Search Results (677)

Objective: Despite most often used in research and medicine, it is unclear how well blood metabolite levels can reflect metabolic changes in tissues. Methods: We used untargeted metabolomic data from plasma, liver, gastrocnemius muscle, kidney, inguinal fat, and gonadal fat tissues from mice treated with lifespan-extending interventions: caloric restriction, rapamycin, canagliflozin, 17-α estradiol, and acarbose. Results: For each tissue, about 37% of the identified metabolites were also found in plasma and used for comparative analyses. We found that plasma metabolites do not primarily reflect the metabolome of a single tissue type. Caloric restriction caused the highest proportion of significantly altered metabolites detected in both organs and blood. Unsaturated triacylglycerols, diacylglycerols, amino acid-derivatives, and sphingomyelins had the most concordant overlaps between four tissues and plasma, followed by carbohydrates with three tissue/plasma intersections. Concordant plasma/tissue changes were found more pronounced in male mice than in female mice. Surprisingly, many compounds that responded similarly to lifespan-extending treatments in tissues and in plasma originated from dietary compounds, specifically, ergothioneine, DHA-containing fats, and diacylglycerides. Ergothioneine, previously associated with healthy aging in humans, showed concordant treatment responses in blood and all tissues except gonadal fat. DHA-containing fats showed consistent regulation between blood and inguinal and gonadal adipose tissue. The kidneys showed coherent trends with blood metabolite levels for LPC 15:0, LPC 17:0, and pinitol. Under treatments with strong life-extending effects, 1,5-anhydro-glucitol blood levels were co-regulated with both liver and kidney levels. Conclusions: Overall, plasma can only serve as limited proxy for tissue metabolism. Yet, several potential blood biomarkers were discovered as concordant in plasma and tissues in lifespan-extending interventions. Full article

Heat stress is frequently associated with reduced dry matter intake (DMI), milk yield, and physiological alterations in Holstein dairy cows. The aim was to evaluate how prior exposure to heat stress affects feed intake, milk production, energy balance, blood metabolites, and infrared thermography, with special emphasis on the cows’ ability to recover and re-establish normal physiological and productive responses. Thirty multiparous lactating Holstein cows (days in milk = 87 ± 19.6 days) and previous milk yield (30.8 ± 3.95 kg/d) were monitored over 21 days, divided into three 7-day phases: thermoneutral (TN), cows kept at a constant temperature–humidity index (THI) of 69; heat stress (HS), cows at a THI of 82 for 9 h and 69 for 15 h, and recovery (REC), cows at a constant THI of 69. Milk yield decreased by 16.1% during HS and remained 17.3% lower during REC compared with TN. Dry matter intake was reduced by 5.8 and 4.2 kg/d for HS and REC compared to TN cows. Plasma insulin was higher in REC compared to HS. Under the conditions of the present study, heat stress was associated with impaired productive performance, altered metabolism, and changes in the physiological status of mid-lactation Holstein dairy cows, with some effects persisting after the cows returned to thermoneutral conditions. Full article

Background/Objectives: Di(2-ethylhexyl) adipate (DEHA), a biocompatible ester plasticizer, has gained interest as a potential pharmaceutical excipient, yet its pharmacokinetics remain poorly characterized. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for DEHA and its primary metabolite, mono(2-ethylhexyl) adipate (MEHA), in rats by integrating in vitro, in vivo, in silico, and physiological data. Methods: In vitro hydrolysis was evaluated across tissues using bis-(p-nitrophenyl) phosphate (BNPP) to distinguish BNPP-sensitive and -insensitive metabolism, and tissue-specific clearances were extrapolated to the whole body using a circulatory topology-based framework accounting for sequential extraction across tissues, venous blood, and lungs. Results: Both adipates underwent rapid BNPP-sensitive hydrolysis across multiple tissues, whereas DEHA additionally exhibited BNPP-insensitive metabolism. The framework yielded reasonable estimates of the observed arterial clearance in vivo. Following oral administration, DEHA showed a reproducible double-peak plasma profile, with lymphatic transport identified as the predominant absorption route responsible for the prolonged terminal phase. The final model adequately reproduced the plasma and mesenteric lymph concentration-time profiles of DEHA and MEHA following both intravenous and oral administration. Conclusions: By integrating multi-tissue metabolism, circulatory topology, and lymphatic absorption, this study provides a quantitative framework applicable to rapidly hydrolyzed, highly lipophilic ester compounds, including pharmaceutical excipients and ester prodrugs. Full article

