PubMed

BioTech (Basel). 2023 May 17;12(2):39. doi: 10.3390/biotech12020039.ABSTRACTMany kinds of Lactobacillus are common occupants of humans' digestive tract that support the preservation of a balanced microbial environment that benefits host health. In this study, the unique lactic acid bacterium strain Limosilactobacillus fermentum U-21, which was isolated from the feces of a healthy human, was examined for its metabolite profile in order to compare it to that of the strain L. fermentum 279, which does not have antioxidant (AO) capabilities. By using GC × GC-MS, the metabolite fingerprint of each strain was identified, and the data were then subjected to multivariate bioinformatics analysis. The L. fermentum U-21 strain has previously been shown to possess distinctive antioxidant properties in in vivo and in vitro studies, positioning it as a drug candidate for the treatment of Parkinsonism. The production of multiple distinct compounds is shown by the metabolite analysis, demonstrating the unique characteristics of the L. fermentum U-21 strain. According to reports, some of the L. fermentum U-21 metabolites found in this study have health-promoting properties. The GC × GC-MS-based metabolomic tests defined strain L. fermentum U-21 as a potential postbiotic with significant antioxidant potential.PMID:37218756 | DOI:10.3390/biotech12020039

Anal Chem. 2023 May 23. doi: 10.1021/acs.analchem.2c04343. Online ahead of print.ABSTRACTSmall molecule structure elucidation using tandem mass spectrometry (MS/MS) plays a crucial role in life science, bioanalytical, and pharmaceutical research. There is a pressing need for increased throughput of compound identification and transformation of historical data into information-rich spectral databases. Meanwhile, molecular networking, a recent bioinformatic framework, provides global displays and system-level understanding of complex LC-MS/MS data sets. Herein we present meRgeION, a multifunctional, modular, and flexible R-based toolbox to streamline spectral database building, automated structural elucidation, and molecular networking. The toolbox offers diverse tuning parameters and the possibility to combine various algorithms in the same pipeline. As an open-source R package, meRgeION is ideally suited for building spectral databases and molecular networks from privacy-sensitive and preliminary data. Using meRgeION, we have created an integrated spectral database covering diverse pharmaceutical compounds that was successfully applied to annotate drug-related metabolites from a published nontargeted metabolomics data set as well as reveal the chemical space behind this complex data set through molecular networking. Moreover, the meRgeION-based processing workflow has demonstrated the usefulness of a spectral library search and molecular networking for pharmaceutical forced degradation studies. meRgeION is freely available at: https://github.com/daniellyz/meRgeION2.PMID:37218737 | DOI:10.1021/acs.analchem.2c04343

Am J Epidemiol. 2023 May 22:kwad122. doi: 10.1093/aje/kwad122. Online ahead of print.ABSTRACTEpidemiologic studies of low-frequency exposures or outcomes using metabolomics analyses of neonatal dried blood spots (DBS) often require assembly of samples with substantial differences in duration of storage. Independent assessment of stability of metabolites in archived DBS will enable improved design and interpretation of epidemiologic research utilizing DBS. Neonatal DBS routinely collected and stored as part of the California Genetic Disease Screening Program between 1983 and 2011 were used. The study population included 899 children without cancer before age 6 born in California. High-resolution metabolomics with liquid chromatography mass spectrometry (LC-MS) was performed and the relative ion intensities of common metabolites and selected xenobiotic metabolites of nicotine (cotinine and hydroxycotinine) were evaluated. In total, we detected 26,235 mass spectral features across two separate chromatography methods (C18 and HILIC). For most of the 39 metabolites related to nutrition and health status, we found no statistically significant annual trends across the years of storage. Nicotine metabolites were captured in the DBS with relatively stable intensities. This study supports the usefulness of DBS stored long-term for epidemiological studies of the metabolome. Omics-based information gained from DBS may also provide a valuable tool for assessing prenatal environmental exposures in child health research.PMID:37218607 | DOI:10.1093/aje/kwad122

Alzheimers Dement. 2023 May 22. doi: 10.1002/alz.13130. Online ahead of print.ABSTRACTINTRODUCTION: A hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest.METHODS: We conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation.RESULTS: We identified 61 proteins significantly associated with the AT category (P < 5.46 × 10-5 ) and 636 significant protein-biomarker associations (P < 6.07 × 10-6 ). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers.DISCUSSION: These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD.HIGHLIGHTS: Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing. Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins. Key glucose/carbon metabolism protein associations independently replicated. CSF proteome outperformed other omics data in predicting amyloid/tau positivity. CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.PMID:37218097 | DOI:10.1002/alz.13130

