OBJECTIVE: To analyze the causal relationship between 486 human serum metabolites and the active tuberculosis (ATB) in European population.
METHODS: In this study, the causal relationship between human serum metabolites and the ATB was analyzed by integrating the genome-wide association study (GWAS). The 486 human serum metabolites were used as the exposure variable, three different ATB GWAS databases in the European population were set as outcome variables, and single nucleotide polymorphisms were used as instrumental variables for Mendelian Randomization. The inverse variance weighting was estimated causality, the MR-Egger intercept to estimate horizontal pleiotropy, and the combined effects of metabolites were also considered in the meta-analysis. Furthermore, the web-based MetaboAnalyst 6.0 was engaged for enrichment pathway analysis, while R (version 4.3.2) software and Review Manager 5.3 were employed for statistical analysis.
RESULTS: A total of 21, 17, and 19 metabolites strongly associated with ATB were found in the three databases after preliminary screening (P < 0.05). The intersecting metabolites across these databases included tryptophan, betaine, 1-linoleoylglycerol (1-monolinolein) (1-LG), 1-eicosatrienoylglycerophosphocholine, and oleoylcarnitine. Among them, betaine (I2 = 24%, P = 0.27) and 1-LG (I2 = 0%, P = 0.62) showed the lowest heterogeneity among the different ATB databases. In addition, the metabolic pathways of phosphatidylethanolamine biosynthesis (P = 0.0068), methionine metabolism (P = 0.0089), betaine metabolism (P = 0.0205) and oxidation of branched-chain fatty acids (P = 0.0309) were also associated with ATB.
CONCLUSIONS: Betaine and 1-LG may be biomarkers or auxiliary diagnostic tools for ATB. They may provide new guidance for medical practice in the early diagnosis and surveillance of ATB. In addition, by interfering with phosphatidylethanolamine biosynthesis, methionine metabolism, betaine metabolism, oxidation of branched-chain fatty acids, and other pathways, it is helpful to develop new anti-tuberculosis drugs and explore the virulence or pathogenesis of ATB at a deeper level, providing an effective reference for future studies.

Choline is an essential nutrient, with high requirements during fetal and postnatal growth. Tissue concentrations of total choline are tightly regulated, requiring an increase in its pool size proportional to growth. Phosphatidylcholine and sphingomyelin, containing a choline headgroup, are constitutive membrane phospholipids, accounting for >85% of total choline, indicating that choline requirements are particularly high during growth. Daily phosphatidylcholine secretion via bile for lipid digestion and very low-density lipoproteins for plasma transport of arachidonic and docosahexaenoic acid to other organs exceed 50% of its hepatic pool. Moreover, phosphatidylcholine is required for converting pro-apoptotic ceramides to sphingomyelin, while choline is the source of betaine as a methyl donor for creatine synthesis, DNA methylation/repair and kidney function. Interrupted choline supply, as during current total parenteral nutrition (TPN), causes a rapid drop in plasma choline concentration and accumulating deficit. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) defined choline as critical to all infants requiring TPN, claiming its inclusion in parenteral feeding regimes. We performed a systematic literature search in Pubmed with the terms \"choline\" and \"parenteral nutrition\", resulting in 47 relevant publications. Their results, together with cross-references, are discussed. While studies on parenteral choline administration in neonates and older children are lacking, preclinical and observational studies, as well as small randomized controlled trials in adults, suggest choline deficiency as a major contributor to acute and chronic TPN-associated liver disease, and the safety and efficacy of parenteral choline administration for its prevention. Hence, we call for choline formulations suitable to be added to TPN solutions and clinical trials to study their efficacy, particularly in growing children including preterm infants.

