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1.
J Nutr ; 150(5): 1208-1213, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32140711

RESUMO

BACKGROUND: Due to a lack of research data on the protein requirements of the elderly in China, the estimated average requirement (EAR) and the recommended nutrient intake (RNI) of protein in the elderly remain the same as those in young and middle-aged people at 0.98 g/(kg·d). OBJECTIVE: The objective of this study was to determine the protein requirements of healthy Chinese adults >65y old through use of the indicator amino acid oxidation (IAAO) method. METHODS: Seven healthy adult men and 7 healthy adult women participated in the study, with protein intakes ranging from 0.3 to 1.8 g/(kg·d). The diets were isocaloric and provided energy at a 1.5 resting energy expenditure. Protein was given based on the lactalbumin. Phenylalanine and tyrosine were added to protein doses of 0.3-1.5 g/kg according to the highest dose of protein content [1.8 g/(kg·d)]. Phenylalanine and tyrosine concentrations were kept constant at each protein dose. The mean protein requirement was determined by applying a nonlinear mixed-effects model analysis to the F13CO2, which identified a breakpoint in F13CO2 in response to graded amounts of protein. This trial was registered with the Chinese clinical trial registry as ChiCTR-BOC-17010930. RESULTS: Protein EAR and RNI for healthy elderly Chinese adults were determined to be 0.91 and 1.17 g/(kg·d), respectively, based on the indicator amino acid oxidation technique. CONCLUSIONS: The estimates of protein requirements for Chinese adults >65 y in the present study are 3.4% and 19.4% higher than the current estimated requirements, 0.88 g/(kg·d) for EAR and 0.98 g/(kg·d) for RNI.


Assuntos
Proteínas na Dieta/administração & dosagem , Necessidades Nutricionais , Recomendações Nutricionais , Idoso , Envelhecimento/fisiologia , Aminoácidos/metabolismo , Peso Corporal , China , Ingestão de Energia , Metabolismo Energético , Feminino , Humanos , Masculino , Oxirredução , Fenilalanina/administração & dosagem , Fenilalanina/metabolismo , Tirosina/administração & dosagem
2.
Biosci Biotechnol Biochem ; 84(4): 824-831, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31852406

RESUMO

We examined the effect of isomaltodextrin (IMD), a soluble dietary fiber, on production of putrefactive products by intestinal bacteria using a tyrosine load test to measure phenol production in IMD-treated rats. We observed a significant increase in phenol and p-cresol concentrations in rats administered with only tyrosine, but not for rats co-administered tyrosine and IMD. To elucidate the mechanism of this effect, we analyzed the intestinal microbiota in each group and found that although IMD had no direct effect on the proportion of bacteria known to produce phenols, it did alter the balance of intestinal microbiota. The results suggested that changes in the intestinal microbiota composition reduced the metabolic capacity for tyrosine and in turn suppressed production of phenol or p-cresol, putrefactive products in the intestine.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Polissacarídeos/farmacologia , Tirosina/metabolismo , Animais , Ceco/metabolismo , Concentração de Íons de Hidrogênio , Masculino , Fenóis/metabolismo , Ratos , Ratos Wistar , Tirosina/administração & dosagem
3.
PLoS One ; 14(7): e0216111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31339892

RESUMO

BACKGROUND AND PURPOSE: The advantage of combined PET-MRI over sequential PET and MRI is the high spatial conformity and the absence of time delay between the examinations. The benefit of this technique for planning of re-irradiation (re-RT) treatment is unkown yet. Imaging data from a phase 1 trial of re-RT for recurrent glioma was analysed to assess whether planning target volumes and treatment margins in glioma re-RT can be adjusted by PET-MRI with rater independent PET based biological tumour volumes (BTVs). PATIENTS AND METHODS: Combined PET-MRI with the tracer O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) prior to re-RT was performed in recurrent glioma patients in a phase I trial. GTVs including all regions suspicious of tumour on contrast enhanced MRI were delineated by three experienced radiation oncologists and included into MRI based consensus GTVs (MRGTVs). BTVs were semi-automatically delineated with a fixed threshold of 1.6 x background activity. Corresponding BTVs and MRGTVs were fused into union volume PET-MRGTVs. The Sørensen-Dice coefficient and the conformity index were used to assess the geometric overlap of the BTVs with the MRGTVs. A recurrence pattern analysis was performed based on the original planning target volumes (PTVs = GTV + 10 mm margin or 5 mm in one case) and the PET-MRGTVs with margins of 10, 8, 5 and 3 mm. RESULTS: Seven recurrent glioma patients, who received PET-MRI prior to re-RT, were included into the present planning study. At the time of re-RT, patients were in median 54 years old and had a median Karnofsky Performance Status (KPS) score of 80. Median post-recurrence survival after the beginning of re-RT was 13 months. Concomitant bevacizumab therapy was applied in six patients and one patient received chemoradiation with temozolomide. Median GTV volumes of the three radiation oncologists were 35.0, 37.5 and 40.5 cubic centimeters (cc) and median MRGTV volume 41.8 cc. Median BTV volume was 36.6 cc and median PET-MRGTV volume 59.3 cc. The median Sørensen-Dice coefficient for the comparison between MRGTV and BTV was 0.61 and the median conformity index 0.44. Recurrence pattern analysis revealed two central, two in-field and one distant recurrence within both, the original PTV, as well as the PET-MRGTV with a reduced margin of 3 mm. CONCLUSION: PET-MRI provides radiation treatment planning imaging with high spatial and timely conformity for high-grade glioma patients treated with re-RT with potential advancements for target volume delineation. Prospective randomised trials are warranted to further investigate the treatment benefits of PET-MRI based re-RT planning.


