Branched-chain Amino Acids Research Articles

Acetohydroxyacid Synthase (AHAS) inhibitors as Antitubercular agents: Insights from Molecular Docking and Dynamics Simulations.

Acetohydroxyacid synthase (AHAS) is a vital enzyme in Mycobacterium tuberculosis, the pathogen causing tuberculosis (TB), involved in branched-chain amino acid synthesis. Targeting AHAS for drug design against TB offers a promising strategy due to its essentiality in bacterial growth. In current investigation, we have designed 160 novel compounds by leveraging key scaffolds identified through structure-based drug design (SBDD) methodologies. Subsequently, these compounds underwent molecular docking analysis to elucidate their potential interactions with the AHAS protein. The top four compounds resulting from the docking studies were subjected to rigorous molecular dynamics simulations, spanning a runtime of 100 nanoseconds, to assess their stability across various parameters including Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Secondary Structure Elements (SSE), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and MM-GBSA free energy values. Remarkably, compounds KG 98 and KG 131 exhibited superior stability profiles across all analyzed parameters. From the detailed interactions analysis, it was found that the nitrogen containg heterocyclic rings (1,3,5-triazine/imidizole) are essential to have the potential binding interactions with the AHAS enzyme. The findings suggest these lead molecules as promising candidates for AHAS inhibition, a potential avenue for tuberculosis treatment and management.

The branched-chain amino acid-related isoleucic acid: recent research advances.

Isoleucic acid (ILA) was identified in human patients with maple syrup urine disease (MSUD) half a century ago. MSUD patients, who are defective in the catabolism of branched-chain amino acids (BCAAs), that is, isoleucine, leucine, and valine, have urine with a unique maple syrup odour related to the accumulation of BCAA breakdown products, largely 2-keto acid derivatives and their reduced 2-hydroxy acids including ILA. A decade ago, ILA was identified in Arabidopsis thaliana. Subsequent studies in other plant species indicated that ILA is a ubiquitously present compound. Since its identification in plants, several efforts have been made to understand the biological significance and metabolic pathway of ILA. ILA plays a positive role in plant signalling for defence responses against bacterial pathogens by increasing the abundance of salicylic acid aglycone through competitive inhibition of SA deactivation by glucosylation. Here, we review recent progress in the characterization of ILA biosynthesis and function in plants and discuss current knowledge gaps and future directions in ILA research.

Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction

Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions.

Quantum chemical study of molecular properties of small branched-chain amino acids in water

Four aliphatic amino acids—α-aminobutyric acid (AABA), β-aminobutyric acid (BABA), α-aminoisobutyric acid (AAIBA) and β-aminoisobutyric acid (BAIBA) were investigated in water as a solvent by two quantum chemical methods. B3LYP hybrid version of DFT was used for geometry optimization and a full vibrational analysis of neutral molecules, their cations and anions in the canonical and zwitterionic forms (6 forms for each species). Ab initio DLPNO-CCSD(T) method was applied in the geometry pre-optimized by B3LYP. Calculated molecular descriptors involve dipole moment, quadrupole moment, dipole polarizability, energy of zero-point vibration and total entropic term which enter the standard Gibbs energy. In addition, a set of collective electronic and thermodynamic properties associated with redox process were evaluated: ionization energy, electron affinity, chemical hardness, molecular electronegativity, electrophilicity index, absolute oxidation and reduction potentials. A mutual comparison of these structural isomers including γ-aminobutyric acid (GABA) shows high degree of similarity in molecular descriptors. However, cluster analysis of 12 electro neutral, linear and branched amino acids with 2 – 6 carbon atoms discriminates them into five clusters. It is found that the electrophilicity index correlates with the absolute reduction potential along a straight line (24 items). The reduction potential for canonical structure varies between 1.21 V (glycine) and 1.45 V (AABA) whereas for the zwitterionic form it is visibly lower 0.52–1.11 V. The highest absolute reduction potential > 1.43 V is shown by α-amino acids: α-alanine, AABA (homoalanine) and AAIBA having 2-methyl or 2-ethyl functional group. The calculated absolute oxidation potential correlates with the adiabatic ionization energy and can be used as a criterion of the antioxidant capacity. According to thermodynamic data, the SPLET mechanism of the electron-proton coupled transfer is favored over the alternative SET-PT mechanism. This work contributes to the creation of a database of molecular properties of amino acids based on the same method and basis set.

