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1.
Nutrients ; 11(11)2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683779

RESUMO

Protein quality is important for patients needing medical nutrition, especially those dependent on tube feeding. A blend of dairy and vegetable proteins (35% whey, 25% casein, 20% soy, 20% pea; P4) developed to obtain a more balanced amino acid profile with higher chemical scores, was compared to its constituent single proteins. Fourteen healthy elderly subjects received P4, whey, casein, soy, and pea (18 g/360 mL bolus) on five separate visits. Blood samples were collected at baseline until 240 min after intake. Amino acid availability was calculated using incremental maximal concentration (iCmax) and area under the curve (iAUC). Availability for P4 as a sum of all amino acids was similar to casein (iCmax and iAUC) and whey (iCmax) and higher vs. soy (iCmax and iAUC) and pea (iCmax). Individual amino acid availability (iCmax and iAUC) showed different profiles reflecting the composition of the protein sources: availability of leucine and methionine was higher for P4 vs. soy and pea; availability of arginine was higher for P4 vs. casein and whey. Conclusions: The P4 amino acid profile was reflected in post-prandial plasma levels and may be regarded as more balanced compared to the constituent single proteins.


Assuntos
Aminoácidos/farmacocinética , Caseínas/farmacocinética , Leite/química , Proteínas de Ervilha/farmacocinética , Proteínas de Soja/farmacocinética , Verduras/química , Proteínas do Soro do Leite/farmacocinética , Idoso , Aminoácidos/sangue , Animais , Disponibilidade Biológica , Caseínas/sangue , Estudos Cross-Over , Proteínas na Dieta/química , Método Duplo-Cego , Feminino , Humanos , Masculino , Proteínas de Ervilha/sangue , Ervilhas/química , Proteínas de Soja/sangue , Soja/química , Proteínas do Soro do Leite/sangue
2.
ACS Appl Mater Interfaces ; 11(32): 28621-28630, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31293148

RESUMO

Multiple amino acid (glutamine and lysine)-modified gold nanoparticles a with pH-switchable zwitterionic surface were fabricated through coordination bonds using ferrous iron (Fe2+) as bridge ions, which are able to spontaneously and selectively assemble in tumor cells for accurate tumor therapy combining enzyme-triggered photothermal therapy and H2O2-dependent catalytic medicine. These gold nanoparticles showed electric neutrality at pH 7.4 (hematological system) to prevent endocytosis of normal cells, which could be positively charged at pH 6.8 (tumor microenvironment) to promote the endocytosis of tumor cells to these nanoparticles, performing great tumor selectivity. After cell uptake, the specific enzyme (transglutaminase) in tumor cells would catalyze the polymerization of glutamine and lysine to cause the intracellular assembly of these gold nanoparticles, resulting in an excellent photothermal property for accurate tumor therapy. Moreover, the Fe2+ ion could decompose excess hydrogen peroxide (H2O2) in tumor cells via the Fenton reaction, resulting in a large amount of hydroxyl radicals (·OH). These radicals would also cause tumor cell damage. This synergetic therapy associating with high tumor selectivity generated an 8-fold in vitro cytotoxicity against tumor cells compared with normal cells under 48 h incubation with 10 min NIR irradiation. Moreover, in vivo data from tumor-bearing nude mice models showed that tumors can be completely inhibited and gradually eliminated after multimode treatment combining catalytic medicine and photothermal therapy for 3 weeks. This system takes advantage of three tumor microenvironment conditions (low pH, enzyme, and H2O2) to trigger the therapeutic actions, which is a promising platform for cancer therapy that achieved prolonged circulation time in the blood system, selective cellular uptake, and accurate tumor therapy in multiple models.


Assuntos
Ouro , Hipertermia Induzida , Melanoma Experimental , Nanopartículas Metálicas , Proteínas de Neoplasias/metabolismo , Fototerapia , Transglutaminases/metabolismo , Aminoácidos/química , Aminoácidos/farmacocinética , Aminoácidos/farmacologia , Animais , Linhagem Celular Tumoral , Materiais Revestidos Biocompatíveis , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Endocitose/efeitos dos fármacos , Feminino , Ouro/química , Ouro/farmacocinética , Ouro/farmacologia , Humanos , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Am J Physiol Endocrinol Metab ; 317(1): E74-E84, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939051