Assuntos
Bevacizumab/administração & dosagem , Neoplasias Encefálicas , Quimiorradioterapia , Glioma , Imagem por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Temozolomida/administração & dosagem , Tirosina/análogos & derivados , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Feminino , Glioma/diagnóstico por imagem , Glioma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Carga Tumoral , Tirosina/administração & dosagem
4.
Science ; 364(6445)2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31196984

RESUMO

The human gut microbiota metabolizes the Parkinson's disease medication Levodopa (l-dopa), potentially reducing drug availability and causing side effects. However, the organisms, genes, and enzymes responsible for this activity in patients and their susceptibility to inhibition by host-targeted drugs are unknown. Here, we describe an interspecies pathway for gut bacterial l-dopa metabolism. Conversion of l-dopa to dopamine by a pyridoxal phosphate-dependent tyrosine decarboxylase from Enterococcus faecalis is followed by transformation of dopamine to m-tyramine by a molybdenum-dependent dehydroxylase from Eggerthella lenta These enzymes predict drug metabolism in complex human gut microbiotas. Although a drug that targets host aromatic amino acid decarboxylase does not prevent gut microbial l-dopa decarboxylation, we identified a compound that inhibits this activity in Parkinson's patient microbiotas and increases l-dopa bioavailability in mice.


Assuntos
Actinobacteria/enzimologia , Antiparkinsonianos/metabolismo , Proteínas de Bactérias/metabolismo , Enterococcus faecalis/enzimologia , Microbioma Gastrointestinal , Levodopa/metabolismo , Tirosina Descarboxilase/metabolismo , Tirosina/análogos & derivados , Actinobacteria/efeitos dos fármacos , Actinobacteria/genética , Animais , Antiparkinsonianos/administração & dosagem , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Descarboxilação/efeitos dos fármacos , Dopamina/metabolismo , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/genética , Microbioma Gastrointestinal/genética , Genoma Bacteriano , Células HeLa , Humanos , Levodopa/administração & dosagem , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Tirosina/administração & dosagem , Tirosina/química , Tirosina/farmacologia , Tirosina Descarboxilase/antagonistas & inibidores , Tirosina Descarboxilase/genética
5.
Drug Res (Stuttg) ; 69(5): 277-283, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30189461

RESUMO

In this study we reported the synthesis of L-phenyl alanine (Phe) & L-tyrosine (Tyr) Natural Amino acids coated iron oxide magnetic nanoparticles under one-pot and in situ reaction. Functionalized iron oxide magnetic nanoparticles were characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Vibrating Sample Magnetometer (VSM), Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM) techniques. Cellular toxicity of amino acids coated iron oxide magnetic nanoparticles was also investigated on HEK-293 cell lines. Additionally, a hemolysis test of as prepared magnetic nanoparticles were performed. It was found that the synthesized Phe and Tyr coated magnetic nanoparticles (F@Phe NPs and F@Tyr NPs) were spherical in shape with an average size less than 25 nm, also the saturation magnetization (Ms) of the F@Phe NPs and F@Tyr NPs were about 30.02 and 58.23 emu/g, respectively, which was lower than those of bare Fe3O4. The TGA results show that apart from this weight loss, the coated sample shows a weight loss of 5.48, and 6.88% respectively corresponding to loss of Tyr, and Phe which is coated on the Fe3O4 nanoparticles. At a high concentration, less than 2.92 and 3.13% hemolytic activity were observed for F@Phe NPs and F@Tyr NPs, respectively. The F@Phe NPs and F@Tyr NPs show the possibility of using this nanoparticles in the development of in vitro and in vivo pharmaceutical and biomedical fields due to do not possess a toxic effect, good ζ-potential and related small and narrow size distribution.


Assuntos
Composição de Medicamentos/métodos , Nanopartículas de Magnetita/toxicidade , Fenilalanina/toxicidade , Tirosina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Eritrócitos , Química Verde/métodos , Células HEK293 , Hemólise/efeitos dos fármacos , Humanos , Nanopartículas de Magnetita/administração & dosagem , Nanopartículas de Magnetita/química , Teste de Materiais/métodos , Tamanho da Partícula , Fenilalanina/administração & dosagem , Fenilalanina/química , Nanomedicina Teranóstica/métodos , Testes de Toxicidade , Tirosina/administração & dosagem , Tirosina/química
6.
Med Sci Sports Exerc ; 51(4): 798-804, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30395050