Perch Hydrolysates from Upcycling of Perch Side Streams Accelerate Wound Healing by Enhancing Fibroblasts to Secrete Procollagen I, Fibronectin, and Hyaluronan.

Wound healing incurs various challenges, making it an important topic in medicine. Short-chain peptides from fish protein hydrolysates possess wound healing properties that may represent a solution. In this study, perch hydrolysates were produced from perch side steams using a designed commercial complex enzyme via a proprietary pressure extraction technique. The average molecular weight of the perch peptides was 1289 kDa, and 62.60% of the peptides had a low molecular weight (≤1 kDa). Similarly to the beneficial amino acid sequence FPSIVGRP, FPSLVRGP accounted for 6.21% abundance may have a potential antihypertensive effect. The concentrations of collagen composition and branched-chain amino acids were 1183 and 1122 mg/100 g, respectively. In a fibroblast model, active perch peptides accelerated wound healing mainly by increasing the secretion of procollagen I, fibronectin, and hyaluronan. In an SD rat model established to mimic human wounds, orally administered perch hydrolysates with a molecular weight below 2.3 kDa accelerated wound healing, which mainly resulted from collagen-forming amino acids, branched-chain amino acids, and matrikine. Collectively, the residue of perch extract can be upcycled via a hydrolysis technique to produce not only bioactive sequences but also short-chain peptides. Considering the therapeutic potential to promote wound healing, such by-products are of great value and may be developed as dietary nutraceuticals.

A Randomized, Placebo-Controlled, Single-Center, Crossover Study to Evaluate the Effects of Pre-Meal Whey Protein Microgel on Post-Prandial Glucometabolic and Amino Acid Response in People with Type 2 Diabetes and Overweight or Obesity.

Purpose: Whey protein (WP) consumption prior to a meal curbs appetite and reduces postprandial glucose (PPG) through stimulating endogenous GLP-1 secretion and insulin. Methods: We assessed the metabolic effects of a concentrated WP, using a new micelle-technology (WPM), in people with type 2 diabetes (T2D) and overweight or obesity (NCT04639726). In a randomized-crossover design, participants performed two 240 min lunch meal (622 kcal) tests 7 ± 4 days apart. After an overnight fast and a standardized breakfast, 10 g (125 mL) WPM (40 kcal) or placebo (125 mL water, 0 kcal) was consumed 15 min ahead of the mixed-nutrient meal. Effects on PPG (primary endpoint), insulin, GLP-1, and branched-chain amino acids (BCAAs) were evaluated with frequent blood sampling. Changes in incremental areas under the concentration curve (iAUC) were compared using a mixed model. Results: Twenty-six individuals (14 females, mean ± SD age 62.0 ± 8.3 years, HbA1c 58 ± 12 mmol/mol/7.5 ± 1.1%, BMI 29.2 ± 4.8 kg/m2) completed both tests. WPM significantly reduced PPG iAUC0-2h by 22% (p = 0.028), and iAUC0-3h numerically by -18% (p = 0.090) vs. placebo. WPM also increased insulin iAUC0-1h by 61% (p < 0.001), and iAUC0-3h by 30% (p = 0.004), respectively. Total GLP-1 iAUC0-2h was enhanced by 66% (p < 0.001). Postprandial plasma BCAA patterns were characterized by a rapid increase and larger iAUC0-2h (all p < 0.001) after WPM. No adverse events were ascribed to consuming WPM. Conclusions: A 125 mL pre-meal drink containing just 10 g WPM before a mixed meal reduced PPG and increased insulin, GLP-1, and BCAAs. WPM may therefore serve as a metabolic modulator in people with T2D living with overweight or obesity.

Caloric restriction exacerbates renal post-ischemic injury and fibrosis by modulating mTORC1 signaling and autophagy.

