RESUMO
The mainstay of phenylketonuria treatment is a low protein diet, supplemented with phenylalanine (Phe)-free protein substitutes and micronutrients. Adhering to this diet is challenging, and even patients with good metabolic control who follow the dietary prescriptions in everyday life ignore the recommendations occasionally. The present study explores the ability of slow-release large neutral amino acids (srLNAAs) to prevent Phe increase following a Phe dietary load. Fourteen phenylketonuric patients aged ≥13 years were enrolled in a 6-week protocol. Oral acute Phe loads of 250 and 500 mg were added to the evening meal together with srLNAAs (0.5 gr/kg). Phe and tyrosine were dosed before dinner, 2h-after dinner, and after the overnight fast. After oral Phe loads, mean plasma Phe remained stable and below 600 µmol/L. No Phe peaks were registered. Tyrosine levels significantly increased, and Phe/Tyrosine ratio decreased. No adverse events were registered. In conclusion, a single oral administration of srLNAAs at the dose of 0.5 gr/kg is effective in maintaining stable plasma Phe during acute oral loads with Phe-containing food and may be added to the dietetic scheme in situations in which patients with generally good adherence to diet foresee a higher than prescribed Phe intake due to their commitments.
Assuntos
Aminoácidos Neutros/administração & dosagem , Suplementos Nutricionais , Fenilalanina/administração & dosagem , Fenilcetonúrias/tratamento farmacológico , Adolescente , Adulto , Aminoácidos/administração & dosagem , Aminoácidos Neutros/sangue , Aminoácidos Neutros/uso terapêutico , Dieta , Feminino , Humanos , Itália , Masculino , Micronutrientes/uso terapêutico , Fenilalanina/sangue , Fenilalanina/uso terapêutico , Fenilcetonúrias/sangue , Tirosina/sangue , Tirosina/uso terapêutico , Adulto JovemRESUMO
Circulating tryptophan/large neutral amino acids (tryptophan/LNAA) ratio, an indicator of brain serotonin levels, may be important in appetite regulation, together with gastrointestinal (gastric emptying, plasma cholecystokinin) mechanisms. We have compared effects of intragastric tryptophan ('Trp') on the plasma tryptophan/LNAA ratio in lean and obese men, and the associations of the tryptophan/LNAA ratio, gastric emptying and CCK concentrations with energy intake. Lean and obese male participants (n = 16 each) received 3 g Trp or volume-matched control intragastrically, 15 min before a mixed-nutrient drink (300 mL, 400 kcal) (t = 0 min) in randomised, double-blind fashion. Plasma amino acid (for calculation of the plasma tryptophan/LNAA ratio) and CCK concentrations were measured from t = -20-60 min. Gastric emptying was assessed from t = 0-60 min, and ad-libitum energy intake from a standardised buffet-style meal from t = 60-90 min. The increase in the plasma tryptophan/LNAA ratio was less in obese, than lean, participants (P < 0.05), and greater in lean participants who reduced their energy intake (by >0 kcal) after Trp compared with those who did not (by ≤0 kcal) (P < 0.05). Moreover, in participants who reduced their energy intake, the ratio was lower in obese, than in lean (P < 0.05). There was a trend for an inverse correlation between energy intake with the plasma tryptophan/LNAA ratio in lean (r = -0.4, P = 0.08), but not in obese, participants. There was no significant difference in gastric emptying or CCK between participants who reduced their energy intake and those who did not. In conclusion, the plasma tryptophan/LNAA ratio appears to be a determinant of the suppression of energy intake in response to tryptophan in normal-weight people, but not in those with obesity. The role of the plasma tryptophan/LNAA ratio to regulate energy intake, and potential changes in obesity, warrant evaluation in prospective studies.
