PubMed

Food Res Int. 2023 Mar;165:112393. doi: 10.1016/j.foodres.2022.112393. Epub 2022 Dec 28.ABSTRACTThe health-promoting activities of procyanidin extracts from hawthorn (HPCs) are closely related to their digestive behaviors, absorption, and colonic metabolism, all of which remain unknown for now and thus hinder further exploration. This study aims to explore the dynamic changes of HPCs during in vitro digestion and fermentation, as well as their Caco-2 permeability, focusing mainly on the interaction between gut microbiota and HPCs. The results showed that the digested HPC samples had characteristic absorption peaks at 280 nm, and there were absorption peaks in the stretching vibration zone, including OH and CC on the benzene ring, which suggested that procyanidins were the main components in HPCs after in vitro digestion. Meanwhile, HPCs had the highest stability in the oral phase. However, the total procyanidin content of HPCs decreased during gastrointestinal digestion, and flavan-3-ol dimers and trimers in HPCs are partially degraded into epicatechin. Uptake of epicatechin (4.07 %), procyanidin B2 (2.15 %), and procyanidin B5 (39.44 %) through Caco-2 monolayer was also observed in HPC treatment, while there was still a large portion of procyanidins that was not absorbed. Subsequent fermentation resulted in a decrease in pH along with the production of short-chain fatty acids (SCFAs), mainly due to the degradation and utilization of HPC, as indicated by a reduction of total procyanidins. Furthermore, the HPCs modulated gut microbial populations: down-regulated the abundances of Bacteroides, Fusobacterium, Enterococcus, Parabacteroides, and Bilophila, and up-regulated Escherichia-Shigella, Klebsiella, Turicibacter, Actinobacillus, Roseburia, and Blautia. Ultimately, epicatechin and procyanidin B2, B5 and C1 were converted into phenolic acids through the metabolism of Bacteroides, Sutterella, Butyrobacter and Blautia. 4-ethylbenzoic acid, 4-hydroxyphenylpropionic acid, 3,4-dihydroxyphenyl acetic acid were confirmed as the significant metabolites in the fermentation. These results elucidated the potential mechanisms of HPCs metabolism and their beneficial effects on gut microbiota and colonic phenolic acids production.PMID:36869464 | DOI:10.1016/j.foodres.2022.112393

Food Res Int. 2023 Mar;165:112376. doi: 10.1016/j.foodres.2022.112376. Epub 2023 Jan 2.ABSTRACTUntargeted metabolomics with the combination of ion mobility separation coupled to high resolution mass spectrometry (IMS-HRMS) was applied to investigate the impact of resveratrol and pterostilbene supplementation on the metabolic fingerprint of the Wistar rats liver with induced liver steatosis. RP-LC and HILIC in both ionisation modes were employed to analyse the liver samples (n = 40) from Wistar rats fed with a high-fat and high-fructose diet, supplemented or not with resveratrol and pterostilbene. After univariate and multivariate statistical analysis, 34 metabolites were highlighted in the different diets and elucidated. Despite the structural similarity, different alterations in liver metabolism were observed by the supplementations. Resveratrol treatment was characterised by the alteration in metabolism of 17 lysophospholipids, while pterostilbene affected some vitamins and derivatives, among others. IMS has demonstrated great potential in the elucidation process thanks to the additional structural descriptor the CCS (Å2), providing more confidence in the identification.PMID:36869462 | DOI:10.1016/j.foodres.2022.112376

Food Res Int. 2023 Mar;165:112350. doi: 10.1016/j.foodres.2022.112350. Epub 2022 Dec 25.ABSTRACTThe purpose of this study was to reveal the relationship between core microorganisms and flavor substances in the fermentation process of corn wine. Microbial diversity, volatile and non-volatile flavor substances were detected by high-throughput sequencing (HTS), headspace solid phase micro-extraction gas chromatography-mass spectrometry (HS-SPME/GC-MS) and gas chromatography time of flight mass spectrometry (GC-TOF-MS). High performance liquid chromatography (HPLC) was used to detect organic acids in corn wine fermentation, and its physiochemical properties were tracked. The results showed that physiochemical factors changed obviously with fermentation time. Bacillus, Prevotella_9, Acinetobacter and Gluconobacter were the predominant bacterial. Rhizopus and Saccharomyces were the dominant fungi. Acetic acid and succinic acid were important organic acids in corn wine. According to variable importance of projection (VIP) > 1 and P < 0.05, 24 volatile flavor substances with significant difference were screened out from 52 volatile flavor substances. Similarly, 25 non-volatile flavor substances with significant differences were screened out from the 97 reliable metabolites identified by 223 chromatographic peaks. Eight key metabolic pathways were enriched from 25 non-volatile flavor substances according to path influence values > 0.1 and P < 0.05. Based on Two-way Orthogonal Partial Least Squares (O2PLS) model and Pearson correlation coefficient, Saccharomyces, Rhizopus, uncultured_bacterium, Aneurinibacillus, Wickerhamomyces and Gluconobacter may be the potential volatile flavor-contributing microorganism genus in corn wine. The Pearson correlation coefficient showed that Saccharomyces was significantly positively correlated with malic acid, oxalic acid, valine and isoleucine, and Rhizopus was positively correlated with glucose-1-phosphate and alanine. These findings enhanced our understanding of the formation mechanism of flavor substances in corn wine and provided the theoretical basis for stabilizing flavor quality of corn wine.PMID:36869445 | DOI:10.1016/j.foodres.2022.112350