Cell Biochem Funct. 2023 May 22. doi: 10.1002/cbf.3811. Online ahead of print.ABSTRACTAutism spectrum disorder (ASD) is a neurodevelopmental disorder, and the etiology is unknown. Metabolic dysfunction is present in patients with ASD. In the current study, untargeted metabolomics was employed to screen the differential metabolites in the liver of BTBR mouse model of autism, and MetaboAnalyst 4.0 was used for metabolic pathway analysis. Mice were killed, and liver samples were collected for untargeted metabolomics analysis and examination of histopathology. Finally, 12 differential metabolites were identified. The intensities of phenylethylamine, 4-Guanidinobutanoic acid, leukotrieneD4, and SM(d18:1/24:1(15Z)) were significantly upregulated (p < .01), and the intensities of estradiol, CMP-N-glycoloylneuraminate, retinoyl β-glucuronide,4-phosphopantothenoylcysteine, aldophosphamide, taurochenodesoxycholic acid, taurocholic acid, and dephospho-CoA were significantly downregulated (p < .01) in the BTBR group compared with C57 control group, indicating that differences between BTBR and C57 groups were observed in metabolic patterns. Disturbed pathways of the BTBR mice involved lipid metabolism, retinol metabolism, and amino acid and energy metabolism, revealing that bile acid-mediated activation of LXRα might contribute to metabolic dysfunction of lipid and leukotriene D4 produced by the activation of 5-LOX led to hepatic inflammation. Pathological changes in the liver tissue, such as hepatocyte vacuolization, and small amounts of inflammatory and cell necrosis, further supported metabolomic results. Moreover, Spearman's rank correlation revealed that there is a strong relationship between metabolites across liver and cortex, suggesting liver may exert action by connecting peripheral and neural systems. These findings were likely to be of pathological importance or a cause/consequence of autism, and may provide insight into key metabolic dysfunction to target potential therapeutic strategies relating to ASD.PMID:37218093 | DOI:10.1002/cbf.3811

Front Immunol. 2023 May 5;14:1124443. doi: 10.3389/fimmu.2023.1124443. eCollection 2023.ABSTRACTBACKGROUND: Abnormal lipid metabolism is common in patients with primary biliary cholangitis (PBC). PBC and Sjögren's syndrome (SS) frequently coexist in clinical practice; however, the lipid characteristics of both diseases are unknown. Therefore, we aimed to analyze the plasma lipid profiles of both diseases.METHODS: Plasma samples from 60 PBC patients, 30 SS patients, and 30 healthy controls (HC) were collected, and untargeted lipidomics was performed using ultrahigh-performance liquid chromatography high-resolution mass spectrometry. Potential lipid biomarkers were screened through an orthogonal projection to latent structure discriminant analysis and further evaluated using receiver operating characteristic (ROC) analysis.RESULTS: A total of 115 lipids were differentially upregulated in PBC patients compared with HC. Seventeen lipids were positively associated with the disease activity of PBC, and ROC analysis showed that all of these lipids could differentiate between ursodeoxycholic acid (UDCA) responders and UDCA non-responders. The top six lipids based on the area under the curve (AUC) values were glycerophosphocholine (PC) (16:0/16:0), PC (18:1/18:1), PC (42:2), PC (16:0/18:1), PC (17:1/14:0), and PC (15:0/18:1). In comparison with SS, 44 lipids were found to be differentially upregulated in PBC. Additionally, eight lipids were found to have a good diagnostic performance of PBC because of the AUC values of more than 0.9 when identified from SS and HC groups, which were lysophosphatidylcholines (LysoPC) (16:1), PC (16:0/16:0), PC (16:0/16:1), PC (16:1/20:4), PC (18:0/20:3), PC (18:1/20:2), PC (20:0/22:5), and PC (20:1/22:5).CONCLUSION: Our study revealed differentially expressed lipid signatures in PBC compared with HC and SS. PC is the main lipid species associated with disease activity and the UDCA response in patients with PBC.PMID:37215104 | PMC:PMC10196160 | DOI:10.3389/fimmu.2023.1124443