Assuntos
Aminoácidos Neutros/sangue , Ingestão de Energia/efeitos dos fármacos , Obesidade/sangue , Triptofano/administração & dosagem , Triptofano/sangue , Adulto , Aminoácidos/sangue , Regulação do Apetite/efeitos dos fármacos , Índice de Massa Corporal , Colecistocinina/sangue , Método Duplo-Cego , Esvaziamento Gástrico/efeitos dos fármacos , Humanos , Peso Corporal Ideal , Infusões Parenterais , Masculino , Refeições/efeitos dos fármacos , Obesidade/tratamento farmacológicoRESUMO
Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in the tyrosine degradation pathway. Neurocognitive deficiencies have been described in TT1 patients, that have, among others, been related to changes in plasma large neutral amino acids (LNAA) that could result in changes in brain LNAA and neurotransmitter concentrations. Therefore, this project aimed to investigate plasma and brain LNAA, brain neurotransmitter concentrations and behavior in C57 Bl/6 fumarylacetoacetate hydrolase deficient (FAH-/-) mice treated with 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and/or diet and wild-type mice. Plasma and brain tyrosine concentrations were clearly increased in all NTBC treated animals, even with diet (p < 0.001). Plasma and brain phenylalanine concentrations tended to be lower in all FAH-/- mice. Other brain LNAA, were often slightly lower in NTBC treated FAH-/- mice. Brain neurotransmitter concentrations were usually within a normal range, although serotonin was negatively correlated with brain tyrosine concentrations (p < 0.001). No clear behavioral differences between the different groups of mice could be found. To conclude, this is the first study measuring plasma and brain biochemistry in FAH-/- mice. Clear changes in plasma and brain LNAA have been shown. Further research should be done to relate the biochemical changes to neurocognitive impairments in TT1 patients.
Assuntos
Aminoácidos Neutros/sangue , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Cicloexanonas/farmacologia , Dieta com Restrição de Proteínas , Inibidores Enzimáticos/farmacologia , Ácido Hidroxi-Indolacético/metabolismo , Nitrobenzoatos/farmacologia , Tirosinemias/terapia , Ração Animal , Animais , Biomarcadores/sangue , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Feminino , Hidrolases/deficiência , Hidrolases/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tirosinemias/sangue , Tirosinemias/fisiopatologia , Tirosinemias/psicologiaRESUMO
In vitro experiments have demonstrated that camel foregut-fluid has the capacity to metabolize indospicine, a natural toxin which causes hepatotoxicosis, but such metabolism is in competition with absorption and outflow of indospicine from the different segments of the digestive system. Six young camels were fed Indigofera spicata (337 µg indospicine/kg BW/day) for 32 days, at which time three camels were euthanized. The remaining camels were monitored for a further 100 days after cessation of this indospicine diet. In a retrospective investigation, relative levels of indospicine foregut-metabolism products were examined by UHPLC-MS/MS in plasma, collected during both accumulation and depletion stages of this experiment. The metabolite 2-aminopimelamic acid could be detected at low levels in almost all plasma samples, whereas 2-aminopimelic acid could not be detected. In the euthanized camels, 2-aminopimelamic acid could be found in all tissues except muscle, whereas 2-aminopimelic acid was only found in the kidney, pancreas, and liver tissues. The clearance rate for these metabolites was considerably greater than for indospicine, which was still present in plasma of the remaining camels 100 days after cessation of Indigofera consumption.
Assuntos
Sistema Digestório/metabolismo , Indigofera , Norleucina/análogos & derivados , Aminoácidos Neutros/sangue , Aminoácidos Neutros/metabolismo , Animais , Camelus , Contaminação de Alimentos , Norleucina/sangue , Norleucina/farmacocinética , Ácidos Pimélicos/sangue , Ácidos Pimélicos/metabolismo , Distribuição TecidualRESUMO
The neuropathological effects of phenylketonuria (PKU) stem from the inability of the body to metabolize excess phenylalanine (Phe), resulting in accumulation of Phe in the blood and brain. Since the kidney normally reabsorbs circulating amino acids with high efficiency, we hypothesized that preventing the renal uptake of Phe might provide a disposal pathway that could lower systemic Phe levels. SLC6A19 is a neutral amino acid transporter responsible for absorption of the majority of free Phe in the small intestine and reuptake of Phe by renal proximal tubule cells. Transgenic KO mice lacking SLC6A19 have elevated levels of Phe and other amino acids in their urine but are otherwise healthy. Here, we crossed the Pahenu2 mouse model of PKU with the Slc6a19-KO mouse. These mutant/KO mice exhibited abundant excretion of Phe in the urine and an approximately 70% decrease in plasma Phe levels. Importantly, brain Phe levels were decreased by 50%, and the levels of key neurotransmitters were increased in the mutant/KO mice. In addition, a deficit in spatial working memory and markers of neuropathology were corrected. Finally, treatment of Pahenu2 mice with Slc6a19 antisense oligonucleotides lowered Phe levels. The results suggest that inhibition of SLC6A19 may represent a novel approach for the treatment of PKU and related aminoacidopathies.