This study evaluated the impact of fermented palm kernel meal (FPKM) on the lactation performance, blood biochemical indices, rumen microbiota, and metabolic functions of Holstein dairy cows, aiming to enhance the nutritional value of palm kernel meal (PKM) through solid-state fermentation. A 3 × 3 Latin square design was used, involving 12 multiparous Holstein cows (parity = 3; body weight = 625 ± 25.8 kg; days in milk = 103 ± 19.6 day(s); milk yield = 32.6 ± 1.58 kg/d) over three 28-day periods. Cows were randomly assigned to three isocaloric and isonitrogenous diets: a basal diet with wheat bran (WB group), a diet with wheat bran replaced by PKM (PKM group), and a diet with wheat bran replaced by FPKM (FPKM group). Solid-state fermentation improved PKM’s nutritional profile by reducing fiber and β-mannan content while increasing protein availability and ruminal degradability. Compared to the WB group, the PKM group showed lower dry matter intake, milk yield, and nutrient digestibility. In contrast, the FPKM group had higher DMI and milk yield than the PKM group, improved nutrient digestibility, and the highest energy-corrected milk yield due to increased milk protein and lactose production. The FPKM group also had higher concentrations of total volatile fatty acids, propionate, acetate, and microbial protein synthesis than the PKM group. Pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-8) were elevated in the PKM group but were reduced to levels similar to the WB group in the FPKM group. Plasma immunoglobulin G levels were higher in both the FPKM and WB groups compared to the PKM group. The FPKM group also showed increased relative abundances of Prevotella, Fibrobacterota, and Verrucomicrobiota, while Bacillota and Ruminococcus were reduced compared to the WB group. Metabolomic profiling revealed that FPKM upregulated energy metabolism and inflammation-related pathways, increasing metabolites such as riboflavin and adenine and decreasing succinic acid and guanine compared to the PKM group. In conclusion, FPKM improved the feeding value of PKM-based material and showed more favorable responses than PKM, with generally comparable responses to WB, supporting its potential as an alternative feed ingredient for lactating dairy cows. Full article

Examining the relationship between an animal’s diet and physiology is crucial to understanding their responses to environmental change. Dietary-induced physiological variation can influence key life history processes, including growth and reproduction, ultimately affecting individual fitness. Reported here are the plasma biochemical parameters related to energy storage, use and nutritional condition in juvenile white sharks (Carcharodon carcharias) in Eastern Australia. Specifically, we used plasma metabolites (triglyceride, cholesterol and β-hydroxybutyrate), thyroid hormone thyroxine and fatty acid profiles from 50 juvenile white sharks (152–340 cm total length) captured on SMART drumlines in Eastern Australia to examine blood biochemistry and nutritional ecology. Concentrations of triglycerides and β-hydroxybutyrate indicated high energy expenditure likely associated with the broad-scale migration of white sharks along the Australian coast, highlighting the importance of β-hydroxybutyrate as an energy source. Seasonal variation in the triglyceride/cholesterol and ω3/ω6 fatty acid ratio, in conjunction with lower docosahexaenoic acid, suggests that lower-quality prey is consumed during winter months, thereby influencing the nutritional condition of these sharks. Additionally, the positive correlation between thyroxine concentrations and water temperature suggests reduced metabolic activity during cooler months. Such fluxes in food quality and nutritional condition may affect juvenile white sharks’ growth and development rate and future reproductive success. Full article