This study investigates the effects of caloric restriction (CR) on renal injury and fibrosis following ischemia-reperfusion injury (IRI), with a focus on the roles of the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signaling and autophagy. A mouse model of unilateral IRI with or without CR was used. Renal function was assessed through serum creatinine and blood urea nitrogen levels, while histological analysis and molecular assays evaluated tubular injury, fibrosis, mTORC1 signaling, and autophagy activation. Inducible renal tubule-specific Atg7 knockout mice and autophagy inhibitor 3-MA were used to elucidate autophagy's role in renal outcomes. CR exacerbated renal dysfunction, tubular injury, and fibrosis in IRI mice, associated with suppressed mTORC1 signaling and enhanced autophagy. Rapamycin, an mTORC1 inhibitor, mimicked the effects of CR, further supporting the involvement of mTORC1-autophagy pathway. Tubule-specific Atg7 knockout and autophagy inhibitor 3-MA mitigated these effects, indicating a central role for autophagy in CR-induced renal damage. Glucose supplementation, but not branched-chain amino acids (BCAAs), alleviated CR-induced renal fibrosis and dysfunction by restoring mTORC1 activation. Finally, we identified leucyl-tRNA synthetase 1 (LARS1) as a key mediator of nutrient sensing and mTORC1 activation, demonstrating its glucose dependency under CR conditions. Our study provides novel insights into the interplay between nutrient metabolism, mTORC1 signaling, and autophagy in IRI-induced renal damages, offering potential therapeutic targets for mitigating CR-associated complications after renal IRI.

Metabolomic in severe traumatic brain injury: exploring primary, secondary injuries, diagnosis, and severity

BackgroundTraumatic brain injury (TBI) is a major public health concern worldwide, contributing to high rates of injury-related death and disability. Severe traumatic brain injury (sTBI), although it accounts for only 10% of all TBI cases, results in a mortality rate of 30–40% and a significant burden of disability in those that survive. This study explored the potential of metabolomics in the diagnosis of sTBI and explored the potential of metabolomics to examine probable primary and secondary brain injury in sTBI.MethodsSerum samples from 59 adult patients with sTBI and 35 age- and sex-matched orthopedic injury controls were subjected to quantitative metabolomics, including proton nuclear magnetic resonance (1H-NMR) and direct infusion/liquid chromatography-tandem mass spectrometry (DI/LC–MS/MS), to identify and quantify metabolites on days 1 and 4 post-injury. In addition, we used advanced analytical methods to discover metabo-patterns associated with sTBI diagnosis and those related to probable primary and secondary brain injury.ResultsOur results showed different serum metabolic profiles between sTBI and orthopedic injury (OI) controls, with significant changes in measured metabolites on day 1 and day 4 post-brain injury. The number of altered metabolites and the extent of their change were more pronounced on day 4 as compared to day 1 post-injury, suggesting an evolution of mechanisms from primary to secondary brain injury. Data showed high sensitivity and specificity in separating sTBI from OI controls for diagnosis. Energy-related metabolites such as glucose, pyruvate, lactate, mannose, and polyamine metabolism metabolites (spermine and putrescine), as well as increased acylcarnitines and sphingomyelins, occurred mainly on day 1 post-injury. Metabolites of neurotransmission, catecholamine, and excitotoxicity mechanisms such as glutamate, phenylalanine, tyrosine, and branched-chain amino acids (BCAAs) increased to a greater degree on day 4. Further, there was an association of multiple metabolites, including acylcarnitines (ACs), lysophosphatidylcholines (LysoPCs), glutamate, and phenylalanine, with injury severity at day 4, while lactate, glucose, and pyruvate correlated with injury severity on day 1.ConclusionThe results demonstrate that serum metabolomics has diagnostic potential for sTBI and may reflect molecular mechanisms of primary and secondary brain injuries when comparing metabolite profiles between day 1 and day 4 post-injury. These early changes in serum metabolites may provide insight into molecular pathways or mechanisms of primary injury and ongoing secondary injuries, revealing potential therapeutic targets for sTBI. This work also highlights the need for further research and validation of sTBI metabolite biomarkers in a larger cohort.

Amino Acid Patterns in Children with Autistic Spectrum Disorder: A Preliminary Biochemical Evaluation.

