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PubMed2025

OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis.

Acute myeloid leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells in vivo before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDXs) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting BCAAs further reduced chemoresistant AML cells, but relapse still occurred. Among the persisting cells, we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate- and iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA. We found that OGFOD1 upregulates protein synthesis in AML, driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML while sparing normal hematopoiesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation. Targeting OGFOD1 may offer a distinctive, translation-modifying means of reducing the chemopersisting cells that drive relapse.

Leukemia, Myeloid, Acute↗
PubMed1985

Systolic properties of normal and septic isolated rat hearts. The effect of branched chain amino acids.

Systolic properties and coronary flow were studied in Langendorff preparations of normal and septic rat hearts paced at 100, 200, 300, and 400 beats per minute. In addition, the effects of amino acid formulations differing in their branched chain amino acid (BCAA) concentration in normal and septic rat hearts were investigated. Our experiments demonstrated the following: in the normal isolated rat heart, Krebs plus glucose and Krebs plus glucose plus 42% BCAA are most effective in maintaining systolic properties, while Krebs plus glucose plus 15% or 100% BCAA were considerably less effective. Sepsis results in a significant decrease in the systolic properties of the isolated rat heart, and in a loss of the negative linear correlation between contractility and heart rate, probably the result of a diminishing intracellular load of contractile calcium. In the isolated septic rat heart, mechanical washout during perfusion has a beneficial effect, suggesting the presence of a myocardial depressant substance in sepsis. The use of a balanced amino acid mixture containing 42% BCAA exerts the greatest benefit in maintaining systolic properties and in improving coronary flow in the isolated septic rat heart.

Amino Acids, Branched-Chain↗
PubMed2001

Metabolic approach of absence seizures in a genetic model of absence epilepsy, the GAERS: study of the leucine-glutamate cycle.

We suggest that a dysregulation of energy metabolism in the brain of genetic absence epilepsy rats from Strasbourg (GAERS) could create a specific cerebral environment that would favor the expression of spike-and-wave discharges (SWD) in the thalamocortical loop, largely dependent on glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurotransmissions. We tested several aspects of metabolic activity in the brain of GAERS compared to a genetic strain of nonepileptic (NE) rats. Glucose metabolism was higher in all brain regions of GAERS compared to those of NE rats along the whole glycolytic and aerobic pathways, as assessed by regional histochemical measurement of lactate dehydrogenase and cytochrome oxidase activities. Branched-chain amino acids (BCAA) and alpha-ketoisocaproate (alpha-KIC), the ketoacid of leucine, when injected intraperitoneally, increased the number of SWD in GAERS but had only a slight effect on their duration. These data speak in favor of a BCAA- or alpha-KIC-induced change in neuronal excitability. Leucine and alpha-KIC decreased the concentration of glutamate in thalamus and cortex without affecting GABA concentrations. Thus, BCAA and alpha-KIC, by decreasing glutamatergic neurotransmission, could favor GABAergic neurotransmission, which is known to increase the occurrence of seizures in GAERS. Finally, the transport of [1-(14)C]alpha-KIC in freshly isolated cortical neurons was lower in GAERS than in NE rats, and this difference was shown to be of metabolic origin. The addition of gabapentin, a specific inhibitor of BCAA transaminase (BCAT), reduced the transport of [1-(14)C]alpha-KIC in GAERS and NE rats to a level that became identical in both strains. This strain-dependent change was not related to a difference in the activity of BCAT, which was identical in GAERS and NE rats. The exact origin of this apparent metabolic dysregulation of energy metabolism in GAERS that could underlie the origin of seizures in that strain remains to be explored further.

Acetates↗
PubMed1988

Essential and non-essential amino acid requirement in injured patients receiving total parenteral nutrition.

The metabolic derangements of injury are known to influence nitrogen (N) requirements whilst less is known about individual amino acid (AA) requirements. This study was designed to investigate prospectively N vs AA requirement in 36 injured patients treated with total parenteral nutrition (TPN). The non-protein caloric input was 30 kcal kg-1 day-1 and three AA solutions were assessed containing the same AAs but in different proportion. Overall N intake was set at 0.35 g N kg-1 day-1 for solution A and B and 0.24 g N kg-1 day-1 for solution C. Solution B was similar to A, both being enriched in branched chain AAs (BCAA: 0.69 g kg-1 day-1 in B compared with 0.55 g kg-1 day-1 in A) while decreased in aromatic and sulphurated forms (1.75 times the normal need). Solution C was designed to maintain a daily input of BCAA similar to A (0.52 g kg-1 day-1) but with the supply of aromatic and sulphurated AA between solutions A and B, the supply of other AAs (lysine, theonine, histidine, arginine, glycine) being dependent on the selected N intake. For all the essential AAs the supply was always greater than normal allowances. Increasing BCAA over 0.55 g kg-1 day-1 did not improve N balance when N intake was 0.35 g kg-1 day-1, whilst nutrition with solution C was unable to maintain N balance. Moreover we found indirect evidence that this N intake, 0.52 g kg-1 day-1 was more sparing than 0.37 g kg-1 day-1 of BCAA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Changes in the exercise-induced hormone response to branched chain amino acid administration.