RESUMO

Intrinsically labeled dietary proteins have been used to trace various aspects of digestion and absorption, including quantifying the contribution of dietary protein to observed postprandial amino acid and protein kinetics in human subjects. Quantification of the rate of appearance in peripheral blood of an unlabeled (tracee) amino acid originating from an intrinsically labeled protein (exogenous Ra) requires the assumption that there is no dilution of the isotope enrichment of the protein-bound amino acid in the gastrointestinal tract or across the splanchnic bed. It must also be assumed that the effective volume of distribution into which the tracer and tracee appear can be reasonably estimated by a single value and that any recycling of the tracer is minimal and thus does not affect calculated rates. We have assessed these assumptions quantitatively using values from published studies. We conclude that the use of intrinsically labeled proteins as currently described to quantify exogenous Ra systematically underestimates the true value. When used with the tracer-determined rates of amino acid kinetics, underestimation of exogenous Ra from the intrinsically labeled protein method likely translates to incorrect conclusions regarding protein breakdown, including the effect of a protein meal and the anabolic impact of the speed of digestion and absorption of amino acids. Estimation of exogenous Ra from the bioavailability of ingested protein has some advantages as compared with the intrinsically labeled protein method. We therefore conclude that the bioavailability method for estimating exogenous Ra is preferable to the intrinsically labeled protein method.


Assuntos
Proteínas na Dieta/farmacocinética , Marcação por Isótopo/métodos , Proteínas/metabolismo , Imagem Corporal Total/métodos , Aminoácidos/metabolismo , Aminoácidos/farmacocinética , Disponibilidade Biológica , Deutério , Proteínas na Dieta/metabolismo , Estudos de Avaliação como Assunto , Humanos , Íleo/metabolismo , Absorção Intestinal/fisiologia , Cinética , Técnicas de Sonda Molecular , Período Pós-Prandial
4.
J Med Chem ; 62(5): 2466-2484, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30714733

RESUMO

Inhibitors that target the glycine transporter 2, GlyT2, show promise as analgesics, but may be limited by their toxicity through complete or irreversible binding. Acyl-glycine inhibitors, however, are selective for GlyT2 and have been shown to provide analgesia in animal models of pain with minimal side effects, but are comparatively weak GlyT2 inhibitors. Here, we modify the simple acyl-glycine by synthesizing lipid analogues with a range of amino acid head groups in both l- and d-configurations, to produce nanomolar affinity, selective GlyT2 inhibitors. The potent inhibitor oleoyl-d-lysine (33) is also resistant to degradation in both human and rat plasma and liver microsomes, and is rapidly absorbed following an intraperitoneal injection to rats and readily crosses the blood-brain barrier. We demonstrate that 33 provides greater analgesia at lower doses, and does not possess the severe side effects of the very slowly reversible GlyT2 inhibitor, ORG25543 (2).


Assuntos
Aminoácidos/uso terapêutico , Analgésicos/uso terapêutico , Dor Crônica/prevenção & controle , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Aminoácidos/química , Aminoácidos/farmacocinética , Animais , Barreira Hematoencefálica , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Meia-Vida , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley
5.
Mater Sci Eng C Mater Biol Appl ; 93: 407-418, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30274073

RESUMO

The present paper reported a biomimetic synthesis of mesoporous silicas (BMSs) at room temperature by using synthesized polymers (C16-l-His, C16-l-Pro and C16-l-Trp) which derived from amino acid with ring structures as template under basic condition via co-structural-directing-agent method. The formation mechanism of BMSs and effect of initial synthesis conditions (such as surfactant structure, pH and co-solvents) on morphology and structure of BMSs were systematically studied. Synthesized BMSs were characterized by transmission electron microscope (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and nitrogen adsorption/desorption isotherms. The results showed that the surfactant structure was the dominant factor to direct the final mesostructure of BMSs, since the structure of surfactant affected the structure and size of clusters. Meanwhile the generation of BMSs required very rigorous alkaline condition which controlled the ionization degree of the surfactant and thus contributing to adequate stacking energy. Higher pH resulted in construction of channels with higher curvature. The presence of ethanol was found to facilitate the formation of BMSs with larger particle size. In application, aspirin can be loaded into BMSs with high efficiency, and the drug crystalline state of aspirin transformed from crystalline state to amorphous state during this process, which undoubtedly lead to the improvement of drug dissolution from 72.8% to 100% within 90 min. It is convincible that the biomimetic method presented here provided novel insight on precisely control of mesoporous silica and undoubtedly promoted the application of mesoporous silica materials.


