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Altered amino acid profile in patients with SARS-CoV-2 infection.
Rees, CA, Rostad, CA, Mantus, G, Anderson, EJ, Chahroudi, A, Jaggi, P, Wrammert, J, Ochoa, JB, Ochoa, A, Basu, RK, et al
Proceedings of the National Academy of Sciences of the United States of America. 2021;(25)
Abstract
Low plasma arginine bioavailability has been implicated in endothelial dysfunction and immune dysregulation. The role of arginine in COVID-19 is unknown, but could contribute to cellular damage if low. Our objective was to determine arginine bioavailability in adults and children with COVID-19 vs. healthy controls. We hypothesized that arginine bioavailability would be low in patients with COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We conducted a prospective observational study of three patient cohorts; arginine bioavailability was determined in asymptomatic healthy controls, adults hospitalized with COVID-19, and hospitalized children/adolescents <21 y old with COVID-19, MIS-C, or asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified on admission screen. Mean patient plasma amino acids were compared to controls using the Student's t test. Arginine-to-ornithine ratio, a biomarker of arginase activity, and global arginine bioavailability ratio (GABR, arginine/[ornithine+citrulline]) were assessed in all three groups. A total of 80 patients were included (28 controls, 32 adults with COVID-19, and 20 pediatric patients with COVID-19/MIS-C). Mean plasma arginine and arginine bioavailability ratios were lower among adult and pediatric patients with COVID-19/MIS-C compared to controls. There was no difference between arginine bioavailability in children with COVID-19 vs. MIS-C. Adults and children with COVID-19 and MIS-C in our cohort had low arginine bioavailability compared to healthy adult controls. This may contribute to immune dysregulation and endothelial dysfunction in COVID-19. Low arginine-to-ornithine ratio in patients with COVID-19 or MIS-C suggests an elevation of arginase activity. Further study is merited to explore the role of arginine dysregulation in COVID-19.
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Altered Plasma Acylcarnitines and Amino Acids Profile in Spinocerebellar Ataxia Type 7.
Nambo-Venegas, R, Valdez-Vargas, C, Cisneros, B, Palacios-González, B, Vela-Amieva, M, Ibarra-González, I, Cerecedo-Zapata, CM, Martínez-Cruz, E, Cortés, H, Reyes-Grajeda, JP, et al
Biomolecules. 2020;(3)
Abstract
Spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disease characterized by cerebellar ataxia and retinal degeneration, is caused by an abnormal CAG repeat expansion in the ATXN7 gene coding region. The onset and severity of SCA7 are highly variable between patients, thus identification of sensitive biomarkers that accurately diagnose the disease and monitoring its progression are needed. With the aim of identified SCA7-specific metabolites with clinical relevance, we report for the first time, to the best of our knowledge, a metabolomics profiling of circulating acylcarnitines and amino acids in SCA7 patients. We identified 21 metabolites with altered levels in SCA7 patients and determined two different sets of metabolites with diagnostic power. The first signature of metabolites (Valine, Leucine, and Tyrosine) has the ability to discriminate between SCA7 patients and healthy controls, while the second one (Methionine, 3-hydroxytetradecanoyl-carnitine, and 3-hydroxyoctadecanoyl-carnitine) possess the capability to differentiate between early-onset and adult-onset patients, as shown by the multivariate model and ROC analyses. Furthermore, enrichment analyses of metabolic pathways suggest alterations in mitochondrial function, energy metabolism, and fatty acid beta-oxidation in SCA7 patients. In summary, circulating SCA7-specific metabolites identified in this study could serve as effective predictors of SCA7 progression in the clinics, as they are sampled in accessible biofluid and assessed by a relatively simple biochemical assay.
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Randomized, placebo-controlled, double-blind, pilot trial to investigate safety and efficacy of Cerebrolysin in patients with aneurysmal subarachnoid hemorrhage.
Woo, PYM, Ho, JWK, Ko, NMW, Li, RPT, Jian, L, Chu, ACH, Kwan, MCL, Chan, Y, Wong, AKS, Wong, HT, et al
BMC neurology. 2020;(1):401
Abstract
ASBTRACT BACKGROUND There are limited neuroprotective treatment options for patients with aneurysmal subarachnoid hemorrhage (SAH). Cerebrolysin, a brain-specific proposed pleiotropic neuroprotective agent, has been suggested to improve global functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of administering Cerebrolysin for SAH patients. METHODS This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. Fifty patients received either daily Cerebrolysin (30 ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Scale (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the modified Ranking Scale (mRS), the Montreal Cognitive Assessment (MOCA) score, occurrence of adverse effects and the occurrence of delayed cerebral ischemia (DCI). RESULTS No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 1.49; 95% confidence interval (CI): 0.43-5.17). Secondary functional outcome measures for favorable six-month recovery i.e. a mRS of 0 to 3 (OR: 3.45; 95% CI 0.79-15.01) were comparable for both groups. Similarly, there was no difference in MOCA neurocognitive performance (p-value: 0.75) and in the incidence of DCI (OR: 0.85 95% CI: 0.28-2.59). CONCLUSIONS Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. However, the neutral results of this trial suggest that it does not improve the six-month global functional performance of patients. CLINICAL TRIAL REGISTRATION Name of Registry: ClinicalTrials.gov Trial Registration Number: NCT01787123 . Date of Registration: 8th February 2013.
