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Valbenazine is a highly potent and selective inhibitor of synaptic vesicular monoamine transporter 2. The current therapeutic doses of valbenazine for tardive dyskinesia (TD) are 40, 60, or 80 mg capsules, given orally, once daily (QD). While 40 and 80 mg were investigated in phase 3 KINECT® 3 trial and initially approved, the approval of valbenazine 60 mg was based on the analysis utilizing the Model‐informed drug development (MIDD) approach, facilitated through the US Food and Drug Administration's MIDD Pilot Program. This study aimed to demonstrate the efficacy of 60 mg QD dose through model simulations using an established exposure‐response (E‐R) relationship between valbenazine active metabolite [+]‐α‐dihydrotetrabenazine exposure and the change from baseline in Abnormal Involuntary Movement Scale total score (AIMS‐CFB). A longitudinal E–R model was constructed based on the 40 and 80 mg data from the KINECT 3 trial. The final Emax model adequately predicted dose‐dependent improvement in the primary endpoint and was used to interpolate AIMS‐CFB for 60 mg at week 6. The efficacy of the unstudied 60 mg dose regimen is expected to be within the range of doses studied clinically with predicted mean AIMS‐CFB (95% confidence interval) of −2.69 (−3.30, −2.13) between observed mean AIMS‐CFB for 40 mg of −1.92 and 80 mg of −3.39. Results from this analysis provided the key evidence to establish efficacy of 60 mg QD without the need for an additional clinical trial. The availability of valbenazine 60 mg dose fills an existing medical need for patients with TD who could benefit from this third effective dose. [ABSTRACT FROM AUTHOR]

Background: The high global prevalence of prediabetes requires its early identification. Amino acids (AAs) have emerged as potential predictors of prediabetes. This study investigates the association between amino acids and prediabetes in the Kazakh population. Materials and Methods: In this case-control study, serum AAs levels were measured using the Trace GC 1310 gas chromatography system coupled with the TSQ 8000 triple quadrupole mass spectrometer (Thermo Scientific, Austin, TX, USA) followed by silylation with the BSTFA + 1% TMCS derivatization method. Biochemical parameters, including total cholesterol, HDL-C, LDL-C, triglycerides, fasting glucose, HbA1c, and Creatinine, were assessed for each participant. Trained professionals conducted anthropometric and physical examinations (which included taking blood pressure and heart rate measurements) and family history collection. Results: A total of 112 Kazakh individuals with prediabetes and 55 without prediabetes, aged 36–65 years, were included in the study. Only Alanine and valine showed a significant association with prediabetes risk among the 13 AAs analyzed. Our findings revealed an inverse relationship between Alanine and Valine and prediabetes in individuals of Kazakh ethnicity. Conclusion: A lower serum level of Alanine and Valine may serve as a predictive biomarker for prediabetes in the Kazakh population. [ABSTRACT FROM AUTHOR]

Background: Diets with high inclusion of corn co-products such as corn fermented protein (CFP) may contain excess Leu, which has a negative impact on feed intake and growth performance of pigs due to increased catabolism of Val and Ile and reduced availability of Trp in the brain for serotonin synthesis. However, we hypothesized that the negative effect of using CFP in diets for weanling pigs may be overcome if diets are fortified with crystalline sources of Val, Trp, and (or) Ile. Methods: Three hundred and twenty weanling pigs were randomly allotted to one of 10 dietary treatments in a completely randomized design, with 4 pigs per pen and 8 replicate pens per treatment. A corn-soybean meal diet and 2 basal diets based on corn and 10% CFP or corn and 20% CFP were formulated. Seven additional diets were formulated by fortifying the basal diet with 20% CFP with Ile, Trp, Val, Ile and Val, Ile and Trp, Trp and Val, or Ile, Trp and Val. A two-phase feeding program was used, with d 1 to 14 being phase 1 and d 15 to 28 being phase 2. Fecal scores were recorded every other day. Blood samples were collected on d 14 and 28 from one pig per pen. On d 14, fecal samples were collected from one pig per pen in 3 of the 10 treatments to determine volatile fatty acids, ammonium concentration, and microbial protein. These pigs were also euthanized and ileal tissue was collected. Results: There were no effects of dietary treatments on any of the parameters evaluated in phase 1. Inclusion of 10% or 20% CFP in diets reduced (P < 0.05) final body weight on d 28, and average daily gain (ADG) and average daily feed intake (ADFI) in phase 2 and for the entire experimental period. However, pigs fed the CFP diet supplemented with Val, Ile, and Trp had final body weight, ADFI, ADG and gain to feed ratio in phase 2 and for the entire experiment that was not different from pigs fed the control diet. Fecal scores in phase 2 were reduced (P < 0.05) if CFP was used. Conclusions: Corn fermented protein may be included by up to 20% in diets for weanling pigs without affecting growth performance, gut health, or hindgut fermentation, if diets are fortified with extra Val, Trp, and Ile. Inclusion of CFP also improved fecal consistency of pigs. [ABSTRACT FROM AUTHOR]

Abstract Background Diets with high inclusion of corn co-products such as corn fermented protein (CFP) may contain excess Leu, which has a negative impact on feed intake and growth performance of pigs due to increased catabolism of Val and Ile and reduced availability of Trp in the brain for serotonin synthesis. However, we hypothesized that the negative effect of using CFP in diets for weanling pigs may be overcome if diets are fortified with crystalline sources of Val, Trp, and (or) Ile. Methods Three hundred and twenty weanling pigs were randomly allotted to one of 10 dietary treatments in a completely randomized design, with 4 pigs per pen and 8 replicate pens per treatment. A corn-soybean meal diet and 2 basal diets based on corn and 10% CFP or corn and 20% CFP were formulated. Seven additional diets were formulated by fortifying the basal diet with 20% CFP with Ile, Trp, Val, Ile and Val, Ile and Trp, Trp and Val, or Ile, Trp and Val. A two-phase feeding program was used, with d 1 to 14 being phase 1 and d 15 to 28 being phase 2. Fecal scores were recorded every other day. Blood samples were collected on d 14 and 28 from one pig per pen. On d 14, fecal samples were collected from one pig per pen in 3 of the 10 treatments to determine volatile fatty acids, ammonium concentration, and microbial protein. These pigs were also euthanized and ileal tissue was collected. Results There were no effects of dietary treatments on any of the parameters evaluated in phase 1. Inclusion of 10% or 20% CFP in diets reduced (P

Branched chain amino acids (BCAAs) are neutral amino acids containing branched aliphatic chains on the α-carbon, including leucine (Leu), isoleucine, and valine (Val), accounting for 18%–20% of the total amino acids in animal and plant proteins. BCAAs are essential amino acids for animal growth; however, they cannot be synthesized in animals and can only be obtained from the diet. BCAAs participate in the metabolism of protein, fat, and carbohydrates; promote intestinal development and intestinal amino acid transport; and improve the immune capacity of the body. However, the imbalance of BCAAs in diets leads to poor growth and metabolic disorders in animals. BCAAs have similar chemical structures and catabolic pathways and compete for the same amino acid transporters when passing through cell membranes, resulting in antagonism. Sea cucumbers (Apostichopus japonicus) have rich nutritional value and are an important seafood source in northern China.In recent decades, the study of amino acid nutritional requirements of aquatic animals mainly focused on individual amino acid requirements, and few studies focused on the interaction between amino acids with strong correlations, particularly BCAAs. At present, the interaction of BCAAs has been studied in species such as Chinook salmon (Oncorhynchus tshawytscha), Rainbow trout (Oncorhynchus mykiss), Channel catfish (Ictalurus punctatus), Tilapia GIFT (Oreochromis niloticus), and Tiger puffer (Takifugu rubripes); however, the results have been inconsistent.The purpose of this experiment was to study the interaction effect of Leu and Val on the growth, body wall composition, and digestive ability of sea cucumbers. In this experiment, white fishmeal, algae powder, and wheat flour were used as the primary protein sources, and fish oil and soybean lecithin were used as the main lipid sources to design a basic diet with crude protein and lipid contents of 18.10% and 2.80%, respectively. In a two-way experimental design, 0%, 1.06%, 2.34%, and 3.40% coated Leu and 0%, 1.74%, 2.50%, and 3.48% coated Val were added to the basic feed. Sixteen groups of isonitrogen and isolipid diets were prepared with four Leu levels (actual content: 1.00%, 1.50%, 2.10%, and 2.60%) and four Val levels (actual content: 0.65%, 1.40%, 1.70%, and 2.20%). A total of 960 healthy sea cucumbers with an initial average weight of 16.80±0.18 g were selected and randomly assigned to 48 cylindrical circulating buckets. They were divided into 16 experimental groups, with three replicates in each group and 20 sea cucumbers in each replicate. The feeding period was 60 d. Bait was fed once a day at a fixed time (16:00). The water was changed every 2 d, and a siphon was used to withdraw the residual bait and feces from the bottom of the bucket. The amount of water changed was 50% of the water level in the bucket. During the breeding period, the water temperature was 14–17 ℃, pH was 7.4–8.2, and dissolved oxygen was at least 6 mg/L. A low-light environment was maintained indoors.The results showed that the Leu and Val contents and their interaction significantly affected the weight gain (WG) and specific growth rate of sea cucumbers. When the Val content was 1.4%, the crude lipid contents of the body wall increased with increasing dietary Leu contents, and there was a synergistic effect between Leu and Val; the L1.0V1.4 group was significantly lower than the other groups. The interaction between Leu and Val significantly affected the Val, Met, Tyr, and Phe contents in the body wall of sea cucumbers. When the Leu content was 2.1%, the intestinal lipase and amylase activities first increased and then decreased with increasing dietary Val contents; the interaction between Leu and Val showed a synergistic and then antagonistic effect. The amylase activity reached a maximum value in the L2.6V1.4 group and was significantly higher than that in other groups. In conclusion, Leu and Val contents and their interaction significantly affected the growth performance, body wall amino acid composition, and digestive ability of sea cucumbers. Taking WG as the evaluation index, the ratios of Leu and Val in sea cucumber feed were 1.90 (Leu content was 2.6%, Val content was 1.4%).