Assuntos
Ácidos Heterocíclicos , Aminoácidos , Materiais Biomiméticos , Dióxido de Silício , Ácidos Heterocíclicos/química , Ácidos Heterocíclicos/farmacocinética , Aminoácidos/química , Aminoácidos/farmacocinética , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Concentração de Íons de Hidrogênio , Porosidade , Dióxido de Silício/química , Dióxido de Silício/farmacocinética
6.
Environ Mol Mutagen ; 59(7): 586-594, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30151952

RESUMO

Existing and future nuclear fusion technologies involve the production and use of large quantities of tritium, a highly volatile, but low toxicity beta-emitting isotope of hydrogen. Tritium has received international attention because of public and scientific concerns over its release to the environment and the potential health impact of its internalization. This article provides a brief summary of the current state of knowledge of both the biological and regulatory aspects of tritium exposure; it also explores the gaps in this knowledge and provides recommendations on the best ways forward for improving our understanding of the health effects of low-level exposure to it. Linking health effects specifically to tritium exposure is challenging in epidemiological studies due to high uncertainty in tritium dosimetry and often suboptimal cohort sizes. We therefore argued that limits for tritium in drinking water should be based on evidence derived from controlled in vivo animal tritium toxicity studies that use realistically low levels of tritium. This article presents one such mouse study, undertaken within an international collaboration, and discusses the implications of its main findings, such as the similarity of the biokinetics of tritiated water (HTO) and organically bound tritium (OBT) and the higher biological effectiveness of OBT. This discussion is consistent with the position expressed in this article that in vivo animal tritium toxicity studies carried out within large, multi-partner collaborations allow evaluation of a great variety of health-related endpoints and essential to the development of international consensus on the regulation of tritium levels in the environment. Environ. Mol. Mutagen. 59:586-594, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.


Assuntos
Água Potável/efeitos adversos , Trítio/efeitos adversos , Aminoácidos/análise , Aminoácidos/farmacocinética , Animais , Sítios de Ligação , Consenso , Água Potável/análise , Raios gama/efeitos adversos , Dosimetria in Vivo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Monitoramento de Radiação , Risco , Distribuição Tecidual , Trítio/análise , Trítio/farmacocinética , Trítio/toxicidade , Organização Mundial da Saúde
7.
J Nutr Biochem ; 59: 114-122, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29986305

RESUMO

High-protein diets are generally considered beneficial for calcium (Ca) economy and bone health. Improved intestinal Ca absorption efficiency may be one mechanism by which higher-protein diets affect Ca homeostasis and bone health. The signaling pathways and individual amino acids (AA) responsible for this effect have not been fully elucidated and may involve the transcellular pathway, paracellular pathway or a combination. The primary aim of this study was to investigate whether a mixture of AA and/or functionally distinct individual AA directly affect paracellular Ca absorption across an intestinal epithelial cell model (Caco-2 Bbe). Using Ussing chambers, we examined the effect of six treatments - vehicle (Veh), 80 mM raffinose (Raf; positive control), 2× mixed AA(2×AA, twice the concentration in standard growth media), the branched-chain amino acid leucine (2-10 mM Leu), the aromatic amino acid phenylalanine (2-10 mM Phe) and the dibasic amino acid lysine (2-10 mM Lys) - on Ca flux. Leu (5 mM) increased Ca flux by 38% (+122 nmol Ca/cm2/h, P<.001) as compared to Veh, while 10 mM Phe reduced Ca flux. No other differences were observed. Leu increased Ca flux through cellular redistribution of the Ca permissive channel Cldn-2 to the tight junction membrane (P<.05). Inhibition of mTORC1 signaling did not abrogate the effect of Leu on Cldn-2 localization, indicating a non-mTORC1-dependent signaling pathway is involved. These data indicate that Leu may improve Ca absorption in a cell model, potentially contributing to the observed benefits of higher-protein diets on bone health in humans.


Assuntos
Aminoácidos/farmacocinética , Cálcio/metabolismo , Aminoácidos/metabolismo , Células CACO-2 , Claudinas/genética , Claudinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Sirolimo/farmacologia
8.
J Nutr ; 148(6): 917-924, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29741697

RESUMO

Background: Maize is a staple food in many regions of the world, particularly in Africa and Latin America. However, maize protein is limiting in the indispensable amino acids lysine and tryptophan, making its protein of poor quality. Objective: The main objective of this study was to determine the protein quality of white African cornmeal by determining the metabolic availability (MA) of lysine and tryptophan. Methods: To determine the MA of lysine, 4 amounts of l-lysine (10, 13, 16, and 18 mg · kg-1 · d-1 totaling 28.6%, 37.1%, 45.7%, and 51.4% of the mean lysine requirement of 35 mg · kg-1 · d-1, respectively) were studied in 6 healthy young men in a repeated-measures design. To determine the MA of tryptophan, 4 amounts of l-tryptophan (0.5, 1, 1.5, and 2 mg · kg-1 · d-1 totaling 12.5%, 25.0%, 37.5%, and 50.0% of the mean tryptophan requirement of 4 mg · kg-1 · d-1, respectively) were studied in 7 healthy young men in a repeated-measures design. The MAs of lysine and tryptophan were estimated by comparing the indicator amino acid oxidation (IAAO) response with varying intakes of lysine and tryptophan in cooked white cornmeal compared with the IAAO response to l-lysine and l-tryptophan intakes in the reference protein (crystalline amino acid mixture patterned after egg protein) with the use of the slope ratio method. Results: The MAs of lysine and tryptophan from African cooked white cornmeal were 71% and 80%, respectively. Conclusion: Our study provides a robust estimate of the availability of lysine and tryptophan in African white maize to healthy young men. This estimate provides a basis for postproduction fortification or supplementation of maize-based diets. This trial was registered at www.clinicaltrials.gov as NCT02402179.