Assuntos
Sistemas de Transporte de Aminoácidos Neutros/análise , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Aminoácidos Neutros/metabolismo , Transporte Biológico/efeitos dos fármacos , Fenilcetonúrias/terapia , Aminas , Sistemas de Transporte de Aminoácidos Neutros/genética , Aminoácidos Neutros/sangue , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Doenças Genéticas Inatas/terapia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Masculino , Memória de Curto Prazo , Camundongos , Camundongos Knockout , Morfolinos/farmacologia , Oligonucleotídeos/farmacologia , Fenilalanina/sangue , Fenilalanina/metabolismo , Fenilcetonúrias/patologia , Reabsorção Renal/efeitos dos fármacosRESUMO
We reassessed data from a previous study on the transcerebral net exchange of large neutral amino acids (LNAAs) using a novel mathematical model of blood-brain barrier (BBB) transport. The study included twelve healthy volunteers who received a 4-h intravenous lipopolysaccharide (LPS) infusion (total dose: 0·3 ng/kg), a human experimental model of the systemic inflammatory response during the early stages of sepsis. Cerebral blood flow and arterial-to-jugular venous LNAA concentrations were measured prior to and after LPS, and the BBB transport and brain extracellular concentrations of LNAAs were calculated. The arterial concentration and unidirectional cerebral influx of phenylalanine increased after LPS. The BBB transport of tyrosine was unaffected, while its concentration in the brain extracellular fluid increased. These findings suggest that LPS infusion leads to an increased cerebral uptake of phenylalanine, which is then metabolized to tyrosine. This may reflect a neuroprotective mechanism that 'detoxifies' excess intracerebral phenylalanine in the clinical setting of sepsis.
Assuntos
Aminoácidos Neutros/sangue , Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar , Inflamação/sangue , Sepse/sangue , Adulto , Velocidade do Fluxo Sanguíneo , Barreira Hematoencefálica/fisiopatologia , Circulação Cerebrovascular , Humanos , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Infusões Intravenosas , Lipopolissacarídeos/administração & dosagem , Masculino , Modelos Biológicos , Fenilalanina/sangue , Sepse/induzido quimicamente , Sepse/fisiopatologia , Tirosina/sangue , Adulto JovemRESUMO
Phenylketonuria treatment mainly consists of a phenylalanine-restricted diet but still results in suboptimal neuropsychological outcome, which is at least partly based on cerebral monoamine deficiencies, while, after childhood, treatment compliance decreases. Supplementation of large neutral amino acids (LNAAs) was previously demonstrated in young phenylketonuria mice to target all three biochemical disturbances underlying brain dysfunction in phenylketonuria. However, both its potential in adult phenylketonuria and the comparison with the phenylalanine-restricted diet remain to be established. To this purpose, several LNAA supplements were compared with a severe phenylalanine-restricted diet with respect to brain monoamine and amino acid concentrations in adult C57Bl/6 Pah-enu2 mice. Adult phenylketonuria mice received a phenylalanine-restricted diet, unrestricted diet supplemented with several combinations of LNAAs or AIN-93M control diet for 6 weeks. In addition, adult wild-type mice on AIN-93M diet served as controls. The severe phenylalanine-restricted diet in adult phenylketonuria mice significantly reduced plasma and brain phenylalanine and restored brain monoamine concentrations, while brain concentrations of most nonphenylalanine LNAAs remained subnormal. Supplementation of eight LNAAs was similarly effective as the severe phenylalanine-restricted diet to restore brain monoamines, while brain and plasma phenylalanine concentrations remained markedly elevated. These results provide biochemical support for the effectiveness of the severe phenylalanine-restricted diet and showed the possibilities of LNAA supplementation being equally effective to restore brain monoamines in adult phenylketonuria mice. Therefore, LNAA supplementation is a promising alternative treatment to phenylalanine restriction in adult phenylketonuria patients to further optimize neuropsychological functioning.
Assuntos
Aminoácidos Neutros/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fenilcetonúrias/dietoterapia , Aminoácidos Neutros/sangue , Aminoácidos Neutros/metabolismo , Animais , Monoaminas Biogênicas/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fenilalanina , Fenilcetonúrias/metabolismoRESUMO
In rodents, transport of large neutral amino acids (LNAAs) across the blood brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier is mediated by high affinity carriers. Net brain LNAA levels are thought to be determined mainly by this competitive transport from plasma. Since the affinity for LNAA transport at the BBB in primates is considerably higher than in rodents, brain influx and by extension LNAA brain levels, should be even more dependent on competitive transport. Given that LNAA levels in CSF and brain interstitial fluid are usually similar, we analyzed serum and CSF of fasted subjects (n=24) undergoing spinal anesthesia and calculated brain influx and transporter occupancy using a conventional model of transport. Despite predicted near-full transporter saturation (99.7%), correlations between CSF levels and brain influx were modest, limited to tyrosine (r=0.60, p<0.002) and tryptophan (r=0.50, p<0.01) and comparable to correlations between CSF and serum levels. We also analyzed serum and CSF in (n=5) fasted vervet monkeys. Tyrosine and phenylalanine levels in CSF were positively correlated with those in serum, but correlations with calculated brain influx, which takes competition into account, were weaker or absent. We conclude that in primates i) baseline CSF LNAA levels do not confirm competitive transport, ii) brain LNAA levels should not be estimated on the basis of serum indices alone. This has implications for amino acid challenge studies and for neuropsychiatric disorders associated with dysregulated LNAA transport in which quantitative information about brain LNAA levels is needed.