Metabolites are important intermediate molecular phenotypes that reflect physiological and biochemical processes within an organism. However, the molecular mechanisms linking genetic variation to metabolite abundance remain poorly understood in dairy cattle. Here, we integrated whole-genome sequencing, whole-blood transcriptomic, and plasma metabolomic data from 80 Jersey cattle to investigate the genetic regulation of circulating metabolites. After quality control, 10,696,212 high-quality SNPs, 15,559 expressed genes, and 841 stable plasma metabolites were retained for downstream analyses. Cis-eQTL mapping identified 1863 eGenes regulated by 1,340,105 significant cis-eQTLs. Transcriptome–metabolome association analysis further detected 258 significant gene–metabolite associations involving 148 genes and 177 metabolites. By integrating cis-eQTLs with gene–metabolite associations, mediation analysis identified 218 significant SNP–gene–metabolite trios involving 124 genes and 157 metabolites. Network analysis further identified several highly connected mediator genes, including MEGF9, S1PR5, and CD27 and revealed two distinct mediation patterns, complete and partial mediation. Together, these findings indicate that gene expression serves as an important intermediate layer connecting genetic variation with circulating metabolites. This study provides a comprehensive multi-omics resource for investigating the genetic regulation of the blood metabolome in Jersey cattle and offers new insights into the molecular basis of metabolic variation. Full article

Objectives: A high-performance liquid chromatography (HPLC) with mass spectrometry (MS) detection method was developed to quantify several tyrosine kinase inhibitors (TKIs) and their relevant metabolites. This method is suitable for therapeutic drug monitoring (TDM) of alectinib, brigatinib, dabrafenib, lenvatinib, lorlatinib, osimertinib and trametinib in patients with solid tumors using volumetric absorptive microsampling (VAMS^®). Methods: The HPLC-MS system contained four pumps, a Turboflow HTLC CycloneTM 1.0 × 50 mm solid phase extraction column for analyte enrichment, and a Kinetex 2.6 µm C18 100Å, 100 × 3.0 mm column for analyte separation. An acetonitrile–water gradient was used for the separation, and the ions generated by ESI (+)-ionization were detected in single-ion mode. This method was validated according to recent European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines. Results: The accuracy and precision shown during method validation were within the acceptable limits for all analytes in plasma and whole blood. All analytes showed acceptable stability in both matrices for at least 28 days when stored at −21 °C. So far, 100 venous plasma and 94 capillary blood samples have been collected and analyzed. Conclusions: We developed a reliable method to quantify several TKIs from plasma and capillary blood, which is intended for TDM purposes in clinical practice. Full article

Background: Dietary metabolizable energy (ME) and crude protein (CP) levels are important for lactation performance and metabolic responses in dairy ruminants. This study aimed to evaluate the effects of dietary ME and CP levels on lactation performance and postprandial metabolic responses in lactating dairy goats. Methods: Goats were randomly assigned to a 4 × 4 two-factor Latin square experiment consisting of four 14 d periods. The dietary treatments were high energy, high protein (HEHCP); high energy, low protein (HELCP); low energy, high protein (LEHCP); and low energy, low protein (LELCP). Serial postprandial arterial blood samples were collected at 17 daytime time points to characterize temporal changes in plasma amino acids, biochemical parameters and hormones. Results: Increasing CP supply elevated milk yield (+6%) and lactose yield (+5%) but decreased milk fat yield (−8%; p ≤ 0.04). Increasing ME supply tended to enhance milk yield and milk fat yield and increased milk lactose content only under the high CP condition (ME × CP interaction: p = 0.04), suggesting that the response to ME supply depended partly on dietary CP level. High CP increased plasma branched chain amino acid concentrations, whereas high ME reduced Leu and Val under the high CP condition. Most plasma amino acids exhibited marked postprandial dynamics, decreasing initially and then stabilizing, with CP × time interactions observed for Leu, Met, and Phe (p ≤ 0.05). High ME decreased plasma AST activity and tended to reduce urea N concentration and also reduced ALT activity and increased glucose concentration under the high CP diet. Following morning feeding, plasma urea N showed a progressive postprandial decline (p = 0.02), with glucagon decreasing and both prolactin and growth hormone increasing, despite no dietary effects on mean plasma hormone concentrations. Conclusions: Overall, dietary ME and CP levels affected lactation performance and selected plasma metabolic indicators in lactating dairy goats. Coordinated energy and protein supply should be considered when formulating diets for lactating dairy goats. Serial postprandial sampling further revealed temporal changes in plasma metabolites and hormones, providing useful information for refining precision nutrition strategies during lactation. Full article

