PubMed

Environ Sci Process Impacts. 2023 Nov 28. doi: 10.1039/d3em00480e. Online ahead of print.ABSTRACTWe report, for the first time, a multimodal investigation of current crude oil reprocessing and storage sites to assess their impact on the environment after 50 years of continuous operation. We have adopted a dual approach to investigate potential soil contamination. The first approach uses conventional analytical techniques i.e. energy dispersive X-ray fluorescence (ED-XRF) for metal analysis, and a complementary metabolomic investigation using hydrophilic liquid interaction chromatography hi-resolution mass spectrometry (HILIC-MS) for organic contaminants. Secondly, the deployment of an unmanned aerial vehicle (UAV) with a multispectral image (MSI) camera, for the remote sensing of vegetation stress, as a proxy for sub-surface soil contamination. The results identified high concentrations of barium (mean 21 017 ± 5950 μg g-1, n = 36) as well as metabolites derived from crude oil (polycyclic aromatic hydrocarbons), cleaning processes (surfactants) and other organic pollutants (e.g. pesticides, plasticizers and pharmaceuticals) in the reprocessing site. This data has then been correlated, with post-flight data analysis derived vegetation indices (NDVI, GNDVI, SAVI and Cl green VI), to assess the potential to identify soil contamination because of vegetation stress. It was found that strong correlations exist (an average R2 of >0.68) between the level of soil contamination and the ground cover vegetation. The potential to deploy aerial remote sensing techniques to provide an initial survey, to inform decision-making, on suspected contaminated land sites can have global implications.PMID:38015510 | DOI:10.1039/d3em00480e

Environ Sci Pollut Res Int. 2023 Nov 28. doi: 10.1007/s11356-023-31045-y. Online ahead of print.ABSTRACTWidespread and improper use of various anthelmintics, genetic, and epidemiological factors has resulted in anthelmintic-resistant (AR) helminth populations in livestock. This is currently quite common globally in different livestock animals including sheep, goats, and cattle to gastrointestinal nematode (GIN) infections. Therefore, the mechanisms underlying AR in parasitic worm species have been the subject of ample research to tackle this challenge. Current and emerging technologies in the disciplines of genomics, transcriptomics, metabolomics, and proteomics in livestock species have advanced the understanding of the intricate molecular AR mechanisms in many major parasites. The technologies have improved the identification of possible biomarkers of resistant parasites, the ability to find actual causative genes, regulatory networks, and pathways of parasites governing the AR development including the dynamics of helminth infection and host-parasite infections. In this review, various "omics"-driven technologies including genome scan, candidate gene, quantitative trait loci, transcriptomic, proteomic, and metabolomic approaches have been described to understand AR of parasites of veterinary importance. Also, challenges and future prospects of these "omics" approaches are also discussed.PMID:38015400 | DOI:10.1007/s11356-023-31045-y

Aging Cell. 2023 Nov 27:e14028. doi: 10.1111/acel.14028. Online ahead of print.ABSTRACTHuman aging is invariably accompanied by a decline in renal function, a process potentially exacerbated by uremic toxins originating from gut microbes. Based on a registered household Chinese Guangxi longevity cohort (n = 151), we conducted comprehensive profiling of the gut microbiota and serum metabolome of individuals from 22 to 111 years of age and validated the findings in two independent East Asian aging cohorts (Japan aging cohort n = 330, Yunnan aging cohort n = 80), identifying unique age-dependent differences in the microbiota and serum metabolome. We discovered that the influence of the gut microbiota on serum metabolites intensifies with advancing age. Furthermore, mediation analyses unveiled putative causal relationships between the gut microbiota (Escherichia coli, Odoribacter splanchnicus, and Desulfovibrio piger) and serum metabolite markers related to impaired renal function (p-cresol, N-phenylacetylglutamine, 2-oxindole, and 4-aminohippuric acid) and aging. The fecal microbiota transplantation experiment demonstrated that the feces of elderly individuals could influence markers related to impaired renal function in the serum. Our findings reveal novel links between age-dependent alterations in the gut microbiota and serum metabolite markers of impaired renal function, providing novel insights into the effects of microbiota-metabolite interplay on renal function and healthy aging.PMID:38015106 | DOI:10.1111/acel.14028

