A study on the correlation between serum branched-chain amino acid levels and disease severity in alcoholic liver cirrhosis patients / 中华临床营养杂志

Objective:To characterize the serum branched-chain amino acid (BCAA) and aromatic amino acid profiles in patients with alcoholic liver cirrhosis (ALC).Methods:Forty patients with ALC were recruited into the study group, twenty patients with hepatitis B-induced liver cirrhosis (HBV-LC) and ten healthy subjects (HC) were recruited as controls from August 2017 to August 2019 in Beijing YouAn Hospital, Capital Medical University. The serum concentrations of isoleucine, leucine, valine, phenylalanine and tyrosine were determined by ultra-fast liquid chromatography tandem quadrupole mass spectrometry (LC-MS/MS) and Fischer ratio was also calculated for the three groups.Results:The serum isoleucine concentration in the study group [(23.74±8.81) μmol/L] was significantly lower than that in the HBV-LC group [(30.85±8.70) μmol/L, P = 0.031] and the HC group [(61.51±23.06) μmol/L, P < 0.01]. The serum leucine concentration in the study group [(127.99±38.54) μmol/L] was significantly lower than that in the HC group [(153.70±11.88) μmol/L, P = 0.036] and was not significantly different compared with the HBV-LC group [(126.70±31.00) μmol/L, P = 0.890]. The concentration of valine in the study group was (39.56±10.51) μmol/L, which was significantly lower than that in the HBV-LC group [(124.71±45.00) μmol/L, P < 0.01] and the HC group [(164.23±37.16) μmol/L, P < 0.01]. The concentration of phenylalanine in the study group was (141.19±29.35) μmol/L, which was significantly higher than that in the HBV-LC group [(116.07±21.52) μmol/L, P = 0.001] and the HC group [(80.94±7.16) μmol/L, P < 0.001]. Fischer ratio in the study group was significantly lower (1.17±0.34) than that in the HBV-LC group (2.07±0.66, P < 0.01) and the HC group (3.36±0.50, P < 0.01). Along with liver function deteriorating from Child-Pugh grade A to C, the isoleucine, leucine and valine levels in the study group decreased gradually. Fischer ratios in subgroups with Child-Pugh grade C and B liver function were 1.01±0.22 and 1.15±0.32, respectively, significantly lower than that in Child-Pugh grade A subgroup (1.52±0.38, P = 0.001 and P = 0.008). Conclusions:Serum BCAA levels and Fischer ratio decreased significantly in ALC patients, which were more prominent in patients with Child-Pugh grade B and C liver function. In Child-Pugh grade A patients, the decline of Fischer ratio developed earlier than the decrease of serum albumin. Monitoring of BCAA level changes should be an important component in nutritional intervention in ALC patients.

Efeitos dos aminoácidos de cadeia ramificada na resposta inflamatória induzida por lipopolissacarídeo em macrófagos de linhagem celular RAW 264. 7 / Effects of branched-chain amino acids in the inflammatory response induced by lipopolysaccharide in a macrophage cell line RAW 264. 7

Os aminoácidos de cadeia ramificada (ACR) são considerados indispensáveis, pois não podem ser sintetizados endogenamente, sendo facilmente obtidos pela dieta. Entretanto, em determinadas condições clínicas, tanto a ingestão quando a absorção desses aminoácidos pode estar comprometida, levando ao estado hipercatabólico e prejudicando a função imune. O papel imunomodulador dos ACR tem sido relacionado com a melhora no balanço nitrogenado e o aumento da síntese e proliferação de células imunes, bem como, da síntese de mediadores inflamatórios. Entretanto, o mecanismo pelo qual os ACR exercem essas funções supracitadas ainda não é claro na literatura científica. Desta forma, esse trabalho teve como objetivo avaliar os efeitos da suplementação com ACR sobre os parâmetros inflamatórios e moleculares em macrófagos RAW 264.7 estimulados com lipopolissacarídeo (LPS). As culturas celulares foram distribuídas em cinco grupos: CTL - sem suplementação com ACR; LEU - suplementado com leucina (2 mmol/L); ISO - suplementado com isoleucina (2mmol/L); VAL - suplementado com valina (2 mmol/L) e LIV - suplementado com leucina (2 mmol/L), isoleucina (2 mmol/L) e valina (2 mmol/L). O estado inflamatório foi induzido pela adição de LPS (1 µg/mL) ao meio de cultura, seguindo quatro protocolos de tratamento: PT - pré-tratamento; TA - tratamento agudo; TC - tratamento crônico e TT - tratamento tardio. O ensaio de viabilidade celular foi realizado pelo teste MTT e a dosagem de óxido nítrico (NO) pela reação de Griess. As citocinas pró e anti-inflamatórias, e a prostaglandina E2 (PGE2) foram analisadas pelo método de ELISA. Para a avaliação dos parâmetros moleculares foi utilizado o método de western blotting. Houve aumento da viabilidade celular em todos os grupos suplementados em relação ao grupo controle no TA, no TC e no TT. Acerca da síntese de NO, a suplementação com ACR foi capaz de aumentar esse parâmetro em três dos quatro tratamentos propostos (PT, TA e TC). Em relação à síntese de citocinas pró e anti-inflamatórias, o PT e o TC foram mais eficazes em aumentar esse parâmetro em comparação aos outros tratamentos. Não houve diferença entre os grupos em relação à capacidade de síntese de PGE2 e à fosforilação de proteínas intracelulares. A partir dos resultados obtidos é possível concluir que os ACR contribuem significativamente para a viabilidade celular, bem como para a síntese de mediadores pró e anti-inflamatórios, sendo que o protocolo de suplementação se apresenta como fator determinante para obtenção desses resultados. Apesar da literatura científica atribuir grande parte dos efeitos imunomodulatórios à leucina, os resultados obtidos nesse estudo atribuem relevante potencial imunomodulador à isoleucina, abrindo espaço para um importante tema de estudo