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Effect of Caloric Restriction on BMI, Gut Microbiota, and Blood Amino Acid Levels in Non-Obese Adults.
Zou, H, Wang, D, Ren, H, Cai, K, Chen, P, Fang, C, Shi, Z, Zhang, P, Wang, J, Yang, H, et al
Nutrients. 2020;(3)
Abstract
Adequate calorie restriction (CR) as a healthy lifestyle is recommended not only for people with metabolic disorders but also for healthy adults. Previous studies have mainly focused on the beneficial metabolic effects of CR on obese subjects, while its effects on non-obese subjects are still scarce. Here, we conducted a three-week non-controlled CR intervention in 41 subjects, with approximately 40% fewer calories than the recommended daily energy intake. We measured BMI, and applied targeted metabolic profiling on fasting blood samples and shotgun metagenomic sequencing on fecal samples, before and after intervention. Subjects were stratified into two enterotypes according to their baseline microbial composition, including 28 enterotype Bacteroides (ETB) subjects and 13 enterotype Prevotella (ETP) subjects. CR decreased BMI in most subjects, and ETP subjects exhibited a significantly higher BMI loss ratio than the ETB subjects. Additionally, CR induced limited changes in gut microbial composition but substantial microbial-independent changes in blood AAs, including a significant increase in 3-methylhistidine, a biomarker of the skeletal muscle protein turnover. Finally, baseline abundances of seven microbial species, rather than baseline AA levels, could well predict CR-induced BMI loss. This non-controlled intervention study revealed associations between baseline gut microbiota and CR-induced BMI loss and provided evidence to accelerate the application of microbiome stratification in future personalized nutrition intervention.
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Tryptophan, glutamine, leucine, and micronutrient supplementation improves environmental enteropathy in Zambian adults: a randomized controlled trial.
Louis-Auguste, J, Besa, E, Zyambo, K, Munkombwe, D, Banda, R, Banda, T, Watson, A, Mayneris-Perxachs, J, Swann, J, Kelly, P
The American journal of clinical nutrition. 2019;(5):1240-1252
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Abstract
BACKGROUND Environmental enteropathy (EE) refers to villus blunting, reduced absorption, and microbial translocation in children and adults in tropical or deprived residential areas. In previous work we observed an effect of micronutrients on villus height (VH). OBJECTIVE We aimed to determine, in a randomized controlled trial, if amino acid (AA) or multiple micronutrient (MM) supplementation can improve intestinal structure or barrier dysfunction in Zambian adults with EE. METHODS AA (tryptophan, leucine, and glutamine) and/or MM supplements were given for 16 wk in a 2 × 2 factorial comparison against placebo. Primary outcomes were changes in VH, in vivo small intestinal barrier dysfunction assessed by confocal laser endomicroscopy (CLE), and mechanistic (or mammalian) target of rapamycin complex 1 (MTORC1) nutrient responsiveness in lamina propria CD4+ lymphocytes. RESULTS Over 16 wk AA, but not MM, supplementation increased VH by 16% (34.5 μm) compared with placebo (P = 0.04). Fluorescein leak, measured by CLE, improved only in those allocated to both AA and MM supplementation. No effect was seen on MTORC1 activation, but posttreatment MTORC1 and VH were correlated (ρ = 0.51; P = 0.001), and change in MTORC1 was correlated with change in VH in the placebo group (ρ = 0.63; P = 0.03). In secondary analyses no effect was observed on biomarkers of microbial translocation. Metabolomic analyses suggest alterations in a number of microbial- and host-derived metabolites including the leucine metabolite β-hydroxy-β-methylbutyrate, which was increased by AA supplementation and correlated with VH. CONCLUSIONS In this phase 2 trial, AA supplementation protected against a decline in VH over the supplementation period, and improved barrier function when combined with micronutrients. Leucine and MTORC1 metabolism may be involved in the mechanism of effect. This trial was registered at www.pactr.org as PACTR201505001104412.
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Reduced Plasma Amino Acid Levels During Allogeneic Hematopoietic Stem Cell Transplantation Are Associated with Systemic Inflammation and Treatment-Related Complications.