J Anim Sci. 2023 May 22:skad165. doi: 10.1093/jas/skad165. Online ahead of print.ABSTRACTIn the immediate time after weaning, piglets often show symptoms of gut inflammation. The change to a plant-based diet, lack of sow milk and the resulting novel gut microbiome and metabolite profile in digesta may be causative factors for the observed inflammation. We used the intestinal loop perfusion assay (ILPA) to investigate jejunal and colonic expression of genes for antimicrobial secretion, oxidative stress, barrier function and inflammatory signaling in suckling and weaned piglets when exposed to 'plant-oriented' microbiome (POM) representing postweaning digesta with gut-site specific microbial and metabolite composition. Two serial ILPA were performed in two replicate batches, with 16 piglets pre- (day 24-27) and 16 piglets postweaning (day 38-41). Two jejunal and colonic loops were perfused with Krebs-Henseleit buffer (control) or with the respective POM for two hours. Afterwards, RNA was isolated from the loop tissue to determine the relative gene expression. Age-related effects in jejunum included higher expression of genes for antimicrobial secretions and barrier function as well as reduced expression of pattern-recognition receptors post- compared to preweaning (P < 0.05). Age-related effects in the colon comprised downregulation of the expression of pattern-recognition receptors post- compared to preweaning (P < 0.05). Likewise, age reduced the colonic expression of genes encoding for cytokines, antimicrobial secretions, antioxidant enzymes and tight-junction proteins post- compared to preweaning. Effect of POM in the jejunum comprised an increased the expression of toll-like receptors compared to the control (P < 0.05), demonstrating a specific response to microbial antigens. Similarly, POM administration upregulated the jejunal expression of antioxidant enzymes (P < 0.05). The POM perfusion strongly upregulated the colonic expression of cytokines and altered the expression of barrier function genes, fatty acid receptors and transporters and antimicrobial secretions (P < 0.05). In conclusion, results indicated that POM signaled via altering the expression of pattern recognition receptors in the jejunum, which in turn activated the secretory defense and decreased mucosal permeability. In the colon, POM may have acted proinflammatory via upregulated cytokine expression. Results are valuable for the formulation of transition feeds for the immediate time after weaning to maintain mucosal immune tolerance towards the novel digesta composition.PMID:37217284 | DOI:10.1093/jas/skad165

Adv Healthc Mater. 2023 May 22:e2300666. doi: 10.1002/adhm.202300666. Online ahead of print.ABSTRACTThe native extracellular matrix is highly dynamic with continuous mutual feedback between cells being responsible for many important cell function regulators. However, establishing bidirectional interaction between complex adaptive microenvironments and cells remains elusive. Herein we report an adaptive biomaterial based on lysozyme monolayers self-assembled at a perfluorocarbon FC40-water interface. The dynamic adaptivity of interfacially assembled protein nanosheets is modulated independently of bulk mechanical properties by covalent crosslinking. This provides a scenario to establish bidirectional interactions of cells with liquid interfaces of varying dynamic adaptivity. We found that growth and multipotency of human mesenchymal stromal cells (hMSCs) are enhanced at the highly adaptive fluid interface. The multipotency retention of hMSCs is mediated by low cell contractility and metabolomic activity involving the continuous mutual feedback between the cells and materials. Consequently, an understanding of the cells' response to dynamic adaptivity has substantial implications for regenerative medicine and tissue engineering. This article is protected by copyright. All rights reserved.PMID:37216966 | DOI:10.1002/adhm.202300666

Bioinformatics. 2023 May 22:btad333. doi: 10.1093/bioinformatics/btad333. Online ahead of print.ABSTRACTMOTIVATION: Many studies have successfully used network information to prioritize candidate omics profiles associated with diseases. The metabolome, as the link between genotypes and phenotypes, has accumulated growing attention. Using a "multi-omics" network constructed with a gene-gene network, a metabolite-metabolite network, and a gene-metabolite network to simultaneously prioritize candidate disease-associated metabolites and gene expressions could further utilize gene-metabolite interactions that are not used when prioritizing them separately. However, the number of metabolites is usually 100 times fewer than that of genes. Without accounting for this imbalance issue, we cannot effectively use gene-metabolite interactions when simultaneously prioritizing disease-associated metabolites and genes.RESULTS: Here we developed a Multi-omics Network Enhancement Prioritization (MultiNEP) framework with a weighting scheme to reweight contributions of different sub-networks in a multi-omics network to effectively prioritize candidate disease-associated metabolites and genes simultaneously. In simulation studies, MultiNEP outperforms competing methods that do not address network imbalances and identifies more true signal genes and metabolites simultaneously when we down-weight relative contributions of the gene-gene network and up-weight that of the metabolite-metabolite network to the gene-metabolite network. Applications to two human cancer cohorts show that MultiNEP prioritizes more cancer-related genes by effectively using both within- and between-omics interactions after handling network imbalance.AVAILABILITY: The developed MultiNEP framework is implemented in an R package and available at: https://github.com/Karenxzr/MultiNep.PMID:37216914 | DOI:10.1093/bioinformatics/btad333