J Med Microbiol. 2023 Nov;72(11). doi: 10.1099/jmm.0.001778.ABSTRACTThe increasing incidence of drug-induced liver injury (DILI) has become a major concern. Gut microbiota, as another organ of the human body, has been studied in various tumors, cardiovascular metabolic diseases, inflammatory bowel disease and human immunity. The studies mentioned above have confirmed its important impact on the occurrence and development of DILI. The gut-liver axis explains the close relationship between the gut and the liver, and it may be a pathway by which gut microbes contribute to DILI. In addition, the interaction between drugs and gut microbes affects both separately, which in turn may have positive or negative effects on the body, including DILI. There are both common and specific changes in liver injury caused by different drugs. The alteration of metabolites in DILI is also a new direction of therapeutic exploration. The application of microbiomics, metabolomics and other multi-omics to DILI has also explored new ideas for DILI. In this review, we conclude the alterations of gut microbes and metabolites under different DILI, and the significance of applying gut microbiome-metabolomics to DILI, so as to explore the metabolic characteristics of DILI and possible novel metabolic biomarkers.PMID:38015063 | DOI:10.1099/jmm.0.001778

J Agric Food Chem. 2023 Nov 28. doi: 10.1021/acs.jafc.3c07349. Online ahead of print.ABSTRACTA variety of active factors in milk and foods have been proven to serve as microbial nutrients that regulate the formation of early gut microbiota (GM), thereby ensuring the healthy development of infants. This study demonstrated that dietary nucleotides (NTs), one of the main nitrogen-containing substances in human milk, promoted the neurodevelopment of neonatal rats and the expression of Sox2, Dcx, Tuj1, and NeuN in the prefrontal cortex and hippocampus, but had no significant regulatory effects in the striatum. 16s rRNA sequencing and metabolomics of the colon contents of neonatal rats at different developmental stages showed that the early intake of NTs promoted an increase in the abundance of beneficial microorganisms related to neurodevelopment, digestion, and gut absorption, such as g_Romboutsia and g_Akkermansia. Changes in the ability of the GM to regulate folate synthesis, riboflavin metabolism, and other processes were also observed. Further analysis revealed significant correlations between the level of characteristic metabolites, namely, trans-3-indoleacrylic acid, urocanic acid, inosine, and adenosine, in the gut with neurodevelopment and characteristic GM components. These findings suggest that NTs in milk may affect neurodevelopment and maturation in early life by regulating the GM composition-gut-brain axis.PMID:38014964 | DOI:10.1021/acs.jafc.3c07349

Appl Environ Microbiol. 2023 Nov 28:e0106023. doi: 10.1128/aem.01060-23. Online ahead of print.ABSTRACTBiodegradable plastics can be used in applications where the end product cannot be efficiently recycled due to high levels of contaminations, e.g., food or soil. Some of these plastics have a dedicated end of life, such as composting, but their degradation in the marine environment is poorly understood. In this study we showed that marine microbial communities can degrade a range of biodegradable polymers with different physical and chemical properties and use these as a sole carbon source for growth. We have also provided insights into the degradation mechanisms using a combined metagenomic and metaproteomic approach. In addition, we have identified three new enzymes that are capable of degrading both aliphatic polymers and aliphatic-aromatic copolymers, which can be used for biotechnological applications.PMID:38014952 | DOI:10.1128/aem.01060-23