Branched chain amino acids (BCAA) are considered indispensable, since they cannot be endogenously synthesized, being easily obtained by diet. However, in certain clinical conditions, both the intake and absorption of these amino acids may be compromised, leading to the hypercatabolic state and impairing the immune function. The immunomodulatory role of BCAA has been associated with the nitrogen balance improvement and the increase of production and proliferation of immune cells, as well as the synthesis of inflammatory mediators. However, the mechanisms by which BCAA modulate the immune system have not yet been completely elucidated. In this sense, this study aimed to evaluate the effects of BCAA supplementation on intracellular mechanisms and inflammatory parameters in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Cell cultures were distributed into five groups: CTL - without ACR supplementation; LEU - supplemented with leucine (2 mmol/L); ISO - supplemented with isoleucine (2mmol / L); VAL - supplemented with valine (2 mmol/L) and LIV - supplemented with leucine (2 mmol/L), isoleucine (2 mmol/L) and valine (2 mmol/L). The inflammatory state was induced by the addition of LPS (1 µg/ml) to the culture medium, following four treatment protocols: PT - pre-treatment; TA - acute treatment; TC - chronic treatment and TT - late treatment. The cell viability assay was performed by the MTT test and the nitric oxide (NO) dosage by the Griess reaction. Pro- and anti-inflammatory cytokines, and prostaglandin E2 (PGE2) were analyzed by ELISA. For the evaluation of the molecular parameters, the western blotting method was used. There was an increase in cell viability in all supplemented groups in relation to the control group in the TA, TC and TT treatments. Regarding NO synthesis, BCAA supplementation was able to increase NO production in three of the four proposed treatments (PT, TA and TC). In relation to the production of pro- and anti-inflammatory cytokines, PT and CT were more effective in increasing this parameter, compared to the other treatments. There was no difference between groups in relation to PGE2 production and intracellular protein phosphorylation. From the obtained results it is possible to conclude that the BCAA significantly contributed to the cell viability, as well as, for the production of pro and anti-inflammatory mediators, and the supplementation protocol presents as determinant factor to obtain these results. Although the scientific literature attributed a large part of the immunomodulatory effects to leucine, the results obtained in this study attribute relevant immunomodulatory potential to isoleucine, opening space for an important study topic

Recent Progress on Branched-Chain Amino Acids in Obesity, Diabetes, and Beyond

Branched-chain amino acids (BCAAs) are essential amino acids that are not synthesized in our body; thus, they need to be obtained from food. They have shown to provide many physiological and metabolic benefits such as stimulation of pancreatic insulin secretion, milk production, adipogenesis, and enhanced immune function, among others, mainly mediated by mammalian target of rapamycin (mTOR) signaling pathway. After identified as a reliable marker of obesity and type 2 diabetes in recent years, an increasing number of studies have surfaced implicating BCAAs in the pathophysiology of other diseases such as cancers, cardiovascular diseases, and even neurodegenerative disorders like Alzheimer's disease. Here we discuss the most recent progress and review studies highlighting both correlational and potentially causative role of BCAAs in the development of these disorders. Although we are just beginning to understand the intricate relationships between BCAAs and some of the most prevalent chronic diseases, current findings raise a possibility that they are linked by a similar putative mechanism.

Risk Assessment of "Other Substances" – L-leucine, L-isoleucine and L-valine, the Branched Chain Amino Acids (BCAA)