Branched-chain amino acids (BCAAs)—leucine (Leu), isoleucine (Ile), and valine (Val)—are essential nutrients with significant roles in protein synthesis, metabolic regulation, and energy production. This review paper offers a detailed examination of the physico-chemical properties of BCAAs, their industrial synthesis, and their critical functions in various biological processes. The unique isomerism of BCAAs is presented, focusing on analytical challenges in their separation and quantification as well as their solubility characteristics, which are crucial for formulation and purification applications. The industrial synthesis of BCAAs, particularly using bacterial strains like Corynebacterium glutamicum, is explored, alongside methods such as genetic engineering aimed at enhancing production, detailing the enzymatic processes and specific precursors. The dietary uptake, distribution, and catabolism of BCAAs are reviewed as fundamental components of their physiological functions. Ultimately, their multifaceted impact on signaling pathways, immune function, and disease progression is discussed, providing insights into their profound influence on muscle protein synthesis and metabolic health. This comprehensive analysis serves as a resource for understanding both the basic and complex roles of BCAAs in biological systems and their industrial application. [ABSTRACT FROM AUTHOR]

This study investigated the effects of dietary L-valine (Val) supplementation and sanitary conditions with lipopolysaccharide injection on growth performance, immune response, and intestinal bacterial profiles and metabolites in weaned pigs. Thirty-two weaned pigs (6.98 ± 0.47 kg) were randomly assigned to treatments in a 2 × 2 factorial arrangement based on dietary Val levels and sanitary conditions (low or high). The pigs were fed either a basal diet containing the standard levels of Val suggested by (NRC), (2012) or a basal diet supplemented with 0.1% L-Val. A room designated as a high sanitary room was washed weekly, whereas the designated low sanitary room was not washed throughout the experiment and 5 kg of manure from the nursery pig barn was spread on the pen floors on day 1. All data were analysed using a mixed procedure of SAS, with the individual pen as the experimental unit. The pigs raised in low sanitary conditions exhibited a lower (p < 0.05) average daily gain, average daily feed intake, and gain-to-feed ratio and a higher (p < 0.05) incidence of diarrhoea than those raised in high sanitary conditions during the 14-d experimental period. The pigs in the low sanitary group also had a lower (p < 0.05) concentration of butyrate in the jejunum and a higher (p < 0.05) concentration of NH3-N in the colon than those in the high sanitary group. Dietary Val supplementation was reduced (p < 0.05) plasma interleukin (IL)-1β and IL-1 receptor antagonist concentrations as well as isovalerate and NH3-N concentrations in the colon, regardless of sanitary conditions. Interactions between dietary Val supplementation and sanitary conditions were observed in the abundances of mRNA-encoding β-defensins 113, 125 and 129 (p < 0.05). In conclusion, dietary Val supplementation beneficially modulates inflammatory responses and microbial metabolites regardless of sanitary conditions while transcriptional levels of β-defensins are regulated by dietary Val supplementation in a manner dependent on housing hygiene conditions. [ABSTRACT FROM AUTHOR]

Astrocytes are considered to possess a noticeable role in brain metabolism and, as a partners in neuron–glia cooperation, to contribute to the synthesis, bioconversion, and regulation of the flux of substrates for neuronal metabolism. With the aim of investigating to what extent human astrocytes are metabolizing amino acids and by which compounds are they enriching their surroundings, we employed a metabolomics analysis of their culture media by 1H-NMR. In addition, we compared the composition of media with either 5 mM or 25 mM glucose. The quantitative analysis of culture media by 1H-NMR revealed that astrocytes readily dispose from their milieu glutamine, branched-chain amino acids, and pyruvate with significantly high rates, while they enrich the culture media with lactate, branched-chain keto acids, citrate, acetate, ketone bodies, and alanine. Hyperglycemia suppressed the capacity of astrocytes to release branched-chain 2-oxo acids, while stimulating the generation of ketone bodies. Our results highlight the active involvement of astrocytes in the metabolism of several amino acids and the regulation of key metabolic intermediates. The observed metabolic activities of astrocytes provide valuable insights into their roles in supporting neuronal function, brain metabolism, and intercellular metabolic interactions within the brain. Understanding the complex metabolic interactions between astrocytes and neurons is essential for elucidating brain homeostasis and the pathophysiology of neurological disorders. The observed metabolic activities of astrocytes provide hints about their putative metabolic roles in brain metabolism. [ABSTRACT FROM AUTHOR]

The incorporation of different ferrocene scaffolds into the peptide sequences induces the formation of hydrogen-bond-based secondary structural elements that are frequently observed in natural peptides and proteins. There are three simple ferrocene scaffolds for conjugation with amino acids and peptides that serve as templates for ferrocene peptidomimetics, namely ferrocene-1,1′-dicarboxylic acid (Fcd, I), 1′-aminoferrocene-1-carboxylic acid (Fca, III), and ferrocene-1,1′-diamine (Fcda, V). Here, we have investigated their ability to induce the turn structure upon conjugation with Val, Leu, and Phe. Furthermore, we also wanted to determine whether the branched side chains of Val, Leu, and Phe interfere with intramolecular hydrogen bonding (IHB). For these purposes, we performed a detailed spectroscopic analysis by measuring the concentration, temperature, and solvent dependence of the IR, NMR, and CD spectra. The effect of the different ferrocene scaffolds on the antioxidant activity of the prepared peptides was tested using the DPPH and ABTS methods, and was further rationalized using electrochemical measurements. It was found that the ferrocene scaffold has the greatest influence on the hydrogen bonding pattern, while the influence of the side branches of the amino acids is less relevant. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids (BCAA) are correlated with severity of insulin resistance, which may partially result from mitochondrial dysfunction. Mitochondrial dysfunction is also common during insulin resistance and is regulated in part by altered mitochondrial fusion and fission (mitochondrial dynamics). To assess the effect of BCAA on mitochondrial dynamics during insulin resistance, the present study examined the effect of BCAA on mitochondrial function and indicators of mitochondrial dynamics in a myotube model of insulin resistance. C2C12 myotubes were treated with stock DMEM or DMEM with additional BCAA at 0.2 mM, 2 mM, or 20 mM to achieve a continuum of concentrations ranging from physiologically attainable to supraphysiological (BCAA overload) both with and without hyperinsulinemia-mediated insulin resistance. qRT-PCR and Western blot were used to measure gene and protein expression of targets associated with mitochondrial dynamics. Mitochondrial function was assessed by oxygen consumption, and mitochondrial content was measured using mitochondrial-specific staining. Insulin resistance reduced mitochondrial function, peroxisome proliferator-activated receptor gamma coactivator 1-alpha mRNA, and citrate synthase expression mRNA, but not protein expression. Excess BCAA at 20 mM also independently reduced mitochondrial function in insulin-sensitive cells. BCAA did not alter indicators of mitochondrial dynamics at the mRNA or protein level, while insulin resistance reduced mitochondrial fission protein 1 mRNA, but not protein expression. Collectively, BCAA at excessively high levels or coupled with insulin resistances reduce mitochondrial function and content but do not appear to alter mitochondrial dynamics under the tested conditions. [ABSTRACT FROM AUTHOR]