J Autoimmun. 2023 May 20;138:103048. doi: 10.1016/j.jaut.2023.103048. Online ahead of print.ABSTRACTMetabolic reprogramming plays a pivotal role in the differentiation and function of immune cells including dendritic cells (DCs). Regulatory DCs can be generated in regional tissue niches like splenic stroma and act as an important part of stromal control of immune response for the maintenance of immune tolerance. However, the metabolic alterations during splenic stroma-driven regulatory DCs differentiation and the metabolic enzyme involved in regulatory DCs function remain poorly understood. By combining metabolomic, transcriptomic, and functional investigations of mature DCs (maDCs) and diffDCs (regulatory DCs differentiated from activated mature DCs through coculturing with splenic stroma), here we identified succinate-CoA ligase subunit beta Suclg2 as a key metabolic enzyme that reprograms the proinflammatory status of mature DCs into a tolerogenic phenotype via preventing NF-κB signaling activation. diffDCs downregulate succinic acid levels and increase the Suclg2 expression along with their differentiation from mature DCs. Suclg2-interference impaired the tolerogenic function of diffDCs in inducing T cell apoptosis and enhanced activation of NF-κB signaling and expression of inflammatory genes CD40, Ccl5, and Il12b in diffDCs. Furthermore, we identified Lactb as a new positive regulator of NF-κB signaling in diffDCs whose succinylation at the lysine 288 residue was inhibited by Suclg2. Our study reveals that the metabolic enzyme Suclg2 is required to maintain the immunoregulatory function of diffDCs, adding mechanistic insights into the metabolic regulation of DC-based immunity and tolerance.PMID:37216870 | DOI:10.1016/j.jaut.2023.103048

Nutr Res. 2023 Apr 25;115:13-25. doi: 10.1016/j.nutres.2023.04.006. Online ahead of print.ABSTRACTMetabolic syndrome (MetS) is a serious global health concern. The objective of this study is to dynamically investigate the changes of metabolic profiles and metabolites in Chinese male MetS subjects after an 18 months diet and exercise intervention. Fifty male MetS patients defined according to International Diabetes Federation 2005 guidelines were subjected to diet and exercise counseling for 18 months. Serum samples were taken at baseline, 12 months, and 18 months, respectively, for clinical evaluation and metabolomics analyses. Diet and exercise intervention for 18 months achieved significant improvements in the metabolic profiles of all participants. Nineteen subjects (38.0%) exhibited MetS remission at the end of the study. A total of 812 relative features were characterized and 61 were successfully identified. Furthermore, 17 differential metabolites were of significance at both time points (baseline-12 months, baseline-18 months) and presented nonlinear trends through time. Eight metabolites (47.1%) were predominantly converged to inflammation and oxidative stress. Pro-inflammatory biomarkers were remarkably decreased after 18 months of intervention, and prostaglandin E2, neuroprotectin D1, and taxiphyllin in combination were firstly found to demonstrate a fair discriminative power (area under curve = 0.911) to predict the improvement of MetS undergone diet and exercise intervention. The significant shift of metabolomic profiling after 18 months of lifestyle counseling provide a novel insight and reveal that earlier inflammation control may be of potential benefit in MetS management.PMID:37216838 | DOI:10.1016/j.nutres.2023.04.006