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. The risk assessments are the scientific basis for NFSA in its efforts to regulate the use of "other substances" to food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of L-leucine, L-isoleucine and L-valine and it is based on previous risk assessments and articles retrieved from a literature search. In this report Lleucine, L-isoleucine and L-valine may occasionally be termed merely leucine, isoleucine or valine. L-leucine, L-isoleucine and L-valine are essential amino acids. L-leucine, L-isoleucine and Lvaline are commonly known as Branched Chain Amino Acids (BCAAs), and are found in food items containing proteins and in particular, in protein-rich foods such as dairy products, meats, eggs, nuts, whole grains, seeds, avocadoes and edible seaweed. According to information from NFSA, L-leucine, L-isoleucine and L-valine are ingredients in food supplements sold in Norway. NFSA has requested a risk assessment of the following doses of L-leucine, L-isoleucine and L-valine in food supplements for adults, adolescents and children 10 years and above: L-leucine: 2500, 3000, 4000, 5000 and 5250 mg/day, Lisoleucine: 1500, 1750, 2000 and 2500 mg/day and L-valine: 1500, 1750, 2000, 2250 and 2500 mg/day. Usual dietary intakes of these amino acids in Norway are not known. Based on data from the 1988–1994 NHANES III, mean daily intakes in adults of leucine, isoleucine and valine from food and supplements are 6.1, 3.6 and 4.0 g/day, respectively (IOM, 2005). Most studies on BCAAs have focused on the three amino acids taken as single amino acids or together combined in food supplements. It has been shown that BCAAs are not metabolized in the liver as is common for most other amino acids but taken up by most peripheral tissues (in particular muscle) where they are either used in protein synthesis or as precursors for nitrogen and/or a number of carbon containing molecules. There is a lack of relevant well-designed supplementation studies with L-leucine, L-isoleucine and L-valine in humans designed to address adverse effects and dose-response relationships as primary outcome. However, daily doses of as much as 30 g BCAA per day given to athletes have been investigated and reported to improve performance. In these reports adverse effects were not addressed and not reported. L-leucine has been administered orally in single doses for one day of up to 50 g without showing any adverse effects. There are no published studies on the effects of longitudinal supplementation with either L-isoleucine or L-valine. Thus, there are no published studies that can be used for suggesting a "value for comparison", and there is no scientific data in the literature suitable for assessing the specific doses in the terms of reference. WHO (2007) recommendations for BCAAs are: Leucine 2730 mg/day, isoleucine 1400 mg/day and valine 1820 mg/day. For a 70 kg person, this corresponds to 39 mg leucine/kg body weight (bw) per day, 20 mg isoleucine/kg bw per day and 26 mg valine/kg bw per day. The acute upper tolerable metabolic limit of L-leucine for men between 20 and 35 years was determined by administration of single doses of 550-700 mg/kg bw over one day. This corresponded to 39 to 50 g/day for a person of 70 kg. Furthermore, based on several studies investigating L-leucine, L-isoleucine and L-valine supplemented as single doses ranging from 10 to 30 g/day without any reported adverse effects. The uncertainties for this consideration are described in chapter 5. VKM concludes that: Due to lack of studies addressing adverse effects for the specified doses 2500, 3000, 4000, 5000 and 5250 mg/day L-leucine, 1500, 1750, 2000 and 2500 mg/day L-isoleucine and 1500, 1750, 2000, 2250 and 2500 mg/day L-valine in food supplements, no conclusions can be made for adults (≥ 18 years), adolescents (≥ 10 and < 18 years) or children (< 10 years).

Synergistic renoprotective effect of a compiled branched-chain amino acids and Cymbopogon schoenanthus extract against experimentally induced oxido-nitrosative renal insult

Objective: To better investigate the protective role of branched-chain amino acids (BCAAs) and Cymbopogon schoenanthus (CS) extract against the potassium dichromate (PDC)-induced oxido-nitrosative nephrotoxic insult in the experimental rat model. Methods: Thirty male rats were randomly divided into five equal groups: The 1st group served as control; the 2

Synergistic renoprotective effect of a compiled branched-chain amino acids and Cymbopogon schoenanthus extract against experimentally induced oxido-nitrosative renal insult

Objective:To better investigate the protective role of branched-chain amino acids (BCAAs) and Cymbopogon schoenanthus (CS) extract against the potassium dichromate (PDC)-induced oxido-nitrosative nephrotoxic insult in the experimental rat model.Methods:Thirty male rats were randomly divided into five equal groups: The 1st group served as control; the 2Results:The PDC-induced nephrotoxic effect caused a depletion of renal oxidative scavengers glutathione, superoxide dismutase with consequent lipo-oxidative cellular membrane deterioration manifested by a rise in malonaldehyde, oxidized glutathione, myeloperoxidase and the concomitant increase in inflammatory response elements tumor necrosis factor α, nitric oxide, and interleukin 1 β. Moreover, the comet assay and increased 8-hydroxy-2-deoxyguanosine proved an accelerated apoptotic DNA fragmentation. These local renal changes were met with global altered blood biochemistry. The BCAAs and CS or their compiled administration showed an ameliorative effect against PDC-induced nephrotoxic in a synergistic pattern.Conclusions:Both BCAAs and CS or their combined administration afford potential competitors against renal insult induced by polyvalent anion pollutants in experimentally studied animals model. As a route for novel drug discovery, further investigation should be attempted to optimize their augmenting reno-protecting potential.

Serum Branched Chain Amino Acids Are Associated with Type 2 Diabetes Mellitus in Jordan / 가정의학회지

BACKGROUND: Diabetes mellitus is a global public health problem that is caused by the lack of insulin secretion (type 1) or resistance to its action (type 2). A low insulin-to-glucagon ratio predicts an increase in the serum levels of branched chain amino acids, a feature confirmed in several populations. This relationship has not been assessed in Jordan. The objective of this study was to investigate the association between serum branched chain amino acids and type 2 diabetes mellitus in patients in Jordan. METHODS: Two hundred type 2 diabetes mellitus patients and an additional 200 non-diabetic controls were recruited. Age, body mass index, and waist circumference of the subjects were recorded. Branched chain amino acid, total cholesterol, and triglyceride levels were measured from the collected serum samples. RESULTS: Serum branched chain amino acid levels were significantly higher in type 2 diabetes mellitus patients than in non-diabetes individuals (P < 0.0001). In binomial regression analysis, serum branched chain amino acid levels remained significantly associated with diabetes mellitus and increased its risk (odds ratio, 1.004; 95% confidence interval, 1.001–1.006; P=0.003). CONCLUSION: Type 2 diabetes mellitus is associated with higher branched chain amino acid levels in Jordan independent of age, sex, body mass index, waist circumference, and total serum cholesterol and serum triglyceride levels.