The metabolism of plasma amino acid (AA) in children with autism spectrum disorder (ASD) has been extensively investigated, yielding inconclusive results. This study aims to characterize the metabolic alterations in AA profiles among early-diagnosed children with ASD and compare the findings with those from non-ASD children. We analyzed plasma AA profiles, measured by ion exchange chromatography, from 1242 ASD children (median age = 4 years; 81% male). Additionally, we studied AA profiles from 488 children, matched for age and free of ASD (control group). Principal component and cluster analysis were employed to explore potential associations within the ASD group and to identify subgroups. We observed lower plasma levels of glutamine in children with ASD compared to non-ASD children (p < 0.001). Six essential, two conditionally essential, and four non-essential AA were found to be increased in children with ASD. The clustering analysis revealed two groups, labeled Neurological (NEU) and Nutritional (NUT), which included a majority of ASD children (94% and 78%, respectively). The NEU group exhibited high levels of taurine, aspartate, glutamic acid, and ornithine, while the NUT group showed elevated levels of branched-chain AA. In children with ASD, we identified some heterogeneous AA patterns that may serve as biochemical signatures of neurological impairment in some individuals, while in others they may indicate nutritional dysregulation.

The relationship between dietary branched-chain and aromatic amino acids with the regulation of leptin and FTO genes in adipose tissue of patients undergoing abdominal surgery

Recent studies have suggested that the interaction between diet and an individual’s genetic predisposition can determine the likelihood of obesity and various metabolic disorders. The current study aimed to examine the association of dietary branched-chain amino acids(BCAAs) and aromatic amino acids(AAAs) with the expression of the leptin and FTO genes in the visceral and subcutaneous adipose tissues of individuals undergoing surgery. This cross-sectional study was conducted on 136 Iranian adults, both men and women, aged ≥18 years. The samples were selected from patients admitted for abdominal surgeries. The dietary intake of BCAAs and AAAs was determined using a valid and reliable 168-item food frequency questionnaire. Using the quantitative PCR method, leptin and FTO mRNA expression was measured in both visceral and subcutaneous fat tissues. The mean age of the participants was 39.8 ± 12.7 years, and the mean intake of BCAAs and AAAs was 17.7 ± 0.9 and 9.3 ± 0.3% of protein per day, respectively. In overweight-obese patients(body mass index = 25–34.9 kg/m2), the intake of BCAAs(β:-0.75,95%CI:-1.47,-0.03), valine(β:-0.78,95%CI:-1.51,-0.05), and tyrosine(β:-0.81,95%CI:-1.55,-0.06) was inversely associated with FTO gene expression in subcutaneous fat tissue in adjusted model. In morbidly obese patients(body mass index ≥ 35 kg/m2), a higher intake of total BCAAs(β:1.10,95%CI:0.07–2.13), leucine(β:1.07,95%CI:0.03–2.13), and isoleucine(β:1.49,95%CI:0.46–2.52) was associated with an increase of leptin gene expression in subcutaneous fat tissue. Our findings suggest that dietary BCAA may associated with gene expression in adipose tissues, potentially influencing obesity-related metabolic pathways. Further prospective studies are warranted to validate results and elucidate the potential for dietary interventions targeting amino acids intake in obesity management.

The supply of branched-chain amino acids and branched-chain keto acids alter lipid metabolism, oxidative stress, and apoptosis in primary bovine hepatocytes.

Fatty liver impairs liver function and reduces productivity in dairy cows. Our previous in vivo findings demonstrated that branched-chain amino acids (BCAA) or branched-chain ketoacid (BCKA) improved liver function and lactation performance in dairy cows; however, the underlying mechanisms remain unclear. This study aimed to assess the impact of BCAA or BCKA supplementation on intracellular triglyceride (TG) accumulation, lipid metabolism, antioxidant response, and apoptosis in hepatocytes. Treatments were: control (CON): customized medium with amino acids, volatile fatty acids, fatty acids (FA), glucose, choline, insulin, and albumin concentrations equal to circulating levels in cows 4d postpartum; BCAA: CON + 33% additional BCAA of plasma BCAA 4d postpartum; and BCKA: CON + 33% additional BCKA of plasma BCAA 4d postpartum. Compared to CON, BCAA and BCKA reduced intracellular TG concentration by 32% and 40%, respectively, after 72 h. BCAA and BCKA enhanced the uptake of palmitic acid, but upregulated the expression of genes regulating FA oxidation. Although mitochondrial membrane potential was reduced, oxidative protein damage (protein carbonyl levels) was decreased in BCAA- and BCKA-treated hepatocytes without changes in mitochondrial copy number. Additionally, compared to CON, BCAA and BCKA decreased the expression of executioner caspases (caspase 3 and caspase 7) and reduced the portion of hepatocytes with activated caspase 3/7, suggesting reduced apoptosis. These findings suggest that BCAA or BCKA supplementation improves hepatocyte lipid metabolism, antioxidant defenses, and apoptosis regulation, potentially mitigating the adverse effects of fatty liver. These mechanisms likely underlie the previously observed improvements in liver function and lactation performance.