RESUMO

INTRODUCTION: Current athlete-specific protein recommendations are based almost exclusively on research in males. PURPOSE: Using the minimally invasive indicator amino acid oxidation technique, we determined the daily protein intake that maximizes whole-body protein synthesis (PS) and net protein balance (NB) after exercise in strength-trained females. METHODS: Eight resistance-trained females (23 ± 3.5 yr, 67.0 ± 7.7 kg, 163.3 ± 3.7 cm, 24.4% ± 6.9% body fat; mean ± SD) completed a 2-d controlled diet during the luteal phase before performing an acute bout of whole-body resistance exercise. During recovery, participants consumed eight hourly meals providing a randomized test protein intake (0.2-2.9 g·kg·d) as crystalline amino acids modeled after egg protein, with constant phenylalanine (30.5 mg·kg·d) and excess tyrosine (40.0 mg·kg·d) intakes. Steady-state whole-body phenylalanine rate of appearance (Ra), oxidation (Ox; the reciprocal of PS), and NB (PS - Ra) were determined from oral [C] phenylalanine ingestion. Total protein oxidation was estimated from the urinary urea-creatinine ratio (U/Cr). RESULTS: A mixed model biphase linear regression revealed a break point (i.e., estimated average requirement) of 1.49 ± 0.44 g·kg·d (mean ± 95% confidence interval) in Ox (r = 0.64) and 1.53 ± 0.32 g·kg·d in NB (r = 0.65), indicating a saturation in whole-body anabolism. U/Cr increased linearly with protein intake (r = 0.56, P < 0.01). CONCLUSIONS: Findings from this investigation indicate that the safe protein intake (upper 95% confidence interval) to maximize anabolism and minimize protein oxidation for strength-trained females during the early ~8-h postexercise recovery period is at the upper end of the recommendations of the American College of Sports Medicine for athletes (i.e., 1.2-2.0 g·kg·d).


Assuntos
Proteínas na Dieta/administração & dosagem , Proteínas Musculares/biossíntese , Músculo Esquelético/metabolismo , Treinamento de Resistência , Adulto , Creatinina/urina , Metabolismo Energético , Feminino , Humanos , Necessidades Nutricionais , Oxirredução , Fenilalanina/administração & dosagem , Fenilalanina/metabolismo , Estudos Prospectivos , Tirosina/administração & dosagem , Tirosina/metabolismo , Ureia/urina , Adulto Jovem
7.
Mar Drugs ; 16(12)2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30572618

RESUMO

Treatment of acute myeloid leukemia (AML) patients is still hindered by resistance and relapse, resulting in an overall poor survival rate. Recently, combining specific B-cell lymphoma (Bcl)-2 inhibitors with compounds downregulating myeloid cell leukemia (Mcl)-1 has been proposed as a new effective strategy to eradicate resistant AML cells. We show here that 1(R), 6(S), 1'(R), 6'(S), 11(R), 17(S)-fistularin-3, a bromotyrosine compound of the fistularin family, isolated from the marine sponge Suberea clavata, synergizes with Bcl-2 inhibitor ABT-199 to efficiently kill Mcl-1/Bcl-2-positive AML cell lines, associated with Mcl-1 downregulation and endoplasmic reticulum stress induction. The absolute configuration of carbons 11 and 17 of the fistularin-3 stereoisomer was fully resolved in this study for the first time, showing that the fistularin we isolated from the marine sponge Subarea clavata is in fact the (+)-11(R), 17(S)-fistularin-3 stereoisomer keeping the known configuration 1(R), 6(S), 1'(R), and 6'(S) for the verongidoic acid part. Docking studies and in vitro assays confirm the potential of this family of molecules to inhibit DNA methyltransferase 1 activity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Isoxazóis/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Tirosina/análogos & derivados , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células HL-60 , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/química , Isoxazóis/isolamento & purificação , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Simulação de Acoplamento Molecular , Poríferos/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/administração & dosagem , Tirosina/administração & dosagem , Tirosina/química , Tirosina/isolamento & purificação , Tirosina/farmacologia , Células U937
8.
Biosci Rep ; 38(6)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30355657

RESUMO

Aims: Acute increases in left ventricular end diastolic pressure (LVEDP) can induce pulmonary edema (PE). The mechanism(s) for this rapid onset edema may involve more than just increased fluid filtration. Lung endothelial cell permeability is regulated by pressure-dependent activation of nitric oxide synthase (NOS). Herein, we demonstrate that pressure-dependent NOS activation contributes to vascular failure and PE in a model of acute heart failure (AHF) caused by hypertension.Methods and results: Male Sprague-Dawley rats were anesthetized and mechanically ventilated. Acute hypertension was induced by norepinephrine (NE) infusion and resulted in an increase in LVEDP and pulmonary artery pressure (Ppa) that were associated with a rapid fall in PaO2, and increases in lung wet/dry ratio and injury scores. Heart failure (HF) lungs showed increased nitrotyrosine content and ROS levels. L-NAME pretreatment mitigated the development of PE and reduced lung ROS concentrations to sham levels. Apocynin (Apo) pretreatment inhibited PE. Addition of tetrahydrobiopterin (BH4) to AHF rats lung lysates and pretreatment of AHF rats with folic acid (FA) prevented ROS production indicating endothelial NOS (eNOS) uncoupling.Conclusion: Pressure-dependent NOS activation leads to acute endothelial hyperpermeability and rapid PE by an increase in NO and ROS in a model of AHF. Acute increases in pulmonary vascular pressure, without NOS activation, was insufficient to cause significant PE. These results suggest a clinically relevant role of endothelial mechanotransduction in the pathogenesis of AHF and further highlights the concept of active barrier failure in AHF. Therapies targetting the prevention or reversal of endothelial hyperpermeability may be a novel therapeutic strategy in AHF.