A comparison of metabolomic changes in type-1 diabetic C57BL/6N mice originating from different sources / 한국실험동물학회지

Animal models have been used to elucidate the pathophysiology of varying diseases and to provide insight into potential targets for therapeutic intervention. Although alternatives to animal testing have been proposed to help overcome potential drawbacks related to animal experiments and avoid ethical issues, their use remains vital for the testing of new drug candidates and to identify the most effective strategies for therapeutic intervention. Particularly, the study of metabolic diseases requires the use of animal models to monitor whole-body physiology. In line with this, the National Institute of Food and Drug Safety Evaluation (NIFDS) in Korea has established their own animal strains to help evaluate both efficacy and safety during new drug development. The objective of this study was to characterize the response of C57BL/6NKorl mice from the NIFDS compared with that of other mice originating from the USA and Japan in a chemical-induced diabetic condition. Multiple low-dose treatments with streptozotocin were used to generate a type-1 diabetic animal model which is closely linked to the known clinical pathology of this disease. There were no significantly different responses observed between the varying streptozotocin-induced type-1 diabetic models tested in this study. When comparing control and diabetic mice, increases in liver weight and disturbances in serum amino acids levels of diabetic mice were most remarkable. Although the relationship between type-1 diabetes and BCAA has not been elucidated in this study, the results, which reveal a characteristic increase in diabetic mice of all origins are considered worthy of further study.

Enhanced production of bacitracin by knocking out of amino acid permease gene yhdG in Bacillus licheniformis DW2 / 生物工程学报

Bacitracin is a broad-spectrum polypeptide antibiotic, which is formed by 11 amino acids residues. Precursor amino acids supply might be the limit factor during bacitracin fermentation. First, our results demonstrated that increasing Ile and Leu supplies were regarded as the efficient strategies for the enhanced titer of bacitracin. Then, the amino acid permease YhdG, which was identified as the BCAA permease, was deleted and overexpressed in DW2, respectively. Our results showed that knocking out of permease YhdG could improve bacitracin production remarkablely. The bacitracin titer of the yhdG deficient strain DW2ΔyhdG reached 917.35 U/mL by flask fermentation, increased by 11% compared with that of DW2. In addition, the bacitracin titer was decreased by 25% in the YhdG overexpressed strain. Meanwhile, the intracellular concentrations of BCAA were higher than DW2 during the biosynthesis of bacitracin. The above results suggested that the permease YhdG might act as an exporter for branched chain amino acids in B. licheniformis DW2. Taken together, the increasing intracellular concentrations of branched chain amino acids by deleting amino acid permease YhdG could improve bacitracin titer. This study provided a new strategy for high-level production of bacitracin.

Research progress of branched-chain amino acid in cardiometabolic diseases / 中华内分泌代谢杂志

The prevalences of cardiometabolic diseases such as obesity, insulin resistance are rising. Abnormal metabolisms of glucose and lipid are associated with cardiometabolic diseases. The amino acids are also play important roles in cardiometabolic diseases. Branched-chain amino acids are important essential amino acids, and studies about branched-chain amino acids in cardiometabolic diseases are rising. In this review we aimed to investigate the progress of branched-chain amino acids in cardiometabolic diseases.

Enfermedad de orina con olor a jarabe de arce: reporte de dos casos / Maple urine disease: two case reports

Introducción: La enfermedad de orina con olor a jarabe de arce (EOJA) es un trastorno del metabolismo de los aminoácidos de cadena ramificada (ACR). Tiene una incidencia de 1 en 85.000­185.000 recién nacidos (RN) vivos, siendo mayor en poblaciones con alta tasa de consanguineidad. Se debe al déficit del complejo enzimático BCKDC (Branched-chain alpha-keto acid dehydrogenase complex). Objetivo: Sensibilizar respecto al diagnóstico precoz, describiendo la presentación y evolución clínica de 2 casos presentados en menos de un año. Presentación del caso: Caso 1: Recién nacido de término (RNT), sin antecedentes mórbidos personales ni familiares, consulta al 11er día de vida (DDV) por cuadro de irritabilidad, rechazo alimentario, mirada fija e hipertonía. Hospitalizado por 55 días con progresiva mejoría neurológica. Al alta solo leve retraso del desarrollo psicomotor (RDSM). Caso 2: RNT, sin antecedentes mórbidos personales ni familiares, consultó al 12° DDV por cuadro de hipoactividad y rechazo alimentario. Hospitalizado por 70 días con evolución clínica y neurológica dificultosa. Al alta con trastorno deglutorio que requirió gastrostomía. En ambos casos se planteó sospecha de EOJA por aminoacidemia y aminoaciduria característica, confirmándose por medición cuantitativa de aminoácidos. Discusión: Existen cinco fenotipos diferentes, clasificados principalmente por presentación clínica y edad de debut, siendo el más frecuente la forma clásica (ambos casos). Resulta muy importante el diagnóstico precoz y manejo por su relación con el pronóstico neurológico, sin embargo, en Chile no se cuenta actualmente con un screening neonatal universal. El tratamiento se basa en un manejo nutricional estricto y la corrección de desequilibrios metabólicos e hidroelectrolíticos, ambos frecuentes en esta condición.