Tetramethylpyrazine (TTMP) is considered a crucial flavor component in Moutaiflavored liquor. Laceyeella sacchari FBKL4.010 (L. sacchari) is the dominant species found in Moutai-flavor Daqu, and this study aims to determine the mechanism by which L. sacchari produces TTMP during liquid fermentation of Moutai-flavor Daqu. The results of the liquid fermentation performance demonstrated a gradual increase in biomass over time, while there was a gradual decline in residual glucose content and pH value. Furthermore, analysis of volatile components revealed that liquid fermentation significantly enhanced the production of TTMP in Moutai-flavor Daqu, with the relative content of TTMP reaching 14.24 mg/L after 96 h of liquid fermentation. Additionally, to explore the synthesis mechanism of TTMP, we compared differentially expressed genes (DEGs) of L. sacchari between 24 and 96 h using comparative transcriptomic techniques. The results indicated that DEGs involved in isoleucine, valine, and leucine biosynthesis pathway were upregulated, while those associated with isoleucine, valine, and leucine degradation pathway were downregulated, suggesting that the valine, leucine, and isoleucine biosynthesis pathway primarily contributes ammonia for TTMP synthesis. The findings of this study present an opportunity for further elucidating the production process of TTMP in Moutaiflavor Daqu during liquid fermentation. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The structural and surface properties of nanomedicines play an important role in determining their biological fate. Surface chemistry of nanomedicines is one of the key parameters, where researchers used various strategies such as PEGylation to avoid the undesired clearance of nanoparticles (NPs) for enhanced targeting effect. Nevertheless, the fine‐tuning of surface chemistry through polymer functionalization remains largely unexplored. In this concise report, we find that the incorporation of only 10 mol% valine residues into the surface‐anchored poly(L‐glutamic acid) significantly lowered the macrophage uptake of NPs. The introduction of other hydrophobic amino acid residues, however, increased the NPs internalization instead. The chirality and the side‐chain structure of valine played an important role in the unexpected uptake behavior. We believe this work highlights the impact of slight changes of the surface‐anchored polymer structure on the behavior of NPs, drawing people's attention to the careful design of surface chemistry to optimize the nanomedicine design. [ABSTRACT FROM AUTHOR]

Tea is a daily drink for most people, and one of its major ingredients, epigallocatechin-3-gallate (EGCG), has been widely recognized as a potent antioxidant with diverse biological activities. However, its low stability and bioavailability hinder its further clinical applications. In this study, we designed and synthesized a novel EGCG-valine derivative 4 by replacing the gallic acid with a valine moiety in four steps. The structural elucidation of derivative 4 was performed using NMR, IR, mass, and UV spectroscopies. Additionally, the physicochemical properties of 4 were predicted by SwissADME, showing improved drug-like parameters and intestinal absorption compared to the parent compound EGCG. [ABSTRACT FROM AUTHOR]

Fructose is a commonly consumed monosaccharide implicated in developing several metabolic diseases. Previously, elevated branched-chain amino acids (BCAA) have been correlated with the severity of insulin resistance. Most recently, the effect of fructose consumption on the downregulation of BCAA catabolic enzymes was observed. Thus, this mechanistic study investigated the effects of physiologically attainable levels of fructose, both with and without concurrent insulin resistance, in a myotube model of skeletal muscle. Methods: C2C12 mouse myoblasts were treated with fructose at a concentration of 100 µM (which approximates physiologically attainable concentrations in peripheral circulation) both with and without hyperinsulinemic-mediated insulin resistance. Gene expression was assessed by qRT-PCR, and protein expression was assessed by Western blot. Oxygen consumption rate and extracellular acidification rate were used to assess mitochondrial oxidative and glycolytic metabolism, respectively. Liquid chromatography-mass spectrometry was utilized to analyze leucine, isoleucine and valine concentration values. Results: Fructose significantly reduced peak glycolytic and peak mitochondrial metabolism without altering related gene or protein expression. Similarly, no effect of fructose on BCAA catabolic enzymes was observed; however, fructose treatment resulted in elevated total extracellular BCAA in insulin-resistant cells. Discussion: Collectively, these observations demonstrate that fructose at physiologically attainable levels does not appear to alter insulin sensitivity or BCAA catabolic potential in cultured myotubes. However, fructose may depress peak cell metabolism and BCAA utilization during insulin resistance. [ABSTRACT FROM AUTHOR]

Acetohydroxyacid synthase (AHAS) is a key enzyme in the first step of the branched-chain amino acid synthesis pathway, and the production of acetohydroxybutyrate from one molecule of 2-ketobutyric acid and one molecule of pyruvate. AHAS is inhibited by feedback from L-valine, L-leucine, and L-isoleucine, and the expression of ilvBN, the gene encoding AHAS, is regulated by all three branched-chain amino acids. A change in amino acids 20–22 on the regulatory subunit (M13 mutation) removes the feedback inhibition by valine. We cloned the gene encoding AHAS (ilvBN) into a vector and then transfected it into Escherichia coli BL21 for expression with targeted changes in amino acids 20–22 on the regulatory subunit, and then determined the activity of the mutated AHAS and its inhibitory effects on valine, isoleucine, and leucine. The enzyme containing the M13 mutation was feedback resistant to all three amino acids. Previous studies have suggested that the binding sites for the three branched-chain amino acids may be at the same variable center. We investigated the enzymatic properties of wild-type and mutant AHAS, modeled their crystal structures, and resolved the mechanism of feedback inhibition induced by mutant M13, which will be useful for continuing the modification of AHAS and the design of broad-spectrum herbicides. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The structural and surface properties of nanomedicines play an important role in determining their biological fate. Surface chemistry of nanomedicines is one of the key parameters, where researchers used various strategies such as PEGylation to avoid the undesired clearance of nanoparticles (NPs) for enhanced targeting effect. Nevertheless, the fine‐tuning of surface chemistry through polymer functionalization remains largely unexplored. In this concise report, we find that the incorporation of only 10 mol% valine residues into the surface‐anchored poly(L‐glutamic acid) significantly lowered the macrophage uptake of NPs. The introduction of other hydrophobic amino acid residues, however, increased the NPs internalization instead. The chirality and the side‐chain structure of valine played an important role in the unexpected uptake behavior. We believe this work highlights the impact of slight changes of the surface‐anchored polymer structure on the behavior of NPs, drawing people's attention to the careful design of surface chemistry to optimize the nanomedicine design. [ABSTRACT FROM AUTHOR]

BackgroundMetabolic syndrome (MetS) is identified by the manifestation of a minimum of three out of five metabolic abnormalities, including insulin resistance, hypertension, hypertriglyceridemia, abdominal obesity, and low levels of high-density lipoprotein cholesterol. The present study aimed to assess the association between dietary branched-chain amino acids (BCAA) intakes and MetS, due to available conflicting evidence.MethodsA total of 4,860 individuals who had participated in the baseline phase of the PERSIAN (Prospective Epidemiological Research Studies in IrAN) Kavar cohort study were included in our study. The daily intake of valine, leucine, and isoleucine were evaluated using a semi-quantitative food frequency questionnaire. The association between dietary BCAA intake with MetS and its components was evaluated using logistic regression analysis.ResultsThe mean intake of BCAA among the included subjects was 7.65 (standard deviation [SD]: 2.92), and the prevalence of MetS was found to be 49.2%. Multivariable logistic regression analysis revealed an inverse association between 1-S.D. increment in dietary valine (odds ratio [OR] = 0.85, 95% confidence interval [CI]: 0.78–0.94), leucine (OR = 0.85, 95% CI: 0.77–0.93), isoleucine (OR = 0.84, 95% CI: 0.76–0.93), and total BCAA (OR = 0.85, 95% CI: 0.77–0.93) intake and the odds of MetS. There were also a significant association between BCAA intakes and hyperglycemia and hypertriglyceridemia.ConclusionWe observed a significant inverse association between dietary BCAA intake and MetS, hyperglycemia, and hypertriglyceridemia, regardless of confounding factors.

The present research assessed the impact of dietary valine on nutritional and energy metabolism, as well as muscle development in swimming crabs (Portunus trituberculatus) over a period of six weeks. Swimming crabs, initially weighing around 23.34 ± 0.03 g, were given six diets identical in nitrogen and lipid levels (45 % and 8 % respectively). These diets contained valine contents of 0.99 %, 1.24 %, 1.56 %, 1.69 %, 1.90 %, and 2.20 % respectively. One hundred and eighty crabs were randomized into six treatments, each treatment including three replicates. The results suggested that significant increases were discovered in FW, PWG, as well as SGR of crabs when dietary valine increasing from 0.99 % to 1.69 %, but these measurements decreased when dietary valine increased to 2.20 %. Compare to the control treatment, crabs that were given diets with 1.90 % and 2.20 % valine showed increased level of muscle protein. Crabs that were given the diets containing 1.56 % and 1.69 % valine showed significantly increased concentration of GLU in hemolymph compared to the control group. Additionally, crabs that were given the diets containing 1.69 % valine and 1.90 % valine respectively showed significantly increased concentrations of T-CHO and TG in hepatopancreas. Hepatic glycogen concentration significantly decreased as the level of valine in diets increased from 0.99 % to 1.56 %, but significantly increased as valine level further increased to 2.20 %. Compared with the control group, crabs that were given diets with 1.90 % valine showed increased expression levels of genes associated to amino acid metabolism (pi3k, akt, alt, ast, 4ebp1 and eif4e3) and energy metabolism (pk, cs1, idh, nd1, cytb and cox2). Crabs given diets containing 2.20 % valine showed significantly increased expression level of pepck in hepatopancreas, while crabs given diets containing 1.24 %, 1.56 %, and 1.69 % valine exhibited significantly increased expression level of cpt1 in hepatopancreas. Crabs given the diet with 1.69 % valine had the highest expression levels of tor and pax7 in muscle. Increased dietary valine significantly reduced myofiber density but promoted higher frequency of myofibers in larger diameters. In conclusion, the optimal valine requirement for P. trituberculatus was 1.56 % of diet based on PWG by a quadratic modeling. 1.69–1.90 % valine promoted amino acid metabolism and muscle growth, moreover, enhanced energy metabolism by driving the consumption of glycogen rather than lipids.

BackgroundDesmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments.MethodsWe conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival.ResultsFrom May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P

Chicks are ideal to follow the development of the intestinal microbiota and to understand how a pathogen perturbs this developing population. Taxonomic/metagenomic analyses captured the development of the chick microbiota in unperturbed chicks and in chicks infected with Salmonella enterica serotype Typhimurium (STm) during development. Taxonomic analysis suggests that colonization by the chicken microbiota takes place in several waves. The cecal microbiota stabilizes at day 12 posthatch with prominent Gammaproteobacteria and Clostridiales. Introduction of S. Typhimurium at day 4 posthatch disrupted the expected waves of intestinal colonization. Taxonomic and metagenomic shotgun sequencing analyses allowed us to identify species present in uninfected chicks. Untargeted metabolomics suggested different metabolic activities in infected chick microbiota. This analysis and gas chromatography-mass spectrometry on ingesta confirmed that lactic acid in cecal content coincides with the stable presence of enterococci in STm-infected chicks. Unique metabolites, including 2-isopropylmalic acid, an intermediate in the biosynthesis of leucine, were present only in the cecal content of STm-infected chicks. The metagenomic data suggested that the microbiota in STm-infected chicks contained a higher abundance of genes, from STm itself, involved in branched-chain amino acid synthesis. We generated an ilvC deletion mutant (STM3909) encoding ketol-acid-reductoisomerase, a gene required for the production of l-isoleucine and l-valine. ΔilvC mutants are disadvantaged for growth during competitive infection with the wild type. Providing the ilvC gene in trans restored the growth of the ΔilvC mutant. Our integrative approach identified biochemical pathways used by STm to establish a colonization niche in the chick intestine during development. IMPORTANCE Chicks are an ideal model to follow the development of the intestinal microbiota and to understand how a pathogen perturbs this developing population. Using taxonomic and metagenomic analyses, we captured the development of chick microbiota to 19 days posthatch in unperturbed chicks and in chicks infected with Salmonella enterica serotype Typhimurium (STm). We show that normal development of the microbiota takes place in waves and is altered in the presence of a pathogen. Metagenomics and metabolomics suggested that branched-chain amino acid biosynthesis is especially important for Salmonella growth in the infected chick intestine. Salmonella mutants unable to make l-isoleucine and l-valine colonize the chick intestine poorly. Restoration of the pathway for biosynthesis of these amino acids restored the colonizing ability of Salmonella. Integration of multiple analyses allowed us to correctly identify biochemical pathways used by Salmonella to establish a niche for colonization in the chick intestine during development.

Selective recognition of fructosyl amino acids in water by arylboronic acid-based receptors is a central field of modern supramolecular chemistry that impacts biological and medicinal chemistry. Fructosyl valine (FV) and fructosyl glycyl histidine (FGH) occur as N-terminal moieties of human glycated hemoglobin; therefore, the molecular design of biomimetic receptors is an attractive, but very challenging goal. Herein, we report three novel cationic Zn-terpyridine complexes bearing a fluorescent N-quinolinium nucleus covalently linked to three different isomers of strongly acidified phenylboronic acids (ortho-, 2Zn; meta-, 3Zn and para-, 4Zn) for the optical recognition of FV, FGH and comparative analytes (D -fructose, Gly, Val and His) in pure water at physiological pH. The complexes were designed to act as fluorescent receptors using a cooperative action of boric acid and a metal chelate. Complex 3Zn was found to display the most acidic –B(OH)2 group (pKa = 6.98) and exceptionally tight affinity for FV (K = 1.43 × 105 M−1) with a strong quenching analytical response in the micromolar concentration range. The addition of fructose and the other amino acids only induced moderate optical changes. On the basis of several spectroscopic tools (1H, 11B NMR, UV-Vis, and fluorescence titrations), ESI mass spectrometry, X-ray crystal structure, and DFT calculations, the interaction mode between 3Zn and FV is proposed in a 1 : 1 model through a cooperative two-point recognition involving a sp3 boronate–diol esterification with simultaneous coordination bonding of the carboxylate group of Val to the Zn atom. Fluorescence quenching is attributed to a static complexation photoinduced electron transfer mechanism as evidenced by lifetime experiments. The addition of FGH to 3Zn notably enhanced its emission intensity with micromolar affinity, but with a lower apparent binding constant than that observed for FV. FGH interacts with 3Zn through boronate–diol complexation and coordination of the imidazole ring of His. DFT-optimized structures of complexes 3Zn–FV and 3Zn–FGH show a picture of binding which shows that the Zn-complex has a suitable (B⋯Zn) distance to the two-point recognition with these analytes. Molecular recognition of fructosyl amino acids by transition-metal-based receptors has not been explored until now. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are crucial components of the innate immune system. Endosomal TLR7 recognizes single-stranded RNAs, yet its endogenous ssRNA ligands are not fully understood. We previously showed that extracellular (ex-) 5'-half molecules of tRNAHisGUG (the 5'-tRNAHisGUG half) in extracellular vesicles (EVs) of human macrophages activate TLR7 when delivered into endosomes of recipient macrophages. Here, we fully explored immunostimulatory ex-5'-tRNA half molecules and identified the 5'-tRNAValCAC/AAC half, the most abundant tRNA-derived RNA in macrophage EVs, as another 5'-tRNA half molecule with strong TLR7 activation capacity. Levels of the ex-5'-tRNAValCAC/AAC half were highly up-regulated in macrophage EVs upon exposure to lipopolysaccharide and in the plasma of patients infected with Mycobacterium tuberculosis. The 5'-tRNAValCAC/AAC half-mediated activation of TLR7 effectively eradicated bacteria infected in macrophages. Mutation analyses of the 5'-tRNAValCAC/AAC half identified the terminal GUUU sequence as a determinant for TLR7 activation. We confirmed that GUUU is the optimal ratio of guanosine and uridine for TLR7 activation; microRNAs or other RNAs with the terminal GUUU motif can indeed stimulate TLR7, establishing the motif as a universal signature for TLR7 activation. These results advance our understanding of endogenous ssRNA ligands of TLR7 and offer insights into diverse TLR7-involved pathologies and their therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: We aimed to examine the association between blood levels of Branched-chain amino acids (BCAAs) - specifically isoleucine, leucine, and valine - and the susceptibility to three neurodegenerative disorders: dementia, Alzheimer's disease (AD), and Parkinson's disease (PD). Methods: Based on data from the UK Biobank, a Cox proportional hazard regression model and a dose-response relationship were used to analyze the association between BCAAs and the risks of dementia, AD, and PD. We also generated a healthy lifestyle score and a polygenic risk score. Besides, we conducted a sensitivity analysis to ensure the robustness of our findings. Results: After adjusting for multiple covariates, blood concentrations of isoleucine, leucine, and valine were significantly associated with a reduced risk of dementia and AD. This association remained robust even in sensitivity analyses. Similarly, higher levels of isoleucine and leucine in the blood were found to be associated with an increased risk of PD, but this positive correlation could potentially be explained by the presence of covariates. Further analysis using a dose-response approach revealed that a blood leucine concentration of 2.14 mmol/L was associated with the lowest risk of dementia. Conclusion: BCAAs have the potential to serve as a biomarker for dementia and AD. However, the specific mechanism through which BCAAs are linked to the development of dementia, AD, and PD remains unclear and necessitates additional investigation. [ABSTRACT FROM AUTHOR]

Amyloid fibrils of transthyretin (TTR) consist of full‐length TTR and C‐terminal fragments starting near residue 50. However, the molecular mechanism underlying the production of the C‐terminal fragment remains unclear. Here, we investigated trypsin‐induced aggregation and urea‐induced unfolding of TTR variants associated with hereditary amyloidosis. Trypsin strongly induced aggregation of variants V30G and V30A, in each of which Val30 in the hydrophobic core of the monomer was mutated to less‐bulky amino acids. Variants V30L and V30M, in each of which Val30 was mutated to bulky amino acids, also exhibited trypsin‐induced aggregation. On the other hand, pathogenic variant I68L as well as the nonpathogenic V30I did not exhibit trypsin‐induced aggregation. The V30G variant was extremely unstable compared with the other variants. The V30G mutation caused the formation of a cavity and the rearrangement of Leu55 in the hydrophobic core of the monomer. These results suggest that highly destabilized transthyretin variants are more susceptible to trypsin digestion. [ABSTRACT FROM AUTHOR]