Background: Polygenic risk scores (PRS) have proven valuable for disease risk prediction, but their predictive utility often remains limited because human traits result from complex interactions between environmental and genetic factors. Blood lipid levels are heritable and clinically important risk factors for cardiovascular disease, yet it remains unclear whether multi-omics integration can enhance lipid trait prediction beyond PRS alone. Methods: We first constructed single-omics scores, where gene expression, plasma protein, and plasma/serum metabolite levels were genetically predicted and weighted by effect sizes estimated via LASSO regression. Subsequently, we implemented two integration strategies to develop composite multi-omics risk scores (MoRS): step-MoRS, which integrates single-omics scores using stepwise regression, and Lasso-MoRS, which directly models all predicted features across omics layers using LASSO regression. Both approaches were evaluated across European, South Asian, and African ancestries within the UK Biobank. Results: MoRS-based methods consistently demonstrated superior predictive accuracy compared to PRS alone for four lipid traits across diverse populations. Notably, Lasso-MoRS prioritized key biomarkers with predictive utility complementary to genomic data. Conclusions: These findings confirm that integrating multi-omics biomarkers with genomic data significantly enhances lipid trait prediction across diverse ancestries, offering biological insights into the molecular regulation of lipid metabolism. Full article

Growing evidence indicates that circulating phenolic metabolites can reach brain tissue and exert neuroprotective effects; however, their combined activity at physiological concentrations remains poorly understood. This study evaluated three metabolite mixtures designed according to previously reported plasma and brain metabolite profiles following a Mediterranean (poly)phenol-rich intervention (Mix Eq, Mix %C, and Mix %T), together with their individual constituent metabolites, in human cellular models of oxidative stress, neuroinflammation, and blood–brain barrier (BBB) dysfunction. All physiological mixtures significantly protected SH-SY5Y neuroblastoma cells against H₂O₂-induced oxidative stress by improving cell viability and reducing intracellular ROS production in a concentration-dependent manner, with cotreatment showing greater efficacy than pretreatment. Individual metabolites also showed protective effects, although none matched the overall efficacy of the mixtures. In HMC3 cells, the mixtures moderately attenuated LPS- and TNF-α-induced inflammatory responses, reducing IL-6 and IL-8. Finally, in HBMECs, TNF-α increased BBB permeability and cytokine release, whereas Mix %C significantly attenuated TNF-α-induced sodium fluorescein permeability. However, none of the mixtures significantly reduced IL-6 or IL-8 secretion in this BBB model. Overall, physiologically relevant combinations of circulating phenolic metabolites showed greater neuroprotective activity than individual metabolites, supporting the contribution of additive or cooperative interactions to the benefits associated with Mediterranean diet-derived phenolics. Full article

Background: Objective body-fluid biomarkers may help characterize exercise-induced physical fatigue; however, heterogeneity in exercise protocols, biological matrices, and analytical platforms complicates biomarker interpretation. Purpose: This study aimed to identify candidate acute exercise-responsive metabolic biomarkers associated with physical fatigue assessment by integrating conventional biomarker evidence, exercise-related metabolomics, and exploratory targeted Liquid chromatography–mass spectrometry (LC-MS) analysis. Methods: We conducted three complementary analyses: (1) a systematic review and random-effects meta-analysis of quantitative biomarkers measured in body-fluid matrices, including blood, plasma, serum, saliva, sweat, urine, and interstitial fluid, at pre-exercise and post-exercise time points; (2) a descriptive fold-change-based synthesis of exercise-related metabolomics studies; and (3) an exploratory paired plasma–saliva liquid chromatography–mass spectrometry pilot analysis in seven apparently healthy young male volunteers. Eligible studies included apparently healthy human participants without reported acute or chronic diseases, major injuries, pregnancy, or clinically diagnosed pathological fatigue, undergoing endurance, resistance, high-intensity interval, or mixed exercise protocols. Biomarkers reported in ≥10 independent comparisons were pooled using log-transformed post-exercise/pre-exercise response ratios. Results: The systematic review and meta-analysis included 110 articles, 129 experiments, and 1826 participants. Lactate showed the strongest pooled response after exercise (response ratio = 4.43, 95% CI: 3.74–5.25, p < 0.00001; I² = 98%), followed by IL-6 (2.15, 95% CI: 1.50–3.07, p < 0.0001; I² = 87%), CK (1.70, 95% CI: 1.56–1.86, p < 0.00001; I² = 90%), and LDH (1.23, 95% CI: 1.11–1.35, p < 0.0001; I² = 93%). Metabolomics synthesis identified lactate, pyruvate, hypoxanthine and xanthine as frequently reported exercise-responsive metabolites related to glycolysis and purine degradation. Exploratory LC-MS analysis showed consistent directional changes in these metabolites in paired plasma and saliva samples. Conclusions: Lactate, pyruvate, hypoxanthine, and xanthine represent candidate metabolism-based acute exercise-responsive biomarkers associated with physical fatigue. However, their fatigue specificity remains to be established and requires validation using independent fatigue criteria, non-fatiguing exercise controls, matrix-specific analyses, and adequately powered diverse cohorts. Full article