Assuntos
Insuficiência Cardíaca/enzimologia , Hipertensão Pulmonar/enzimologia , Mecanotransdução Celular , Óxido Nítrico Sintase/genética , Edema Pulmonar/enzimologia , Animais , Biopterina/administração & dosagem , Biopterina/análogos & derivados , Pressão Sanguínea/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Ácido Fólico/administração & dosagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Norepinefrina/efeitos adversos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Tirosina/administração & dosagem , Tirosina/análogos & derivados
9.
Br J Nutr ; 120(12): 1321-1331, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30375295

RESUMO

Ca2+-sensing receptor (CaSR) represents a potential therapeutic target for inflammatory bowel diseases and strongly prefers aromatic amino acid ligands. We investigated the regulatory effects of dietary supplementation with aromatic amino acids - tryptophan, phenylalanine and tyrosine (TPT) - on the CaSR signalling pathway and intestinal inflammatory response. The in vivo study was conducted with weanling piglets using a 2 × 2 factorial arrangement in a randomised complete block design. Piglets were fed a basal diet or a basal diet supplemented with TPT and with or without inflammatory challenge. The in vitro study was performed in porcine intestinal epithelial cell line to investigate the effects of TPT on inflammatory response using NPS-2143 to inhibit CaSR. Dietary supplementation of TPT alleviated histopathological injury and decreased myeloperoxidase activity in intestine challenged with lipopolysaccharide. Dietary supplementation of TPT decreased serum concentration of pro-inflammatory cytokines (IL-1ß, IL-6, IL-8, IL-12, granulocyte-macrophage colony-stimulating factor, TNF-α), as well as the mRNA abundances of pro-inflammatory cytokines in intestine but enhanced anti-inflammatory cytokines IL-4 and transforming growth factor-ß mRNA levels compared with pigs fed control diet and infected by lipopolysaccharide. Supplementation of TPT increased CaSR and phospholipase Cß2 protein levels, but decreased inhibitor of NF-κB kinase α/ß and inhibitor of NF-κB (IκB) protein levels in the lipopolysaccharide-challenged piglets. When the CaSR signalling pathway was blocked by NPS-2143, supplementation of TPT decreased the CaSR protein level, but enhanced phosphorylated NF-κB and IκB levels in IPEC-J2 cells. To conclude, supplementation of aromatic amino acids alleviated intestinal inflammation as mediated through the CaSR signalling pathway.


Assuntos
Aminoácidos Aromáticos/administração & dosagem , Inflamação/metabolismo , Intestinos/patologia , Receptores de Detecção de Cálcio/metabolismo , Animais , Colo/metabolismo , Citocinas/sangue , Dieta , Suplementos Nutricionais , Células Epiteliais/metabolismo , Feminino , Quinase I-kappa B/metabolismo , Jejuno/metabolismo , Lipopolissacarídeos , NF-kappa B/metabolismo , Peroxidase/metabolismo , Fenilalanina/administração & dosagem , Fosforilação , RNA Mensageiro/metabolismo , Distribuição Aleatória , Transdução de Sinais , Sus scrofa , Suínos , Triptofano/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/administração & dosagem
10.
J Exp Clin Cancer Res ; 37(1): 234, 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30241549

RESUMO

BACKGROUND: The L-type amino acid transporter 1 (LAT1/SLC7A5) transports essential amino acids across the plasma membrane. While LAT1 is overexpressed in a variety of human neoplasms, its expression and its role in thyroid cancer is currently unknown. Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy for which no effective therapy exists. The purpose of this study was to explore whether the inhibition of LAT1 in ATC would affect tumor growth both in vitro and in vivo. METHODS: LAT1 was pharmacologically blocked by JPH203 in human ATC and papillary thyroid cancer (PTC) cell lines. The effects on proliferation and mTORC1 activity were addressed in vitro. A genetically engineered mouse model of ATC was used to address the effect of blocking LAT1 on tumor growth in vivo. SLC7A5 transcription was measured in patient-derived ATC samples to address the clinical relevance of the findings. RESULTS: LAT1 block by JPH203 reduced proliferation and mTORC1 signaling in human thyroid cancer cell lines. SLC7A5 transcription was upregulated in ATC tissues derived from a genetically engineered mouse model and in ATC samples recovered from patients. JPH203 treatment induced thyroid tumor growth arrest in vivo in a fully immunocompetent mouse model of thyroid cancer. Additionally, analysis of publicly available datasets of thyroid carcinomas revealed that high LAT1 expression is associated with potentially untreatable PTC presenting reduced NIS/SLC5A5 transcription and with ATC. CONCLUSIONS: These preclinical results show that LAT1 inhibition is a novel therapeutic approach in the context of thyroid cancers, and more interestingly in untreatable thyroid cancers.