Simple Summary: The silkworm is an economically important insect, and the popularity of artificial feed has promoted the development of the sericulture industry. However, the improvement of feed efficiency remains a challenge. This study used metabolomics-based methods to analyze the differences in silkworm cocoons and hemolymph between the mulberry-leaf group and the artificial-feed group. It was found that the concentration of amino acids was significantly higher in the mulberry-leaf group than in the artificial-diet group. In a comparison of the effects of different concentrations of valine on silkworms fed the artificial diet, it was found that the food intake of the 2% and 4% valine groups was significantly lower than that of the 0% valine group, but the cocoon-production efficiency was significantly improved. This study demonstrates that valine is an important amino acid that can regulate feed efficiency, providing a new direction for the improvement of artificial feed. Artificial silkworm diets significantly impact farm profitability. Sustainable cocoon production depends on the continuous improvement of feed efficiency to reduce costs and nutrient losses in the feed. This study used metabolomics to explore the differences in silkworm cocoons and hemolymph under two modes of rearing: an artificial diet and a mulberry-leaf diet. Nine metabolites of silkworm cocoons and hemolymph in the mulberry-leaf group were higher than those in the artificial-diet group. Enrichment analysis of the KEGG pathways for these metabolites revealed that they were mainly enriched in the valine, leucine, and isoleucine biosynthesis and degradation pathways. Hence, the artificial silkworm diet was supplemented various concentrations of valine were supplemented to with the aim of examining the impact of valine on their feeding and digestion of the artificial diet. The results indicated that valine addition had no significant effect on feed digestibility in the fifth-instar silkworm. Food intake in the 2% and 4% valine groups was significantly lower than that in the 0% valine group. However, the 2% and 4% valine groups showed significantly improved cocoon-production efficiency, at 11.3% and 25.1% higher, respectively. However, the cocoon-layer-production efficiencies of the 2% and 4% valine groups decreased by 7.7% and 13.9%, respectively. The research confirmed that valine is an effective substance for enhancing the feed efficiency of silkworms. [ABSTRACT FROM AUTHOR]

Menthyl ester of valine (MV) has been developed as a plant defense potentiator to induce pest resistance in crops. In this study, we attempted to establish MV hydrochloride (MV-HCl) in lettuce and tomato crops. When MV-HCl solutions were used to treat soil or leaves of potted tomato and lettuce plants, 1 µM MV-HCl solution applied to potted plant soil was most effective in increasing the transcript level of defense genes such as pathogenesis-related 1 (PR1). As a result, leaf damage caused by Spodoptera litura and oviposition by Tetranychus urticae were significantly reduced. In addition, MV-HCl-treated plants showed an increased ability to attract Phytoseiulus persimilis, a predatory mite of T. urticae, when they were attacked by T. urticae. Overall, our findings showed that MV-HCl is likely to be effective in promoting not only direct defense by activating defense genes, but also indirect defense mediated by herbivore-induced plant volatiles. Moreover, based on the results of the sustainability of PR1 expression in tomato plants treated with MV-HCl every 3 days, field trials were conducted and showed a 70% reduction in natural leaf damage. Our results suggest a practical approach to promoting organic tomato and lettuce production using this new plant defense potentiator. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Japanese quail has a rapid growth rate (3 to 4 generations per year) and is relatively resistant to many diseases. Due to its high productivity, it has gained importance as an animal model in biological and genetic studies worldwide. Nutrition is a key factor that affects production efficiency in quails. Japanese quails require a diet that contains high-quality protein and a balanced profile of amino acids. Branched-chain amino acids (leucine, isoleucine, and valine) not only contribute to protein synthesis but also play a role in other metabolic activities. Among the branched-chain amino acids, valine is a limiting amino acid in corn-soy-based diets. Protein is the most expensive component of the diet and has a significant impact on production costs in poultry. Nowadays, reducing the protein level in the diet has garnered attention for cost reduction in farming and for mitigating environmental pollution resulting from ammonia emissions and nitrogen excretion in the poultry industry. However, reducing the protein level in the feed without proper supplementation of amino acids can lead to decreased feed intake, reduced production levels, and changes in social behavior in birds. Published reports indicate that adding crystalline amino acids to low-protein diets in meat birds can have similar performance to high-protein diets at different growth stages. In most cases, valine becomes limiting with reduced protein levels in the diet. Considering the important metabolic roles of branched-chain amino acids, especially valine, in rapidly growing birds, the aim of this experiment was to investigate the effects of using diets containing different digestible valine levels on the performance, growth traits, and histology of the liver and magnum in Japanese quails during the growth period. Material and Methods: All experimental procedures for the care and use of animals in the present study were approved by the animal care committee of the University of Tehran. Thousand one-day-old quails were given 5 dietary treatments, such that each treatment was replicated 5 times and 40 birds per replicate in a completely randomized design, during 1-42 days of age. Experimental diets were formulated to meet nutrients recommendation of growing quails with different levels of dietary digestible valine concentration (0.75, 0.85, 0.95, 1.05 and 1.15 %) in diets with a low protein (17.7-17% protein). The experimental diets provided 2,9 kcal metabolizable energy per gram. Other nutrients were provided based on the recommended nutritional requirements for growing quails. Other nutrients were formulated based on the recommended nutritional requirements for growing quails. The experimental diets were adjusted for two age periods: 1-21 days and 22-42 days. The birds received 24 hours of light until three days of age, followed by 23 hours of light and one hour of darkness daily. The parameters investigated in this experiment included growth performance, feed consumption, conversion ratio and carcass performance. The bird weights were measured at the beginning of the experiment and on days 21 and 42. Feed consumption on days 21 and 42 was calculated based on the difference between the amount of feed provided and the remaining feed. The weight of dead birds was used to correct the amount of feed consumption. On day 42, one male quail and one female quail were randomly selected from each replicate and killed after 6 hours of starvation. Additionally, after sampling the liver and magnum tissues, their histomorphological characteristics (nuclear diameter of hepatocytes, diameter of sinusoids in the liver tissue; epithelial height, inner muscle thickness, outer muscle thickness, gland diameter, and gland depth in the magnum tissue) were investigated. Results: During the breeding period, the quails that received the diet containing 0.95% and 1.05% digestible valine had higher body weight gain (BWG) and feed conversion ratio (FCR), respectively. Feed intake (FI) and mortality were not affected by the treatments. Dietary treatments did not have any significant effect on the carcass characteristics (both male and female). However, the carcass yield was higher in male quails and the relative weight of breast and intestines was higher in female quails. In the treatments containing 1.05% and 1.15% of valine, the diameter of Liver cell nucleus and the diameter of liver hepatocytes were the highest, which indicates liver damage. The volume of sinusoids in female birds increased with increasing valine levels in the diet; So that in birds that received diets containing levels higher than 0.95% valine was more than birds fed with rations containing 0.75% valine. Based on the results of this study, different levels of valine in diets containing 17% crude protein had a significant effect on the histology of the magnum tissue (epithelial height, inner muscle thickness, outer muscle thickness, gland diameter), although only the depth of the glands showed a tendency for significance with 0.85% valine. Conclusion: Based on the results, increasing the level of digestible valine in low protein diets up to 0.95% improves growth performance and feed conversion ratio in growing quails. However, it seems that the use of high levels of digestible valine in low protein diets (more than 0.85%) may lead to tissue damage in the liver and have a negative effect on growth performance. Further studies are recommended in this field. [ABSTRACT FROM AUTHOR]

Aqueous zinc (Zn) based batteries show great promise as energy storage devices, cost‐effectiveness, and intrinsic safety. However, the development of Zn‐based batteries faces significant challenges, primarily stemming from poor electrochemical reversibility caused by dendrite growth, hydrogen generation, and byproduct formation on the Zn anode. In this study, valine (Val) is investigated as an electrolyte additive to finely tune the interface microenvironment, resulting in enhanced electrochemical stability of the Zn anode across a wide pH range, marking the first time such an approach has been explored. Val ions preferably adsorb onto the active sites of the Zn anode surface, enabling efficient isolation of water and SO42− from the desolvated shell layer and thus effectively inhibiting dendrite growth. The Zn||Zn symmetric cells are demonstrated with Val electrolyte additives present a remarkable cycling performance of 5400 h. Furthermore, Zn||MnO2 full cells exhibit stable operation for 5000 cycles at 3 A g−1. Notably, the Val additive also functions effectively in rechargeable alkaline cells, enabling the alkaline symmetric cells and Zn||Ni0.8Co0.1Mn0.1O2 full cells to operate durably across a wide temperature range. This work offers unique insights into electrolyte engineering for aqueous rechargeable batteries, especially in terms of their compatibility with a wide pH range. [ABSTRACT FROM AUTHOR]