It was the aim of the present experiment to detect possible effects of branched-chain amino acids (BCAA) on the endocrine response to 1 h of continuous running. Blood samples were collected from 14 long-distance runners (age 24-42 years) in two different trials performed at 1-week intervals. In both trials (E and P) blood samples were collected at the following times: 9 a.m. (basal values sample), 10.30 a.m. (sample 90), 11.30 a.m. (sample 150), 12.30 p.m. (sample 210); the athletes performed 1 h of running at a constant predetermined speed between samples 90 and 150. Following the basal sample a mixture containing BCAA (E trial), or not containing BCAA (P trial) was ingested. In both trials no hormone basal concentrations, except insulin, were changed before exercise. In P trial, following exercise (sample 150), human growth hormone (HGH), prolactin (PRL), adrenocorticotropic hormone (ACTH) and cortisol (C) increased, while testosterone (T) decreased. In sample 210, after 1 h of rest, while ACTH, PRL and HGH had recovered to basal concentrations, C remained elevated and T displayed a further decrease. In the E trial a similar pattern of change was observed in sample 150 for HGH, PRL, ACTH and C; in sample 210 HGH and PRL displayed significantly lower values than in the corresponding P trial samples. The T was not modified by the running exercise and increased during the recovery period. It is, therefore, suggested that BCAA administration before exercise affects the response of some anabolic hormones, mainly HGH and T.

Adrenocorticotropic Hormone↗
PubMed1994

Effect of infusing branched-chain amino acid during incremental exercise with reduced muscle glycogen content.

The aim of this study was to investigate whether, when muscle glycogen is reduced, a pre-exercise infusion of branched-chain amino acids (BCAA) modifies exercise performance or the metabolic and respiratory responses to incremental exercise. Six moderately trained volunteers took part in the following protocol on two occasions. On day 1, at 9 a.m. in the postabsorptive state, they performed a graded incremental exercise (increases of 35 W every 4 min) to exhaustion (Ex-1). A meal of 1,000 kcal (4,200 kJ; 60% protein, 40% fat) was consumed at 12 p.m. No food was then allowed until the end of the experiment (20-21 h later). A 90-min period of exercise at alternating high and moderate intensities, designed to deplete muscle glycogen, was performed between 6 p.m. and 7.30 p.m. The morning after (day 2), the subjects randomly received either a mixed solution of BCAA (260 mg x kg-1 x h-1 for 70 min), or saline. They then repeated the graded incremental exercise to exhaustion (Ex-2). Metabolic and respiratory measurements suggested a muscle glycogen-depleted state had been achieved. No significant differences were observed in total work performed, maximal oxygen uptake or plasma ammonia, alanine, and blood pyruvate concentrations in the two treatments. After BCAA infusion, higher blood lactate concentrations were observed at maximal power output in comparison with those during saline [BCAA 4.97 (SEM 0.41) mmol x l-1, Saline 3.88 (SEM 0.47) mmol x l-1, P < 0.05].(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1999

Ratio of branched chain amino acid to tyrosine after hepatectomy.

The roles of branched chain amino acids (BCAAs) and the tyrosine (Tyr) profile after liver resection were investigated using an inexpensive enzymatic method that was recently developed to quantify their concentrations. The preoperative BCAAs-to-Tyr ratio (BTR) was significantly correlated with the preoperative indocyanin green clearance ratio. The BTR decreased immediately after surgery in all patients, but it was significantly lower in those who had undergone major hepatectomies. After the infusion of BCAA-enriched amino acid solution, the BTR increased substantially, being significantly higher in patients who had not suffered an elevation in total bilirubin after liver resection. These findings indicate that this new enzymatic method to quantify the concentration of BCAAs and Tyr is useful to control the infusion of amino acids and to study the role of amino acid metabolization during the perioperative period.

Amino Acids, Branched-Chain↗
PubMed1989

Influence of branched-chain amino acid composition of culture media on the synthesis of plasma proteins by serum-free cultured rat hepatocytes.

