compared with ad libitum trial (mean: ad libitum 43·8 (95 % CI 28·3, 59·3) nmol/l × 240 min and maximal 67·7 (95 % CI 47·0, 88·5) nmol/l × 240 min, P < 0·01), but glucose iAUC did not differ between trials (ad libitum 94·3 (95 % CI 30·3, 158·2) mmol/l × 240 min and maximal 126·5 (95 % CI 76·9, 176·0) mmol/l × 240 min, P = 0·19). TAG iAUC was approximately 1·5-fold greater in the maximal v. ad libitum trial (ad libitum 98·6 (95 % CI 69·9, 127·2) mmol/l × 240 min and maximal 146·4 (95 % CI 88·6, 204·1) mmol/l × 240 min, P < 0·01). Total glucagon-like peptide-1, glucose-dependent insulinotropic peptide and peptide tyrosine-tyrosine iAUC were greater in the maximal compared with ad libitum trial (P < 0·05). Total ghrelin concentrations decreased to a similar extent, but AUC was slightly lower in the maximal v. ad libitum trial (P = 0·02). There were marked differences on appetite and mood between trials, most notably maximal eating caused a prolonged increase in lethargy. Healthy men have the capacity to eat twice the energy content required to achieve comfortable fullness at a single meal. Postprandial glycaemia is well regulated following initial overeating, with elevated postprandial insulinaemia probably contributing.


Assuntos
Afeto/fisiologia , Apetite/fisiologia , Hiperfagia/sangue , Refeições/fisiologia , Período Pós-Prandial/fisiologia , Adulto , Área Sob a Curva , Glicemia/análise , Índice de Massa Corporal , Estudos Cross-Over , Dipeptídeos/sangue , Ingestão de Energia/fisiologia , Polipeptídeo Inibidor Gástrico/sangue , Grelina/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Insulina/sangue , Masculino , Adulto Jovem
6.
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
7.
Bull Exp Biol Med ; 167(5): 637-640, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31625065

RESUMO

Pharmacokinetics and relative bioavailability of antidepressant GSB-106 (hexamethylendiamide bis-(N-monosuccinyl-L-seryl-L-lysine) were determined in rabbits after single oral administration of the pharmaceutical substance and tablet mass. GSB-106 concentrations in the blood plasma were determined by HPLC-mass spectrometry. Relative bioavailability of GSB-106 tablet form was 160.79±24.33%.


Assuntos
Antidepressivos/farmacocinética , Dipeptídeos/farmacocinética , Administração Oral , Animais , Antidepressivos/sangue , Área Sob a Curva , Disponibilidade Biológica , Dipeptídeos/sangue , Avaliação Pré-Clínica de Medicamentos , Masculino , Coelhos , Comprimidos
8.
Mol Nutr Food Res ; 63(21): e1900263, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31394017

RESUMO

SCOPE: The role of PEPT1 in the uptake of intact peptides as compared to hydrolysis prior to uptake of their constituents is unknown. Here, dipeptides, tripeptides, and amino acids are quantified to study the fate of selected peptides in different intestinal models. METHODS AND RESULTS: An LC-MS/MS-based method is applied for the simultaneous assessment of rates of hydrolysis and transport of a peptide panel in Caco-2 transwell cell culture, in vitro and in vivo in mice expressing or lacking PEPT1, and in hydrolysis studies in vitro using human intestinal samples. It is shown that susceptibility to hydrolysis of peptides at the brush border membrane or within epithelial cells is practically identical in all tested models and strictly structure-dependent. Peptides with high luminal disappearance show substantial hydrolysis and low basolateral appearance, while peptides with low disappearance show strong PEPT1 dependency and high basolateral appearance in intact form in Caco-2 transwell culture. CONCLUSION: Hydrolysis and transport of intact peptides are highly variable and structure-dependent. For peptides possessing less polar N-terminal residues, hydrolysis usually dominates over transport via PEPT1. For other peptides with high intrinsic hydrolysis resistance, including anserine, carnosine, ɣ-glutamyl-dipeptides, and aminocephalosporins, PEPT1 is the main determinant for appearance in peripheral blood.