Assuntos
Aminoácidos/farmacocinética , Lisina/farmacocinética , Triptofano/farmacocinética , Zea mays/química , Adulto , Aminoácidos/administração & dosagem , Aminoácidos/química , Aminoácidos/metabolismo , Disponibilidade Biológica , Análise de Alimentos , Humanos , Lisina/administração & dosagem , Lisina/química , Lisina/metabolismo , Masculino , Oxirredução , Triptofano/administração & dosagem , Triptofano/química , Triptofano/metabolismo , Adulto Jovem
9.
Nutrients ; 10(4)2018 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-29671767

RESUMO

To stimulate muscle protein synthesis, it is important to increase the plasma levels of essential amino acids (EAA), especially leucine, by ingesting proteins. Protein hydrolysate ingestion can induce postprandial hyperaminoacidemia; however, it is unclear whether protein hydrolysate is associated with higher levels of aminoacidemia compared with a free amino acid mixture when both are ingested orally. We assessed the effects of whey protein hydrolysate (WPH) ingestion on postprandial aminoacidemia, especially plasma leucine levels, compared to ingestion of a free amino acid mixture. This study was an open-label, randomized, 4 × 4 Latin square design. After 12⁻15 h of fasting, 11 healthy young men ingested the WPH (3.3, 5.0, or 7.5 g of protein) or the EAA mixture (2.5 g). Blood samples were collected before ingestion and at time points from 10 to 120 min after ingestion, and amino acids, insulin, glucose and insulin-like growth factor-1 (IGF-1) concentrations in plasma were measured. Even though the EAA mixture and 5.0 g of the WPH contained similar amounts of EAA and leucine, the WPH was associated with significantly higher plasma EAA and leucine levels. These results suggest that the WPH can induce a higher level of aminoacidemia compared with a free amino acid mixture when both are ingested orally.


Assuntos
Aminoácidos/administração & dosagem , Aminoácidos/sangue , Período Pós-Prandial , Proteínas do Soro do Leite/química , Adulto , Aminoácidos/farmacocinética , Glicemia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrólise , Insulina/sangue , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino
10.
Front Biosci (Landmark Ed) ; 23: 1721-1739, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29293459

RESUMO

The main function of the porcine intestinal tract is nutrient digestion and absorption. This function is performed by the absorptive enterocytes, which are differentiated from the intestinal stem cells residing at the bottom of the crypt. Nutrients such as glucose and amino acids are transported, absorbed by various transporters embedded on the membranes of these enterocytes. Metabolism occurs in each cell along the crypt-villus axis (CVA). Because the intestinal epithelial cells are the most vigorous, self-renewing cells, regenerating from the crypt bottom to the villus tip in only three to five days, the CVA is an appealing organ for studying cell maturation. In this review, we examine the glucose and amino acid transporters expressed in the apical membrane, basolateral membrane, or the inside of the absorptive enterocytes. We also discuss glucose and amino acid metabolism in small epithelial cells, and show how these nutrients influence the proliferation and differentiation of an intestinal stem cell into one specialized cell type when they migrate from the bottom of the crypt to the tip of the villus.


Assuntos
Aminoácidos/metabolismo , Enterócitos/metabolismo , Glucose/metabolismo , Mucosa Intestinal/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos/farmacocinética , Animais , Diferenciação Celular , Enterócitos/citologia , Glucose/farmacocinética , Absorção Intestinal , Mucosa Intestinal/citologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Suínos
11.
Mol Nutr Food Res ; 62(2)2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28994235