Assuntos
Aminoácidos Neutros/sangue , Aminoácidos Neutros/líquido cefalorraquidiano , Barreira Hematoencefálica/metabolismo , Idoso , Animais , Transporte Biológico , Chlorocebus aethiops , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Tryptophan (Trp) plays an essential role in pig behavior and growth performances. However, little is known about Trp's effects on tight junction barrier and intestinal health in weaned pigs. In the present study, twenty-four (24) weaned pigs were randomly assigned to one of the three treatments with 8 piglets/treatments. The piglets were fed different amounts of L-tryptophan (L-Trp) as follows: 0.0%, 0.15, and 0.75%, respectively, named zero Trp (ZTS), low Trp (LTS), and high Trp (HTS), respectively. No significant differences were observed in average daily gain (ADG), average daily feed intake (ADFI), and gain: feed (G/F) ratio between the groups. After 21 days of the feeding trial, results showed that dietary Trp significantly increased (P < 0.05) crypt depth and significantly decreased (P < 0.05) villus height to crypt depth ratio (VH/CD) in the jejunum of pig fed HTS. In addition, pig fed HTS had higher (P < 0.05) serum diamine oxidase (DAO) and D-lactate. Furthermore, pig fed HTS significantly decreased mRNA expression of tight junction proteins occludin and ZO-1 but not claudin-1 in the jejunum. The number of intraepithelial lymphocytes and goblet cells were not significantly different (P > 0.05) between the groups. Collectively, these data suggest that dietary Trp supplementation at a certain level (0.75%) may negatively affect the small intestinal structure in weaned pig.
Assuntos
Suplementos Nutricionais , Intestinos/anatomia & histologia , Proteínas de Junções Íntimas/metabolismo , Triptofano/farmacologia , Desmame , Amina Oxidase (contendo Cobre)/sangue , Aminoácidos Neutros/sangue , Animais , Crescimento e Desenvolvimento/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sus scrofaRESUMO
It is commonly assumed that food can affect mood. One prevalent notion is that food containing tryptophan increases serotonin levels in the brain and alters neural processing in mood-regulating neurocircuits. However, tryptophan competes with other long-neutral-amino-acids (LNAA) for transport across the blood-brain-barrier, a limitation that can be mitigated by increasing the tryptophan/LNAA ratio. We therefore tested in a double-blind, placebo-controlled crossover study (N=32) whether a drink with a favourable tryptophan/LNAA ratio improves mood and modulates specific brain processes as assessed by functional magnetic resonance imaging (fMRI). We show that one serving of this drink increases the tryptophan/LNAA ratio in blood plasma, lifts mood in healthy young women and alters task-specific and resting-state processing in brain regions implicated in mood regulation. Specifically, Test-drink consumption reduced neural responses of the dorsal caudate nucleus during reward anticipation, increased neural responses in the dorsal cingulate cortex during fear processing, and increased ventromedial prefrontal-lateral prefrontal connectivity under resting-state conditions. Our results suggest that increasing tryptophan/LNAA ratios can lift mood by affecting mood-regulating neurocircuits.