Assuntos
Absorção Intestinal/fisiologia , Transportador 1 de Peptídeos/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacocinética , Aminoácidos/sangue , Aminoácidos/metabolismo , Animais , Células CACO-2 , Cromatografia Líquida , Dipeptídeos/sangue , Dipeptídeos/metabolismo , Dipeptídeos/farmacocinética , Feminino , Humanos , Hidrólise , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transportador 1 de Peptídeos/genética , Peptídeos/química , Transporte Proteico , Proteólise , Espectrometria de Massas em Tandem
9.
Clin Ther ; 41(8): 1545-1563, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31266654

RESUMO

PURPOSE: Fixed-combination drug products (FCDPs) for patients with type 2 diabetes mellitus (T2DM) may show efficacy comparable to their individual components (ICs) while improving adherence to treatment. This study evaluated the bioequivalence and safety of 2 dapagliflozin/saxagliptin/metformin extended-release (XR) FCDPs relative to their ICs: saxagliptin and dapagliflozin/metformin XR. METHODS: This randomized, open-label, single-dose, single-center crossover study was conducted in 84 healthy subjects aged 18-55 years. The primary objective was to evaluate the fed-state bioequivalence of a dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP and a dapagliflozin 10-mg/saxagliptin 5-mg/metformin 1000-mg XR FCDP relative to the ICs. Secondary objectives included the evaluation of the effect of food on the pharmacokinetic (PK) parameters of saxagliptin, dapagliflozin, and metformin in both FCDPs and characterization of the PK parameters of the active metabolite of saxagliptin, 5-hydroxy saxagliptin, in healthy subjects. PK parameters (AUC0-∞, AUC0-t, and Cmax) were used to assess the bioequivalence of the 2 FCDPs with their ICs. The Cmax and AUC0-t of the study drugs were compared between female and male subjects to assess sex differences in exposure. Safety and tolerability of both FCDPs and ICs were also assessed with adverse events, vital signs (systolic and diastolic blood pressures and pulse rate), 12-lead ECG, physical examinations, and laboratory assessments. FINDINGS: Both dapagliflozin/saxagliptin/metformin XR FCDPs were bioequivalent to their ICs. For the dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP, the 90% CI for the geometric mean ratio of dapagliflozin Cmax was slightly above the 80%-125% bioequivalence limit, which is unlikely to be clinically relevant. Food delayed the absorption of the study drugs in both FCDPs, which is unlikely to have a clinically relevant impact on efficacy. In both cohorts, exposure was higher in female subjects compared with male subjects, potentially due to the lower body weight of the female subjects. The safety profile and tolerability of the FCDPs were similar to those of their ICs, and no deaths or serious adverse events were reported. IMPLICATIONS: These data support the use of the dapagliflozin/saxagliptin/metformin XR FCDP in patients with T2DM. ClinicalTrials.gov identifier: NCT03169959.


Assuntos
Adamantano/análogos & derivados , Compostos Benzidrílicos/farmacocinética , Dipeptídeos/farmacocinética , Glucosídeos/farmacocinética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Adamantano/administração & dosagem , Adamantano/sangue , Adamantano/farmacocinética , Adolescente , Adulto , Compostos Benzidrílicos/administração & dosagem , Estudos Cross-Over , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Dipeptídeos/administração & dosagem , Dipeptídeos/sangue , Combinação de Medicamentos , Feminino , Glucosídeos/administração & dosagem , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Comprimidos , Equivalência Terapêutica , Adulto Jovem
10.
Exp Physiol ; 104(6): 826-836, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30801859

RESUMO

NEW FINDINGS: What is the central question of this study? What are the interactions between sleep and appetite following early evening high-intensity interval exercise (HIIE)? What is the main finding and its importance? HIIE can be performed in the early evening without subsequent sleep disruptions and may favourably alter appetite-related hormone concentrations. Nonetheless, perceived appetite and energy intake do not change with acute HIIE regardless of time of day. ABSTRACT: Despite exercise benefits for sleep and appetite, due to increased time restraints, many adults remain inactive. Methods to improve exercise compliance include preferential time-of-day or engaging in short-duration, high-intensity interval exercise (HIIE). Hence, this study aimed to compare effects of HIIE time-of-day on sleep and appetite. Eleven inactive men undertook sleep monitoring to determine baseline (BASE) sleep stages and exclude sleep disorders. On separate days, participants completed 30 min HIIE (60 s work at 100% V ̇ O 2 peak , 240 s rest at 50% V ̇ O 2 peak ) in (1) the morning (MORN; 06.00-07.00 h), (2) the afternoon (AFT; 14.00-16.00 h) and (3) the early evening (EVEN: 19.00-20.00 h). Measures included appetite-related hormones (acylated ghrelin, leptin, peptide tyrosine tyrosine) and glucose pre-exercise, 30 min post-exercise and the next morning; overnight polysomnography (PSG; sleep stages); and actigraphy, self-reported sleep and food diaries for 48 h post-exercise. There were no between-trial differences for total sleep time (P = 0.46). Greater stage N3 sleep was recorded for MORN (23 ± 7%) compared to BASE (18 ± 7%; P = 0.02); however, no between-trial differences existed (P > 0.05). Rapid eye movement (REM) sleep was lower and non-REM sleep was higher for EVEN compared to BASE (P ≤ 0.05). At 30 min post-exercise, ghrelin was higher for AFT compared to MORN and EVEN (P = 0.01), while glucose was higher for MORN compared to AFT and EVEN (P ≤ 0.02). No between-trial differences were observed for perceived appetite (P ≥ 0.21) or energy intake (P = 0.57). Early evening HIIE can be performed without subsequent sleep disruptions and reduces acylated ghrelin. However, perceived appetite and energy intake appear to be unaffected by HIIE time of day.