Betaine improves growth performance and health in monogastric animals under both thermoneutral and heat stress conditions, but results in ruminants have been more equivocal. This meta-analysis investigated the effects of betaine supplementation on productive performance, milk production and composition, and carcass traits of ruminants due to betaine supplementation. A comprehensive search for published studies investigating the effect of betaine was performed using Google Scholar, ScienceDirect, PubMed, and Scopus databases. Effect size analysis, random effects models, I2 statistics, and meta-regression analysis were utilized to assess differences in production parameters. Dietary betaine supplementation increased milk yield (+1.0 kg/d (weighted mean differences presented in this abstract), p < 0.001), dry matter intake (+0.15 kg/d, p < 0.001), and milk lactose (+0.05%, p = 0.010) in dairy cows housed under thermoneutral conditions. In the few studies conducted on small ruminants, there was an increase in milk yield in response to dietary betaine (0.45 kg/d, p = 0.040). Under heat stress conditions or grazing pasture during summer, dietary betaine increased milk yield (+1.0 kg/d, p < 0.001) and dry matter intake (+0.21 kg/d, p = 0.020). Dietary betaine increased final liveweight (+2.33 kg, p = 0.050) and back fat thickness (+0.74 cm, p < 0.001) in beef cattle. Dietary betaine increased final liveweight (0.14 kg, p = 0.010), daily gain (+0.019 kg/d, p < 0.001), and carcass weight (+0.80 kg, p < 0.001) but not backfat in small ruminants. These meta-analyses showed that dietary betaine increases liveweight in small ruminants and beef cattle and increases feed intake and milk yield in dairy cattle.

Macrophage inhibitory factor (MIF) is a multipotent cytokine, involved in the inflammatory response to infections or injuries. This study investigates the role of MIF in liver fibrosis and the modulating effect of betaine on MIF in thioacetamide (TAA)-induced liver fibrosis. The wild-type and knockout MIF-/- C57BL/6 mice were divided into the following groups: control; Bet group, which received betaine; MIF-/-; MIF-/-+Bet; TAA group, which received TAA; TAA+Bet; MIF-/-+TAA; and MIF-/-+TAA+Bet group. After eight weeks of treatment, liver tissue was collected for further analysis. The results revealed that TAA-treated MIF-deficient mice had elevated levels of hepatic TGF-β1 and PDGF-BB, as well as MMP-2, MMP-9, and TIMP-1 compared to TAA-treated wild-type mice. However, the administration of betaine to TAA-treated MIF-deficient mice reduced hepatic TGF-β1 and PDGF-BB levels and also the relative activities of MMP-2, MMP-9 and TIMP-1, albeit less effectively than in TAA-treated mice without MIF deficiency. Furthermore, the antifibrogenic effect of MIF was demonstrated by an increase in MMP2/TIMP1 and MMP9/TIMP1 ratios. The changes in the hepatic levels of fibrogenic factors were confirmed by a histological examination of liver tissue. Overall, the dual nature of MIF highlights its involvement in the progression of liver fibrosis. Its prooxidant and proinflammatory effects may exacerbate tissue damage and inflammation initially, but its antifibrogenic activity suggests a potential protective role against fibrosis development. The study showed that betaine modulates the antifibrogenic effects of MIF in TAA-induced liver fibrosis, by decreasing TGF-β1, PDGF-BB, MMP-2, MMP-9, TIMP-1, and the deposition of ECM (Coll1 and Coll3) in the liver.

BACKGROUND: The intestine of young ruminants is in the developmental stage and has weaker resistance to the changes of external environment. Improving intestinal health is vital to promoting growth of young ruminants. This study investigated effects of guanidino acetic acid (GAA) and rumen-protected betaine (RPB) supplementation on growth, dietary nutrient digestion and GAA metabolism in the small intestine of sheep.
METHODS: Eighteen healthy Kazakh rams (27.46 ± 0.10 kg of body weight and 3-month old) were categorized into control, test group I and test group II, which were fed a basal diet, 1500 mg/kg GAA and 1500 mg/kg GAA + 600 mg/kg RPB, respectively.
RESULTS: Compared with control group, test group II had increased (p < 0.05) average daily gain, plasma creatine level, ether extract (EE) and phosphorus digestibility on day 30. On day 60, the EE apparent digestibility, jugular venous plasma GAA, GAA content in the duodenal mucosa and GAA content in the jejunal and ileal mucosa of test group II were higher (p < 0.05) than other groups. Transcriptome analysis revealed that the differentially expressed genes (DEGs) involved in the duodenal pathways of oxidative phosphorylation and non-alcoholic fatty liver disease were significantly altered in test group II versus test group I (p < 0.05). Moreover, in the jejunum, the MAPK signalling pathway, complement and coagulation cascade and B-cell receptor signalling pathway were significantly enriched, with ATPase, solute carrier transporter protein, DHFR, SI, GCK, ACACA and FASN being the significantly DEGs (p < 0.05).
CONCLUSIONS: Dietary supplementation of RPB on top of GAA in sheep diets may promote sheep growth and development by improving the body\'s energy, amino acid, glucose and lipid metabolism capacity.