Objective: Maternal blood microbiome signatures during pregnancy have been linked to adverse birth outcomes. We conducted a pilot study to examine whether they are also associated with early childhood growth in offspring and to explore maternal metabolites as potential mediators of these relationships. Methods: This study included 50 mother-child dyads from a prospective pregnancy cohort. Children were selected based on distinct body mass index (BMI) growth trajectories from birth to 4 years, including 25 children in a rising-high-BMI trajectory and 25 in a low-BMI trajectory. Maternal plasma collected during the second trimester underwent 16S rRNA gene sequencing for microbial profiling and an untargeted metabolomics analysis. Microbial diversity indices were compared between groups. Multivariable logistic regression models assessed associations between microbial taxa and BMI trajectories with adjustment for covariates. Mediation analyses evaluated whether maternal metabolites mediated observed associations. Results: Higher maternal blood microbial α-diversity was observed among mothers of children in the rising-high-BMI trajectory. Greater abundance of Gammaproteobacteria/Proteobacteria (class/phylum) was associated with lower odds of membership in the rising-high-BMI trajectory, whereas Bacteroidia/Bacteroidota and Actinobacteria/Actinobacteriota were associated with a greater risk. Mediation analyses identified several maternal metabolites that potentially linked prenatal microbial taxa to child growth outcomes. Key mediators included metabolites involved in benzoate metabolism (e.g., 4-vinylphenol sulfate for taxa Gammaproteobacteria/Proteobacteria), lipid metabolism (e.g., 1-linoleoyl-GPG (18:2) for Bacteroidia/Bacteroidota), glutathione metabolism (cysteinylglycine disulfide for Bacteroidia/Bacteroidota), branched-chain amino acid metabolism (3-hydroxy-2-ethylpropionate for Bacteroidia/Bacteroidota), histidine metabolism (imidazole propionate for Actinobacteria/Actinobacteriota), and TCA cycle (glutaconate for Actinobacteria/Actinobacteriota). These pathways are implicated in oxidative stress, adipocyte differentiation, insulin signaling, and energy metabolism, processes that are highly relevant to obesity development. Conclusion: Findings suggest that prenatal blood microbial signatures may influence early childhood growth through metabolic pathways related to obesity. These pilot study findings support further investigation into the role of prenatal blood microbial signatures in child development and health outcome prediction in larger studies. Full article

Postpartum dairy cows fed more rapidly fermentable starch sources have depressed dry matter intake (DMI), compounding the risk of negative energy balance and hepatic lipid accumulation. Rumen-protected choline (RPC) is supplemented to periparturient dairy cows to facilitate hepatic lipid export. Our objective was to evaluate the interaction of dietary starch fermentability (DF) and RPC supplementation on postpartum DMI and performance. Prepartum supplementation of a low dose of RPC (no RPC [C−] vs. RPC [C+; 30 g/d]) began 21 d before the expected calving date for Holstein cows with at least one parity. Postpartum, cows were assigned to 1 of 4 postpartum treatments for 21 d with a 2 × 2 factorial arrangement of starch fermentability rate (low [dry-rolled corn; LFERM] vs. high [dry-rolled wheat; HFERM]) and RPC (C− vs. C+). Prepartum, C+ decreased DMI by 2.3 kg compared with C−, but there was no evidence of treatment effect on DMI postpartum. Time and DF interacted on milk yield, with HFERM increasing milk yield after d 3 compared with LFERM. Compared with LFERM, HFERM decreased milk fat content but not fat yield. For blood metabolites, C+ decreased plasma beta-hydroxybutyrate by 0.3 mmol/L and tended to increase glucose concentration compared to C−. In conclusion, supplementation with RPC at a low rate of inclusion reduced DMI in prepartum cows and decreased postpartum plasma BHB concentrations. Further work is required to elucidate potential mechanisms of action for RPC-mediated reductions in DMI. Full article