Multimodal Metabolomics Analysis Reveals That Classic Decoction Mitigates Myocardial Ischemia-Induced Damage by Modulating Energy and Branched-Chain Amino Acid Metabolism.

Gualou-Xiebai-Banxia (GXB) decoction shows potential for treating myocardial ischemia (MI), although its underlying mechanism is not fully understood. In this study, a multimodal metabolomics approach, combining gas chromatography-mass spectrometry (GC-MS) and 1H-NMR, was employed to investigate the cardioprotective effects of GXB in a rat model of myocardial ischemia induced by ligation. ELISA assays and HE staining demonstrated that GXB effectively reduced myocardial injury, oxidative stress markers, and myocardial fibrosis. Orthogonal partial least-squares discriminant analysis identified 62 biomarkers, 20 of which were confirmed using standard compounds. The GC-MS method showed excellent linearity across a wide concentration range (0.004-29.7 μg/mL, R2 > 0.9995), with intra- and inter-day precision RSD values below 4.72% and 4.96%, respectively. Method recoveries ranged from 95.40% to 104.83%, with RSD values under 4.84%. Pathway enrichment analysis revealed that GXB decoction alleviates myocardial ischemia-induced damage primarily by modulating energy metabolism and branched-chain amino acid metabolism. These findings provide valuable support for the clinical application of GXB decoction in treating myocardial ischemia.

Exploration of Novel Metabolic Mechanisms Underlying Primary Biliary Cholangitis Using Hepatic Metabolomics, Lipidomics, and Proteomics Analysis.

Metabolic reprogramming is important in primary biliary cholangitis (PBC) development. However, studies investigating the metabolic signature within the liver of PBC patients are limited. In this study, liver biopsies from 31 PBC patients and 15 healthy controls were collected, and comprehensive metabolomics, lipidomics, and proteomics analysis were conducted to characterize the metabolic landscape in PBC. We observed distinct lipidome remodeling in PBC with increased polyunsaturated fatty acid levels and augmented fatty acid β-oxidation (FAO), evidenced by the increased acylcarnitine levels and upregulated expression of proteins involved in FAO. Notably, PBC patients exhibited an increase in glucose-6-phosphate (G6P) and purines, alongside a reduction in pyruvate, suggesting impaired glycolysis and increased purines biosynthesis in PBC. Additionally, the accumulation of bile acids as well as a decrease in branched chain amino acids and aromatic amino acids were observed in PBC liver. We also observed an aberrant upregulation of proteins associated with ductular reaction, apoptosis, and autophagy. In conclusion, our study highlighted substantial metabolic reprogramming in glycolysis, fatty acid metabolism, and purine biosynthesis, coupled with aberrant upregulation of proteins associated with apoptosis and autophagy in PBC patients. Targeting the specific metabolic reprogramming may offer potential targets for the therapeutic intervention of PBC.

Obesity Incidence According to Branched-Chain Amino Acid Intake and Plant-Based Diet Index Among Brazilian Adults: A Six-Year Follow-Up of the CUME Study.