This case–control study investigated the link between dietary branched-chain amino acids (BCAAs) and the risk and severity of rheumatoid arthritis (RA). We assessed dietary BCAA intake in 95 RA patients and 190 matched controls using a food frequency questionnaire. We also assessed the disease severity using the disease activity score 28 (DAS-28), ESR, VAS, morning stiffness, and tender and swollen joints. Higher BCAA intake, expressed as a percentage of total protein, was significantly associated with increased risk of RA for total BCAAs (OR 2.14, 95% CI 1.53–3.00, P < 0.001), leucine (OR 2.40, 95% CI 1.70–3.38, P < 0.001), isoleucine (OR 2.04, 95% CI 1.46–2.85, P < 0.001), and valine (OR 1.87, 95% CI 1.35–2.59, P < 0.001). These associations remained significant even after adjusting for potential confounders (P < 0.001). However, BCAA intake did not show any significant association with RA severity in either crude or multivariate models (P > 0.05). Our findings suggest that higher dietary BCAA intake may contribute to the development of RA, but further research is needed to confirm these observations and explore the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: The growth and development of crops are permanently affected by various environmental factors, and environmental stress is one of the most important factors that reduce the yield of crops in the world. Drought is one of the most important abiotic stresses in plants. Drought stress also aggravates the effect of other stresses or causes them to appear. Considering that Iran is one of the dry and semi-arid regions, water management in the agricultural sector is of particular importance. In this regard, the aim of this research was to investigate the effect of deficit irrigation and foliar application of amino acid on some morphological traits and grain yield of soybean. Materials and Methods: The experiment was carried out in the two years of 2018 and 2019 in the farm of the Faculty of Agriculture of Tarbiat Modares University. This research was designed and implemented as a split plot based on a randomized complete block design with three replications. The experimental factors include three irrigation levels (full irrigation, moderate deficit irrigation and severe deficit irrigation), which were placed in the main plots, and foliar spraying of amino acids with five levels (leucine, valine, cysteine, commercial amino acids, without foliar spraying) as sub-plots were considered. The number of experimental plots was 54. In each repetition, three main plots were created at a distance of one meter from each other and 6 sub-plots were created inside each main plot. The distance between the plants on the cultivated rows was 8 cm. Some morphological traits and grain yield of soybean were measured. Results and Discussion: Based on the results of the interaction of the year in the irrigation regime, the height of the plant decreased in each year with the decrease in irrigation, but this decrease was not significant in the first year. The results showed that by spraying the plants with amino acids, the height of the soybean plant increased significantly compared to the control, and among the amino acids, commercial amino acid (91.77 cm) and cysteine (91.06 cm) had the greatest effect on the height of the plant, although there was no significant difference with other amino acids. The highest leaf area was related to the plants sprayed by valin in the second year. The results showed that in each year, with the application of amino acids, the leaf area of the soybean plant increased significantly compared to the control. Valine amino acid with the greatest effect on leaf dry weight increased it by 29.57% compared to the control treatment. The results showed that foliar spraying of all four types of amino acids had a significant increasing effect on the dry weight of the stem compared to the control, and cysteine had a 34.6% increase in the dry weight of the stem compared to the control, although there was no significant difference with other amino acid treatments. The results showed that in both years, with the application of amino acids, the wet weight of pods increased compared to the control, and it was significant in the second year. The three interaction effects of the year in the irrigation regime in amino acids had a significant effect only on the characteristics of stem wet weight and pod dry weight. Conclusion: The results indicated that foliar spraying of amino acids had a positive increasing effect on morphological traits. Valine and cysteine amino acids had the most significant positive effect on grain yield of soybean. [ABSTRACT FROM AUTHOR]

This study evaluates the effects of valine on the growth, digestion, antioxidant capacity, and intestinal health of triploid rainbow trout (Oncorhynchus mykiss) fed a low fish meal diet (10 %). The trouts with an initial body weight of 15.08±0.20 g were fed with five different isonitrogenous and isoenergetic diets containing levels of valine: 0.86 % (G1), 1.79 % (G2), 2.43 % (G3), 3.02 % (G4), and 3.68 % (G5) for 56 days. The results showed that the weight growth rate and specific growth rate of the 2.43 % group were significantly higher than those of the 0.86 % control group (P

Anabolic metabolism of carbon in mammals is mediated via the one- and two-carbon carriers S-adenosyl methionine and acetyl-coenzyme A. In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one nonoxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three- to six-carbon reaction conserved in humans and mice that utilizes propionate.

Among the branched-chain amino acids, leucine and isoleucine have been well studied for their roles in improving mitochondrial function and reducing oxidative stress. However, role of valine in mitochondrial function regulation and oxidative stress management remains elusive. This study investigated valine effect on mitochondrial function and oxidative stress in vitro. Valine increased expression of genes involved in mitochondrial biogenesis and dynamics. It upregulates mitochondrial function at complexes I, II, and IV levels of electron transport chain. Flow cytometry studies revealed, valine reduced oxidative stress by significantly lowering mitochondrial reactive oxygen species and protein expression of 4-hydroxynonenal. Functional role of valine against oxidative stress was analyzed by XFe96 Analyzer. Valine sustained oxidative phosphorylation and improved ATP generation rates during oxidative stress. In conclusion, our findings shed more light on the critical function of valine in protecting mitochondrial function thereby preventing mitochondrial/cellular damage induced by oxidative stress. [ABSTRACT FROM AUTHOR]

Objective: Genetic studies have suggested that the branched‐chain amino acids (BCAAs) valine, leucine, and isoleucine have a causal association with type 2 diabetes (T2D). However, inferences are based on a limited number of genetic loci associated with BCAAs. Methods: Instrumental variables (IVs) for each BCAA were constructed and validated using large well‐powered data sets and their association with T2D was tested using a two‐sample inverse‐variance weighted Mendelian randomization approach. Sensitivity analyses were performed to ensure the accuracy of the findings. A reverse association was assessed using instrumental variables for T2D. Results: Estimated effect sizes between BCAA IVs and T2D, excluding outliers, were as follows: valine (β = 0.14 change in log‐odds per SD change in valine, 95% CI: −0.06 to 0.33, p = 0.17), leucine (β = 0.15, 95% CI: −0.02 to 0.32, p = 0.09), and isoleucine (β = 0.13, 95% CI: −0.08 to 0.34, p = 0.24). In contrast, T2D IVs were positively associated with each BCAA, i.e., valine (β = 0.08 per SD change in levels per log‐odds change in T2D, 95% CI: 0.05 to 0.10, p = 1.8 × 10−9), leucine (β = 0.06, 95% CI: 0.04 to 0.09, p = 4.5 × 10−8), and isoleucine (β = 0.06, 95% CI: 0.04 to 0.08, p = 2.8 × 10−8). Conclusions: These data suggest that the BCAAs are not mediators of T2D risk but are biomarkers of diabetes. [ABSTRACT FROM AUTHOR]

Purpose of the study: Breast density is an established risk factor for breast cancer. However, little is known about metabolic influences on breast density phenotypes. We conducted untargeted serum metabolomics analyses to identify metabolic signatures associated with breast density phenotypes among young women. Methods: In a cross-sectional study of 173 young women aged 25–29 who participated in the Dietary Intervention Study in Children 2006 Follow-up Study, 449 metabolites were measured in fasting serum samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. Multivariable-adjusted mixed-effects linear regression identified metabolites associated with magnetic resonance imaging measured breast density phenotypes: percent dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute non-dense breast volume (ANDBV). Metabolite results were corrected for multiple comparisons using a false discovery rate adjusted p-value (q). Results: The amino acids valine and leucine were significantly inversely associated with %DBV. For each 1 SD increase in valine and leucine, %DBV decreased by 20.9% (q = 0.02) and 18.4% (q = 0.04), respectively. ANDBV was significantly positively associated with 16 lipid and one amino acid metabolites, whereas no metabolites were associated with ADBV. Metabolite set enrichment analysis also revealed associations of distinct metabolic signatures with %DBV, ADBV, and ANDBV; branched chain amino acids had the strongest inverse association with %DBV (p = 0.002); whereas, diacylglycerols and phospholipids were positively associated with ANDBV (p ≤ 0.002), no significant associations were observed for ADBV. Conclusion: Our results suggest an inverse association of branched chain amino acids with %DBV. Larger studies in diverse populations are needed. [ABSTRACT FROM AUTHOR]