Phytomedicine. 2024 Jan;122:155124. doi: 10.1016/j.phymed.2023.155124. Epub 2023 Sep 29.ABSTRACTBACKGROUND: Cholestatic liver diseases (CLD) comprise a variety of disorders of bile formation, which causes chronic exposure to bile acid (BA) in the liver generally and results in hepatotoxicity and progressive hepatobiliary injury. Wedelolactone (7-methoxy-5, 11, 12-trihydroxy-coumestan, WED), the natural active compound derived from Ecliptae Herba, has been reported with valuable bioactivity for liver protection. Nevertheless, the effect of WED on cholestatic liver injury (CLI) remains unexplored.PURPOSE: The present study aims to elucidate the protective effect of WED on Alpha-naphthylisothiocyanate (ANIT)-induced CLI mice, and to investigate its potential pharmacological mechanism.METHODS: The anit-cholestatic and hepatoprotective effects of WED were evaluated in ANIT-induced CLI mice. Non-targeted metabolomics study combined with ingenuity pathway analysis (IPA) was used to explore the key mechanism of WED. The BA metabolic profile in enterohepatic circulation was analyzed to evaluate the effect of WED in regulating BA metabolism. Furthermore, molecular dynamics (MD) simulation and cellular thermal shift assay (CETSA) were used to simulate and verify the targeting activation of WED on the Farnesoid X receptor (FXR). The core role of FXR in WED promoting BA transportation, and alleviating BA accumulation-induced hepatotoxicity was further evaluated in WT and FXR knockout mice or hepatocytes.RESULTS: WED dose-dependently alleviated ANIT-induced cholestasis and liver injury in mice, and simultaneously suppressed the signaling pathway of nuclear factor-kappa B/nuclear factor-erythroid 2-related factor 2 (NF-κB/NRF2) to relieve inflammation and oxidative stress. At the metabolite level, WED improved the metabolic disorder in CLI mice focusing on the metabolism of BA, arachidonic acid, and glycerophospholipid, that closely related to the process of BA regulation, inflammation, and oxidative damage. WED targeting activated FXR, which then transcribed its target genes, including the bile salt export pump (BSEP) and the BA transporter, and subsequently increased BA transportation to restore the damaged enterohepatic circulation of BA. Meanwhile, WED alleviated hepatic BA accumulation and protected the liver from BA-induced damage via NF-κB/NRF2 signaling pathway. Furthermore, FXR deficiency suppressed the protective effect of WED in vitro and in vivo.CONCLUSION: WED regulated BA metabolism and alleviated hepatic damage in cholestasis. It protected the liver according to adjusted BA transportation and relieved BA accumulation-related hepatotoxicity via FXR-bile acid-NF-κB/NRF2 axis. Our study provides novel insights that WED might be a promising strategy for cholestatic liver disease.PMID:38014837 | DOI:10.1016/j.phymed.2023.155124

J Agric Food Chem. 2023 Nov 28. doi: 10.1021/acs.jafc.3c05788. Online ahead of print.ABSTRACTTree-crop intercropping is of great significance in food security, land protection, and sustainable agriculture. However, the mechanisms of allelopathy between plant species during intercropping are still limited. This study focuses on the allelopathic effects in the intercropping between Camellia oleifera and Arachis hypogaea L. in southern China. We use different parts of the C. oleifera extract to evaluate their impact on peanut seed germination. The results showed that it has inhibitory effects on peanut germination and growth, with the fruit shell having the strongest inhibitory effect. Three main allelopathic substances affecting A. hypogaea germination and growth were identified using gas chromatography-mass spectrometry (GC-MS) analysis, namely, 2,4-di-tert-butylphenol, hexanal, and benzaldehyde. Transcriptomics and metabolomics analyses revealed their effects on glutathione metabolism pathways and specific gene expression. In summary, this study reveals the allelopathic interaction mechanism between C. oleifera and A. hypogaea, which helps to better understand the role of allelopathy in intercropping practices between trees and crops.PMID:38014643 | DOI:10.1021/acs.jafc.3c05788

J Exp Bot. 2023 Nov 28:erad453. doi: 10.1093/jxb/erad453. Online ahead of print.ABSTRACTExtreme weather conditions lead to significant imbalances in crop productivity, which in turn affect food security. Flooding events cause serious problems to many crop species such as wheat. Although metabolic readjustments under flooding are important for plant regeneration, underlying processes remain poorly understood. Here, we investigated the systemic response of wheat to waterlogging using metabolomics and transcriptomics. A 12-days exposure to excess water triggered nutritional imbalances and disruption of metabolite synthesis and translocation, reflected by reduction of plant biomass and growth performance. Metabolic and transcriptomic profiling in roots, xylem sap and leaves indicated anaerobic fermentation processes as a local response of the roots. Differentially expressed genes and ontological categories revealed that carbohydrate metabolism plays an important role in the systemic response. Analysis of the composition of xylem exudates exhibited decreased root-to-shoot translocation of nutrients, hormones and amino acids. Interestingly, among all metabolites determined in the xylem exudates, alanine was the most abundant. Alanine supplementation to excised leaves lead to increased glucose concentration when leaves derived from waterlogged plants. Our results suggest an important role of alanine not only as an amino-nitrogen donor but also as a vehicle for carbon skeletons to produce glucose de novo and meet the energy demand during waterlogging.PMID:38014629 | DOI:10.1093/jxb/erad453