Microbiome. 2023 Mar 3;11(1):40. doi: 10.1186/s40168-023-01492-3.ABSTRACTBACKGROUND: Postpartum dairy cows experiencing excessive lipolysis are prone to severe immunosuppression. Despite the extensive understanding of the gut microbial regulation of host immunity and metabolism, its role during excessive lipolysis in cows is largely unknown. Herein, we investigated the potential links between the gut microbiome and postpartum immunosuppression in periparturient dairy cows with excessive lipolysis using single immune cell transcriptome, 16S amplicon sequencing, metagenomics, and targeted metabolomics.RESULTS: The use of single-cell RNA sequencing identified 26 clusters that were annotated to 10 different immune cell types. Enrichment of functions of these clusters revealed a downregulation of functions in immune cells isolated from a cow with excessive lipolysis compared to a cow with low/normal lipolysis. The results of metagenomic sequencing and targeted metabolome analysis together revealed that secondary bile acid (SBA) biosynthesis was significantly activated in the cows with excessive lipolysis. Moreover, the relative abundance of gut Bacteroides sp. OF04 - 15BH, Paraprevotella clara, Paraprevotella xylaniphila, and Treponema sp. JC4 was mainly associated with SBA synthesis. The use of an integrated analysis showed that the reduction of plasma glycolithocholic acid and taurolithocholic acid could contribute to the immunosuppression of monocytes (CD14+MON) during excessive lipolysis by decreasing the expression of GPBAR1.CONCLUSIONS: Our results suggest that alterations in the gut microbiota and their functions related to SBA synthesis suppressed the functions of monocytes during excessive lipolysis in transition dairy cows. Therefore, we concluded that altered microbial SBA synthesis during excessive lipolysis could lead to postpartum immunosuppression in transition cows. Video Abstract.PMID:36869370 | DOI:10.1186/s40168-023-01492-3

J Transl Med. 2023 Mar 3;21(1):169. doi: 10.1186/s12967-023-03935-9.ABSTRACTBACKGROUND: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.METHODS: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model.RESULTS: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model.CONCLUSIONS: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.PMID:36869333 | DOI:10.1186/s12967-023-03935-9

Pharm Res. 2023 Mar 3. doi: 10.1007/s11095-023-03488-y. Online ahead of print.ABSTRACTINTRODUCTION: The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) posed a severe challenge to tuberculosis (TB) management. The treatment of MDR-TB involves second-line anti-TB agents, most of which are injectable and highly toxic. Previous metabolomics study of the Mtb membrane revealed that two antimicrobial peptides, D-LAK120-A and D-LAK120-HP13, can potentiate the efficacy of capreomycin against mycobacteria.AIMS: As both capreomycin and peptides are not orally available, this study aimed to formulate combined formulations of capreomycin and D-LAK peptides as inhalable dry powder by spray drying.METHODS AND RESULTS: A total of 16 formulations were prepared with different levels of drug content and capreomycin to peptide ratios. A good production yield of over 60% (w/w) was achieved in most formulations. The co-spray dried particles exhibited spherical shape with a smooth surface and contained low residual moisture of below 2%. Both capreomycin and D-LAK peptides were enriched at the surface of the particles. The aerosol performance of the formulations was evaluated with Next Generation Impactor (NGI) coupled with Breezhaler®. While no significant difference was observed in terms of emitted fraction (EF) and fine particle fraction (FPF) among the different formulations, lowering the flow rate from 90 L/min to 60 L/min could reduce the impaction at the throat and improve the FPF to over 50%.CONCLUSIONS: Overall, this study showed the feasibility of producing co-spray dried formulation of capreomycin and antimicrobial peptides for pulmonary delivery. Future study on their antibacterial effect is warranted.PMID:36869245 | DOI:10.1007/s11095-023-03488-y