RESUMO

SCOPE: Food structure is a key factor controlling digestion and nutrient absorption. We test the hypothesis that protein emulsion structure in the diet may affect digestive and absorptive processes. METHODS & RESULTS: Rats (n = 40) are fed for 3 weeks with two diets chemically identical but based on lipid-protein liquid-fine (LFE) or gelled-coarse (GCE) emulsions that differ at the macro- and microstructure levels. After an overnight fasting, they ingest a 15 N-labeled LFE or GCE test meal and are euthanized 0, 15 min, 1 h, and 5 h later. 15 N enrichment in intestinal contents and blood are measured. Gastric emptying, protein digestion kinetics, 15 N absorption, and incorporation in blood protein and urea are faster with LFE than GCE. At 15 min time point, LFE group shows higher increase in GIP portal levels than GCE. Three weeks of dietary adaptation leads to higher expression of cationic amino acid transporters in ileum of LFE compared to GCE. LFE diet raises cecal butyrate and isovalerate proportion relative to GCE, suggesting increased protein fermentation. LFE diet increases fecal Parabacteroides relative abundance but decreases Bifidobacterium, Sutterella, Parasutterella genera, and Clostridium cluster XIV abundance. CONCLUSION: Protein emulsion structure regulates digestion kinetics and gastrointestinal physiology, and could be targeted to improve food health value.


Assuntos
Emulsões/química , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Lipoproteínas/química , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Aminoácidos/farmacocinética , Animais , Peso Corporal/efeitos dos fármacos , Dieta , Proteínas na Dieta/farmacocinética , Digestão , Emulsões/farmacologia , Mucosa Intestinal/fisiologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Lipoproteínas/farmacologia , Masculino , Isótopos de Nitrogênio/análise , Isótopos de Nitrogênio/farmacocinética , Ratos Wistar
12.
Mol Neurobiol ; 55(1): 359-369, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28875428

RESUMO

Previous studies from our laboratory show that intraperitoneal injections of 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP, 20 mg/kg) daily within 2-h intervals for 5 days in mice induce Parkinson's disease (PD)-like symptoms on the 8th day. A significant decrease in dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) along with a marked decrease in the number of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta (SNpc) and striatum (STr) confirms the validity of this model for studying PD. Since cerebrolysin (CBL) is a well-balanced composition of several neurotrophic factors and active peptide fragments, in the present investigation we examined the timed release of CBL using titanate nanospheres (TiNS) in treating PD in our mouse model. Our observations show that TiNS-CBL (in a dose of 3 ml/kg, i.v.) given after 2 days of MPTP administration for 5 days resulted in a marked increase in TH-positive cells in the SNpc and STr as compared to normal CBL. Also, TiNS-CBL resulted in significantly higher levels of DA, DOPAC, and HVA in SNpc and STr on the 8th day as compared to normal CBL therapy. TiNS-CBL also thwarted increased α-synuclein levels in the brain and in the cerebrospinal fluid (CSF) as well as neuronal nitric oxide synthase (nNOS) in the in PD brain as compared to untreated group. Behavioral function was also significantly improved in MPTP-treated animals that received TiNS-CBL. These observations are the first to demonstrate that timed release of TiNS-CBL has far more superior neuroprotective effects in PD than normal CBL.


Assuntos
Aminoácidos/administração & dosagem , Encéfalo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Nanosferas/administração & dosagem , Transtornos Parkinsonianos/tratamento farmacológico , Titânio/administração & dosagem , Aminoácidos/farmacocinética , Animais , Encéfalo/patologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Nanosferas/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia
13.
Bioconjug Chem ; 29(3): 657-671, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28876902

RESUMO

The field of medical diagnostics and therapeutics is being revolutionized by nanotechnology, from targeted drug delivery to cancer immunotherapy. Inorganic nanoparticles are widely used, albeit problems with agglutination, cytotoxicity, free radical generation, and instability in some biological environments limits their utility. Conjugation of biomolecules such as peptides to the surface of nanoparticles can mitigate such problems, as well as confer specialized theranostic (therapeutic and/or diagnostic) properties, useful across biomedical applications such as vaccines, drug delivery, and in vivo imaging. Coating with amino acids, rather than peptides, offers further a highly cost-effective approach (due to their ease of purification and availability), but is currently an underutilized way to decrease toxicity and enhance stability. Amino acid molecules are small (<200 Da) and have both positive and negative charge groups (zwitterionic) facilitating charge-specific molecule binding. Additionally, amino acids exert by themselves some useful biological functions, with antibacterial and viability enhancing properties (for eukaryotic cells). Overall particle size, nanoparticle core, and the specific amino acid used to functionalize their surface influence their biodistribution, and their effects on host immunity. In this review, we provide for the first time an overview of this emerging field, and identify gaps in knowledge for future research.