One-carbon metabolism (OCM) is a complex and interconnected network that undergoes drastic changes during pregnancy. In this study, we investigated the longitudinal distribution of OCM-related metabolites in maternal and cord blood and explored their relationships. Additionally, we conducted cross-sectional analyses to examine the interrelationships among these metabolites. This study included 146 healthy pregnant women who participated in the Chiba Study of Mother and Child Health. Maternal blood samples were collected during early pregnancy, late pregnancy, and delivery, along with cord blood samples. We analyzed 18 OCM-related metabolites in serum using stable isotope dilution liquid chromatography/tandem mass spectrometry. We found that serum S-adenosylmethionine (SAM) concentrations in maternal blood remained stable throughout pregnancy. Conversely, S-adenosylhomocysteine (SAH) concentrations increased, and the total homocysteine/total cysteine ratio significantly increased with advancing gestational age. The betaine/dimethylglycine ratio was negatively correlated with total homocysteine in maternal blood for all sampling periods, and this correlation strengthened with advances in gestational age. Most OCM-related metabolites measured in this study showed significant positive correlations between maternal blood at delivery and cord blood. These findings suggest that maternal OCM status may impact fetal development and indicate the need for comprehensive and longitudinal evaluations of OCM during pregnancy.

Esterquats constitute a unique group of quaternary ammonium salts (QASs) that contain an ester bond in the structure of the cation. Despite the numerous advantages of this class of compounds, only two mini-reviews discuss the subject of esterquats: the first one (2007) briefly summarizes their types, synthesis, and structural elements required for a beneficial environmental profile and only briefly covers their applications whereas the second one only reviews the stability of selected betaine-type esterquats in aqueous solutions. The rationale for writing this review is to critically reevaluate the relevant literature and provide others with a \"state-of-the-art\" snapshot of choline-type esterquats and betaine-type esterquats. Hence, the first part of this survey thoroughly summarizes the most important scientific reports demonstrating effective synthesis routes leading to the formation of both types of esterquats. In the second section, the susceptibility of esterquats to hydrolysis is explained, and the influence of various factors, such as the pH, the degree of salinity, or the temperature of the solution, was subjected to thorough analysis that includes quantitative components. The next two sections refer to various aspects associated with the ecotoxicity of esterquats. Consequently, their biodegradation and toxic effects on microorganisms are extensively analyzed as crucial factors that can affect their commercialization. Then, the reported applications of esterquats are briefly discussed, including the functionalization of macromolecules, such as cotton fabric as well as their successful utilization on a commercial scale. The last section demonstrates the most essential conclusions and reported drawbacks that allow us to elucidate future recommendations regarding the development of these promising chemicals.