Assuntos
Ingestão de Energia/fisiologia , Grelina/sangue , Treinamento Intervalado de Alta Intensidade , Sobrepeso/terapia , Sono/fisiologia , Adulto , Regulação do Apetite/fisiologia , Dipeptídeos/sangue , Humanos , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Sobrepeso/sangue , Consumo de Oxigênio/fisiologia
11.
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
12.
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
13.
Clin Pharmacol Drug Dev ; 8(4): 549-558, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30500110

RESUMO

Saxagliptin is an orally administered, highly potent, and selective dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus. This study was conducted to determine the effect of magnesium and aluminum hydroxides plus simethicone, famotidine, and omeprazole on the pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin. This was an open-label, randomized, 5-treatment, 5-period, 3-way crossover study in 15 healthy subjects. Mean Cmax of saxagliptin was 26% lower, but AUC was almost unchanged when saxagliptin was coadministered with Maalox Max. Mean Cmax was 14% higher, but AUC was almost unchanged when saxagliptin was coadministered with famotidine. Changes in pharmacokinetics of 5-hydroxy saxagliptin generally paralleled the changes in saxagliptin. These pharmacokinetic changes were unlikely to be clinically meaningful. Coadministration of omeprazole did not affect saxagliptin Cmax or AUC. Saxagliptin in combination with these medicines resulted in no unexpected safety or tolerability findings in these healthy subjects. No dose adjustment of saxagliptin or separation in the time of saxagliptin dosing is necessary with medicines that raise gastric pH when coadministered with saxagliptin.


Assuntos
Adamantano/análogos & derivados , Hidróxido de Alumínio/administração & dosagem , Dipeptídeos/farmacocinética , Famotidina/administração & dosagem , Hidróxido de Magnésio/administração & dosagem , Omeprazol/administração & dosagem , Simeticone/administração & dosagem , Adamantano/administração & dosagem , Adamantano/sangue , Adamantano/farmacocinética , Adulto , Área Sob a Curva , Estudos Cross-Over , Dipeptídeos/administração & dosagem , Dipeptídeos/sangue , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Adulto Jovem
14.
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
15.
JPEN J Parenter Enteral Nutr ; 43(6): 726-733, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30357864

RESUMO

BACKGROUND: The citrulline generation test (CGT) has been proposed as a tool to determine gut function. However, the increase in plasma citrulline concentration that follows a bolus dose of alanyl-glutamine may also result from a reduction in citrulline clearance due to competition with glutamine for transport. MATERIALS AND METHODS: A swine model was developed, and stable isotope tracers were used to determine the mechanism behind the increase in plasma citrulline that follows a bolus dose of alanyl-glutamine. Plasma concentrations and enrichments were determined, and a non-steady-state model was used to calculate rates of appearance, disappearance, and conversion. RESULTS: The pig model recapitulated the increase in plasma citrulline observed in humans after a dose of alanyl-glutamine. The dipeptide was rapidly hydrolyzed to its constitutive amino acids. Both citrulline plasma concentration and citrulline rate of appearance increased by ≈45% after the bolus dose of alanyl-glutamine. The conversion of citrulline to arginine and the rate of appearance of arginine also increased. Glutamine contributed up to 25% ± 2% of the rate of appearance of citrulline. No changes in the rate of disappearance of citrulline were observed. CONCLUSION: Our results indicate that a single bolus dose of alanyl-glutamine increases plasma citrulline concentration by increasing citrulline production without any effect on citrulline disposal. Our findings strongly indicate that the CGT assesses the metabolic response of the gut and that CGT can become a useful tool to evaluate gut mass and function.


Assuntos
Citrulina/sangue , Trato Gastrointestinal/fisiologia , Glutamina/sangue , Animais , Arginina/sangue , Dipeptídeos/administração & dosagem , Dipeptídeos/sangue , Nutrição Enteral , Feminino , Glutamina/administração & dosagem , Infusões Intravenosas , Rim , Masculino , Modelos Animais , Isótopos de Nitrogênio/sangue , Nutrição Parenteral , Suínos
16.
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
17.
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
18.
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
19.
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
20.
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
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