Assuntos
Afeto/fisiologia , Encéfalo/fisiologia , Alimentos , Serotonina/administração & dosagem , Triptofano/administração & dosagem , Adolescente , Adulto , Afeto/efeitos dos fármacos , Aminoácidos Neutros/administração & dosagem , Aminoácidos Neutros/sangue , Encéfalo/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Serotonina/sangue , Inquéritos e Questionários , Triptofano/sangue , Adulto JovemRESUMO
Dietary components may affect brain function and influence behaviour by inducing the synthesis of neurotransmitters. The aim of the present study was to examine the influence of consumption of a whey protein-containing breakfast drink v. a carbohydrate drink v. control on subjective and physiological responses to mental workload in simulated work. In a randomised cross-over design, ten healthy subjects (seven women, median age 26 years, median BMI 23 kg/m(2)) participated in a single-blinded, placebo-controlled study. The subjects performed demanding work-like tasks after having a breakfast drink high in protein (HP) or high in carbohydrate (HC) or a control drink on separate sessions. Subjective states were assessed using the NASA Task Load Index (NASA-TLX), the Karolinska sleepiness scale (KSS) and the modified Profile of Mood States. Heart rate was recorded during task performance. The ratio of plasma tryptophan (Trp) to the sum of the other large neutral amino acids (LNAA) and salivary cortisol were also analysed. The plasma Trp:LNAA ratio was 30 % higher after the test drinks HP (median 0·13 (µmol/l)/(µmol/l)) and HC (median 0·13 (µmol/l)/(µmol/l)) than after the control drink (median 0·10 (µmol/l)/(µmol/l)). The increase in heart rate was smaller after the HP (median 2·7 beats/min) and HC (median 1·9 beats/min) drinks when compared with the control drink (median 7·2 beats/min) during task performance. Subjective sleepiness was reduced more after the HC drink (median KSS - 1·5) than after the control drink (median KSS - 0·5). There were no significant differences between the breakfast types in the NASA-TLX index, cortisol levels or task performance. We conclude that a breakfast drink high in whey protein or carbohydrates may improve coping with mental tasks in healthy subjects.
Assuntos
Aminoácidos/sangue , Desjejum/fisiologia , Carboidratos da Dieta/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Processos Mentais/fisiologia , Proteínas do Leite/farmacologia , Fases do Sono/efeitos dos fármacos , Adulto , Aminoácidos Neutros/sangue , Encéfalo/efeitos dos fármacos , Estudos Cross-Over , Dieta , Método Duplo-Cego , Feminino , Humanos , Hidrocortisona/metabolismo , Masculino , Valores de Referência , Saliva/metabolismo , Método Simples-Cego , Sono/efeitos dos fármacos , Triptofano/sangue , Proteínas do Soro do Leite , Carga de Trabalho , Adulto JovemRESUMO
The ingestion of large neutral amino acids (LNAA), notably tryptophan, tyrosine and the branched-chain amino acids (BCAA), modifies tryptophan and tyrosine uptake into brain and their conversion to serotonin and catecholamines, respectively. The particular effect reflects the competitive nature of the transporter for LNAA at the blood-brain barrier. For example, raising blood tryptophan or tyrosine levels raises their uptake into brain, while raising blood BCAA levels lowers tryptophan and tyrosine uptake; serotonin and catecholamine synthesis in brain parallel the tryptophan and tyrosine changes. By changing blood LNAA levels, the ingestion of particular proteins causes surprisingly large variations in brain tryptophan uptake and serotonin synthesis, with minimal effects on tyrosine uptake and catecholamine synthesis. Such variations elicit predictable effects on mood, cognition and hormone secretion (prolactin, cortisol). The ingestion of mixtures of LNAA, particularly BCAA, lowers brain tryptophan uptake and serotonin synthesis. Though argued to improve physical performance by reducing serotonin function, such effects are generally considered modest at best. However, BCAA ingestion also lowers tyrosine uptake, and dopamine synthesis in brain. Increasing dopamine function in brain improves performance, suggesting that BCAA may fail to increase performance because dopamine is reduced. Conceivably, BCAA administered with tyrosine could prevent the decline in dopamine, while still eliciting a drop in serotonin. Such an LNAA mixture might thus prove an effective enhancer of physical performance. The thoughtful development and application of dietary proteins and LNAA mixtures may thus produce treatments with predictable and useful functional effects.
Assuntos
Aminoácidos Neutros/química , Aminoácidos Neutros/metabolismo , Química Encefálica , Encéfalo/metabolismo , Suplementos Nutricionais , Aminoácidos Neutros/sangue , Aminoácidos Neutros/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Proteínas Alimentares/química , Proteínas Alimentares/metabolismo , Proteínas Alimentares/farmacologia , HumanosRESUMO
Genetic selection strategies towards increased prolificacy have resulted in more and more increased littler size and incidences of impaired fetal development. Low birth weight (LBW) piglets, with long-term alterations in structure, physiology and metabolism, have lower survival rates and poor growth performance. The aim of the study was to compare the plasma, liver and skeletal muscle contents of neutral amino acids (NAA) and the intestinal expression of NAA transporters between LBW and high birth weight (HBW) suckling Huanjiang mini-piglets. Forty piglets with either LBW or HBW (20 piglets per group) were sampled on day 0, 7, 14 and 21 of age to give 5 observations per day per group. The contents of NAA in plasma, liver and skeletal muscle were measured, and jejunal expression of transporters for NAA, including Slc6a19 (B(0)AT1) and Slc1a5 (ASCT2), were determined by real-time RT-PCR and Western Blot, respectively. Results showed that the suckling piglets with LBW had higher contents of Thr, Ser, Gly, Ala, Val, Met, Ile, Leu, Tyr, Phe and Pro in liver, and Gly in skeletal muscle, whereas lower contents of Met, Ser and Ala in plasma when compared with the HBW littermates. Consistent with the content differences in plasma NAA, the jejunal expression profiles of both Slc6a19 (B(0)AT1) and Slc1a5 (ASCT2) in the LBW piglets were lower in compared with the HBW littermates during the early suckling period. These findings suggested that intestinal dysfunction in the LBW piglets may be one of the reasons in altered physiology and metabolism states of other organs, which result in lower survival and growth rate.