Introduction: The maple syrup urine disease (MSUD) is a metabolic disorder of branchedchain amino acids. It has an incidence of 1/85000 ­ 185000 live newborns being higher in in populations with a high rate of consanguinity. It is due to deficit BKDC enzyme complex (Branched-chain alpha-keto acid dehydrogenase complex). Objective: To raise awareness to early diagnosis, describing the presentation and clinical course of 2 cases presented in less than one year. Case report: Case 1: Full-term newborn with no personal or family history of morbidity presented the 11th day of life with irritability, food rejection, fixed stare and hypertonia. He was hospitalized for 55 days with progressive neurological improvement. At discharge only slightly delayed psychomotor development. Case 2: Full-term newborn with no personal or family history of morbidity presented the 12th day of life with hipoactivity and food rejection. He was hospitalized for 70 days with difficult clinical and neurological outcome. The patient was discharged with swallowing disorder that required gastrostomy. In both cases MSUP suspicion arises by aminoacidemia and aminoaciduria and confirmed by quantitative measurement of amino acids. Discussion: There are 5 different phenotypes classified chiefly by clinical presentation and age, being most frequent the classical form. It is very important to do an early diagnosis and management for its impact on neurological outcome; however, Chile does not currently has an universal neonatal screening. The treatment is based on a strict nutritional management and correction of metabolic and electrolyte imbalances, both common in this condition.

Alterations in the levels of plasma amino acids in polycystic ovary syndrome- A pilot study.

Background & objectives: Plasma amino acid levels are known to be altered in conditions like sepsis and burns which are situations of metabolic stress. Polycystic ovary syndrome (PCOS), a condition which affects a woman throughout her life, is said to be associated with metabolic stress. This study was undertaken to assess if there were significant alterations in the levels of plasma amino acids in women with PCOS. Methods: Sixty five women with PCOS along with the similar number of age matched normal controls were included in this study. Levels of 14 amino acids were determined using reverse phase high performance liquid chromatography. Results: The levels of methionine, cystine, isoleucine, phenylalanine, valine, tyrosine, proline, glycine, lysine and histidine were found to be significantly (P<0.001) lower in cases than in controls. Arginine and alanine levels were found to be significantly (P<0.001) higher in cases compared with controls. Interpretation & conclusions: Our findings showed significant derangement in the levels of plasma amino acids in women with PCOS which might be due to the oxidative and metabolic stress associated with it. Further studies need to be done to confirm the findings.

Efeito da suplementação crônica de leucina nas vias de sinalização da síntese e degradação proteica no tecido muscular de ratos destreinados submetidos à restrição calórica / Effect of chronic supplementation of leucine in signaling pathways of protein synthesis and degradation in muscle tissue of detrained rats subjected to caloric restriction

INTRODUÇÃO: O destreinamento físico está relacionado com alterações moleculares associadas à perda de massa muscular, rápido acréscimo da massa adiposa, ganho de peso e resistência à insulina. Estudos apontam que a restrição calórica reduz a gordura corporal, contudo, associada com a inatividade física, altera o metabolismo proteico acelerando o catabolismo muscular. Nesse sentido, estudos com suplementação de aminoácidos essenciais, em especial a leucina, observam aumento na síntese proteica e redução da degradação proteica em situações de restrição ou recuperação nutricional. Dessa forma sugere-se que a restrição calórica associada à suplementação com leucina poderia atenuar os efeitos desencadeados pelo destreinamento físico. OBJETIVO: Investigar a influência da suplementação crônica de leucina na via de sinalização da síntese proteica e degradação proteica no tecido muscular a partir de parâmetros moleculares em ratos destreinados, submetidos à restrição calórica. MÉTODOS: Foram utilizados 64 ratos Sprague-Dawley machos e adultos, inicialmente distribuídos em 2 grupos: Controle (CON) (n = 16) representados pelos animais sedentários, e Treinamento (TREIN) (n = 48) que foram submetidos ao treinamento em esteira ergométrica durante oito semanas. Após esse período, os animais foram redistribuído em 6 grupos: Sedentário (SED), Treinamento (TREIN), Destreinamento (DT), Destreinamento + Leucina (LEU), Destreinamento + Restrição Calórica (DTRC) e Destreinamento + Restrição Calórica + Leucina (DTRC + LEU). Foram analisados massa corporal, consumo da ração, composição corporal, sensibilidade a insulina bem como os marcadores de inflamação (IL-6; IL-10; MCP-1; TNF-α; 1L-1α; PAI-1; leptina; adponectina) e parâmetros moleculares como genes e proteínas envolvidas na via de sinalização da síntese protéica (mTOR, P-4EBP1, P-s6K1 e eIF4E); degradação proteica (MAFBx e MURF) além de transportadores de aminoácidos (LAT-1 e SNAT 2 e CD98). ESTATÍSTICA: Os valores foram expressos em média e desvio padrão. As comparações entre os grupos após o período de destreinamento físico foram avaliadas por meio de análise de variância (ANOVA), seguida do teste de Tukey. Em todas as análises foi considerado nível de significância de 5%. A análise estatística foi realizada no software SPSS versão 17.0. RESULTADOS: Em relação à composição corporal, foi observada diferença estatisticamente significativa na gordura corporal e massa livre de gordura entre os grupos DTRC e DTRC+LEU, em relação aos demais grupos experimentais. Porém não houve diferença estatística entre o DTRC e DTRC+LEU. No entanto não foi observada diferença estatisticamente significativa quando avaliado a proteína da carcaça. Em relação aos parâmetros moleculares, não foi observada diferença estatisticamente significativa entre os grupos, quando avaliada a expressão de proteínas relacionadas com a via de sinalização de síntese proteica (mTOR, P-4EBP1, P-s6K1 e eIF4E) e transportadores de leucina (LAT- 1;SNAT-2;CD(98). Quanto avaliada a expressão gênica da via de degradação, foi observada uma menor expressão do gene MURF quando suplementado com leucina, porém sem diferença estatisticamente significativa. CONCLUSÃO: A restrição calórica associada com a suplementação com leucina foi efetiva na redução da gordura corporal, e aumento da massa livre de gordura, porém não houve diferença estatisticamente significante entre os dois grupos DTRC e DTRC+LEU, tampouco quando avaliada a proteína da carcaça desses animais. Dessa forma, pode-se concluir que a suplementação crônica com leucina não reverteu os efeitos desencadeados pelo destreinamento físico, e, além disso, não foi suficiente para alterar os parâmetros moleculares envolvidos na via de sinalização de síntese e degradação proteica desses animais