Initiating translation of most eukaryotic mRNAs depends on recruitment of methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2) to the small (40S) ribosomal subunit, forming a 43S preinitiation complex (PIC) that attaches to the mRNA and scans the 5'-untranslated region (5' UTR) for an AUG start codon. Previous studies have implicated mammalian eIF2A in GTP-independent binding of Met-tRNAi to the 40S subunit and its recruitment to specialized mRNAs that do not require scanning, and in initiation at non-AUG start codons, when eIF2 function is attenuated by phosphorylation of its α-subunit during stress. The role of eIF2A in translation in vivo is poorly understood however, and it was unknown whether the conserved ortholog in budding yeast can functionally substitute for eIF2. We performed ribosome profiling of a yeast deletion mutant lacking eIF2A and isogenic wild-type (WT) cells in the presence or absence of eIF2α phosphorylation induced by starvation for amino acids isoleucine and valine. Whereas starvation of WT confers changes in translational efficiencies (TEs) of hundreds of mRNAs, the eIF2A? mutation conferred no significant TE reductions for any mRNAs in non-starved cells, and it reduced the TEs of only a small number of transcripts in starved cells containing phosphorylated eIF2α. We found no evidence that eliminating eIF2A altered the translation of mRNAs containing putative internal ribosome entry site (IRES) elements, or harboring uORFs initiated by AUG or near-cognate start codons, in non-starved or starved cells. Thus, very few mRNAs (possibly only one) appear to employ eIF2A for Met-tRNAi recruitment in yeast cells, even when eIF2 function is attenuated by stress. [ABSTRACT FROM AUTHOR]

The GG genotype of the Patatin-like phosphatase domain-containing 3 (PNPLA3), dietary fat, short-chain fatty acids (SCFA) and branched-chain amino acids (BCAA) are linked with non-alcoholic fatty liver disease. We studied the impact of the quality of dietary fat on plasma (p) and fecal (f) SCFA and p-BCAA in men homozygous for the PNPLA3 rs738409 variant (I148M). Eighty-eight randomly assigned men (age 67.8 ± 4.3 years, body mass index 27.1 ± 2.5 kg/m2) participated in a 12-week diet intervention. The recommended diet (RD) group followed the National and Nordic nutrition recommendations for fat intake. The average diet (AD) group followed the average fat intake in Finland. The intervention resulted in a decrease in total p-SCFAs and iso-butyric acid in the RD group (p = 0.041 and p = 0.002). Valeric acid (p-VA) increased in participants with the GG genotype regardless of the diet (RD, 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.005 and AD, 3.8 ± 0.3 to 9.7 ± 8.5 µmol/g, p = 0.015). Also, genotype relation to p-VA was seen statistically significantly in the RD group (CC: 3.7 ± 0.4 to 4.2 ± 1.7 µmol/g and GG: 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.0026 for time and p = 0.004 for time and genotype). P-VA, unlike any other SCFA, correlated positively with plasma gamma-glutamyl transferase (r = 0.240, p = 0.025). Total p-BCAAs concentration changed in the AD group comparing PNPLA3 CC and GG genotypes (CC: 612 ± 184 to 532 ± 149 µmol/g and GG: 587 ± 182 to 590 ± 130 µmol/g, p = 0.015 for time). Valine decreased in the RD group (p = 0.009), and leucine decreased in the AD group (p = 0.043). RD decreased total fecal SCFA, acetic acid (f-AA), and butyric acid (f-BA) in those with CC genotype (p = 0.006, 0.013 and 0.005, respectively). Our results suggest that the PNPLA3 genotype modifies the effect of dietary fat modification for p-VA, total f-SCFA, f-AA and f-BA, and total p-BCAA. [ABSTRACT FROM AUTHOR]

Breast milk is known to contain bioactive peptides that are released during digestion, being a major source of bioactive peptides to the new-born, some of which act against invading pathogens. However, the formation of bioactive peptides during digestion of human colostrum remains largely uninvestigated. This study aimed to investigate the formation of peptides during simulated digestion of human colostrum from adult women and to prospect antimicrobial peptides. For this purpose, we used high-resolution MS to monitor the release of peptides during in vitro digestion. Bioinformatics was used for the prospection of antimicrobial activity of peptides. During simulated digestion (oral, gastric and duodenal phases), 2318 peptide sequences derived from 112 precursor proteins were identified. At the end of simulated digestion, casein-derived peptide sequences were the most frequently observed. Among precursors, some proteins were seen for the first time in this study. The resulting peptides were rich in proline, glutamine, valine and leucine residues, providing characteristic traits of antimicrobial peptides. From bioinformatics analysis, seven peptides showed potentially high antimicrobial activity towards bacteria, viruses and fungi, from which the latter was the most prominent predicted activity. Antimicrobial peptides released during digestion may provide a defence platform with controlled release for the new-born. [ABSTRACT FROM AUTHOR]

The recent global outbreak of mpox, caused by monkeypox virus (MPV) emerged in Europe in 2022 and rapidly spread to over 40 countries. The Americas are currently facing the highest impact, reporting over 50,000 cases by early 2023. In this study, we analyzed 880 MPV isolates worldwide to gain insights into the evolutionary patterns and initial introduction events of the virus in Mexico. We found that MPV entered Mexico on multiple occasions, from the United Kingdom, Portugal, and Canada, and subsequently spread locally in different regions of Mexico. Additionally, we show that MPV has an open pangenome, highlighting the role of gene turnover in shaping its genomic diversity, rather than single-nucleotide polymorphisms (SNPs), which do not contribute significantly to genome diversity. Although the genome contains multiple SNPs in coding regions, these remain under purifying selection, suggesting their evolutionary conservation. One notable exception is amino acid position 63 of the protein encoded by the Cop-A4L gene, which is intricately related to viral maturity, which we found to be under strong positive selection. Ancestral state reconstruction indicated that the ancestral state at position 63 corresponds to the amino acid valine, which is present only in isolates of clade I. However, the isolates from the current outbreak contained threonine at position 63. Our findings contribute new information about the evolution of monkeypox virus. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the relationship between dietary branched-chain amino acids (BCAAs) and the risk of developing hypertension. Methods: A cohort study of 14,883 Chinese adults without hypertension at baseline with were followed for an average of 8.9 years. Dietary intakes of BCAAs, including Ile, Leu, and Val, were collected using 3-day 24-h meal recall and household condiment weighing. Cox proportional hazards regression, restricted cubic splines, interaction analysis, and sensitivity analysis were used to assess the relationship between dietary BCAAs and risk of developing self-reported hypertension, adjusting for age, gender, region, body mass index (BMI), smoking and drinking status, physical activity, energy intake, salt intake. Results: Among 14,883 study subjects, 6386(42.9%) subjects aged ≥ 45 years at baseline, 2692 (18.1%) had new-onset hypertension during the study period, with a median age of 56 years. High levels of dietary BCAAs were associated with an increased risk of new-onset hypertension. Compared with the 41st–60th percentile, multivariable adjusted hazard ratio (HR) for new-onset hypertension was 1.16 (95% CI 1.01–1.32) for dietary BCAAs 61st–80th percentiles, 1.30 (1.13–1.50) for 81st–95th, 1.60 (1.32–1.95) for 96th–100th. The cut-off value of new-onset hypertension risk, total BCAAs, Ile, Leu, and Val were 15.7 g/day, 4.1 g/day, 6.9 g/day, 4.6 g/day, respectively, and the proportion of the population above these intake values were 13.9%, 13.1%, 15.4%, and 14.4%, respectively. Age, BMI, and salt intake had an interactive effect on this relationship (P < 0.001). Conclusion: There was a significant positive association between total dietary BCAAs, Ile, Leu, Val intake and the risk of developing hypertension, after adjustment for confounders. This relationship was influenced by age, BMI, and salt intake. Further research is needed to clarify the mechanism and potential role of BCAAs in the pathogenesis of hypertension. [ABSTRACT FROM AUTHOR]