Assuntos
Aminoácidos/química , Anti-Infecciosos/química , Nanomedicina/métodos , Nanopartículas/química , Aminoácidos/farmacocinética , Aminoácidos/uso terapêutico , Animais , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/uso terapêutico , Técnicas Biossensoriais/métodos , Sistemas de Liberação de Medicamentos/métodos , Técnicas de Transferência de Genes , Humanos , Imagem por Ressonância Magnética/métodos , Modelos Moleculares , Nanopartículas/uso terapêutico , Nanopartículas/ultraestrutura
14.
Ann N Y Acad Sci ; 1411(1): 65-82, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29044608

RESUMO

Pancreatic beta cells sense changes in nutrients during the cycles of fasting and feeding and release insulin accordingly to maintain glucose homeostasis. Abnormal beta cell nutrient sensing resulting from gene mutations leads to hypoglycemia or diabetes. Glucokinase (GCK) plays a key role in beta cell glucose sensing. As one form of congenital hyperinsulinism (CHI), activating mutations of GCK result in a decreased threshold for glucose-stimulated insulin secretion and hypoglycemia. In contrast, inactivating mutations of GCK result in diabetes, including a mild form (MODY2) and a severe form (permanent neonatal diabetes mellitus (PNDM)). Mutations of beta cell ion channels involved in insulin secretion regulation also alter glucose sensing. Activating or inactivating mutations of ATP-dependent potassium (KATP ) channel genes result in severe but completely opposite clinical phenotypes, including PNDM and CHI. Mutations of the other ion channels, including voltage-gated potassium channels (Kv 7.1) and voltage-gated calcium channels, also lead to abnormal glucose sensing and CHI. Furthermore, amino acids can stimulate insulin secretion in a glucose-independent manner in some forms of CHI, including activating mutations of the glutamate dehydrogenase gene, HDAH deficiency, and inactivating mutations of KATP channel genes. These genetic defects have provided insight into a better understanding of the complicated nature of beta cell fuel-sensing mechanisms.


Assuntos
Hiperinsulinismo Congênito/fisiopatologia , Diabetes Mellitus/fisiopatologia , Glucoquinase/fisiologia , Canais Iônicos/fisiologia , Ilhotas Pancreáticas/fisiologia , Nutrientes/farmacocinética , 3-Hidroxiacil-CoA Desidrogenases/deficiência , Aminoácidos/farmacocinética , Animais , Glicemia/metabolismo , Hiperinsulinismo Congênito/genética , Diabetes Mellitus/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Ácidos Graxos/metabolismo , Glucoquinase/deficiência , Glucoquinase/genética , Glucose/farmacocinética , Humanos , Insulina/fisiologia , Canais Iônicos/genética , Erros Inatos do Metabolismo/fisiopatologia , Camundongos , Camundongos Knockout , Mutação , Oxirredução
15.
Am J Physiol Endocrinol Metab ; 314(5): E457-E467, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28536184

RESUMO

The purpose of this study was to determine the impact of ingesting 30 g casein protein with and without 2 g free leucine before sleep on myofibrillar protein synthesis rates during postexercise overnight recovery. Thirty-six healthy young men performed a single bout of resistance-type exercise in the evening (1945) after a full day of dietary standardization. Thirty minutes before sleep (2330), subjects ingested 30 g intrinsically l-[1-13C]phenylalanine-labeled protein with (PRO+leu, n = 12) or without (PRO, n = 12) 2 g free leucine, or a noncaloric placebo (PLA, n = 12). Continuous intravenous l-[ ring-2H5]phenylalanine, l-[1-13C]leucine, and l-[ ring-2H2]tyrosine infusions were applied. Blood and muscle tissue samples were collected to assess whole body protein net balance, myofibrillar protein synthesis rates, and overnight incorporation of dietary protein-derived amino acids into myofibrillar protein. Protein ingestion before sleep improved overnight whole body protein net balance ( P < 0.001). Myofibrillar protein synthesis rates did not differ significantly between treatments as assessed by l-[ ring-2H5]phenylalanine (0.057 ± 0.002, 0.055 ± 0.002, and 0.055 ± 0.004%/h for PLA, PRO, and PRO+leu, respectively; means ± SE; P = 0.850) or l-[1-13C]leucine (0.080 ± 0.004, 0.073 ± 0.004, and 0.083 ± 0.006%/h, respectively; P = 0.328). Myofibrillar l-[1-13C]phenylalanine enrichments increased following protein ingestion but did not differ between the PRO and PRO+leu treatments. In conclusion, protein ingestion before sleep improves whole body protein net balance and provides amino acids that are incorporated into myofibrillar protein during sleep. However, the ingestion of 30 g casein protein with or without additional free leucine before sleep does not increase muscle protein synthesis rates during postexercise overnight recovery.


