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Early metabolic support for critically ill trauma patients: A prospective randomized controlled trial.
Stolarski, AE, Young, L, Weinberg, J, Kim, J, Lusczek, E, Remick, DG, Bistrian, B, Burke, P
The journal of trauma and acute care surgery. 2022;(2):255-265
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Abstract
BACKGROUND There is a lack of consensus regarding the optimal nutritional support for trauma patients. We hypothesize that early postinjury metabolic support focusing on adequate protein would modify the metabolic signature and alter the inflammatory environment for critically ill trauma patients. METHODS We conducted a prospective randomized controlled pilot trial for adult patients admitted to the surgical intensive care unit following traumatic injury. Patients were randomized to receive early metabolic support (EMS) (peripheral amino acid infusions) or standard of care (enteral nutrition as soon as feasible). Routine laboratory assessments, nitrogen balance, cytokines, and metabolomic analyses were assessed at baseline and day 5 after intervention. RESULTS A total of 42 trauma patients were randomized into well-balanced groups with similar age (32 years), Injury Severity Score (25), and body mass index (27.4 kg/m2). Early metabolic support provided significantly more protein (1.43 g/kg vs. 0.35 g/kg; p < 0.0001) and more calories (12.6 kcal/kg vs. 7.5 g/kg; p = 0.0012) over the first 5 days as compared with the standard of care. Early metabolic support modified protein catabolism and synthesis as demonstrated by a larger median negative nitrogen balance (-16.3 g vs. -5.3 g; p = 0.03) and a unique metabolomic profile at day 5. The biochemical profile of patients who received EMS was defined by greater declines in circulating levels of stress hormone precursors and increased levels of amino acids. The inflammatory response following EMS resulted in a greater decrease in interleukin-1B (p = 0.02) and increase in soluble interleukin-6 receptor (p = 0.01) between baseline and day 5 as compared with the standard of care. The EMS group had a decreased length of stay (15 vs. 22 days) and decreased surgical intensive care unit length of stay (8 vs. 9 days); however, this disappeared after adjustment for Injury Severity Score in this small population. CONCLUSIONS Early metabolic support with amino acid is safe, modifies metabolism, and may downregulate the inflammatory state associated with significant trauma, warranting a larger trial to assess for improved outcomes. LEVEL OF EVIDENCE Therapeutic/Care Management; Level II.
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Making Sense of "Nonsense" and More: Challenges and Opportunities in the Genetic Code Expansion, in the World of tRNA Modifications.
Lateef, OM, Akintubosun, MO, Olaoba, OT, Samson, SO, Adamczyk, M
International journal of molecular sciences. 2022;(2)
Abstract
The evolutional development of the RNA translation process that leads to protein synthesis based on naturally occurring amino acids has its continuation via synthetic biology, the so-called rational bioengineering. Genetic code expansion (GCE) explores beyond the natural translational processes to further enhance the structural properties and augment the functionality of a wide range of proteins. Prokaryotic and eukaryotic ribosomal machinery have been proven to accept engineered tRNAs from orthogonal organisms to efficiently incorporate noncanonical amino acids (ncAAs) with rationally designed side chains. These side chains can be reactive or functional groups, which can be extensively utilized in biochemical, biophysical, and cellular studies. Genetic code extension offers the contingency of introducing more than one ncAA into protein through frameshift suppression, multi-site-specific incorporation of ncAAs, thereby increasing the vast number of possible applications. However, different mediating factors reduce the yield and efficiency of ncAA incorporation into synthetic proteins. In this review, we comment on the recent advancements in genetic code expansion to signify the relevance of systems biology in improving ncAA incorporation efficiency. We discuss the emerging impact of tRNA modifications and metabolism in protein design. We also provide examples of the latest successful accomplishments in synthetic protein therapeutics and show how codon expansion has been employed in various scientific and biotechnological applications.
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Amino Acid Metabolism in Cancer Drug Resistance.
Yoo, HC, Han, JM
Cells. 2022;(1)
Abstract
Despite the numerous investigations on resistance mechanisms, drug resistance in cancer therapies still limits favorable outcomes in cancer patients. The complexities of the inherent characteristics of tumors, such as tumor heterogeneity and the complicated interaction within the tumor microenvironment, still hinder efforts to overcome drug resistance in cancer cells, requiring innovative approaches. In this review, we describe recent studies offering evidence for the essential roles of amino acid metabolism in driving drug resistance in cancer cells. Amino acids support cancer cells in counteracting therapies by maintaining redox homeostasis, sustaining biosynthetic processes, regulating epigenetic modification, and providing metabolic intermediates for energy generation. In addition, amino acid metabolism impacts anticancer immune responses, creating an immunosuppressive or immunoeffective microenvironment. A comprehensive understanding of amino acid metabolism as it relates to therapeutic resistance mechanisms will improve anticancer therapeutic strategies.