INTRODUCTION: Physical detraining is related to molecular changes associated with loss of muscle mass, rapid increase in fat mass, weight gain and insulin resistance. Studies show that caloric restriction reduces body fat; however, associated with physical inactivity, it alters protein metabolism accelerating muscle catabolism. Accordingly, studies with supplementation of essential amino acids, particularly leucine, observed increase in protein synthesis and reduced protein degradation in situation of nutritional restriction or recovery. Thus, it is suggested that caloric restriction associated with leucine supplementation could attenuate the effects triggered by physical detraining. OBJECTIVE: To investigate the influence of chronic leucine supplementation in the signaling pathway of protein synthesis and degradation in muscle tissue from molecular parameters in detrained rats, subjected to caloric restriction. METHODS: Sixty-four adult male and female Sprague-Dawley rats were used, initially divided into 2 groups: Control (CON) (n = 16) represented by sedentary animals, and Trained (TRAIN) (n = 48) who underwent treadmill training for eight weeks. After this period, the animals were re-distributed into 6 groups: Sedentary (SED), Trained (TRAIN), Detrained (DT), Detrained + Leucine (LEU), Detrained + Caloric Restriction (DTRC) and Detrained + Caloric Restriction + Leucine (DTRC + LEU). Body mass, food consumption, body composition, insulin sensitivity were analyzed, as well as inflammation markers (IL-6; IL-10; MCP-1; TNF-α; 1L-1α; PAI-1; leptin; adiponectin) and molecular parameters, such as genes and proteins involved in signaling pathways of protein synthesis (mTOR, P-4EBP1, P-s6K1 and eIF4E); protein degradation (MAFBx and MURF) and also amino acid transporters (LAT-1, SNAT 2 and CD98). STATISTICAL ANALYSIS: Values were expressed as mean and standard deviation. Analysis of variance (ANOVA) was used for comparisons between groups after physical detraining, followed by Tukey's test. A 5% significance level was considered in all analyses. Statistical analysis was performed using SPSS software, version 17.0. RESULTS: In relation to body composition, a statistically significant difference was observed in body fat and fat free mass between groups DTRC and DTRC+LEU, compared with other experimental groups. However, there was no statistical difference between groups DTRC and DTRC+LEU. Nevertheless, no statistically significant difference was found when carcass protein was assessed. In relation to molecular parameters, no statistically significant difference was observed between groups, when protein expression related to the signaling pathway of protein synthesis (mTOR, P-4EBP1, P-s6K1 and eIF4E) and leucine transporters (LAT-1;SNAT-2;CD(98) was assessed. When gene expression of the degradation pathway was investigated, a lower expression of gene MURF was found with leucine supplementation; however, this was not statistically different. CONCLUSION: Caloric restriction associated with leucine supplementation was effective in reducing body fat, and increasing fat free mass; however, no statistically significant difference was found between groups DTRC and DTRC+LEU, nor when carcass protein of these animals was assessed. Therefore, it was concluded that chronic leucine supplementation did not reverse the effects triggered by physical detraining and, in addition, it was not sufficient to change the molecular parameters involved in the signaling pathway of protein synthesis and degradation of these animals

Effects of Different Acupuncture Therapies on Serum BACC and F-Trp in High-intensity Military Training Soldiers / 上海针灸杂志

Objective To investigate the effects of different acupuncture therapies on serum branched-chain amino acids (BAC and free tryptophan (F-Trp) in high-intensity military training soldiers. Methods Ninety healthy soldiers were randomly allocated to groups A, B and C, 30 soldiers each. Group A received treatment with electroacupuncture at Zusanli; group B, treatment by cupping on Zusanli;group C, no treatment. The three groups did a high-intensity 5 km running exercise after two weeks of treatment. Serum BACC and F-Trp contents were measured in the three groups before and at the end of treatment and at five days after treatment. Results It can be seen from table 2 that there were no statistically significant pre-treatment differences in serum BACC and F-Trp contents between the three groups of soldier subjects (P>0.05); there were statistically significant pre-/post-treatment differences in serum BACC and F-Trp contents in the three groups of soldier subjects (P＜0.05). There was a statistically significant post-treatment difference in serum BACC content between group A or B and group C (P＜0.05). There was a statistically significant difference in serum F-Trp content between group A or B and group C at the end of treatment and at five days after treatment (P＜0.05). Conclusion Acupuncture therapy can effectively improve bodily anti-fatigue ability and reduce high-intensity exercise induced muscular injury in military training soldiers.