Assuntos
Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos Neutros/metabolismo , Peso ao Nascer/fisiologia , Jejuno/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Aminoácidos Neutros/sangue , Animais , Suínos , Porco MiniaturaRESUMO
INTRODUCTION: Studying the amino acids in cerebrospinal fluid (CSF) is essential in the diagnosis of some neurological diseases and is an important aid in the diagnosis of others. No research has been published in the literature to prove the physiological relationship between the values of amino acids in CSF and plasma in the paediatric population. AIM: To define a set of ratios for amino acids in plasma and CSF in the paediatric population that can be used in daily clinical practice. PATIENTS AND METHODS: The aminograms in plasma and CSF of 105 patients with ages between 0 and 12 months were collected and analysed retrospectively. Aminograms with amino acid values that are considered to be normal according to the reference values of our laboratory were included in the sample. The quantitative analysis of amino acids was performed using high-resolution liquid chromatography and statistical analysis with the software application SPSS 19.0. RESULTS: The mean values, range and standard deviation of the amino acid concentrations in plasma and CSF, together with the CSF/plasma ratios, are reported. Significant correlations were found from 0.6 onwards between different neutral amino acids, above all in those with smaller molecular weights (Thr, Ser, Gly and Ala). CONCLUSIONS: The existence of significant correlations between the different neutral amino acids supports the idea that they share the same transporters in the blood-brain barrier. Standardising the amino acid ratios will make it possible to increase sensitivity in the detection of pathological values in plasma and CSF, to further knowledge of the pathophysiology of neurological diseases and perhaps to describe new aminoacidopathies.
Assuntos
Aminoácidos/sangue , Aminoácidos/líquido cefalorraquidiano , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Aminoácidos Neutros/sangue , Aminoácidos Neutros/síntese química , Barreira Hematoencefálica , Cromatografia Líquida de Alta Pressão , Feminino , Doença de Hartnup/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/líquido cefalorraquidiano , Peso Molecular , Malformações do Sistema Nervoso/sangue , Malformações do Sistema Nervoso/líquido cefalorraquidiano , Valores de Referência , Estudos Retrospectivos , Punção EspinalRESUMO
The goal of this investigation was to examine plasma amino acid (AA) levels in children with Autism Spectrum Disorders (ASD, N = 27) and neuro-typically developing controls (N = 20). We observed reduced plasma levels of most polar neutral AA and leucine in children with ASD. This AA profile conferred significant post hoc power for discriminating children with ASD from healthy children. Furthermore, statistical correlations suggested the lack of a typical decrease of glutamate and aspartate with age, and a non-typical increase of isoleucine and lysine with age in the ASD group. Findings from this limited prospective study warrant further examination of plasma AA levels in larger cross-sectional and longitudinal cohorts to adequately assess for relationships with developmental and clinical features of ASD.