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Metalloprotein-Specific or Critical Amino Acid Residues: Perspectives on Plant-Precise Detoxification and Recognition Mechanisms under Cadmium Stress.
Li, D, He, T, Saleem, M, He, G
International journal of molecular sciences. 2022;(3)
Abstract
Cadmium (Cd) pollution in cultivated land is caused by irresistible geological factors and human activities; intense diffusion and migration have seriously affected the safety of food crops. Plants have evolved mechanisms to control excessive influx of Cd in the environment, such as directional transport, chelation and detoxification. This is done by some specific metalloproteins, whose key amino acid motifs have been investigated by scientists one by one. The application of powerful cell biology, crystal structure science, and molecular probe targeted labeling technology has identified a series of protein families involved in the influx, transport and detoxification of the heavy metal Cd. This review summarizes them as influx proteins (NRAMP, ZIP), chelating proteins (MT, PDF), vacuolar proteins (CAX, ABCC, MTP), long-distance transport proteins (OPT, HMA) and efflux proteins (PCR, ABCG). We selected representative proteins from each family, and compared their amino acid sequence, motif structure, subcellular location, tissue specific distribution and other characteristics of differences and common points, so as to summarize the key residues of the Cd binding target. Then, we explain its special mechanism of action from the molecular structure. In conclusion, this review is expected to provide a reference for the exploration of key amino acid targets of Cd, and lay a foundation for the intelligent design and breeding of crops with high/low Cd accumulation.
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Tolerance development in cow's milk-allergic infants receiving amino acid-based formula: A randomized controlled trial.
Chatchatee, P, Nowak-Wegrzyn, A, Lange, L, Benjaponpitak, S, Chong, KW, Sangsupawanich, P, van Ampting, MTJ, Oude Nijhuis, MM, Harthoorn, LF, Langford, JE, et al
The Journal of allergy and clinical immunology. 2022;(2):650-658.e5
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Abstract
BACKGROUND Tolerance development is an important clinical outcome for infants with cow's milk allergy. OBJECTIVE This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid-based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy. METHODS Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set. RESULTS At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036). CONCLUSIONS After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections.
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Parahydrogen-Induced Polarization of Amino Acids.
Pravdivtsev, AN, Buntkowsky, G, Duckett, SB, Koptyug, IV, Hövener, JB
Angewandte Chemie (International ed. in English). 2021;(44):23496-23507
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Abstract
Nuclear magnetic resonance (NMR) has become a universal method for biochemical and biomedical studies, including metabolomics, proteomics, and magnetic resonance imaging (MRI). By increasing the signal of selected molecules, the hyperpolarization of nuclear spin has expanded the reach of NMR and MRI even further (e.g. hyperpolarized solid-state NMR and metabolic imaging in vivo). Parahydrogen (pH2 ) offers a fast and cost-efficient way to achieve hyperpolarization, and the last decade has seen extensive advances, including the synthesis of new tracers, catalysts, and transfer methods. The portfolio of hyperpolarized molecules now includes amino acids, which are of great interest for many applications. Here, we provide an overview of the current literature and developments in the hyperpolarization of amino acids and peptides.
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Effects of Micronutrients or Conditional Amino Acids on COVID-19-Related Outcomes: An Evidence Analysis Center Scoping Review.
Rozga, M, Cheng, FW, Moloney, L, Handu, D
Journal of the Academy of Nutrition and Dietetics. 2021;(7):1354-1363
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Abstract
Recent narrative reviews have described the potential efficacy of providing individuals infected with coronavirus disease 2019 (COVID-19) with additional micronutrients to reduce disease severity. Although there are compelling reasons why providing additional micronutrients or conditional amino acids may affect COVID-19-related outcomes, evidence is lacking. The objective of this scoping review is to explore and describe the literature examining the effect of providing additional micronutrients or conditional amino acids (glutamine, arginine) in adults with conditions or infections similar to COVID-19 infection on COVID-19-related health outcomes. A literature search of the MEDLINE database and hand search of Cochrane Database of systematic reviews retrieved 1,423 unique studies, and 8 studies were included in this scoping review. Four studies examined a target population with ventilator-related pneumonia and acute respiratory distress syndrome, and the other 4 studies included patients who were at risk for ventilator-associated pneumonia. Interventions included intravenous ascorbic acid, intramuscular cholecalciferol, enteral and intramuscular vitamin E, enteral zinc sulfate, and oral and parenteral glutamine. In 6 of the 8 included studies, baseline status of the nutrient of interest was not reported and, thus, it is uncertain how outcomes may vary in the context of nutrient deficiency or insufficiency compared with sufficiency. In the absence of direct evidence examining efficacy of providing additional micronutrients or conditional amino acids to standard care, registered dietitian nutritionists must rely on clinical expertise and indirect evidence to guide medical nutrition therapy for patients infected with COVID-19.