Background: To determine plasma free amino acid (FAA) and carnitine levels in pregnant women with hydatidiform mole (HM). Materials and Methods: Twenty-three pregnant women with HM, and 24 healthy pregnant women as controls were enrolled in the study. FAA and carnitine concentrations were measured in plasma using liquid chromatography/tandem mass spectrometry (LC-MS). Results: The levels of alanine, arginine, and valine from the 14 amino acids examined were significantly lower in the HM group than in the healthy group (p = 0.019, p = 0.009, and p = 0.03, respectively). In addition, several carnitines, C8DC, C16:1, and C18, of the 27 carnitines examined were significantly higher in the HM group than in the control group (p = 0.021, p = 0.03, and p = 0.021, respectively). Conclusions: This study demonstrated that a decrease in some plasma FAAs and an increase in some plasma carnitine levels might be effective in the pathogenesis of HM. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids (BCAA) are essential for maintaining intestinal mucosal integrity. However, only a few studies have explored the role of BCAA in the modulation of intestinal inflammation. In this study, we investigated in vitro effects of BCAA on the inflammatory response induced by lipopolysaccharide (LPS) (1 µg/mL) in Caco-2 cells. Caco-2 cells were assigned to six groups: control without BCAA (CTL0), normal BCAA (CTL; 0.8 mM leucine, 0.8 mM isoleucine, and 0.8 mM valine); leucine (LEU; 2 mM leucine), isoleucine (ISO; 2 mM isoleucine), valine (VAL; 2 mM valine), and high BCAA (LIV; 2 mM leucine, 2 mM isoleucine, and 2 mM valine). BCAA was added to the culture medium 24 h before LPS stimulation. Our results indicated that BCAA supplementation did not impair cell viability. The amino acids leucine and isoleucine attenuated the synthesis of IL-8 and JNK and NF-kB phosphorylation induced by LPS. Furthermore, neither BCAA supplementation nor LPS treatment modulated the activity of glutathione peroxidase or the intracellular reduced glutathione/oxidized glutathione ratio. Therefore, leucine and isoleucine exert anti-inflammatory effects in Caco-2 cells exposed to LPS by modulating JNK and NF-kB phosphorylation and IL-8 production. Further in vivo studies are required to validate these findings and gather valuable information for potential therapeutic or dietary interventions. [ABSTRACT FROM AUTHOR]

Isoleucyl‐tRNA synthetase (IleRS) links isoleucine to cognate tRNA via the Ile‐AMP intermediate. Non‐cognate valine is often mistakenly recognized as the IleRS substrate; therefore, to maintain the accuracy of translation, IleRS hydrolyzes Val‐AMP within the synthetic site (pre‐transfer editing). As this activity is not efficient enough, Val‐tRNAIle is formed and hydrolyzed in the distant post‐transfer editing site. A strictly conserved synthetic site residue Gly56 was previously shown to safeguard Ile‐to‐Val discrimination during aminoacyl (aa)‐AMP formation. Here, we show that the Gly56Ala variant lost its specificity in pre‐transfer editing, confirming that this residue ensures the selectivity of all synthetic site reactions. Moreover, we found that the Gly56Ala mutation affects IleRS interaction with aa‐tRNA likely by disturbing tRNA‐dependent communication between the two active sites. [ABSTRACT FROM AUTHOR]

Observational studies have demonstrated that serum branched-chain amino acids (BCAAs) are associated with the risk of various cardiovascular diseases (CVDs) and their risk factors. However, the causal effect is unclear. The aim of this study was to investigate the effect of genetically determined BCAA levels on CVDs and their risk factors using Mendelian randomization (MR). We performed univariable and multivariable MR analyses using summary-level data from multiple GWASs and the FinnGen consortium to investigate the association between BCAA levels and the risk of CVDs (myocardial infarction, ischemic stroke, and intracerebral hemorrhage) and their risk factors (atrial fibrillation, hypertension, heart failure, and valvular heart disease). We used the random-effects IVW approach as the primary statistical method and incorporated MR estimates from different data sources using the fixed-effects model. We found genetically determined total and individual BCAA levels and a high risk of hypertension. However, there is no evidence of a causal relationship between BCAA levels and 3 cardiovascular diseases and other their risk factors. The odds of hypertension increased per 1-SD increase in BCAA levels (OR = 1.02 95% CI: 1.01, 1.04; P = 0.005), valine (OR = 1.02 95% CI: 1.01, 1.03; P<0.0001), leucine (OR = 1.02 95% CI: 1.01, 1.04; P＜0.01), and isoleucine (OR = 1.02 95% CI: 1.01, 1.03; P < 0.0001). This result was also significant in the multivariable MR. This MR study suggests that total and individual BCAA levels could be associated with a high risk of hypertension. [Display omitted] • Observational studies have shown an association between serum BCAAs and the risk of CVDs and their risk factors, but the causal relationship remains uncertain. • This MR study suggests that total and individual BCAA levels could be associated with a high risk of hypertension. [ABSTRACT FROM AUTHOR]

Background: Anticancer therapies are associated with significant adverse side effects and few treatments that alleviate symptoms exist. Branched-chain amino acids (BCAAs) have been investigated as an intervention for reducing anticancer therapy side effects, although a review of the literature results has yet to be published. Aim: The current review summarizes evidence surrounding this topic and suggests both support and caution in using BCAAs as a treatment for patients receiving anticancer therapies. Methods: In this review, two literature searches were completed. Google Scholar, PubMed, EBSCOhost, and Cochrane databases were searched using the terms "branched-chain amino acids and cancer" and "BCAA and cancer." Results: Two bodies of evidence emerged: One supporting beneficial effects and the other showing adverse outcomes of BCAA supplementation in patients with cancer. Evidence of benefit was a decrease in malnourishment and unintentional weight loss during and after chemotherapy. Potential harms included the idea cancer cells may utilize BCAAs as a source of energy for growth. Conclusions: Supplementation of BCAAs in individuals with cancer should be implemented cautiously. Those who are severely malnourished due to anticancer therapy may benefit the most. BCAA supplementation may also be provided once cancer has been destroyed from the individual's body to aid with recovery. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that amino acids dictate the effector functions of immune cells; however, whether and how phenylalanine (Phe) orchestrates the polarization of macrophages is not understood. Here, we determined that Phe attenuated lipopolysaccharide (LPS) and P. multocida serotype A strain CQ2 (PmCQ2) infection-induced inflammation in vivo. Furthermore, we demonstrated that Phe inhibited the production of interleukin (IL)-1β and tumor necrosis factor (TNF)-α in proinflammatory (M1) macrophages. Phe reprogrammed the transcriptomic and metabolic profiles and enhanced oxidative phosphorylation in M1 macrophages, which reduced the activation of caspase-1. Notably, the valine-succinyl-CoA axis played a critical role in Phe-mediated inhibition of IL-1β production in M1 macrophages. Taken together, our findings suggest that manipulating the valine-succinyl-CoA axis provides a potential target for preventing and/or treating macrophage-related diseases. [ABSTRACT FROM AUTHOR]

Tea is a daily drink for most people, and one of its major ingredients, epigallocatechin-3-gallate (EGCG), has been widely recognized as a potent antioxidant with diverse biological activities. However, its low stability and bioavailability hinder its further clinical applications. In this study, we designed and synthesized a novel EGCG-valine derivative 4 by replacing the gallic acid with a valine moiety in four steps. The structural elucidation of derivative 4 was performed using NMR, IR, mass, and UV spectroscopies. Additionally, the physicochemical properties of 4 were predicted by SwissADME, showing improved drug-like parameters and intestinal absorption compared to the parent compound EGCG.

IntroductionThe branched-chain amino acids (BCAAs) are essential to mammalian growth and development but aberrantly elevated in obesity and diabetes. Each BCAA has an independent and specific physio-biochemical effect on the host. However, the exact molecular mechanism of the detrimental effect of valine on metabolic health remains largely unknown.Methods and resultsThis study showed that for lean mice treated with valine, the hepatic lipid metabolism and adipogenesis were enhanced, and the villus height and crypt depth of the ileum were significantly increased. Transcriptome profiling on white and brown adipose tissues revealed that valine disturbed multiple signaling pathways (e.g., inflammation and fatty acid metabolism). Integrative cecal metagenome and metabolome analyses found that abundances of Bacteroidetes decreased, but Proteobacteria and Helicobacter increased, respectively; and 87 differential metabolites were enriched in several molecular pathways (e.g., inflammation and lipid and bile acid metabolism). Furthermore, abundances of two metabolites (stercobilin and 3-IAA), proteins (AMPK/pAMPK and SCD1), and inflammation and adipogenesis-related genes were validated.DiscussionValine treatment affects the intestinal microbiota and metabolite compositions, induces gut inflammation, and aggravates hepatic lipid deposition and adipogenesis. Our findings provide novel insights into and resources for further exploring the molecular mechanism and biological function of valine on lipid metabolism.

SUMMARY: A total of 3 broiler diets were pelleted to determine the effects of diet formulation on pellet quality. Dietary treatments consisted of corn and soybean meal-based control, the control with crystalline valine (Val), and the control with crystalline Val and isoleucine (Ile). As crystalline amino acids (AA) increased in the diets, corn concentrations increased as soybean meal and the fat source were removed to balance for nitrogen-corrected metabolizable energy (MEn). There were 3 replicates per treatment with time of processing as a blocking factor and treatment order randomized within each block. Cooled pellet samples were collected to determine pellet fines, standard pellet durability index (PDI), modified PDI, and Holmen NHP100. Pellet mill kW increased (P < 0.05) in pelleted Val + Ile diets compared to the control and Val diets. Pellet fines decreased (P < 0.01) and PDI increased (P < 0.01) as crystalline AA increased and added fat decreased in the diet. In conclusion, diets with increasing crystalline AA, Val, and Val + Ile, led to improved pellet quality which can be explained by the 0.4% or 0.6% reduction in added fat with increasing crystalline AA and balancing for MEn in the diet.