Assuntos
Aminoácidos Neutros/sangue , Transtornos Globais do Desenvolvimento Infantil/sangue , Ácido Glutâmico/sangue , Leucina/sangue , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Reduced levels of serotonin (5-HT) within prefrontal cortex (PFC)-amygdala circuits have long been implicated in impulsive aggression. However, whether lowering 5-HT alters the dynamic interplay between the PFC and the amygdala has not been directly tested in humans. It is known that manipulating 5-HT via acute tryptophan depletion (ATD) causes variable effects on brain responses to a variety of emotional stimuli, but it remains unclear whether ATD affects functional connectivity in neural networks involved in processing social signals of aggression (e.g., angry faces). METHODS: Thirty healthy individuals were enrolled in a randomized, double-blind, placebo-controlled ATD study. On each treatment, brain responses to angry, sad, and neutral faces were measured with functional magnetic resonance imaging. Two methods (psycho-physiological-interaction in a general linear model and dynamic causal modeling) were used to assess the impact of ATD on the functional connectivity between PFC and amygdala. RESULTS: Data from 19 subjects were available for the final analyses. A whole-brain psycho-physiological-interaction in a general linear model showed that ATD significantly modulated the connectivity between the amygdala and two PFC regions (ventral anterior cingulate cortex and ventrolateral PFC) when processing angry vs. neutral and angry vs. sad but not sad vs. neutral faces. Dynamic causal modeling corroborated and extended these findings by showing that 5-HT depletion reduced the influence of processing angry vs. neutral faces on circuits within PFC and on PFC-amygdala pathways. CONCLUSIONS: We provide strong support for neurobiological accounts positing that 5-HT significantly influences PFC-amygdala circuits implicated in aggression and other affective behaviors.
Assuntos
Tonsila do Cerebelo/metabolismo , Ira/fisiologia , Expressão Facial , Córtex Pré-Frontal/metabolismo , Triptofano/deficiência , Adulto , Aminoácidos Neutros/sangue , Tonsila do Cerebelo/irrigação sanguínea , Análise de Variância , Mapeamento Encefálico , Método Duplo-Cego , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Oxigênio/sangue , Estimulação Luminosa , Córtex Pré-Frontal/irrigação sanguínea , Escalas de Graduação Psiquiátrica , Serotonina/metabolismo , Inquéritos e Questionários , Fatores de Tempo , Triptofano/sangue , Adulto JovemRESUMO
This study investigated the effects of high-dose large neutral amino acid (LNAA) supplementation on attenuating fatigue-induced decrements in exercise and motor skill performance in Australian Rules Football (ARF) players. Fifteen subelite ARF players participated in 3 testing sessions separated by 7 days. Players completed an initial control trial involving a reactive motor skills test (RMST) and a reactive agility test (RAT) carried out before and after fatiguing exercise. In the subsequent experimental trials, players ingested a serotonin-depleting or protein control (PC) LNAA mixture 3 h before testing, allocated in a double-blind randomized cross-over design. Blood samples were taken at presupplementation and pre- and postexercise for analysis of plasma amino acid, insulin, and metabolite concentrations. The effect of the LNAA was established as the difference in the change in the mean RMST and RAT test scores among the depleting, PC, and baseline (BL) trials. Mean overall repetition time of the RAT was moderately improved by -5.2% ± 3.4% (mean ± 90% confidence limits; effect size -0.45 ± 0.28) after ingestion of the serotonin-depleting mixture compared with the BL trial. Serotonin-depleting and PC supplements had a divergent effect on mean repetition time after fatiguing exercise in RMST: depleting serotonin elicited a small improvement (-3.0% ± 2.7%) in motor skill performance in contrast to a small decrement (2.4% ± 2.7%) after ingestion of the PC mixture, when compared to the BL. High-dose serotonin-"depleting" LNAA supplementation given 3 h prior to intermittent high-intensity exercise improved reactive motor skill and agility performance in ARF players.
Assuntos
Aminoácidos Neutros/uso terapêutico , Desempenho Atlético , Cognição , Tomada de Decisões , Suplementos Nutricionais , Fadiga/prevenção & controle , Destreza Motora , Adulto , Aminoácidos Neutros/administração & dosagem , Aminoácidos Neutros/sangue , Atletas/psicologia , Desempenho Atlético/psicologia , Austrália , Estudos Cross-Over , Proteínas Alimentares/administração & dosagem , Proteínas Alimentares/uso terapêutico , Método Duplo-Cego , Fadiga/sangue , Fadiga/fisiopatologia , Fadiga/psicologia , Futebol Americano , Humanos , Masculino , Resistência Física , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/sangue , Antagonistas da Serotonina/uso terapêutico , Triptofano/antagonistas & inibidores , Triptofano/sangue , Adulto JovemRESUMO
Serotonin synthesis critically depends on plasma levels of tryptophan (TRP). Earlier studies have shown that for mood and cognitive benefits to occur, the ratio between TRP and other large neutral amino acids (LNAA) has to be increased by approximately 40 %. The present study investigated the dose-dependent effects of a TRP-rich hydrolysed protein (egg-protein hydrolysate, EPH) on the plasma TRP:LNAA. Moreover, it was investigated whether EPH could increase TRP:LNAA in the presence of 2 g of milk protein (MP). In a randomised double-blind crossover design, plasma amino acids were measured every 30 min for 3·5 h after ingestion of a drink containing either three different doses of 4, 8 and 12 g EPH containing 270, 560 or 800 mg of TRP, respectively, the combination of 4 g EPH and 2 g MP (74 mg TRP), or 4 g MP (148 mg TRP) in twenty healthy subjects with a mean age of 52 years. All three EPH doses caused significant increases of TRP:LNAA above 40 % at 30, 60 and 90 min after consumption in a dose-dependent manner. Compared with the 4 g EPH, the increase in TRP:LNAA in the 4 g EPH with 2 g MP condition was significantly lower at 60 min (63 v. 44 %, P < 0·001) and did not differ significantly at 90 min (58 v. 53 %, P>0·05). The present study showed that a low dose of 4 g EPH with even the addition of 2 g MP was sufficient to increase the ratio of TRP:LNAA above 40 %. Thus, EPH offers a viable ingredient to increase TRP availability.