The capacity of combinations of feed enzymes, natural betaine and a probiotic, combined with alternative plant-based ingredients, to totally replace soybean meal (SBM) in a broiler diet was evaluated. Day-old Ross 308 males (2,574) were assigned to 9 treatments (13 pens/treatment, 22 birds/pen) in a completely randomized design. All diets were pelleted and fed ad libitum in 4 phases: starter, grower, finisher 1, finisher 2 (0-10, 10-21, 21-35, and 35-42 d of age, respectively). Treatments included: 1) control diet containing SBM (SBM control), supplemented with phytase (PhyG), at 2,000, 1,500, 1000 and 1,000 FTU/kg in each phase and xylanase (X) at 750 U/kg, [crude protein (CP): 23.5%, 22.0%, 20.2% and 19.3% in each phase]; 2) to 5), alternative (ALT), SBM-free diets, containing the same CP level as the control (\"CP high\"), supplemented with PhyG as in the control, protease (P, 800 U/kg) and in 2) xylanase (750 U/kg) (ALT+PhyG+P+X), 3) xylanase-β-glucanase (XB, 1,200 U/kg and 152 U/kg) (Alt+PhyG+P+XB), 4) XB plus betaine (800 g/ton) (ALT+PhyG+P+XB+Bet), and 5) XB plus a probiotic [150,000 colony forming units (CFU)/g] (ALT+PhyG+P+XB+Prob); 6) to 9) as treatments 2) to 5) but with CP reduced by -2.0 to -1.5% points vs. control (\'CP low\'). Final (d 42) BW and overall (d 0-42) feed conversion ratio (FCR) of birds fed the SBM control exceeded breeder objectives (+3.8% and -1.9%, respectively). Overall FCR was reduced and d 42 BW increased in birds fed \"low\" vs. \"high\" CP (P < 0.01). Overall FCR and feed intake were not different in ALT+PhyG+XB+P+Bet and ALT+PhyG+XB+P+Prob vs. the control, whereas final BW was reduced (P < 0.05) in all ALT treatments but close to breeder objectives (98.3%) in ALT+PhyG+XB+P+Prob. Feed costs of this treatment were similar to the control. Total replacement of SBM with alternative plant-based ingredients in a CP-low diet supplemented with hydrolytic enzymes and probiotics can achieve growth performance outcomes close to commercial breeder objectives.

L-ascorbic acid (AA), a potent antioxidant, is commonly used topically in the pharmaceutical and cosmetic fields. However, the incorporation of AA into topical formulations is difficult because of its highly unstable nature and relatively poor skin permeability. In this study, we propose an alternative strategy for improving the solubility and topical delivery of AA through its conversion to a therapeutic deep eutectic system (THEDES). AA and betaine (Bet)-based THEDESs were prepared at certain molar ratios and characterized using polarized optical microscopy, Fourier transform infrared spectroscopy, and differential scanning calorimetry. Solubility tests showed that AA in the form of THEDES was readily soluble in various polyols (glycerin, 1,3-butylene glycol, dipropylene glycol, and 1,3-propanediol) at a high concentration (approximately 40%). Furthermore, compared to AA alone or the physical mixture of AA and Bet, AA-based THEDES significantly enhanced AA delivery through porcine skin. In an in vivo human study, THEDES-containing serum reduced the markers of aging and induced an even skin tone. These findings indicate the utility of AA and Bet-based THEDES as novel transdermal delivery systems for AA. Furthermore, our approach also showed good extension to developing gluconolactone, a well-known natural antioxidant, and Bet-based THEDES, showing potential application in transdermal delivery systems.

Various studies have shown that Hypogymnia physodes are a source of many biologically active compounds, including lichen acids. These lichen-specific compounds are characterized by antioxidant, antiproliferative, and antimicrobial properties, and they can be used in the cosmetic and pharmaceutical industries. The main aim of this study was to optimize the composition of natural deep eutectic solvents based on proline or betaine and lactic acid for the extraction of metabolites from H. physodes. The design of the experimental method and the response surface approach allowed the optimization of the extraction process of specific lichen metabolites. Based on preliminary research, a multivariate model of the experiment was developed. For optimization, the following parameters were employed in the experiment to confirm the model: a proline/lactic acid/water molar ratio of 1:2:2. Such a mixture allowed the efficient extraction of three depsidones (i.e., physodic acid, physodalic acid, 3-hydroyphysodic acid) and one depside (i.e., atranorin). The developed composition of the solvent mixtures ensured good efficiency when extracting the metabolites from the thallus of H. physodes with high antioxidant properties.