Assuntos
Proliferação de Células/efeitos dos fármacos , Transportador 1 de Aminoácidos Neutros Grandes/genética , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Animais , Animais Geneticamente Modificados/genética , Apoptose/efeitos dos fármacos , Benzoxazóis/administração & dosagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/efeitos dos fármacos , Camundongos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais/efeitos dos fármacos , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/patologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/patologia , Tirosina/administração & dosagem , Tirosina/análogos & derivados
11.
Sci Rep ; 8(1): 11490, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30065346

RESUMO

L-tyrosine supplementation may provide benefit to nemaline myopathy (NM) patients, however previous studies are inconclusive, with no elevation of L-tyrosine levels in blood or tissue reported. We evaluated the ability of L-tyrosine treatments to improve skeletal muscle function in all three published animal models of NM caused by dominant skeletal muscle α-actin (ACTA1) mutations. Highest safe L-tyrosine concentrations were determined for dosing water and feed of wildtype zebrafish and mice respectively. NM TgACTA1D286G-eGFP zebrafish treated with 10 µM L-tyrosine from 24 hours to 6 days post fertilization displayed no improvement in swimming distance. NM TgACTA1D286G mice consuming 2% L-tyrosine supplemented feed from preconception had significant elevations in free L-tyrosine levels in sera (57%) and quadriceps muscle (45%) when examined at 6-7 weeks old. However indicators of skeletal muscle integrity (voluntary exercise, bodyweight, rotarod performance) were not improved. Additionally no benefit on the mechanical properties, energy metabolism, or atrophy of skeletal muscles of 6-7 month old TgACTA1D286G and KIActa1H40Y mice eventuated from consuming a 2% L-tyrosine supplemented diet for 4 weeks. Therefore this study yields important information on aspects of the clinical utility of L-tyrosine for ACTA1 NM.


Assuntos
Actinas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Miopatias da Nemalina/tratamento farmacológico , Miopatias da Nemalina/metabolismo , Tirosina/administração & dosagem , Peixe-Zebra/metabolismo , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/efeitos dos fármacos
12.
Br Poult Sci ; 59(6): 646-653, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30113210

RESUMO

1. The objective of this study was to evaluate the effect of ferric tyrosine on the reduction of Campylobacter spp. and zootechnical performance in broilers exposed to Campylobacter spp. using a natural challenge model to simulate commercial conditions. Additionally, the minimum inhibitory concentrations (MICs) of ferric tyrosine against common enteropathogens were evaluated. 2. At the start of the trial, 840 healthy male 1-d-old birds (Ross 308) were randomly allocated to 6 replicate pens of 35 birds each and fed diets containing different concentrations of ferric tyrosine (0, 0.02, 0.05 and 0.2 g/kg) in mash form for 42 d. 3. Broilers fed diets containing ferric tyrosine showed significantly higher body weight at d 42 and weight gain compared to the control group. However, birds fed ferric tyrosine ate significantly more than the control birds so significant improvements in feed conversion rate were not observed. 4. Microbiological analyses of caecal samples collected on d 42 of the study showed, per gram of sample, 2-3 log10 reduction in Campylobacter spp. and 1 log10 reduction in Escherichia coli in the groups fed diets containing ferric tyrosine compared to the control. 5. The MICs of ferric tyrosine was >400 mg/l for C. jejuni and >200 mg/l for E. coli and Salmonella enterica, indicating that ferric tyrosine did not exert antimicrobial activity. 6. The results showed that birds fed ferric tyrosine grew faster and consumed more feed compared to the control group, indicating potential benefits of faster time to reach slaughter weight with no significant reduction on feed efficiency. Moreover, ferric tyrosine significantly reduced caecal Campylobacter spp. and E. coli indicating potential as a non-antibiotic feed additive to lower the risk of infections transmitted through the food chain.


Assuntos
Campylobacter/efeitos dos fármacos , Ceco/microbiologia , Galinhas/crescimento & desenvolvimento , Galinhas/microbiologia , Compostos Férricos/administração & dosagem , Tirosina/administração & dosagem , Ração Animal , Animais , Carga Bacteriana/efeitos dos fármacos , Campylobacter/isolamento & purificação , Campylobacter jejuni/efeitos dos fármacos , Suplementos Nutricionais , Escherichia coli/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Mycoplasma pneumoniae , Salmonella/efeitos dos fármacos
13.
eNeuro ; 5(2)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30094335

RESUMO

The aging brain is characterized by altered dopamine signaling. The amino acid tyrosine, a catecholamine precursor, is known to improve cognitive performance in young adults, especially during high environmental demands. Tyrosine administration might also affect catecholamine transmission in the aging brain, thereby improving cognitive functioning. In healthy older adults, impairments have been demonstrated in two forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipatory response slowing) under high information load. However, no study has directly compared the effects of a catecholamine precursor on reactive and load-dependent proactive inhibition. In this study we explored the effects of tyrosine on reactive and proactive response inhibition and signal in dopaminergically innervated fronto-striatal regions. Depending on age, tyrosine might lead to beneficial or detrimental neurocognitive effects. We aimed to address these hypotheses in 24 healthy older human adults (aged 61-72 years) using fMRI in a double blind, counterbalanced, placebo-controlled, within-subject design. Across the group, tyrosine did not alter reactive or proactive inhibition behaviorally but did increase fronto-parietal proactive inhibition-related activation. When taking age into account, tyrosine affected proactive inhibition both behaviorally and neurally. Specifically, increasing age was associated with a greater detrimental effect of tyrosine compared with placebo on proactive slowing. Moreover, with increasing age, tyrosine decreased fronto-striatal and parietal proactive signal, which correlated positively with tyrosine's effects on proactive slowing. Concluding, tyrosine negatively affected proactive response slowing and associated fronto-striatal activation in an age-dependent manner, highlighting the importance of catecholamines, perhaps particularly dopamine, for proactive response inhibition in older adults.