Commun Med (Lond). 2023 Mar 3;3(1):35. doi: 10.1038/s43856-023-00265-1.ABSTRACTBACKGROUND: Cavernous angiomas (CAs) affect 0.5% of the population, predisposing to serious neurologic sequelae from brain bleeding. A leaky gut epithelium associated with a permissive gut microbiome, was identified in patients who develop CAs, favoring lipid polysaccharide producing bacterial species. Micro-ribonucleic acids along with plasma levels of proteins reflecting angiogenesis and inflammation were also previously correlated with CA and CA with symptomatic hemorrhage.METHODS: The plasma metabolome of CA patients and CA patients with symptomatic hemorrhage was assessed using liquid-chromatography mass spectrometry. Differential metabolites were identified using partial least squares-discriminant analysis (p < 0.05, FDR corrected). Interactions between these metabolites and the previously established CA transcriptome, microbiome, and differential proteins were queried for mechanistic relevance. Differential metabolites in CA patients with symptomatic hemorrhage were then validated in an independent, propensity matched cohort. A machine learning-implemented, Bayesian approach was used to integrate proteins, micro-RNAs and metabolites to develop a diagnostic model for CA patients with symptomatic hemorrhage.RESULTS: Here we identify plasma metabolites, including cholic acid and hypoxanthine distinguishing CA patients, while arachidonic and linoleic acids distinguish those with symptomatic hemorrhage. Plasma metabolites are linked to the permissive microbiome genes, and to previously implicated disease mechanisms. The metabolites distinguishing CA with symptomatic hemorrhage are validated in an independent propensity-matched cohort, and their integration, along with levels of circulating miRNAs, enhance the performance of plasma protein biomarkers (up to 85% sensitivity and 80% specificity).CONCLUSIONS: Plasma metabolites reflect CAs and their hemorrhagic activity. A model of their multiomic integration is applicable to other pathologies.PMID:36869161 | DOI:10.1038/s43856-023-00265-1

J Nutr Biochem. 2023 Mar 1:109307. doi: 10.1016/j.jnutbio.2023.109307. Online ahead of print.ABSTRACTNon-alcoholic fatty liver disease (NAFLD) pathogenesis remains poorly understood due to the complex metabolic and inflammatory changes in the liver. This study aimed to elucidate hepatic events related to inflammation and lipid metabolism and their linkage with metabolic alterations during NAFLD in American lifestyle-induced obesity syndrome (ALIOS) diet-fed mice. 48 JaxC57BL/6J male mice were fed with ALIOS diet (n=24) or control chow diet (n=24) for 8, 12, and 16 weeks. At the end of each timepoint, 8 mice were sacrificed where plasma and liver were collected. Hepatic fat accumulation was followed using magnetic resonance imaging and confirmed with histology. Further, targeted gene expression and non-targeted metabolomics analysis were conducted. Our results showed higher hepatic steatosis, body weight, energy consumption, and liver mass in ALIOS diet-fed mice compared to control mice. ALIOS diet altered expression of genes related to inflammation (Tnfa and IL-6) and lipid metabolism (Cd36, Fasn, Scd1, Cpt1a, and Ppara). Metabolomics analysis indicated decrease of lipids containing polyunsaturated fatty acids such as LPE(20:5) and LPC(20:5) with increase of other lipid species such as LPI(16:0) and LPC(16:2) and peptides such as alanyl-phenylalanine and glutamyl-arginine. We further observed novel correlations between different metabolites including sphingolipid, lysophospholipids, peptides, and bile acid with inflammation, lipid uptake and synthesis. Together with the reduction of antioxidant metabolites and gut microbiota-derived metabolites contribute to NAFLD development and progression. The combination of non-targeted metabolomics with gene expression in future studies can further identify key metabolic routes during NAFLD which could be the targets of potential novel therapeutics.PMID:36868506 | DOI:10.1016/j.jnutbio.2023.109307