Supplementation of Ham's F12 culture medium with essential amino acids (EAA) up to the rat plasma levels increased the rates of synthesis of albumin and transferrin by cultured rat hepatocytes by 1.3 and 1.7, respectively. Fifty percent of this increase could be attributed to three of the EAA: the branched-chain amino acids (BCAA: Leu Ile and Val). Non-branched-chain essential amino acids (non-BC-EAA) stimulated only 25% of the increase produced by the whole EAA mixture. When each EAA was tested individually, none of them caused an appreciable increase in albumin and transferrin in culture medium. When the concentrations of all EAA were raised to rat postprandial portal levels, albumin and transferrin synthesis rates reached a maximum, increasing by 3.2 and 3.5, respectively. Supplementation with BCAA at postprandial portal concentrations increased albumin and transferrin synthesis rates by 2.2 and 2.0, respectively, and had no noteworthy effect on the synthesis of cellular proteins. Non-BC-EAA at their postprandial portal concentrations increased albumin and transferrin synthesis rates by 1.7 and 1.9, respectively. Supplementation with alanine to reach a nitrogen content equal to that of the modified EAA-enriched medium had no stimulatory effect. Our results show that EAA have a specific effect on the synthesis of plasma proteins by cultured hepatocytes, and that BCAA at physiologic concentrations account for the major part of this stimulatory effect. Consequently, EAA and particularly BCAA concentration should be elevated in serum-free nutrient media to sustain maximum plasma protein synthesis.

Amino Acids, Branched-Chain↗
PubMed1981

Treatment of liver cirrhosis with branched chain amino acid-supplemented diet.

Seven patients with compensated liver cirrhosis were tested for branched chain amino acid (BCAA)-supplemented diet to evaluate dietetic therapy of the disease. Serum prealbumin and albumin levels, hepaplastin tests, nitrogen balance and molar ratio of serum BCAA and aromatic amino acid (AAA) were mostly improved during 2 weeks of the special diet supplemented with daily 5 g BCAA in three meals. The results indicate that BCAA-supplemented diet may be useful for treatment of impaired protein metabolism frequently observed in cirrhotic patients.

Amino Acids, Branched-Chain↗
PubMed1982

Characteristics change in serum amino acid levels in different types of hepatic encephalopathy.

Serum amino acid patterns in patients with different types of hepatic encephalopathy were investigated. Marked elevations in most of serum amino acids observed in untreated patients with acute type of fulminant hepatitis were not remarkable in the patients who have already treated; particularly branched chain amino acids (BCAA), phenylalanine and tyrosine were much lower in the latter group. However, elevation of serum methionine levels and lower ratio of BCAA/(phenylalanine + tyrosine) were similarly observed in both groups. In encephalopathic patients with decompensated cirrhosis, many amino acids such as phenylalanine, tyrosine and methionine were elevated with a slight depressed levels of serum BCAA. Highly significant decrease in serum BCAA levels and no elevation of phenylalanine and methionine with a minimal increase of tyrosine were observed in patients with chronic type of hepatic encephalopathy; other amino acids except for glutamine and arginine were much lower as compared to those in decompensated cirrhotics and even to the control values.

Adolescent↗
PubMedDate not supplied

Effects of total parenteral nutrition enriched with branched chain amino acid infusion on liver function and serum amino acid pattern in dogs undergoing hepatectomy.

In order to study effects of different total parenteral nutritional regimens on the recovery of liver function and on plasma amino acid pattern after major hepatectomy, twelve healthy mongrel dogs were submitted to 70% liver resection and randomly divided into three different groups: group I (control group) received only 10% glucose; group II received 10% glucose plus 8.5% Freamine; group III received 10% glucose plus 100% branched chain amino acid (BCAA) solution. Blood samples were analyzed for determining biochemical parameters, including plasma amino acid levels, before surgery and on 3rd and 7th postoperative day. The 'BCAA group', compared to other groups, showed higher values of plasma proteins (p less than 0.01) and prothrombin activity (p less than 0.05) on the 3rd postoperative day. The total concentration of plasma amino acids decreased after hepatectomy. Gluconeogenetic amino acids alanine and glutamine were markedly decreased in groups II and III, likely due to their increased consumption during gluconeogenesis. Aromatic amino acids were increased in all groups, due to the transient liver insufficiency. BCAA markedly increased in group III on 3rd postoperative day and returned to basal values on 7th postoperative day; possible explanations of such alterations are discussed. Our findings suggest that BCAA may represent a first choice substrate in the early phase after hepatectomy.

Amino Acids↗
PubMed1997

Metabolism of branched-chain amino acids in maple syrup urine disease.