Few studies have evaluated the impact of branched-chain amino acid (BCAA) intake on the risk of obesity in adults. The results are contradictory, and the causality has not been explored. This study assessed the association between BCAA intake and obesity incidence among Brazilian adults and investigated the potential moderating role of the plant-based index (PDI) in this relationship. A longitudinal study was conducted between 2016 and 2022, with 3090 participants (2043 women, 1047 men; mean age 34 years) from the Cohort of Universities of Minas Gerais (CUME) Study. Data were collected through an online questionnaire. The relationship between BCAA intake and obesity incidence was assessed using crude and adjusted Cox regression models. Restricted cubic spline analysis (RCS) was used to estimate the nonlinearity. The multiplicative interaction with PDI was tested. The overall incidence of obesity was 192 cases (6.21%). The incidence was 16.4/1000 person-years in females; 21.8/1000 person-years in males; and 18.3/1000 person-years total, with a mean follow-up period of 3.4 years. Compared to the first tertile, the highest intake tertiles for BCAA (HR = 1.50, 95% CI = 1.03-2.18), isoleucine (HR = 1.52, 95% CI = 1.04-2.22), and leucine (HR = 1.51, 95% CI = 1.03-2.20) were independently associated with obesity risk. BCAA intake above 16 g/day increases the risk of obesity. There was a positive association between the intake of BCAA, isoleucine, and leucine with the risk of obesity. The PDI accentuated the association between BCAA intake and obesity in both the lowest and highest quintiles.

Interlinking the Cross Talk on Branched Chain Amino Acids, Water Soluble Vitamins and Adipokines in the Type 2 Diabetes Mellitus Etiology.

Type 2 Diabetes Mellitus (T2DM) is an etiologically diverse metabolic dysfunction that, if untreated, leads to chronic hyperglycemia. Understanding the etiology of T2DM is critical, as it represents one of the most formidable medical challenges of the twenty-first century. Traditionally, insulin resistance has been recognized as the primary risk factor and a well-known consequence of type 2 diabetes. Emerging evidence suggests that branched-chain amino acids (BCAAs), adipokines, and deficiencies in water-soluble vitamins, such as thiamine and pyridoxine, play significant roles in the development of insulin resistance, a key feature of T2DM. These factors are interconnected through the AMP-activated protein kinase (AMPK) pathway, which regulates various metabolic processes, including glucose transport, lipid synthesis, and inflammatory responses. Dysregulation of AMPK is linked to insulin resistance and metabolic syndrome-related illnesses. Understanding the interplay between BCAAs, adipokines, vitamins, and AMPK may offer new therapeutic targets for the prevention and treatment of diabetes mellitus.

Amino Acid Supplementation May Help Prevent Muscle Wasting After Orthopedic Surgery, but Additional Studies Are Warranted: A Systematic Review of Randomized Clinical Trials.

Background: Essential amino acid (EAA) supplementation, including conditionally essential amino acid (CEAA) and branched-chain amino acids (BCAA) supplementation, has been suggested as a mechanism to optimize patient outcomes by counteracting the atrophy associated with orthopedic procedures. Purpose: We sought to investigate the effect of EAA supplementation in the perioperative period on patients undergoing orthopedic and spine surgery, specifically whether it is associated with (1) reductions in postoperative muscle atrophy and (2) improved postoperative function including range of motion, strength, and mobility. Methods: We conducted a systematic review of the literature. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used, and the protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO) database (CRD42023447774). Studies of interest were prospective, placebo-controlled, randomized clinical trials (RCTs) published between 2002 and 2023 evaluating the impact of EAA supplementation on patients undergoing orthopedic and spine surgery. Results: Ten RCTs evaluating EAA supplementation in trauma, adult reconstruction, and spine surgery were identified; half of these focused on adult reconstruction. The EAA supplementation dose (3.4-20 g), frequency (daily to 3 times per day), and duration (14-49 days) varied widely across studies. Seven studies reported parameters relating to muscle size and/or composition, with 3 studies reporting superior muscle size/composition in patients receiving perioperative EAA supplementation, when compared with controls. Three studies reported favorable mobility outcomes for patients receiving EAA. Meta-analysis was prohibited by variation in measurement and outcome variables across the studies. Conclusions: Pooled data from level I studies supports the use of EAA, BCAA, and CEAA supplementations across several orthopedic subspecialties. However, significant heterogeneity exists in the quantity, duration, and content of EAA administered. Further prospective studies are needed to determine optimal/standardized parameters for supplementation.

A Review on Branched-Chain Amino Acid Aminotransferase (BCAT) Inhibitors: Current Status, Challenges and Perspectives.