Circ Genom Precis Med. 2023 Nov 28:e004230. doi: 10.1161/CIRCGEN.123.004230. Online ahead of print.ABSTRACTBACKGROUND: Life's essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about the LE8 score, its metabolic correlates, and its predictive implications among Black Americans and low-income individuals.METHODS: In a nested case-control study of coronary heart disease (CHD) among 299 pairs of Black and 298 pairs of White low-income Americans from the Southern Community Cohort Study, we estimated LE8 score and applied untargeted plasma metabolomics and elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8. Associations of LE8 score and MetaSig with incident CHD were examined using conditional logistic regression. The mediation effect of MetaSig on the LE8-CHD association was also examined. The external validity of MetaSig was evaluated in another nested CHD case-control study among 299 pairs of Chinese adults.RESULTS: Higher LE8 score was associated with lower CHD risk (standardized odds ratio, 0.61 [95% CI, 0.53-0.69]). The MetaSig, consisting of 133 metabolites, showed significant correlation with LE8 score (r=0.61) and inverse association with CHD (odds ratio, 0.57 [0.49-0.65]), robust to adjustment for LE8 score and across participants with different sociodemographic and health status ([odds ratios, 0.42-0.69]; all P<0.05). MetaSig mediated a large portion of the LE8-CHD association: 53% (32%-80%). Significant associations of MetaSig with LE8 score and CHD risk were found in validation cohort (r=0.49; odds ratio, 0.57 [0.46-0.69]).CONCLUSIONS: Higher LE8 score and its MetaSig were associated with lower CHD risk among low-income Black and White Americans. Metabolomics may offer an objective measure of LE8 and its metabolic phenotype relevant to CHD prevention among diverse populations.PMID:38014580 | DOI:10.1161/CIRCGEN.123.004230

Allergy. 2023 Nov 28. doi: 10.1111/all.15942. Online ahead of print.ABSTRACTBACKGROUND: While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship.METHODS: We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together.RESULTS: We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes.CONCLUSION: This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.PMID:38014461 | DOI:10.1111/all.15942

Am J Physiol Gastrointest Liver Physiol. 2023 Nov 28. doi: 10.1152/ajpgi.00188.2023. Online ahead of print.ABSTRACTDried blood spot (DBS) analysis has existed for >50 years, but application of this technique to fecal analysis remains limited. To address whether dried fecal spots (DFS) could be used to measure fecal bile acids, we collected feces from five subjects for each of the following cohorts: i) healthy individuals, ii) individuals with diarrhea, and iii) Clostridioides difficile-infected patients. Homogenized fecal extracts were loaded onto quantitative DBS (qDBS) devices, dried overnight, and shipped to the bioanalytical lab at ambient temperature. For comparison, source fecal extracts were shipped on dry ice and stored frozen. After four months, frozen fecal extracts and ambient DFS samples were processed and subjected to targeted LC-MS/MS-based metabolomics with stable isotope-labeled standards. We observed no differences in the bile acid levels measured between the traditional extraction and the qDBS-based DFS methods. This pilot data demonstrate that DFS-based analysis is feasible and warrants further development for fecal compounds and microbiome applications.PMID:38014449 | DOI:10.1152/ajpgi.00188.2023

bioRxiv. 2023 Nov 16:2023.11.15.567095. doi: 10.1101/2023.11.15.567095. Preprint.ABSTRACTMetabolomics has gained much attraction due to its potential to reveal molecular disease mechanisms and present viable biomarkers. In this work we used a panel of untargeted serum metabolomes in 602 childhood patients of the COPSAC2010 mother-child cohort. The annotated part of the metabolome consists of 493 chemical compounds curated using automated procedures. Using predicted quantitative-structure-bioactivity relationships for the Tox21 database on nuclear receptors and stress response in cell lines, we created a filtering method for the vast number of quantified metabolites. The metabolites measured in childrens serums used here have predicted potential against the chosen target modelled targets. The targets from Tox21 have been used with quantitative structure-activity relationships (QSARs) and were trained for ~7000 structures, saved as models, and then applied to 493 metabolites to predict their potential bioactivities. The models were selected based on strict accuracy criteria surpassing random effects. After application, 52 metabolites showed potential bioactivity based on structural similarity with known active compounds from the Tox21 set. The filtered compounds were subsequently used and weighted by their bioactive potential to show an association with early childhood hs-CRP levels at six months in a linear model supporting a physiological adverse effect on systemic low-grade inflammation. The significant metabolites were reported.PMID:38014335 | PMC:PMC10680762 | DOI:10.1101/2023.11.15.567095