Weischendorff, S, Kielsen, K, Nederby, M, Schmidt, L, Burrin, D, Heilmann, C, Ifversen, M, Sengeløv, H, Mølgaard, C, Müller, K
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019;(7):1432-1440
Abstract
Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are challenged by cytotoxic effects of the conditioning regimen, resulting in tissue damage, systemic inflammation, and increased metabolic demands for amino acids to regenerate damaged tissues, reconstitute hematopoietic cells, and establish antioxidant defenses. To date, few studies have addressed the role of plasma amino acid (PAA) levels during transplantation, and it remains unknown if amino acid deficiency can aggravate treatment-related morbidity. We determined plasma levels of the 23 human amino acids in 80 HSCT recipients (age 1.1 to 55.4 years) before conditioning and on days +7 and +21 post-transplant along with C-reactive protein (CRP) and IL-6 levels on day +7. Significant changes were observed in plasma concentrations of several human amino acids during HSCT. On day +7, numerous amino acids were inversely correlated with both CRP and IL-6, including glutamic acid, serine, alanine, glutamine, arginine, cysteine, glycine, histidine, lysine, tryptophan, threonine, taurine, proline, and methionine (r = -.22 to -.66; all P < .05). Patients who developed sinusoidal obstruction syndrome (SOS) had significantly lower mean total PAA levels compared with patients without SOS (2013 ng/L [95% confidence interval (CI), 1709 to 2318 ng/L] versus 2706 ng/L [95% CI, 2261 to 3150 ng/L]; P = .006), along with lower individual levels of glutamic acid, serine, arginine, glycine, lysine, valine, tryptophan, threonine, and proline on day +7 (all P < .05). Patients with severe acute graft-versus-host disease had a lower mean total PAA level (1922 ng/L [95% CI, 1738 to 2106 ng/L] versus 2649 ng/L [95% CI, 2244 to 3055 ng/L]; P = .014) and lower levels of serine, glutamine, cysteine, glycine, lysine, and threonine on day +7 (all P < .05). These results indicate a relationship between low concentrations of certain amino acids and the risk of treatment-related complications.
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Metabolite normalization with local radiotherapy following breast tumor resection.
Arenas, M, Rodríguez, E, García-Heredia, A, Fernández-Arroyo, S, Sabater, S, Robaina, R, Gascón, M, Rodríguez-Pla, M, Cabré, N, Luciano-Mateo, F, et al
PloS one. 2018;(11):e0207474
Abstract
The aims of this study were to investigate changes in energy balance-associated metabolites associated with radiotherapy in patients with breast cancer, and to relate these changes to the clinical and pathological response-to-treatment. We studied 151 women with breast cancer who received radiotherapy following surgical excision of the tumor. Blood was obtained before and after the irradiation procedure. The control group was composed of 44 healthy women with a similar age distribution to that of the patients. We analyzed the concentrations of metabolites involved in glycolysis, citric acid cycle and amino acid metabolism using targeted quantitative metabolomics. Post-surgery, pre-radiotherapy, patients had major alterations in the serum concentrations of products of glycolysis, citric acid cycle and amino acid metabolism. The strongest alterations were decreases in serine, leucine and isoleucine concentrations. Alterations in metabolite levels were partially, or totally, reversed after irradiation; the concentrations of serine, leucine and isoleucine approached equivalence to those of the control group. Estrogen receptor-positive patients were those with lower concentrations, while triple negative patients had higher concentrations of these amino acids. The normalization of the amino acids serine, leucine and isoleucine concentrations could be clinically relevant because the normalization of these energy-balance metabolites would suggest that residual micro-metastatic disease had been effectively diminished by the radiotherapy, and may be an indicator of its efficacy.
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Ingestion of Insect Protein Isolate Enhances Blood Amino Acid Concentrations Similar to Soy Protein in A Human Trial.