Branched-chain amino acids (BCAAs) are essential amino acids for humans and play an indispensable role in many physiological and pathological processes. Branched-chain amino acid aminotransferase (BCAT) is a key enzyme that catalyzes the metabolism of BCAAs. BCAT is upregulated in many cancers and implicated in the development and progress of some other diseases, such as metabolic and neurological diseases; and therefore, targeting BCAT might be a potential therapeutic approach for these diseases. There are two isoforms of BCAT, i.e., cytoplasmic BCAT1 (or BCATc) and mitochondrial BCAT2 (or BCATm). The discovery of BCAT inhibitors was initiated by Warner-Lambert, a subsidiary of Pfizer, in 2000, followed by many other pharmaceutical companies, such as GlaxoSmithKline (GSK), Ergon, Icagen, Agios, and Bayer. Strategies of high-throughput screening (HTS), DNA-Encoded library technology (ELT), and fragment-based screening (FBS) have been employed for hit identification, followed by structural optimization. Despite low selectivity, both BCAT1 and BCAT2 selective inhibitors were individually developed, each with a few chemical structural classes. The most advanced BCAT1 inhibitor is BAY-069, discovered by Bayer, which has a potent enzymatic inhibitory activity against BCAT1 and a decent in vitro and in vivo pharmacokinetic profile but displayed weaker cellular inhibitory activity and almost no anti-proliferative activity. There are no BCAT inhibitors currently under investigation in clinical trials. Further studies are still needed to discover BCAT inhibitors with a more druggable profile for proof of concept. This review focuses on the latest progress of studies on the understanding of the physiology and pathology of BCAT and the discovery and development of BCAT inhibitors. The structure-activity relationship (SAR) and the druggability, and the challenges of BCAT inhibitors are discussed, with the aim of inspiring the discovery and development of BCAT inhibitors in the future.

Branched-Chain Amino Acids (BCAAs): Revisiting Their Role in Sport and Health

Branched-Chain Amino Acids (BCAAs): Revisiting Their Role in Sport and Health

Branched-chain amino acids levels associated with risk of erectile dysfunction: A Mendelian randomization analysis.

Erectile dysfunction (ED) is a prevalent male sexual dysfunction that remarkably impacts patients' quality of life and is also recognized as a precursor to cardiovascular disease (CVD) events. Branched-chain amino acids (BCAAs) are derived from dietary intake and mainly involved in energy metabolism. Previous studies have underscored the association between BCAAs and CVD, but the causal link between BCAAs and ED remains uncertain. The bidirectional Mendelian randomization (MR) study used the genetic data from genome-wide association studies (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with total BCAAs, leucine, isoleucine, and valine. The genetic data for ED were acquired from the FinnGen study (n = 95,178). The primary method used to assess causal associations was the inverse variance-weighted (IVW) method, supplemented by MR-Egger, weighted median, and simple median analyses. Cochrane's Q test was utilized to evaluate heterogeneity within the results, while the MR-Egger intercept test was utilized to evaluate the Level pleiotropy. A sensitivity analysis was performed employing leave-one-out analysis. The MR analysis results indicate a positive correlation between levels of total BCAA (OR = 1.984, 95 % CI = 1.018-3.868, P = 0.044), leucine (OR = 2.277, 95 % CI = 1.121-4.626, P = 0.023), isoleucine (OR = 2.584, 95 % CI = 1.167-5.722, P = 0.019), valine (OR = 1.894, 95 % CI = 1.119-3.206, P = 0.017), and the risk of ED. Sensitivity tests confirmed the accuracy and robustness of the study findings. Moreover, the reverse MR analysis found no association between ED and the BCAAs. The results of this analysis indicate a positive association between the circulating BCAA concentrations and the risk of ED, but their underlying mechanisms require further investigation.

In vivo itaconate tracing reveals degradation pathway and turnover kinetics.

Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized via tricarboxylic acid (TCA) metabolism downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation, and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13 C itaconate tracing, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine, and fuels TCA cycle metabolism specifically in the liver and kidneys. These studies further revealed that itaconate is converted into acetyl-CoA, mesaconate, and citramalate in mitochondria. Itaconate administration also influenced branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase (SDH) and methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered a previously unknown aspect of the itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.