Assuntos
Aminoácidos/farmacocinética , Proteínas na Dieta/farmacocinética , Exercício Físico/fisiologia , Proteínas Musculares/metabolismo , Sono/fisiologia , Adulto , Metabolismo Basal/fisiologia , Ritmo Circadiano/fisiologia , Humanos , Masculino , Período Pós-Prandial , Recuperação de Função Fisiológica , Treinamento de Resistência , Descanso/fisiologia , Fatores de Tempo , Adulto Jovem
16.
Bioorg Chem ; 76: 370-379, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29241109

RESUMO

Naproxen (nap) is belonging to Non-steriodal anti-inflammatory drugs (NSAIDs) group of drugs that characterized by their free carboxylic group. The therapeutic activity of nap is usually accompanied by GI untoward side effects. Recently synthesized naproxen amides of some amino acid esters prodrugs to mask the free carboxylic group were reported. Those prodrugs showed a promising colorectal cancer chemopreventive activity. The current study aims to investigate the fate and hydrolysis of the prodrugs kinetically in different pH conditions, simulated gastric and intestinal fluids with pHs of 1.2, 5.5 and 7.4 in vitro at 37 °C. The effect of enzymes on the hydrolysis of prodrugs was also studied through incubation of these prodrugs at 37 °C in human plasma and rat liver homogenates. The pharmacokinetic parameters of selected prodrugs and the liberated nap were studied after oral and intraperitoneal administration in male wistar rats. The results showed the hydrolysis of naproxen amides of amino acid esters to nap through two steps first by degradation of the ester moiety to form the amide of nap with amino acid and the second was through the degradation of the amide link to liberate nap. The two reactions were followed and studied kinetically where K1 and K2 (rate constants of degradation) is reported. The hydrolysis of prodrugs was faster in liver homogenates than in plasma. The relative bioavailability of the liberated nap in vivo was higher in case of prodrug containing ethyl glycinate moiety than that occupied l-valine ethyl ester moiety. Each of nap. prodrugs containing ethyl glycinate and l-valine ethyl ester moieties appears promising in liberating nap, decreasing direct GI side effect and consequently their colorectal cancer chemopreventive activity.


Assuntos
Amidas/farmacocinética , Aminoácidos/farmacocinética , Anticarcinógenos/farmacocinética , Naproxeno/análogos & derivados , Naproxeno/farmacocinética , Pró-Fármacos/farmacocinética , Administração Oral , Amidas/administração & dosagem , Amidas/sangue , Amidas/química , Aminoácidos/administração & dosagem , Aminoácidos/sangue , Aminoácidos/química , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/sangue , Anticarcinógenos/química , Neoplasias Colorretais/tratamento farmacológico , Estabilidade de Medicamentos , Ésteres/administração & dosagem , Ésteres/sangue , Ésteres/química , Ésteres/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Injeções Intraperitoneais , Cinética , Fígado/metabolismo , Masculino , Naproxeno/administração & dosagem , Naproxeno/sangue , Pró-Fármacos/administração & dosagem , Pró-Fármacos/análise , Pró-Fármacos/química , Ratos Wistar
17.
Biometals ; 30(5): 643-661, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28717982

RESUMO

Zn is essential for growth and development. The bioavailability of Zn is affected by several factors such as other food components. It is therefore of interest, to understand uptake mechanisms of Zn delivering compounds to identify ways to bypass the inhibitory effects of these factors. Here, we studied the effect of Zn amino acid conjugates (ZnAAs) on the bioavailabilty of Zn. We used Caco-2 cells and enterocytes differentiated from human induced pluripotent stem cells from a control and Acrodermatitis enteropathica (AE) patient, and performed fluorescence based assays, protein biochemistry and atomic absorption spectrometry to characterize cellular uptake and absorption of ZnAAs. The results show that ZnAAs are taken up by AA transporters, leading to an intracellular enrichment of Zn mostly uninhibited by Zn uptake antagonists. Enterocytes from AE patients were unable to gain significant Zn through exposure to ZnCl2 but did not show differences with respect to ZnAAs. We conclude that ZnAAs may possess an advantage over classical Zn supplements such as Zn salts, as they may be able to increase bioavailability of Zn, and may be more efficient in patients with AE.


Assuntos
Acrodermatite/tratamento farmacológico , Aminoácidos/farmacocinética , Complexos de Coordenação/farmacocinética , Enterócitos/efeitos dos fármacos , Zinco/deficiência , Zinco/farmacocinética , Acrodermatite/metabolismo , Acrodermatite/patologia , Aminoácidos/química , Aminoácidos/metabolismo , Animais , Disponibilidade Biológica , Transporte Biológico , Células CACO-2 , Proteínas de Transporte/metabolismo , Diferenciação Celular , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Enterócitos/citologia , Enterócitos/metabolismo , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Zinco/química , Zinco/metabolismo
18.
Adv Exp Med Biol ; 977: 59-65, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28685428

RESUMO

Nausea and diarrhea are common yet inconsistent side effects of abdominal and pelvic irradiation. Their frequency, chronicity, and severity vary greatly, and the reasons for inter-subject variability are unknown. We studied the potential for radiation-induced changes in amino acid absorption and mucosal barrier function to lead to gastrointestinal toxicity. We found profound and prolonged changes in the absorption and secretion of several electrolytes and nutrients, caused by changes in transporter function, after radiation doses as low as 1 to 3 Gy. After identifying absorbed and non-absorbed amino acids, we demonstrated the role of a beneficial amino acid drink to alleviate radiation-related gastrointestinal symptoms in a mouse model.