J Nutr Biochem. 2023 Mar 1:109308. doi: 10.1016/j.jnutbio.2023.109308. Online ahead of print.ABSTRACTColorectal cancer (CRC) is one of the most common and deadly cancers worldwide. Grape pomace (GP) is a rich source of bioactive compounds with anti-inflammatory, and anticancer effects. We recently found that dietary GP had protective effects against CRC development in the azoxymethane (AOM)/dextran sulfate sodium (DSS) CRC mouse model through suppression of cell proliferation and modulation of DNA methylation. However, the underlying molecular mechanisms associated with changes in metabolites remain unexamined. This study profiled fecal metabolomic changes in a mouse CRC model in response to GP supplementation using gas chromatography-mass spectrometry (GC-MS) based metabolomic analysis. A total of 29 compounds showed significant changes due to GP supplementation, including bile acids, amino acids, fatty acids, phenols/flavonoids, glycerolipids, carbohydrates, organic acids, and others. The major changes in metabolites of feces include increased deoxycholic acid (DCA) and decreased amino acid content. Dietary GP upregulated the expression of farnesoid X receptor (FXR) downstream genes while decreasing fecal urease activity. DNA repair enzyme MutS Homolog 2 (MSH2) was upregulated by GP supplementation. Consistently, γ-H2AX, as a DNA damage marker, decreased in GP supplemented mice. Moreover, MDM2, a protein in the ataxia telangiectasia mutated (ATM) signaling, was decreased by GP supplementation. These data provided valuable metabolic clues for unraveling the protective effects of GP supplementation against CRC development.PMID:36868505 | DOI:10.1016/j.jnutbio.2023.109308

Chem Biol Interact. 2023 Mar 1:110430. doi: 10.1016/j.cbi.2023.110430. Online ahead of print.ABSTRACTThe mechanism of indomethacin toxicity at the systemic level is largely unknown. In this study, multi-specimen molecular characterization was conducted in rats treated with three doses of indomethacin (2.5, 5, and 10 mg/kg) for 1 week. Kidney, liver, urine, and serum samples were collected and analyzed using untargeted metabolomics. The kidney and liver transcriptomics data (10 mg indomethacin/kg and control) were subjected to a comprehensive omics-based analysis. Indomethacin exposure at 2.5 and 5 mg/kg doses did not cause significant metabolome changes, whereas considerable alterations in the metabolic profile compared to the control were induced by a dose of 10 mg/kg. Decreased levels of metabolites and an increase creatine level in the urine metabolome indicated injury to the kidney. The integrated omics analysis in both liver and kidney revealed an oxidant-antioxidant imbalance due to an excess of reactive oxygen species, likely originating from dysfunctional mitochondria. Specifically, indomethacin exposure induced changes in metabolites related to the citrate cycle, cell membrane composition, and DNA synthesis in the kidney. The dysregulation of genes related to ferroptosis and suppression of amino acid and fatty acid metabolism were evidence of indomethacin-induced nephrotoxicity. In conclusion, a multi-specimen omics investigation provided important insights into the mechanism of indomethacin toxicity. The identification of targets that ameliorate indomethacin toxicity will enhance the therapeutic utility of this drug.PMID:36868495 | DOI:10.1016/j.cbi.2023.110430

J Ethnopharmacol. 2023 Mar 1:116264. doi: 10.1016/j.jep.2023.116264. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: At present, the colorectal cancer (CRC) is a malignant tumor of the colon and rectum that is often found at the junction of the two, and it will invade many visceral organs and organizations, causing very serious damage to the body of the patient. Patrinia villosa Juss. (P.V), is a well-known traditional chinese medicine (TCM), and is recorded in the Compendium of Materia Medica as a necessary article for the treatment of intestinal carbuncle. It has been incorporated into traditional cancer treatment prescriptions in modern medicine. While the mechanism of action of P.V in the treatment of CRC remains unclear.AIM OF THE STUDY: To investigate P.V in treating CRC and clarify the underlying mechanism.MATERIALS AND METHODS: This study was based on Azoxymethane (AOM) combined with the Dextran Sulfate Sodium Salt (DSS)-induced CRC mouse model to clarify the pharmacological effects of P.V. The mechanism of action was found by metabolites and metabolomics. The rationality of metabolomics results was verified through the clinical target database of network pharmacology, and find the upstream and downstream target information of relevant action pathways. Apart from that, the targets of associated pathways were confirmed, and the mechanism of action was made clear, using quantitative PCR (q-PCR) and Western blot.RESULTS: The number and the diameter of tumors were decreased when mice were treated with P.V. P.V group section results showed newly generated cells which improved the degree of colon cell injury. Pathological indicators presented a trend of recovery to normal cells. Compared to the model group, P.V groups had significantly lower levels of the CRC biomarkers CEA, CA19-9, and CA72-4. Through the evaluation of metabolites and metabolomics, it was found that a total of 50 endogenous metabolites had significant changes. Most of these are modulated and recovered after P.V treatment. It alters glycerol phospholipid metabolites, which are closely related to PI3K target, suggesting that P.V can treat CRC though the PI3K target and PI3K/Akt signaling pathway. q-PCR and Western blot results also verified that the expression of VEGF, PI3K, Akt, P38, JNK, ERK1/2, TP53, IL-6, TNF-α and Caspase-3 were significantly decreased, whereas that of Caspase-9 was increased after treatment.CONCLUSION: P.V is dependent on PI3K target and PI3K/Akt signaling pathway for CRC treatment.PMID:36868440 | DOI:10.1016/j.jep.2023.116264