Vangsoe, MT, Thogersen, R, Bertram, HC, Heckmann, LL, Hansen, M
Nutrients. 2018;(10)
Abstract
BACKGROUND Increased amino acid availability stimulates muscle protein synthesis (MPS), which is critical for maintaining or increasing muscle mass when combined with training. Previous research suggests that whey protein is superior to soy protein in regard to stimulating MPS and muscle mass. Nevertheless, with respect to a future lack of dietary protein and an increasing need for using eco-friendly protein sources it is of great interest to investigate the quality of alternative protein sources, like insect protein. OBJECTIVE Our aim was to compare the postprandial amino acid (AA) availability and AA profile in the blood after ingestion of protein isolate from the lesser mealworm, whey isolate, and soy isolate. DESIGN Six healthy young men participated in a randomized cross-over study and received three different protein supplementations (25 g of crude protein from whey, soy, insect or placebo (water)) on four separate days. Blood samples were collected at pre, 0 min, 20 min, 40 min, 60 min, 90 min, and 120 min. Physical activity and dietary intake were standardized before each trial, and participants were instructed to be fasting from the night before. AA concentrations in blood samples were determined using ¹H NMR spectroscopy. RESULTS A significant rise in blood concentration of essential amino acids (EAA), branched-chain amino acids (BCAA) and leucine was detected over the 120 min period for all protein supplements. Nevertheless, the change in AA profile was significantly greater after ingestion of whey than soy and insect protein (p < 0.05). Area under the curve (AUC) analysis and AA profile revealed comparable AA concentrations for soy and insect protein, whereas whey promoted a ~97% and ~140% greater AUC value than soy and insect protein, respectively. A tendency towards higher AA concentrations beyond the 120 min period was observed for insect protein. CONCLUSION We report that ingestion of whey, soy, and insect protein isolate increases blood concentrations of EAA, BCAA, and leucine over a 120 min period (whey > insect = soy). Insect protein induced blood AA concentrations similar to soy protein. However, a tendency towards higher blood AA concentrations at the end of the 120 min period post ingestion was observed for insect protein, which indicates that it can be considered a "slow" digestible protein source.
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Family history and obesity in youth, their effect on acylcarnitine/aminoacids metabolomics and non-alcoholic fatty liver disease (NAFLD). Structural equation modeling approach.
Romero-Ibarguengoitia, ME, Vadillo-Ortega, F, Caballero, AE, Ibarra-González, I, Herrera-Rosas, A, Serratos-Canales, MF, León-Hernández, M, González-Chávez, A, Mummidi, S, Duggirala, R, et al
PloS one. 2018;(2):e0193138
Abstract
BACKGROUND Structural equation modeling (SEM) can help understanding complex functional relationships among obesity, non-alcoholic fatty liver disease (NAFLD), family history of obesity, targeted metabolomics and pro-inflammatory markers. We tested two hypotheses: 1) If obesity precedes an excess of free fatty acids that increase oxidative stress and mitochondrial dysfunction, there would be an increase of serum acylcarnitines, amino acids and cytokines in obese subjects. Acylcarnitines would be related to non-alcoholic fatty disease that will induce insulin resistance. 2) If a positive family history of obesity and type 2 diabetes are the major determinants of the metabolomic profile, there would be higher concentration of amino acids and acylcarnitines in patients with this background that will induce obesity and NAFLD which in turn will induce insulin resistance. METHODS/RESULTS 137 normoglycemic subjects, mean age (SD) of 30.61 (8.6) years divided in three groups: BMI<25 with absence of NAFLD (G1), n = 82; BMI>30 with absence of NAFLD (G2), n = 24; and BMI>30 with NAFLD (G3), n = 31. Family history of obesity (any) was present in 53%. Both models were adjusted in SEM. Family history of obesity predicted obesity but could not predict acylcarnitines and amino acid concentrations (effect size <0.2), but did predict obesity phenotype. CONCLUSION Family history of obesity is the major predictor of obesity, and the metabolic abnormalities on amino acids, acylcarnitines, inflammation, insulin resistance, and NAFLD.
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Amino acids intake and physical fitness among adolescents.
Gracia-Marco, L, Bel-Serrat, S, Cuenca-Garcia, M, Gonzalez-Gross, M, Pedrero-Chamizo, R, Manios, Y, Marcos, A, Molnar, D, Widhalm, K, Polito, A, et al
Amino acids. 2017;(6):1041-1052
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Abstract
The aim was to investigate whether there was an association between amino acid (AA) intake and physical fitness and if so, to assess whether this association was independent of carbohydrates intake. European adolescents (n = 1481, 12.5-17.5 years) were measured. Intake was assessed via two non-consecutive 24-h dietary recalls. Lower and upper limbs muscular fitness was assessed by standing long jump and handgrip strength tests, respectively. Cardiorespiratory fitness was assessed by the 20-m shuttle run test. Physical activity was objectively measured. Socioeconomic status was obtained via questionnaires. Lower limbs muscular fitness seems to be positively associated with tryptophan, histidine and methionine intake in boys, regardless of centre, age, socioeconomic status, physical activity and total energy intake (model 1). However, these associations disappeared once carbohydrates intake was controlled for (model 2). In girls, only proline intake seems to be positively associated with lower limbs muscular fitness (model 2) while cardiorespiratory fitness seems to be positively associated with leucine (model 1) and proline intake (models 1 and 2). None of the observed significant associations remained significant once multiple testing was controlled for. In conclusion, we failed to detect any associations between any of the evaluated AAs and physical fitness after taking into account the effect of multiple testing.