Biochem Biophys Res Commun. 2023 May 16;667:120-126. doi: 10.1016/j.bbrc.2023.05.027. Online ahead of print.ABSTRACTBACKGROUND: Hepatocyte lipotoxicity mediated by sphingolipids was considered one of important factors in NAFLD development. Knocking out key enzymes for sphingolipids synthesis, such as DES-1, SPHK1 and CerS6, could reduce hepatocyte lipotoxicity and improve NAFLD progression. Previous studies showed that roles of CerS5 and CerS6 in sphingolipids metabolism were similar, but the role of CerS5 was controversial in NAFLD development. This study aimed to clarify the role and mechanism of CerS5 in NAFLD development.METHODS: Hepatocyte conditional CerS5 knockout (CerS5 CKO) and wild type (WT) mice were fed with standard control diet (SC) and choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) and then divided into four groups: CerS5 CKO-SC, CerS5 CKO-CDAHFD, WT-SC and WT-CDAHFD. RT-PCR, IHC and WB were used to analyze the expression of inflammatory, fibrosis and bile acids (BA) metabolism factors. RNA-seq was used to analyze differences of transcriptional levels of liver molecules among the four groups. Metabolomics was used to measured differences of hepatic BAs among the four groups.RESULTS: Hepatocyte specific knockout of CerS5 did not increase or reduce the severity of 8-weeks CDAHFD induced hepatic steatosis and inflammation, but significantly worsened the progression of liver fibrosis in these mice. At the molecular level, hepatocyte specific knockout of CerS5 did not increase or reduce expression of hepatic inflammatory factors: CD68, F4/80 and MCP-1, but increased expression of hepatic fibrosis factors: α-SMA, COL1α and TGF-β in mice fed with CDAHFD. Transcriptome analysis showed that hepatocyte specific knockout of CerS5 significantly decreased the expression of hepatic cyp27a1, and decreased expression of cyp27a1 was further validated by RT-PCR and WB. Considering that cyp27a1 was a key enzyme in the alternative pathway of BA synthesis, we further found that hepatic BA pools in CerS5 CKO mice were more conducive to the progression of liver fibrosis, which were characterized by elevated hydrophobic 12α-OH BAs and decreased hydrophilic non-12α-OH BAs.CONCLUSION: CerS5 played an important role in the progression of NAFLD related fibrosis, and hepatocyte specific knockout of CerS5 accelerated the progression of NAFLD related fibrosis, which was possibly due to the inhibition of BA synthesis alternative pathway by knocking out hepatocyte CerS5.PMID:37216827 | DOI:10.1016/j.bbrc.2023.05.027

Food Chem. 2023 May 10;424:136341. doi: 10.1016/j.foodchem.2023.136341. Online ahead of print.ABSTRACTData on changes in non-volatile components and metabolic pathways during pork storage were inadequately investigated. Herein, an untargeted metabolomics coupled with random forests machine learning algorithm was proposed to identify the potential marker compounds and their effects on non-volatile production during pork storage by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS). A total of 873 differential metabolites were identified based on analysis of variance (ANOVA). Bioinformatics analysis shows that the key metabolic pathways for protein degradation and amino acid transport are amino acid metabolism and nucleotide metabolism. Finally, 40 potential marker compounds were screened using the random forest regression model, innovatively proposing the key role of pentose-related metabolism in pork spoilage. Multiple linear regression analysis revealed that d-xylose, xanthine, and pyruvaldehyde could be key marker compounds related to the freshness of refrigerated pork. Therefore, this study could provide new ideas for the identification of marker compounds in refrigerated pork.PMID:37216778 | DOI:10.1016/j.foodchem.2023.136341

J Neuroinflammation. 2023 May 22;20(1):122. doi: 10.1186/s12974-023-02808-8.ABSTRACTBACKGROUND: Autoimmune neuropathies are common peripheral nervous system (PNS) disorders. Environmental influences and dietary components are known to affect the course of autoimmune diseases. Intestinal microorganisms can be dynamically regulated through diet, and this study combines intestinal microorganisms with diseases to open up new therapeutic ideas.METHODS: In Lewis rats, a model of EAN was established with P0 peptide, Lactobacillus were used as treatment, serum T-cell ratio, inflammatory factors, sciatic neuropathological changes, and pathological inflammatory effects on intestinal mucosa were detected, and fecal metabolomics and 16 s microbiome analysis were performed to further explore the mechanism.RESULTS: In the EAN rat model, Lactobacillus paracasei L9 (LP) could dynamically regulate the CD4+/CD8+T balance in serum, reduce serum IL-1, IL-6 and TNF-α expression levels, improve sciatic nerve demyelination and inflammatory infiltration, and reduce nervous system score. In the rat model of EAN, intestinal mucosa was damaged. Occludin and ZO-1 were downregulated. IL-1, TNF-α and Reg3γ were upregulated. LP gavage induced intestinal mucosa recovery; occludin and ZO-1 upregulation; IL-1, TNF-α and Reg3γ downregulation. Finally, metabolomics and 16 s microbiome analysis were performed, and differential metabolites were enriched with an important metabolic pathway, arginine and proline metabolism.CONCLUSION: LP improved EAN in rats by influencing intestinal community and the lysine and proline metabolism.PMID:37217991 | DOI:10.1186/s12974-023-02808-8