Assuntos
Aminoácidos/administração & dosagem , Hidratação/métodos , Náusea/terapia , Pica/terapia , Lesões por Radiação/terapia , Soluções para Reidratação/uso terapêutico , Aminoácidos/farmacocinética , Animais , Modelos Animais de Doenças , Eletrólitos/farmacocinética , Absorção Gastrointestinal , Gastroenteropatias/etiologia , Gastroenteropatias/terapia , Glucose/farmacocinética , Masculino , Camundongos , Náusea/etiologia , Pica/patologia , Lesões por Radiação/complicações , Soluções para Reidratação/química
19.
J Nutr ; 147(8): 1537-1545, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28659408

RESUMO

Background: Although previous growth studies in rodents have indicated the importance of dietary nonessential amino acids (NEAAs) as nitrogen sources, individual NEAAs have different growth-promoting activities. This phenomenon might be attributable to differences in the nitrogen metabolism of individual NEAAs. Objective: The aim of this study was to compare nitrogen metabolism across dietary NEAAs with the use of their 15N isotopologues.Methods: Male Fischer rats (8 wk old) were given 1.0 g amino acid-defined diets containing either 15N-labeled glutamate, glutamine (amino or amide), aspartate, alanine, proline, glycine, or serine hourly for 5-6 h. Then, steady-state amino acid concentrations and their 15N enrichments in the gut and in portal and arterial plasma were measured by an amino acid analyzer and LC tandem mass spectrometry, respectively.Results: The intestinal 15N distribution and portal-arterial balance of 15N metabolites indicated that most dietary glutamate nitrogen (>90% of dietary input) was incorporated into various amino acids, including alanine, proline, and citrulline, in the gut. Dietary aspartate nitrogen, alanine nitrogen, and amino nitrogen of glutamine were distributed similarly to other amino acids both in the gut and in the circulation. In contrast, incorporation of the nitrogen moieties of dietary proline, serine, and glycine into other amino acids was less than that of other NEAAs, although interconversion between serine and glycine was very active. Cluster analysis of 15N enrichment data also indicated that dietary glutamate nitrogen, aspartate nitrogen, alanine nitrogen, and the amino nitrogen of glutamine were distributed similarly to intestinal and circulating amino acids. Further, the analysis revealed close relations between intestinal and arterial 15N enrichment for each amino acid. The steady-state 15N enrichment of arterial amino acids indicated that substantial amounts of circulating amino acid nitrogen are derived from dietary NEAAs.Conclusions: The present results revealed similarities and differences among NEAAs in terms of their intestinal nitrogen metabolism in rats and indicated substantial entry of dietary NEAA nitrogen into circulating amino acid nitrogen, presumably primarily through metabolism in the gut.


Assuntos
Aminoácidos/farmacocinética , Dieta , Proteínas na Dieta/metabolismo , Mucosa Intestinal/metabolismo , Nitrogênio/metabolismo , Aminoácidos/sangue , Aminoácidos/metabolismo , Animais , Fígado/metabolismo , Masculino , Isótopos de Nitrogênio , Ratos Endogâmicos F344 , Espectrometria de Massas em Tandem
20.
Int J Toxicol ; 36(1_suppl): 17S-56S, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28553738

RESUMO

The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the product use, formulation, and safety data of 115 amino acid alkyl amides, which function as skin and hair conditioning agents and as surfactants-cleansing agents in personal care products. Safety test data on dermal irritation and sensitization for the ingredients with the highest use concentrations, lauroyl lysine and sodium lauroyl glutamate, were reviewed and determined to adequately support the safe use of the ingredients in this report. The Panel concluded that amino acid alkyl amides are safe in the present practices of use and concentration in cosmetics, when formulated to be nonirritating.


Assuntos
Amidas/toxicidade , Aminoácidos/toxicidade , Cosméticos/toxicidade , Tensoativos/toxicidade , Amidas/química , Amidas/farmacocinética , Aminoácidos/química , Aminoácidos/farmacocinética , Animais , Qualidade de Produtos para o Consumidor , Cosméticos/química , Cosméticos/farmacocinética , Humanos , Medição de Risco , Tensoativos/química , Tensoativos/farmacocinética , Testes de Toxicidade
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