bioRxiv. 2023 Nov 15:2023.11.10.564562. doi: 10.1101/2023.11.10.564562. Preprint.ABSTRACTHypertrophic cardiomyopathy (HCM) results from pathogenic variants in sarcomeric protein genes, that increase myocyte energy demand and lead to cardiac hypertrophy. But it is unknown whether a common metabolic trait underlies the cardiac phenotype at early disease stage. This study characterized two HCM mouse models (R92W-TnT, R403Q-MyHC) that demonstrate differences in mitochondrial function at early disease stage. Using a combination of cardiac phenotyping, transcriptomics, mass spectrometry-based metabolomics and computational modeling, we discovered allele-specific differences in cardiac structure/function and metabolic changes. TnT-mutant hearts had impaired energy substrate metabolism and increased phospholipid remodeling compared to MyHC-mutants. TnT-mutants showed increased incorporation of saturated fatty acid residues into ceramides, cardiolipin, and increased lipid peroxidation, that could underlie allele-specific differences in mitochondrial function and cardiomyopathy.PMID:38014251 | PMC:PMC10680657 | DOI:10.1101/2023.11.10.564562

bioRxiv. 2023 Nov 15:2023.11.13.566691. doi: 10.1101/2023.11.13.566691. Preprint.ABSTRACTDifferences in affective behavioral expression from early to late adulthood is thought to involve changes in frontal cortical responsiveness to negative valence stimuli. In mice, similar maturational changes in affective behaviors have also been reported but the functional neural circuitry remains unclear. In the present study we investigated age variations in affective behaviors and functional connectivity in male and female C57BL6/J mice. Mice aged 10, 30 and 60 weeks (wo) were tested over 8 weeks for open field activity, sucrose reward preference, social interactions and fear conditioning and functional neuroimaging. Frontal cortical and hippocampal tissues were excised for metabolomics analysis. Our results indicate that young 10wo mice display greater levels of anxiety-like locomotor behavior and develop robust fear conditioning compared to older adult and late middle-aged mice (30-60wo). This was accompanied by greater functional connectivity between a temporal cortical/auditory cortex network and subregions of the anterior cingulate cortex and ventral hippocampus, and a greater network modularity and assortative mixing of nodes in young versus older adult mice. Metabolome analyses identified differences in several essential amino acids between 10wo mice and the other age groups. The results support high 'emotionality' in younger versus older adult mice involving greater prefrontal-hippocampal connectivity.PMID:38014219 | PMC:PMC10680600 | DOI:10.1101/2023.11.13.566691

bioRxiv. 2023 Nov 16:2023.11.14.566937. doi: 10.1101/2023.11.14.566937. Preprint.ABSTRACTTelomerase reverse transcriptase (TERT) is essential for glioblastoma (GBM) proliferation. Delineating metabolic vulnerabilities induced by TERT can lead to novel GBM therapies. We previously showed that TERT upregulates glutathione (GSH) pool size in GBMs. Here, we show that TERT acts via the FOXO1 transcription factor to upregulate expression of the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme of de novo GSH synthesis. Inhibiting GCLC using siRNA or buthionine sulfoximine (BSO) reduces synthesis of 13 C-GSH from [U- 13 C]-glutamine and inhibits clonogenicity. However, GCLC inhibition does not induce cell death, an effect that is associated with elevated [U- 13 C]-glutamine metabolism to glutamate and pyrimidine nucleotide biosynthesis. Mechanistically, GCLC inhibition activates MYC and leads to compensatory upregulation of two key glutamine-utilizing enzymes i.e., glutaminase (GLS), which generates glutamate from glutamine, and CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotatase), the enzyme that converts glutamine to the pyrimidine nucleotide precursor dihydroorotate. We then examined the therapeutic potential of inhibiting GLS and CAD in combination with GCLC. 6-diazo-5-oxy-L-norleucin (DON) is a potent inhibitor of glutamine-utilizing enzymes including GLS and CAD. The combination of BSO and DON suppresses GSH and pyrimidine nucleotide biosynthesis and is synergistically lethal in GBM cells. Importantly, in vivo stable isotope tracing indicates that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH and pyrimidine nucleotides from [U- 13 C]-glutamine and induces tumor shrinkage in mice bearing intracranial GBM xenografts. Collectively, our studies exploit a mechanistic understanding of TERT biology to identify synthetically lethal metabolic vulnerabilities in GBMs.SIGNIFICANCE: Using in vivo stable isotope tracing, metabolomics, and loss-of-function studies, we demonstrate that TERT expression is associated with metabolic alterations that can be synergistically targeted for therapy in glioblastomas.PMID:38014170 | PMC:PMC10680720 | DOI:10.1101/2023.11.14.566937