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Amino Acid-Induced Impairment of Insulin Signaling and Involvement of G-Protein Coupling Receptor.
Zakaria, NF, Hamid, M, Khayat, ME
Nutrients. 2021;(7)
Abstract
Amino acids are needed for general bodily function and well-being. Despite their importance, augmentation in their serum concentration is closely related to metabolic disorder, insulin resistance (IR), or worse, diabetes mellitus. Essential amino acids such as the branched-chain amino acids (BCAAs) have been heavily studied as a plausible biomarker or even a cause of IR. Although there is a long list of benefits, in subjects with abnormal amino acids profiles, some amino acids are correlated with a higher risk of IR. Metabolic dysfunction, upregulation of the mammalian target of the rapamycin (mTOR) pathway, the gut microbiome, 3-hydroxyisobutyrate, inflammation, and the collusion of G-protein coupled receptors (GPCRs) are among the indicators and causes of metabolic disorders generating from amino acids that contribute to IR and the onset of type 2 diabetes mellitus (T2DM). This review summarizes the current understanding of the true involvement of amino acids with IR. Additionally, the involvement of GPCRs in IR will be further discussed in this review.
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Gluconeogenesis in Plants: A Key Interface between Organic Acid/Amino Acid/Lipid and Sugar Metabolism.
Walker, RP, Chen, ZH, Famiani, F
Molecules (Basel, Switzerland). 2021;(17)
Abstract
Gluconeogenesis is a key interface between organic acid/amino acid/lipid and sugar metabolism. The aims of this article are four-fold. First, to provide a concise overview of plant gluconeogenesis. Second, to emphasise the widespread occurrence of gluconeogenesis and its utilisation in diverse processes. Third, to stress the importance of the vacuolar storage and release of Krebs cycle acids/nitrogenous compounds, and of the role of gluconeogenesis and malic enzyme in this process. Fourth, to outline the contribution of fine control of enzyme activity to the coordinate-regulation of gluconeogenesis and malate metabolism, and the importance of cytosolic pH in this.
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DIOXYGENASE FOR AUXIN OXIDATION 1 catalyzes the oxidation of IAA amino acid conjugates.
Müller, K, Dobrev, PI, Pěnčík, A, Hošek, P, Vondráková, Z, Filepová, R, Malínská, K, Brunoni, F, Helusová, L, Moravec, T, et al
Plant physiology. 2021;(1):103-115
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Abstract
Together with auxin transport, auxin metabolism is a key determinant of auxin signaling output by plant cells. Enzymatic machinery involved in auxin metabolism is subject to regulation based on numerous inputs, including the concentration of auxin itself. Therefore, experiments characterizing altered auxin availability and subsequent changes in auxin metabolism could elucidate the function and regulatory role of individual elements in the auxin metabolic machinery. Here, we studied auxin metabolism in auxin-dependent tobacco BY-2 cells. We revealed that the concentration of N-(2-oxindole-3-acetyl)-l-aspartic acid (oxIAA-Asp), the most abundant auxin metabolite produced in the control culture, dramatically decreased in auxin-starved BY-2 cells. Analysis of the transcriptome and proteome in auxin-starved cells uncovered significant downregulation of all tobacco (Nicotiana tabacum) homologs of Arabidopsis (Arabidopsis thaliana) DIOXYGENASE FOR AUXIN OXIDATION 1 (DAO1), at both transcript and protein levels. Auxin metabolism profiling in BY-2 mutants carrying either siRNA-silenced or CRISPR-Cas9-mutated NtDAO1, as well as in dao1-1 Arabidopsis plants, showed not only the expected lower levels of oxIAA, but also significantly lower abundance of oxIAA-Asp. Finally, ability of DAO1 to oxidize IAA-Asp was confirmed by an enzyme assay in AtDAO1-producing bacterial culture. Our results thus represent direct evidence of DAO1 activity on IAA amino acid conjugates.