Nat Metab. 2023 May 22. doi: 10.1038/s42255-023-00802-1. Online ahead of print.ABSTRACTDistinct niches of the mammalian gut are populated by diverse microbiota, but the contribution of spatial variation to intestinal metabolism remains unclear. Here we present a map of the longitudinal metabolome along the gut of healthy colonized and germ-free male mice. With this map, we reveal a general shift from amino acids in the small intestine to organic acids, vitamins and nucleotides in the large intestine. We compare the metabolic landscapes in colonized versus germ-free mice to disentangle the origin of many metabolites in different niches, which in some cases allows us to infer the underlying processes or identify the producing species. Beyond the known impact of diet on the small intestinal metabolic niche, distinct spatial patterns suggest specific microbial influence on the metabolome in the small intestine. Thus, we present a map of intestinal metabolism and identify metabolite-microbe associations, which provide a basis to connect the spatial occurrence of bioactive compounds to host or microorganism metabolism.PMID:37217759 | DOI:10.1038/s42255-023-00802-1

Nucleic Acids Res. 2023 May 22:gkad444. doi: 10.1093/nar/gkad444. Online ahead of print.ABSTRACTQuantitative assessment of single cell fluxome is critical for understanding the metabolic heterogeneity in diseases. Unfortunately, laboratory-based single cell fluxomics is currently impractical, and the current computational tools for flux estimation are not designed for single cell-level prediction. Given the well-established link between transcriptomic and metabolomic profiles, leveraging single cell transcriptomics data to predict single cell fluxome is not only feasible but also an urgent task. In this study, we present FLUXestimator, an online platform for predicting metabolic fluxome and variations using single cell or general transcriptomics data of large sample-size. The FLUXestimator webserver implements a recently developed unsupervised approach called single cell flux estimation analysis (scFEA), which uses a new neural network architecture to estimate reaction rates from transcriptomics data. To the best of our knowledge, FLUXestimator is the first web-based tool dedicated to predicting cell-/sample-wise metabolic flux and metabolite variations using transcriptomics data of human, mouse and 15 other common experimental organisms. The FLUXestimator webserver is available at http://scFLUX.org/, and stand-alone tools for local use are available at https://github.com/changwn/scFEA. Our tool provides a new avenue for studying metabolic heterogeneity in diseases and has the potential to facilitate the development of new therapeutic strategies.PMID:37216602 | DOI:10.1093/nar/gkad444

Anal Chem. 2023 May 22. doi: 10.1021/acs.analchem.3c01364. Online ahead of print.ABSTRACTThe importance of element-selective detection with inductively coupled plasma mass spectrometry (ICPMS) has been significantly increased in recent years following the introduction of tandem ICPMS (ICPMS/MS), which unlocked access to nonmetal speciation analysis. However, nonmetals are ubiquitous, and the feasibility of nonmetal speciation analysis in matrices with complex metabolomes is yet to be demonstrated. Herein, we report the first phosphorous speciation study by HPLC-ICPMS/MS in a human sample, namely, urine, involving the determination of the natural metabolite and biomarker phosphoethanolamine. A simple one-step derivatization procedure was employed to enable the separation of the target compound from the hydrophilic phosphorous metabolome in urine. The challenge of eluting the hydrophobic derivative under ICPMS-compatible chromatographic conditions was addressed by employing hexanediol, a novel chromatographic eluent recently described in our previous work but has not yet been exploited in a real-world application. The developed method features fast chromatographic separation (<5 min), no need for an isotopically labeled internal standard, and an instrumental LOD of 0.5 μg P L-1. The method was evaluated for recovery (90-110%), repeatability (RSD ±5%), and linearity (r2 = 0.9998). The method accuracy was thoroughly examined by comparing with an independently developed method based on HPLC-ESIMS/MS without derivatization, where agreement was found within ±5-20%. An application is presented to gain first insight into the variability in the human excretion of phosphoethanolamine, which is key for the interpretation of its levels as a biomarker, by repeated urine collection from a group of volunteers over 4 weeks.PMID:37216218 | DOI:10.1021/acs.analchem.3c01364