Res Sq. 2023 Nov 17:rs.3.rs-3600439. doi: 10.21203/rs.3.rs-3600439/v1. Preprint.ABSTRACTBackground The INSPIRE randomized clinical trial demonstrated that a high protein diet (HPRO) combined with neuromuscular electrical stimulation (NMES) attenuates muscle atrophy and may improve functional outcomes after aSAH. Using an untargeted metabolomics approach, we sought to identify specific metabolites mediating these effects. Methods Blood samples were collected from subjects on admission prior to randomization to either standard of care (SOC; N=12) or HPRO+NMES (N=12) and at 7 days as part of the INSPIRE protocol. Untargeted metabolomics were performed for each plasma sample. Paired fold changes were calculated for each metabolite among subjects in the HPRO+NMES group at baseline and 7 days after intervention. Changes in metabolites from baseline to 7 days were compared for the HPRO+NMES and SOC groups. Sparse partial least squared discriminant analysis (sPLS-DA) identified metabolites discriminating each group. Pearson's correlation coefficients were calculated between each metabolite and total protein per day, nitrogen balance, and muscle volume Multivariable models were developed to determine associations between each metabolite and muscle volume. Results A total of 18 unique metabolites were identified including pre and post treatment and differentiating SOC vs HPRO+NMES. Of these, 9 had significant positive correlations with protein intake: N-acetylserine (ρ=0.61, P =1.56x10 -3 ), N-acetylleucine (ρ=0.58, P =2.97x10 -3 ), β-hydroxyisovaleroylcarnitine (ρ=0.53, P =8.35x10 -3 ), tiglyl carnitine (ρ=0.48, P =0.0168), N-acetylisoleucine (ρ=0.48, P =0.0183), N-acetylthreonine (ρ=0.47, P =0.0218), N-acetylkynurenine (ρ=0.45, P =0.0263), N-acetylvaline (ρ=0.44, P =0.0306), and urea (ρ=0.43, P =0.0381). In multivariable regression models, N-acetylleucine was significantly associated with preserved temporalis [OR 1.08 (95%CI 1.01, 1.16)] and quadricep [OR 1.08 (95%CI 1.02, 1.15)] muscle volume. Quinolinate was also significantly associated with preserved temporalis [OR 1.05 (95%CI 1.01, 1.09)] and quadricep [OR 1.04 (95%CI 1.00, 1.07)] muscle volume. N-acetylserine, N-acetylcitrulline, and b-hydroxyisovaleroylcarnitine were also associated with preserved temporalis or quadricep volume. Conclusions Metabolites defining the HPRO+NMES intervention mainly consisted of amino acid derivatives. These metabolites had strong correlations with protein intake and were associated with preserved muscle volume.PMID:38014126 | PMC:PMC10680941 | DOI:10.21203/rs.3.rs-3600439/v1