Maple syrup urine disease (MSUD) is an autosomal recessive disorder. Impaired activity of the branched-chain 2-oxo acid dehydrogenase complex (BCOA-DH) causes accumulation of branched-chain L-amino (BCAA) and 2-oxo acids (BCOA) that can exert neurotoxic effects. MSUD presents as a heterogeneous clinical and molecular phenotype. Severity of the disease, ranging from classical to mild variant types, is commonly classified on the basis of indirect parameters, e.g. onset, leucine tolerance and/or residual enzyme activity in cells. Available information on BCAA turnover in vivo suggests that renal clearance is low and that the main route of BCAA disposal in MSUD is via protein synthesis, similar to healthy subjects. Information on BCAA oxidation is poor. In vivo oxidation rates have been assessed in a few studies in patients with claimed classical form of MSUD, using (stable) isotopically labelled L-leucine and both the (primed) continuous infusion and the oral bolus test approach. However, highly variable results have been obtained with both methods not only with respect to the number of patients exhibiting measurable leucine oxidation (range: 0%-100%; two to seven patients investigated) but also considering the extent of residual whole body leucine oxidation (range: < or = 2%-43% of control). Whether the different findings on whole body leucine oxidation actually reflect the variability of in vivo severity in classical MSUD as opposed to the measurements in cultured cells (generally < or = 2% of control), alternative pathways of leucine oxidation in some patients or were rather attributable to inadequate classification of patients or/and to inherent methodological problems remains to be clarified.

Amino Acids, Branched-Chain↗
PubMed2006

Emotion-based decision-making in healthy subjects: short-term effects of reducing dopamine levels.

INTRODUCTION: Converging evidences from animal and human studies suggest that addiction is associated with dopaminergic dysfunction in brain reward circuits. So far, it is unclear what aspects of addictive behaviors are related to a dopaminergic dysfunction. DISCUSSION: We hypothesize that a decrease in dopaminergic activity impairs emotion-based decision-making. To demonstrate this hypothesis, we investigated the effects of a decrease in dopaminergic activity on the performance of an emotion-based decision-making task, the Iowa gambling task (IGT), in 11 healthy human subjects. MATERIALS AND METHODS: We used a double-blind, placebo-controlled, within-subject design to examine the effect of a mixture containing the branched-chain amino acids (BCAA) valine, isoleucine and leucine on prolactin, IGT performance, perceptual competency and visual aspects of visuospatial working memory, visual attention and working memory, and verbal memory. The expectancy-valence model was used to determine the relative contributions of distinct IGT components (attention to past outcomes, relative weight of wins and losses, and choice strategies) in the decision-making process. OBSERVATIONS AND RESULTS: Compared to placebo, the BCAA mixture increased prolactin levels and impaired IGT performance. BCAA administration interfered with a particular component process of decision-making related to attention to more recent events as compared to more distant events. There were no differences between placebo and BCAA conditions for other aspects of cognition. Our results suggest a direct link between a reduced dopaminergic activity and poor emotion-based decision-making characterized by shortsightedness, and thus difficulties resisting short-term reward, despite long-term negative consequences. These findings have implications for behavioral and pharmacological interventions targeting impaired emotion-based decision-making in addictive disorders.

Amino Acids, Branched-Chain↗
PubMed2005

Differential p70S6k and 4E-BP1 regulation by insulin and amino acids in vascular endothelial and smooth muscle cells.

Differential stimulation of vascular endothelial and smooth muscle cells proliferation is responsible for atherosclerotic lesions. Amino acids and insulin modulate p70S6k and 4E-BP1 activity, regulating cell growth and proliferation. We hypothesised that nutritional (amino acids) and hormonal (insulin) signals differently modulate protein anabolism in human vascular endothelial (HUVEC) and smooth muscle (HVSMC) cells. We evaluated p70S6kinase and 4E-BP1 phosphorylation in the two cell types, grown in amino acid-free medium with or without insulin (INS, 100 nM) or/and amino acids mixture (AA, 3 mM) and with the selective addition or deprivation of branched chain amino acids (BCAA, 0.5 mM). INS stimulated p70S6k and 4E-BP1 phosphorylation transiently in HUVEC and persistently in HVSMC. AA and INS+AA stimulated p70S6k and 4E-BP1 phosphorylation persistently in HUVEC and HVSMC. AA, but not BCAA alone or BCAA-deprived AA, induced p70S6k phosphorylation in HUVEC. BCAA deprivation decreased the p70S6k phosphorylation induced by AA with or without insulin in HVSMC. These results show that anabolic stimuli modulate p70S6k and 4E-BP1 activity differently in the two vascular cell types, suggesting that insulin stimulates protein synthesis for a longer time in HUSMC than in HUVEC. We speculate that hyperinsulinaemia frequently associated with atherosclerosis could induce a selective HVSMC proliferation.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy.