Assuntos
Envelhecimento/efeitos dos fármacos , Função Executiva/efeitos dos fármacos , Lobo Parietal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Inibição Proativa , Putamen/efeitos dos fármacos , Inibição Reativa , Tirosina/farmacologia , Idoso , Antecipação Psicológica/fisiologia , Método Duplo-Cego , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Pessoa de Meia-Idade , Lobo Parietal/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Desempenho Psicomotor/efeitos dos fármacos , Putamen/diagnóstico por imagem , Tirosina/administração & dosagem , Tirosina/efeitos adversos
14.
Wei Sheng Yan Jiu ; 47(3): 345-351, 2018 May.
Artigo em Chinês | MEDLINE | ID: mdl-30081997

RESUMO

OBJECTIVE: To study the effects of oxidized tyrosine products and dityrosine on the myocardial injury and inflammatory response in 10-week-gavaged mice. METHODS: A total of 30 female Kunming mice were assigned to three groups: gavagedwith saline( Con), oxidized tyrosine products( O-Tyr) and dityrosine( Dityr) for 320µg/kg BW for 10 weeks. Levels of oxidized protein products( DT, AOPPs, 3-NT) and lipid peroxidation products( MDA), oxidative stress( T-AOC and GSH/GSSG), markers of myocardium injury( CK, CK-MB, cTnI and Ca~(2+)-ATPase), markers of inflammatory factor( CRP and TNF-α) were investigated and the genes related to inflammatory response were detected by Real-time quantitative( PCR). RESULTS: 10 weeks of gavage experiments enhanced the levels of dityrosine( DT), advanced oxidation protein products( AOPPs), 3-nitrotyrosine( 3-NT), and malondialdehyde( MDA), and decreased total antioxidant capacity( T-AOC) and the ratio of reduced glutathione to oxidized glutathione( GSH/GSSG) in mice plasma and myocardium. Besides, O-Tyr and Dityr increased the levels of creatine kinase( CK), creatine kinase isoenzymes( CK-MB), cardiac troponin I( cTnI) in plasma anddecreased the activities of Ca~(2+)-ATPase in myocardium. O-Tyr and Dityr increased the levels of C-reactive protein( CRP) and tumour necrosis factor α( TNF-α) in plasma. The gene expression of inflammatory response were up-regulated. CONCLUSION: O-Tyr and Dityr increase the accumulation of myocardial protein oxidation and lipid peroxidation products and induce oxidative damage to myocardium. O-Tyr and Dityr may cause myocardial tissue injury and inflammatory response. Dityrosine, as the main component of tyrosine oxidative products, may play a major role in the process of oxidized tyrosine products causing myocardial injury in mice.


Assuntos
Traumatismos Cardíacos/induzido quimicamente , Coração/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tirosina/análogos & derivados , Animais , Feminino , Malondialdeído , Camundongos , Oxirredução/efeitos dos fármacos , Tirosina/administração & dosagem
15.
Theranostics ; 8(14): 3991-4002, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30083276

RESUMO

The extent of surgical resection is significantly correlated with outcome in glioma; however, current intraoperative navigational tools are useful only in a subset of patients. We show here that a new optical intraoperative technique, Cerenkov luminescence imaging (CLI) following intravenous injection of O­(2-[18F]fluoroethyl)-L-tyrosine (FET), can be used to accurately delineate glioma margins, performing better than the current standard of fluorescence imaging with 5-aminolevulinic acid (5-ALA). Methods: Rats implanted orthotopically with U87, F98 and C6 glioblastoma cells were injected with FET and 5-aminolevulinic acid (5-ALA). Positive and negative tumor regions on histopathology were compared with CL and fluorescence images. The capability of FET CLI and 5-ALA fluorescence imaging to detect tumor was assessed using receptor operator characteristic curves and optimal thresholds (CLIOptROC and 5-ALAOptROC) separating tumor from healthy brain tissue were determined. These thresholds were used to guide prospective tumor resections, where the presence of tumor cells in the resected material and in the remaining brain were assessed by Ki-67 staining. Results: FET CLI signal was correlated with signal in preoperative PET images (y = 1.06x - 0.01; p < 0.0001) and with expression of the amino acid transporter SLC7A5 (LAT1). FET CLI (AUC = 97%) discriminated between glioblastoma and normal brain in human and rat orthografts more accurately than 5-ALA fluorescence (AUC = 91%), with a sensitivity >92% and specificity >91%, and resulted in a more complete tumor resection. Conclusion: FET CLI can be used to accurately delineate glioblastoma tumor margins, performing better than the current standard of fluorescence imaging following 5-ALA administration, and is therefore a promising technique for clinical translation.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Medições Luminescentes/métodos , Cirurgia Assistida por Computador/métodos , Tirosina/análogos & derivados , Administração Intravenosa , Animais , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Glioma/patologia , Xenoenxertos , Histocitoquímica , Transplante de Neoplasias , Ratos , Resultado do Tratamento , Tirosina/administração & dosagem
16.
Nutrients ; 10(7)2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30011836