Enfermedad de la orina con olor a jarabe de arce. Caso único en Cuba / Maple syrup urine disease. A unique case in Cuba

La leucinosis, también conocida como enfermedad de la orina olor a jarabe de arce, es un error innato del metabolismo de los aminoácidos de cadena ramificada (valina, isoleucina y leucina), cuya acumulación produce una encefalopatía neonatal grave, que de no ser diagnosticada y tratada de forma precoz y oportuna, lleva invariablemente a una aparición de secuelas neurológicas permanentes y un posterior desenlace letal. El diagnóstico se hace por la clínica, de la que existen 5 formas; y por la presencia de aminoácidos de cadena ramificada (leucina, isoleucina y valina y sus correspondientes cetoácidos) elevados en orina y sangre. Se trata del primer y único caso reportado en Cuba, con diagnóstico y seguimiento por equipo multidisciplinario (a nivel provincial y nacional) en el Hospital Provincial Pediátrico Docente Eliseo Noel Caamaño, de Matanzas. Se realizó una revisión de la literatura sobre la enfermedad, resaltando su fisiopatología, formas clínicas, diagnóstico, así como el tratamiento a seguir, demostrando cómo el país dispone de todos los recursos necesarios para el costoso tratamiento de la enfermedad, logrando una vez más evadir el bloqueo impuesto por los Estados Unidos.

Leucinosis, also known as maple syrup urine disease, is an innate mistake of the branched chain amino acids (valine, isoleucine and leucine), which concentration produces a serious neonatal encephalopathy that, if it is not precociously and timely diagnosed and treated, unavoidably leads to the emergence of permanent neurologic sequels and the subsequent lethal outcome. The diagnosis is reached clinically, in five different ways, and based on the presence of higher levels of branched chain amino acids (leucine, isoleucine and valine and their correspondent ceto acids) in urine and blood. We dealt with the first and unique case reported in Cuba, diagnosed and followed up by a multidisciplinary team (at the national and provincial level) in the Teaching Pediatric Provincial Hospital Eliseo Noel Caamaño, of Matanzas. We carried out a review of the literature on the disease, highlighting its physiopathology, clinical forms, diagnosis, and also the treatment to apply, showing that the country has the necessary recourses for the disease expensive treatment, evading again the blockade imposed by the United States of America.

Consumo de aminoácido de cadeia ramificada na esclerose lateral amiotrófica: suplemento proteico ou substância neurotóxica? / Branched-chain amino acid consumption in amyotrophic lateral sclerosis: protein supplement or neurotoxic substance?

Estudos demonstraram efeito positivo principalmente no ganho ponderalem pacientes com esclerose lateral amiotrófica (ELA), suplementadoscom aminoácidos de cadeia ramificada (AACR). Achados recentes têm mostrado que o consumo excessivo e crônico de AACR pode contribuir para a progressão da doença, provavelmente devido a estes serem precursores do glutamato. O objetivo deste estudo foi avaliar a evidência acerca da utilização dos AACR por pacientes com ELA, a fim de elucidar questões pertinentes a sua ingestão. Foi feita busca em base de dados de artigos científicos relacionados ao consumo de AACR na ELA, no período de 1988 a 2013. Foram encontrados seis artigos relacionados ao consumo de AACR por pacientes com ELA. Desses, um referiu melhora da força, enquanto os outros relataram ganho ponderal ou não mostraram resultados significativosem relação aos desfechos. Além disso, foi possível observar uma estreita relação entre o consumo excessivo e crônico dos AACR com o agravamento da doença. À luz dos conhecimentos ora disponíveis, a suplementação com AACR não é recomendada devido aos possíveis efeitos nocivos. O consumo adequado de alimentos proteicos, fontes desses aminoácidos, deve ser utilizado pelos pacientes, respeitando as recomendações estabelecidas. No entanto, estudos adicionais devem ser desenvolvidos em virtude do escasso número de publicações disponíveis.

Studies have shown positive effect mainly in weight gain inpatients with amyotrophic lateral sclerosis (ALS) supplemented with branched chain amino acids (BCAA). However, recent studies have shown that excessive and chronic intake has contributed to the worsening of the disease progression, probably because the amino acids are glutamate precursors. The objective of this study was to assess the evidence about the use of BCAA by patients with ALS, with the aim to clarify pertinent issues for its intake. A search was conducted in data bases for scientific papers related to the intake of BCAA in ALS, between 1988 and 2013. For these review six articles related to the use of BCAA in ALS were found. Of these, one described strength improvement, while the remaining reported weight gain or no significant effects in relation to the outcome. Additionally, it waspossible to observe a close relationship between the excessive and chronic BCAA intake with the worsening of the disease. Considering the presente day available knowledge BCAA supplementation should not be indicated due to the possible harmful effect. The intake of appropriated protein foods should be consumed by these patients, respecting the suggested recommendation. However, more studies are necessary due to the scarce papers in this area.