The increase of the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin (5-HT). To study the role of tryptophan on the increased brain 5-HT metabolism in HE, we attempted to monitor brain levels of tryptophan in rats with thioacetamide-induced acute liver failure by intravenous infusion of branched-chain amino acids (BCAA). The effect of this treatment on 5-HT synthesis and metabolism was investigated in five brain areas. BCAA-infusions (1 and 2 gm/kg/24 h) increased the ratio BCAA/aromatic amino acids in plasma two- and fourfold, respectively, and lowered both plasma and brain levels of tryptophan. At the higher BCAA-dose all parameters suggesting an altered brain 5-HT metabolism (increased brain levels of 5-HT and 5-HIAA, increased 5-HIAA/5-HT ratio) were almost completely normalized. These results provide further evidence for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the treatment of HE.

Amino Acids↗
PubMed2004

Branched chain amino acids as a parameter for catabolism in treated phenylketonuria.

This study was performed to study an association between nutritional status on one hand and BCAA- and Phe-concentrations on the other hand in PKU patients free of infection. AA profiles from 70 PKU patients were measured. 9 patients (subgroup I) with elevated Phe- and BCAA-concentrations as well as 23 patients (subgroup II) with only elevated Phe-levels were included. Dietary records were obtained from both groups; low caloric intake in subgroup I was increased with Duocal or p-am ANAMIX without modifying total protein- and Phe-intake. AA profiles were controlled after 2 weeks. Additionally, we investigated AA profiles from 26 liver transplanted patients with increased carbohydrate and caloric intake as an example for anabolism. In subgroup I Phe- and Isoleu-concentrations decreased sign. After dietary intervention. Leu, Val and Tyr levels decreased not sign. Initial Phe-levels correlated negatively with protein and caloric intake. BCAA concentrations of liver transplanted patients receiving high amounts of carbohydrates were in the lower range of normal. Increased caloric intake lowered most of the elevated Phe- and BCAA- concentrations.

Adolescent↗
PubMed2006

Atypical phenotype in a boy with a maple syrup urine disease.

Maple syrup urine disease (MSUD) is a metabolic disorder due to a block in the decarboxylation step in the catabolic pathways of the branched-chain amino acids (BCAAs). We describe an atypical presentation in an infant male. The patient presented with psychomotor retardation, profound hypotonia and elevated plasma levels of BCAAs, but no elevation of alloisoleucine. Cranial magnetic resonance imaging showed prominent diffuse CSF spaces, delayed myelin maturation and symmetrical signal abnormality within the globi pallidi, midbrain, dorsal pons and medulla. The cerebellar white matter was specifically spared. A mitochondrial disorder was suggested. After correction of feeding problems with G-tube feeds, his high BCAAs persisted and, on fourth analysis, alloisoleucine was seen. Subsequent fibroblast enzyme and mutation analysis confirmed MSUD due to E(1)-alpha subunit deficiency. After starting dietary treatment, there was no significant improvement in his hypotonia or his psychomotor development. However, the high signal within the globi pallidi had resolved. MSUD may have diverse clinical presentations, and should be considered in children who present with chronic psychomotor delay but no acute encephalopathic episodes. BCAA levels may not be very high, alloisoleucine may not always be detected in MSUD even with severe enzyme deficiency, and imaging may be misleading if seen in the chronic phase only.

Amino Acids, Branched-Chain↗
PubMed1978

Blood amine acid levels in patients with insulin excess (functioning insulinoma) and insulin deficiency (diabetic ketosis).

Blood amino acid concentrations were determined in the postabsorptive state in nine patients with insulin excess (functioning insulinomas), nine juvenile-type diabetics with insulin deficiency (diabetic ketosis due to insulin withdrawal), six juvenile diabetics in moderate metabolic control, and five healthy control subjects. Blood branched-chain amino acid (BCAA) levels were elevated in diabetic ketosis and decreased in patients with insulinomas. Blood concentrations of BCAA were significantly correlated to blood glucose levels, and in diabetics they were also correlated to blood ketone bodies, serum free fatty acids, and glycerol levels. These data indicate an inverse relationship between circulating effective insulin levels and blood BCAA concentrations. It is suggested that blood levels of BCAA might represent an indicator of insulin-dependent alterations of protein metabolism.

Adenoma, Islet Cell↗