Anal Chem. 2023 May 22. doi: 10.1021/acs.analchem.3c00867. Online ahead of print.ABSTRACTProfiling drug-protein interactions is critical for understanding a drug's mechanism of action and predicting the possible adverse side effects. However, to comprehensively profile drug-protein interactions remains a challenge. To address this issue, we proposed a strategy that integrates multiple mass spectrometry-based omics analysis to provided global drug-protein interactions, including physical interactions and functional interactions, with rapamycin (Rap) as a model. Chemoproteomics profiling reveals 47 Rap binding proteins including the known target protein FKBP12 with high confidence. Gen Ontology enrichment analysis suggested that the Rap binding proteins are implicated in several important cellular processes, such as DNA replication, immunity, autophagy, programmed cell death, aging, transcription modulation, vesicle-mediated transport, membrane organization, and carbohydrate and nucleobase metabolic processes. The phosphoproteomics profiling revealed 255 down-regulated and 150 up-regulated phosphoproteins responding to Rap stimulation; they mainly involve the PI3K-Akt-mTORC1 signaling axis. Untargeted metabolomic profiling revealed 22 down-regulated metabolites and 75 up-regulated metabolites responding to Rap stimulation; they are mainly associated with the synthesis processes of pyrimidine and purine. The integrative multiomics data analysis provides deep insight into the drug-protein interactions and reveals Rap's complicated mechanism of action.PMID:37216191 | DOI:10.1021/acs.analchem.3c00867

Front Cell Infect Microbiol. 2023 May 5;13:1152198. doi: 10.3389/fcimb.2023.1152198. eCollection 2023.ABSTRACTPrototheca species are the only microalgae known to cause opportunistic infections in vertebrates and humans. Most cases of protothecosis in humans are caused by Prototheca wickerhamii, but knowledge of the pathogenicity and biology of Prototheca is limited. Globally, the diagnostic rate of Prototheca species infection is much lower than the actual rate of P. wickerhamii. The precise mechanisms underlying the pathogenesis of Prototheca infections remain unclear. In this study, we identified a strain of P. wickerhamii with atypical colony morphology. To reveal the morphological differences between P. wickerhamii S1 (mucous) and the molecular basis of its pathogenicity, the transcriptomics, proteomics, and metabolomics of two pathogenic P. wickerhamii strains and one environmental strain were analysed. Interestingly, mannan endo-1,4-β-mannosidase was significantly downregulated in P. wickerhamii S1, which contributes to a thinner cell wall in S1 compared to strains with typical colony morphology, and the toxicity of macrophages is reduced. Metabolite analysis revealed that the mucoid appearance of P. wickerhamii S1 may have been caused by an increase in linoleic acid, glycerol, and other metabolites. There is still a need to better understand the ecology, aetiology, and pathogenesis of P. wickerhamii, and in particular, its transmission between humans, animals, and the environment, from a One Health perspective.PMID:37216181 | PMC:PMC10196235 | DOI:10.3389/fcimb.2023.1152198

Oncol Lett. 2023 May 3;25(6):265. doi: 10.3892/ol.2023.13851. eCollection 2023 Jun.ABSTRACTLate diagnosis is one of the major contributing factors to the high mortality rate of lung cancer, which is now the leading cause of cancer-associated mortality worldwide. At present, low-dose CT (LDCT) screening in the high-risk population, in which lung cancer incidence is higher than that of the low-risk population is the predominant diagnostic strategy. Although this has efficiently reduced lung cancer mortality in large randomized trials, LDCT screening has high false-positive rates, resulting in excessive subsequent follow-up procedures and radiation exposure. Complementation of LDCT examination with biofluid-based biomarkers has been documented to increase efficacy, and this type of preliminary screening can potentially reduce potential radioactive damage to low-risk populations and the burden of hospital resources. Several molecular signatures based on components of the biofluid metabolome that can possibly discriminate patients with lung cancer from healthy individuals have been proposed over the past two decades. In the present review, advancements in currently available technologies in metabolomics were reviewed, with particular focus on their possible application in lung cancer screening and early detection.PMID:37216157 | PMC:PMC10193366 | DOI:10.3892/ol.2023.13851