Effect of Oral Supplementation with Branched-chain Amino Acid (BCAA) during Radiotherapy in Patients with Hepatocellular Carcinoma: A Double-Blind Randomized Study / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The present study evaluated whether oral supplementation with a branched-chain amino acid (BCAA) improves the biochemical and amino acid profiles of liver tumor patients undergoing radiotherapy. MATERIALS AND METHODS: Patients were randomly assigned to one of 2 groups: a group given oral supplementation with BCAA granules (LIVACT granules; Samil Pharm Co., Korea, each granule containing L-isoleucine 952 mg, L-leucine 1,904 mg, and L-valine 1,144 mg) during radiotherapy, or a placebo group. Physical and biochemical examinations and measurements, including subjective symptoms, Child-Pugh class, body mass index, plasma albumin concentration, and plasma amino acid profiles were monitored. RESULTS: Fifty were enrolled between November 2005 and November 2006. We also analyzed data from 37 hepatocellular carcinoma (HCC) patients in order to evaluate a more homogenous group. The two groups of patients were comparable in terms of age, gender, Child-Pugh score, and underlying hepatitis virus type. Serum albumin, total protein, liver enzymes, and cholesterol showed a tendency to increase in the BCAA group. In this group, the percentage of cases that reverted to normal serum albumin levels between 3 and 10 weeks after administration of BCAA was significantly higher (41.18%) than in the placebo group (p=0.043). CONCLUSION: Oral supplementation with a BCAA preparation seems to help HCC patients undergoing radiotherapy by increasing the BCAA concentration.

Effect of Oral Supplementation with Branched-chain Amino Acid (BCAA) during Radiotherapy in Patients with Hepatocellular Carcinoma: A Double-Blind Randomized Study / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The present study evaluated whether oral supplementation with a branched-chain amino acid (BCAA) improves the biochemical and amino acid profiles of liver tumor patients undergoing radiotherapy. MATERIALS AND METHODS: Patients were randomly assigned to one of 2 groups: a group given oral supplementation with BCAA granules (LIVACT granules; Samil Pharm Co., Korea, each granule containing L-isoleucine 952 mg, L-leucine 1,904 mg, and L-valine 1,144 mg) during radiotherapy, or a placebo group. Physical and biochemical examinations and measurements, including subjective symptoms, Child-Pugh class, body mass index, plasma albumin concentration, and plasma amino acid profiles were monitored. RESULTS: Fifty were enrolled between November 2005 and November 2006. We also analyzed data from 37 hepatocellular carcinoma (HCC) patients in order to evaluate a more homogenous group. The two groups of patients were comparable in terms of age, gender, Child-Pugh score, and underlying hepatitis virus type. Serum albumin, total protein, liver enzymes, and cholesterol showed a tendency to increase in the BCAA group. In this group, the percentage of cases that reverted to normal serum albumin levels between 3 and 10 weeks after administration of BCAA was significantly higher (41.18%) than in the placebo group (p=0.043). CONCLUSION: Oral supplementation with a BCAA preparation seems to help HCC patients undergoing radiotherapy by increasing the BCAA concentration.

Efficacy of high branched-chain amino acids in surgical patients with liver dysfunction requiring parenteral nutrition / 中华肝胆外科杂志

Objective To confirm the safety and nutritional efficacy of high branched-chain amino acids through a pragmatic study allowing its use as an alternative to 15AA in patients with liver dysfunction. Methods The study was performed as a randomized, prospective trial. Eighty two patients with liver dysfunction undergoing operation were randomly assigned to receive high branchedchain amino acids or 15AA as part of their TPN regimens for 7 days. Daily parenteral intakes of energy nitrogen and lipid were equal in the two groups. Results Efficacy analysis showed that high branched-chain amino acids were as efficient as 15AA in avoiding protein catablosim. No serious adverse event was reported in the two groups. For hematology, renal, hepatic safety criteria and for the vital signs,no significant difference was observed between the 2 groups. No significant difference was observed concerning nitrogen balance and protein catablosim. For peripheral immunoglobulin and lymphocytes, a statistically significant difference was observed between the high branched-chain amino acids and the 15AA groups. Conclusion High branched-chain amino acids is new, safe and efficient amino acids for parenteral nutrition.

Effects of corn gluten hydrolyzates, branched chain amino acids, and leucine on body weight reduction in obese rats induced by a high fat diet

In this study, we compared corn gluten hydrolyzates, BCAAs, and leucine for their effects on body weight reduction in high fat-induced obese rats in order to determine the major active components in the corn gluten hydrolyzates. After obesity was induced for 13 weeks with high fat diet, the overweight-induced SD rats (n = 64) were stratified according to body weight, randomly blocked into eight treatments, and raised for 8 weeks. Four groups were changed to a normal diet and the other groups remained on the high fat diet. Each of the groups within both diets was fed either casein, corn gluten hydrolyzates, leucine, or branched chain amino acids, respectively. Daily food intake, body weight gain, and food efficiency ratio were significantly lower in the corn gluten hydrolyzate groups compared to the other groups, regardless of the high fat diet or normal fat diet. The rats fed the corn gluten hydrolyzates diet had the lowest perirenal fat pad weights whereas muscle weight was significantly increased in the corn gluten hydrolyzates groups. Plasma triglyceride, hepatic total lipid, and total cholesterol contents were significantly reduced in the corn gluten hydrolyzates groups. Other lipid profile measurements were not significantly changed. Plasma triglyceride and hepatic total lipid were also significantly reduced in the BCAA and leucine groups. Leptin levels were significantly lower and adiponectin was significantly higher in the corn gluten hydrolyzates groups. Fasting blood glucose, insulin, C-peptide, and HOMA-IR levels were also significantly reduced in the corn gluten hydrozylates groups, regardless of fat level.