RESUMO

Background: Previous epidemiological and clinical studies have shown that dairy products have beneficial effects on cognitive decline and dementia. Enzymatic digestion of whey protein produces a whey peptide rich in tryptophan-tyrosine-related peptides which improve cognitive performance in mice. We evaluated the effects of whey peptides on cognitive functions in healthy adults in a randomized, double-blind, placebo-controlled design. Methods: 101 healthy adults (45 to 64 years), with a self-awareness of cognitive decline received either whey peptide or placebo supplements for 12 weeks. Changes in cognitive function were assessed using neuropsychological tests at 6 and 12 weeks after the start of supplementation. Results: Verbal fluency test (VFT) score changes tended to be higher in the whey peptide group compared with the placebo at 12 weeks. Subgroup analysis classified by the degree of subjective fatigue showed that changes in the VFT as well as the Stroop and subjective memory function tests between baseline and 6 weeks of intervention were significantly better in subjects with high-level fatigue from the whey peptide group as compared to the placebo group. CONCLUSIONS: Intake of whey peptide might improve cognitive function in healthy middle- and older-aged adults with high subjective fatigue levels. Further studies will elucidate the relationship among cognitive improvement, whey peptides, and psychological fatigue.


Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/dietoterapia , Suplementos Nutricionais , Fadiga Mental/dietoterapia , Triptofano/administração & dosagem , Tirosina/administração & dosagem , Proteínas do Soro do Leite/administração & dosagem , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Japão , Masculino , Memória/efeitos dos fármacos , Fadiga Mental/diagnóstico , Fadiga Mental/psicologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Tempo , Resultado do Tratamento , Comportamento Verbal/efeitos dos fármacos
17.
Medicine (Baltimore) ; 97(21): e10850, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29794782

RESUMO

The aim of this study was to compare the efficacy and safety of 2 approaches for intra-coronary administration of tirofiban (aspiration catheter versus guiding catheter) in patients over 60 years of age undergoing percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). It has been suggested that the administration of tirofiban by intra-coronary injection could promote drug absorption in the diseased region and enhance the inhibition of platelet aggregation, decreasing bleeding rates, but little is known about the comparative efficiency and safety of using guiding catheter versus aspiration catheter for delivery.Eighty-nine patients over 60 years of age with STEMI undergoing PCI were randomly divided into 2 groups according to the injection route for intracoronary administration of tirofiban [guiding catheter (n = 41) and aspiration catheter (n = 48)]. Baseline features, epicardial and myocardial perfusion, major adverse cardiac and cerebrovascular events (MACCEs), and bleeding rate were compared.No differences in age, gender, and history of hypertension, hypercholesterolemia, diabetes, and so on were observed (P > .05). The patients in the aspiration catheter group generally had a higher incidence of cerebral vascular disease. Compared with those in the guiding catheter group, patients in the aspiration catheter group obtained more favorable myocardial perfusion (P < .05). In-hospital and at 3-month and 6-month follow-ups, the MACCE rate and frequency of bleeding events were similar between the 2 groups (P > .05).Intra-coronary delivery of tirofiban through aspiration catheter led to better myocardial perfusion in STEMI patients over 60 years of age undergoing PCI compared with intra-coronary injection of tirofiban through guiding catheter. The 2 delivery routes were associated with similar rates of MACCEs and bleeding events.


Assuntos
Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Tirosina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Angiografia , Angioplastia Coronária com Balão/métodos , Cateteres/estatística & dados numéricos , Cateteres/tendências , Vias de Administração de Medicamentos , Feminino , Hemorragia/tratamento farmacológico , Hemorragia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Imagem de Perfusão do Miocárdio/instrumentação , Miocárdio/metabolismo , Inibidores da Agregação de Plaquetas/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/mortalidade , Tirofibana , Resultado do Tratamento , Tirosina/administração & dosagem , Tirosina/uso terapêutico
18.
World Neurosurg ; 114: e1211-e1224, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29625311

RESUMO

BACKGROUND: Distinguishing radiation necrosis from brain tumor recurrence remains challenging. We performed a meta-analysis to assess the diagnostic accuracy of 2 different amino acid tracers used in positron emission tomography/computed tomography scans: 18F-FDOPA (6-[18F]-fluoro-L-3,4-dihydroxyphenylalanine) and 18F-FET (O-(2-18F-fluoroethyl)-L-tyrosine). METHODS: We searched for studies in 3 databases: PubMed, Embase, and Chinese Biomedical databases. The data were extracted from eligible studies and then processed with heterogeneity test, threshold effect test, and calculations of sensitivity, specificity, and area under the summary receiver operating characteristic curve. Meta-regression and subgroup analyses were performed to explore the source of heterogeneity. RESULTS: A total of 48 studies (18F-FDOPA, n = 21; 18F-FET, n = 27) were included. Quantitative synthesis determined pooled weight values in the 18F-FDOPA and 18F-FET groups: sensitivity, 0.85 versus 0.82; specificity, 0.77 versus 0.80; diagnostic odds ratio, 21.7 versus 23.03; area under the curve (AUC) values, 0.8771 versus 0.8976 (P = 0.46). Moreover, the type of tumor was identified as the possible source of the significant heterogeneity (I2 = 52%; P = 0.003) found in the 18F-FDOPA group. In meta-regression and subgroup analyses, 18F-FDOPA showed better diagnostic accuracy in patients with glioma compared with patients with brain metastases (AUC values, 0.9691 vs. 0.837; P < 0.01). 18F-FDOPA also showed a significant advantage in the diagnosis of glioma recurrence compared with 18F-FET (AUC values, 0.9691 vs. 0.9124; P = 0.015). CONCLUSIONS: Both 18F-FDOPA and 18F-FET exhibit moderate overall accuracy in diagnosing brain tumor recurrence from radiation necrosis. However, 18F-FDOPA is more adept at diagnosing glioma recurrence compared with brain metastases, and it is more effective than 18F-FET in diagnosing glioma recurrence.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Di-Hidroxifenilalanina/análogos & derivados , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/normas , Lesões por Radiação/diagnóstico por imagem , Tirosina/análogos & derivados , Neoplasias Encefálicas/epidemiologia , Diagnóstico Diferencial , Di-Hidroxifenilalanina/administração & dosagem , Di-Hidroxifenilalanina/normas , Humanos , Recidiva Local de Neoplasia/epidemiologia , Estudos Prospectivos , Lesões por Radiação/epidemiologia , Estudos Retrospectivos , Tirosina/administração & dosagem , Tirosina/normas
19.
Antiviral Res ; 153: 1-9, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29510156