Assuntos
Encéfalo/metabolismo , Proteínas Alimentares/metabolismo , Ovos , Triptofano/metabolismo , Adulto , Aminoácidos Neutros/sangue , Animais , Estudos Cross-Over , Dieta , Método Duplo-Cego , Feminino , Humanos , Hidrólise , Masculino , Pessoa de Meia-Idade , Leite/metabolismo , Serotonina/metabolismo , Triptofano/farmacocinéticaRESUMO
Tryptophan is the precursor of kynurenine and kynurenic acid, an α-7 nicotinic acetylcholine receptor antagonist and a N-methyl-D-aspartate (NMDA) receptor antagonist, both of which have been implicated in schizophrenia (SCH), as well as of serotonin. Glucocorticoids can activate the tryptophan-kynurenine pathway and lower plasma tryptophan concentrations. Some previous studies have reported decreases in the plasma tryptophan concentration and the tryptophan/large neutral amino acid (LNAA) ratio, a measure reflecting the brain tryptophan concentration, in patients with SCH. However, the influence of plasma cortisol, which has been reported to be increased in patients with SCH, on plasma tryptophan levels has not been examined in prior studies. Thus, we examined plasma tryptophan concentrations, tryptophan/LNAA ratios, and their relationships with plasma cortisol concentrations in treatment-resistant SCH (TR-SCH) patients, in non-treatment-resistant SCH (NTR-SCH) patients, and in normal controls (NC). Plasma tryptophan concentrations were significantly lower in TR-SCH patients (n=74) than in NTR-SCH patients (n=85) and NC subjects (n=55). In addition, tryptophan/LNAA ratios were significantly lower in TR-SCH patients than in NC subjects. No difference was observed in either measure between NTR-SCH patients and NC subjects. Tryptophan/LNAA ratios and plasma tryptophan concentrations showed a significant negative correlation and a trend-level correlation, respectively, with plasma cortisol concentrations in TR-SCH patients, but not in NTR-SCH patients or in NC subjects. These results suggest the tryptophan-kynurenine pathway may be particularly relevant to TR-SCH and that this may be influenced by the activity of the hypothalamic-pituitary-adrenal axis.
Assuntos
Aminoácidos Neutros/sangue , Hidrocortisona/sangue , Esquizofrenia/sangue , Triptofano/sangue , Adulto , Análise de Variância , Antipsicóticos/uso terapêutico , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Radioimunoensaio , Esquizofrenia/tratamento farmacológico , Estatística como Assunto , Adulto JovemRESUMO
Analysis of trace amino acids (AA) in physiological fluids has received more attention, because the analysis of these compounds could provide fundamental and important information for medical, biological, and clinical researches. More accurate method for the determination of those compounds is highly desirable and valuable. In the present study, we developed a selective and sensitive method for trace AA determination in biological samples using 2-[2-(7H-dibenzo [a,g]carbazol-7-yl)-ethoxy] ethyl chloroformate (DBCEC) as labeling reagent by HPLC-FLD-MS/MS. Response surface methodology (RSM) was first employed to optimize the derivatization reaction between DBCEC and AA. Compared with traditional single-factor design, RSM was capable of lessening laborious, time and reagents consumption. The complete derivatization can be achieved within 6.3 min at room temperature. In conjunction with a gradient elution, a baseline resolution of 20 AA containing acidic, neutral, and basic AA was achieved on a reversed-phase Hypersil BDS C(18) column. This method showed excellent reproducibility and correlation coefficient, and offered the exciting detection limits of 0.19-1.17 fmol/µL. The developed method was successfully applied to determinate AA in human serum. The sensitive and prognostic index of serum AA for liver diseases has also been discussed.