bioRxiv. 2023 Nov 16:2023.11.15.567158. doi: 10.1101/2023.11.15.567158. Preprint.ABSTRACTFatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous bioactive lipids known for their anti-inflammatory and anti-diabetic properties. Despite their therapeutic potential, little is known about the sex-specific variations in FAHFA metabolism. This study investigated the role of Androgen Dependent TFPI Regulating Protein (ADTRP), a FAHFA hydrolase. Additionally, tissue-specific differences in FAHFA levels, focusing on the perigonadal white adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), brown adipose tissue (BAT), plasma, and liver, were evaluated using metabolomics and lipidomics. We found that female mice exhibited higher FAHFA levels in pgWAT, scWAT, and BAT compared to males. FAHFA levels were inversely related to Adtrp mRNA, which showed significantly lower expression in females compared with males in pgWAT and scWAT. However, no significant differences between the sexes were observed in plasma and liver FAHFA levels. Adtrp deletion had minimal impact on both sexes' metabolome and lipidome of pgWAT. However, we discovered higher endogenous levels of triacylglycerol estolides containing FAHFAs, a FAHFA metabolic reservoir, in the pgWAT of female mice. These findings suggest that sex-dependent differences in FAHFA levels occur primarily in specific WAT depots and may modulate local insulin sensitivity in adipocytes. However, further investigations are warranted to fully comprehend the underlying mechanisms and implications of sex effects on FAHFA metabolism in humans.PMID:38014093 | PMC:PMC10680750 | DOI:10.1101/2023.11.15.567158

Res Sq. 2023 Nov 15:rs.3.rs-3597052. doi: 10.21203/rs.3.rs-3597052/v1. Preprint.ABSTRACTThiamine (Vitamin B1) is an essential micronutrient and a co-factor for metabolic functions related to energy metabolism. We determined the association between whole blood thiamine pyrophosphate (TPP) concentrations and plasma metabolites using high resolution metabolomics in critically ill patients. Methods Cross-sectional study performed in Erciyes University Hospital, Kayseri, Turkey and Emory University, Atlanta, GA, USA. Participants were ≥ 18 years of age, with an expected length of ICU stay longer than 48 hours, receiving furosemide therapy for at least 6 months before ICU admission. Results Blood for TPP and metabolomics was obtained on the day of ICU admission. Whole blood TPP concentrations were measured using high-performance liquid chromatography (HPLC). Liquid chromatography/mass spectrometry was used for plasma high-resolution metabolomics. Data was analyzed using regression analysis of TPP levels against all plasma metabolomic features in metabolome-wide association studies. We also compared metabolomic features from patients in the highest TPP concentration tertile to patients in the lowest TPP tertile as a secondary analysis. We enrolled 76 participants with a median age of 69 (range, 62.5-79.5) years. Specific metabolic pathways associated with whole blood TPP levels, using both regression and tertile analysis, included pentose phosphate, fructose and mannose, branched chain amino acid, arginine and proline, linoleate, and butanoate pathways. Conclusions Plasma high-resolution metabolomics analysis showed that whole blood TPP concentrations are significantly associated with metabolites and metabolic pathways linked to the metabolism of energy, amino acids, lipids, and the gut microbiome in adult critically ill patients.PMID:38014088 | PMC:PMC10680934 | DOI:10.21203/rs.3.rs-3597052/v1

medRxiv. 2023 Nov 13:2023.11.13.23298467. doi: 10.1101/2023.11.13.23298467. Preprint.ABSTRACTThe influence of genotype on defining the human gut microbiome has been extensively studied, but definite conclusions have not yet been found. To fill this knowledge gap, we leverage data from children enrolled in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) from 6 months to 8 years old. We focus on a pool of 12 genes previously found to be associated with the gut microbiome in independent studies, establishing a Bonferroni corrected significance level of p-value < 2.29 × 10 -6 . We identified significant associations between SNPs in the FHIT gene (known to be associated with obesity and type 2 diabetes) and obesity-related microbiome features, and the children's BMI through their childhood. Based on these associations, we defined a set of SNPs of interest and a set of taxa of interest. Taking a multi-omics approach, we integrated plasma metabolome data into our analysis and found simultaneous associations among children's BMI, the SNPs of interest, and the taxa of interest, involving amino acids, lipids, nucleotides, and xenobiotics. Using our association results, we constructed a quadripartite graph where each disjoint node set represents SNPs in the FHIT gene, microbial taxa, plasma metabolites, or BMI measurements. Network analysis led to the discovery of patterns that identify several genetic variants, microbial taxa and metabolites as new potential markers for obesity, type 2 diabetes, or insulin resistance risk.PMID:38014043 | PMC:PMC10680902 | DOI:10.1101/2023.11.13.23298467