RESUMO

Human adenoviruses (AdV) cause generally mild infections of the respiratory and GI tracts as well as some other tissues. However, AdV can cause serious infection in severely immunosuppressed individuals, especially pediatric patients undergoing allogeneic hematopoietic stem cell transplantation, where mortality rates are up to 80% with disseminated disease. Despite the seriousness of AdV disease, there are no drugs approved specifically to treat AdV infections. We report here that USC-087, an N-alkyl tyrosinamide phosphonate ester prodrug of HPMPA, the adenine analog of cidofovir, is highly effective against multiple AdV types in cell culture. USC-087 is also effective against AdV-C6 in our immunosuppressed permissive Syrian hamster model. In this model, hamsters are immunosuppressed by treatment with high dose cyclophosphamide. Injection of AdV-C6 (or AdV-C5) intravenously leads to a disseminated infection that resembles the disease seen in humans, including death. We have tested the efficacy of orally-administered USC-087 against the median lethal dose of intravenously administered AdV-C6. USC-087 completely prevented or significantly decreased mortality when administered up to 4 days post challenge. USC-087 also prevented or significantly decreased liver damage caused by AdV-C6 infection, and suppressed virus replication even when administered 4 days post challenge. These results imply that USC-087 is a promising candidate for drug development against HAdV infections.


Assuntos
Adenina/análogos & derivados , Infecções por Adenovirus Humanos/tratamento farmacológico , Adenovírus Humanos/efeitos dos fármacos , Antivirais/administração & dosagem , Organofosfonatos/administração & dosagem , Pró-Fármacos/administração & dosagem , Tirosina/análogos & derivados , Adenina/administração & dosagem , Administração Oral , Animais , Modelos Animais de Doenças , Hospedeiro Imunocomprometido , Fígado/patologia , Mesocricetus , Análise de Sobrevida , Resultado do Tratamento , Tirosina/administração & dosagem
20.
Neurosurgery ; 82(1): 76-84, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28419294

RESUMO

BACKGROUND: There have been some reports on the use of intra-arterial tirofiban in ruptured intracranial aneurysms, but few studies have reported on the use of 24 h of intravenous tirofiban infusion in patients with subarachnoid hemorrhage. OBJECTIVE: To present our experience with intravenous tirofiban infusion, in the form of a monotherapy as well as in addition to intra-arterial tirofiban, as a prophylactic, and as a rescue management for thrombus in patients who have undergone embolization with coils for ruptured intracranial aneurysms. METHODS: Between December 2008 and January 2015, we retrospectively reviewed 249 ruptured intracranial aneurysms that were treated with coiling at our institutions. A total of 28 patients harboring 28 ruptured and 3 unruptured intracranial aneurysms underwent intravenous tirofiban infusion during or after coil embolization of an aneurysm. Intra-arterial infusion of tirofiban via a microcatheter was also performed in 26 patients. RESULTS: Thromboembolic formation during the procedure was detected in 25 cases. Intra-arterial tirofiban dissolved the thromboembolus under angiographic control after 10 or more minutes in 19 (76%) of 25 patients. Two intracranial hemorrhagic complications (increase in the extent of hematoma) occurred during the follow-up period. Two cases of other complications occurred: hematuria and perioral bleeding. CONCLUSION: Intravenous tirofiban, as a monotherapy or in addition to intra-arterial tirofiban for thrombotic complications, seems to be useful as a treatment for acute aneurysm. However, alternatives to tirofiban should be considered if an associated hematoma is discovered before a patient receives a tirofiban infusion.


Assuntos
Aneurisma Roto/tratamento farmacológico , Embolização Terapêutica/métodos , Fibrinolíticos/administração & dosagem , Infusões Intra-Arteriais/métodos , Aneurisma Intracraniano/tratamento farmacológico , Tirosina/análogos & derivados , Adulto , Idoso , Aneurisma Roto/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Aneurisma Intracraniano/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tirofibana , Resultado do Tratamento , Tirosina/administração & dosagem
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