Background/Objectives: Direct-fed microbials (DFMs) are widely used in dairy calves to improve gut health and mitigate neonatal disorders, yet their systemic metabolic effects remain poorly defined. This study evaluated the impact of DFM supplementation on the plasma metabolome of pre-weaned dairy calves using untargeted liquid chromatography–mass spectrometry (LC–MS). Methods: Eighty-six Holstein bull calves (2 to 5 days old) were assigned to one of four treatments in a 2 × 2 factorial randomized complete block design: Lactobacillus plantarum in starter (CLP), a culture mix of Bifidobacterium animalis and Lactobacillus animalis in milk replacer (BBCM), and a combination of both (CMLP), or no supplementation (CON). Blood samples collected on days 0 and 56 were subjected to metabolomic profiling, and metabolites were annotated using Human Metabolome Database and Kyoto Encyclopedia of Genes and Genomes databases. Results: A total of 231 plasma metabolites were detected. Compared with CON, 24 metabolites were differentially abundant in DFM-treated calves (fold change ≥ 1.2 or ≤ 0.83; p ≤ 0.05). Supplemented calves exhibited increased abundances of ketone functional groups, aldehydes and amino acid-related metabolites. Metabolite set enrichment analysis identified 11 significantly enriched pathways. Branched-chain amino acid degradation pathways (valine, leucine, and isoleucine) were enriched in CLP and CMLP calves, whereas carbohydrate metabolism pathways, including pentose and glucuronate interconversions, were enriched in the CLP and BBCM groups. Conclusions: These findings demonstrate that DFM supplementation modulates systemic metabolism in dairy calves, particularly pathways involved in amino acid and carbohydrate utilization, suggesting enhanced metabolic efficiency during early life. Full article

Chiang Mai, Thailand, experiences seasonal fine particulate matter (PM_2.5) pollution associated with metabolic diseases, but the underlying mechanisms remain unclear. This prospective observational study compared plasma metabolomes of 25 healthy adults in Samoeng District, a highly affected area, between low and high PM_2.5 exposure seasons using proton nuclear magnetic resonance (¹H-NMR) spectroscopy. Twenty-six metabolites differentiating haze and non-haze seasons were identified using PLS-DA (VIP > 1.5). During the haze season, 11 were elevated, whereas 15 were decreased. Among the elevated metabolites, the top five—maleylacetoacetic acid, deoxyribose 5-phosphate, betaine, 3-hydroxyanthranilic acid, and 1-methyladenosine—were associated with inflammation, increased reactive oxygen species, nitric oxide inhibition, and altered amino acid metabolism. The top five decreased metabolites—deoxyguanosine, D-arabitol, glycerophosphocholine, ophthalmic acid, and oxaloacetic acid—were involved in several metabolic pathways, particularly those involved in energy metabolism. A total of 56 metabolic pathways were altered by high PM_2.5 exposure, including pathways related to amino acids, lipids, sugars, nucleotides, vitamins, and energy metabolism. High PM_2.5 exposure disrupts metabolites and pathways, inducing inflammation, oxidative stress, impaired lipid/energy metabolism, insulin resistance, and high blood pressure. These alterations may increase the risk of metabolic and cardiovascular diseases, with dysregulated metabolites serving as potential biomarkers. These findings highlight the molecular impact of air pollution in affected populations and may support preventive strategies and public health policy development in affected regions. Further studies are needed to clarify these findings. Full article