J Ethnopharmacol. 2023 Mar 1:116330. doi: 10.1016/j.jep.2023.116330. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Clinopodium chinense Kuntze (CC), traditional Chinese medicine with anti-inflammatory, anti-diarrheal, and hemostatic activities, has been used to treat dysentery and bleeding diseases for thousands of years, which are similar to the symptoms of ulcerative colitis (UC).AIM OF THE STUDY: To obtain a novel treatment for UC, an integrated strategy was developed in this study to investigate the effect and mechanism of CC against UC.MATERIALS AND METHODS: The chemical characterization of CC was scanned by UPLC-MS/MS. Network pharmacology analysis was performed to predict the active ingredients and pharmacological mechanisms of CC against UC. Further, the results of network pharmacology were validated using LPS-induced RAW 264.7 cells and DSS-induced UC mice. The production of pro-inflammatory mediators and biochemical parameters was tested using the ELISA kits. The expression of NF-κB, COX-2, and iNOS proteins was evaluated using Western blot analysis. Body weight, disease activity index, colon length, histopathological examination, and metabolomics analysis in colon tissues were carried out to confirm the effect and mechanism of CC.RESULTS: Based on the chemical characterization and literature collection, a rich database of ingredients in CC was constructed. Network pharmacology analysis provided five core components as well as revealed that the mechanism of CC against UC was highly related to inflammation, especially the NF-κB signaling pathway. In vitro experiments showed CC could inhibit inflammation by LPS-TLR4-NF-κB-iNOS/COX-2 signaling pathway in RAW264.7 cells. Meanwhile, in vivo experimental results proved that CC significantly alleviated pathological features with increased body weight and colonic length, decreased DAI and oxidative damage, as well as mediated inflammatory factors like NO, PGE2, IL-6, IL-10, and TNF-ɑ. In addition, colon metabolomics analysis revealed CC could restore the abnormal endogenous metabolite levels in UC. 18 screened biomarkers were further enriched in four pathways including Arachidonic acid metabolism, Histidine metabolism, Alanine, aspartate and glutamate metabolism as well as the Pentose phosphate pathway.CONCLUSION: This study demonstrates that CC could alleviate UC by reducing systematic inflammation and regulating metabolism, which is beneficial for providing scientific data for the development of UC treatment.PMID:36868438 | DOI:10.1016/j.jep.2023.116330

Chemosphere. 2023 Mar 1:138257. doi: 10.1016/j.chemosphere.2023.138257. Online ahead of print.ABSTRACTSilicon dioxide nanoparticles (nSiO2) are one of the widely utilized nanoparticle (NPSs) materials, and exposure to nSiO2 is ubiquitous. With the increasing commercialization of nSiO2, the potential risk of nSiO2 release to the health and the ecological environment have been attracted more attention. In this study, the domesticated lepidopteran insect model silkworm (Bombyx mori) was utilized to evaluate the biological effects of dietary exposure to nSiO2. Histological investigations showed that nSiO2 exposure resulted in midgut tissue injury in a dose-dependent manner. Larval body mass and cocoon production were reduced by nSiO2 exposure. ROS burst was not triggered, and the activities of antioxidant enzymes were induced in the midgut of silkworm exposure to nSiO2. RNA-sequencing revealed that the differentially expressed genes induced by nSiO2 exposure were predominantly enriched into xenobiotics biodegradation and metabolism, lipid, and amino acid metabolism pathways. 16 S rDNA sequencing revealed that nSiO2 exposure altered the microbial diversity in the gut of the silkworm. Metabolomics analysis showed that the combined uni- and multivariate analysis identified 28 significant differential metabolites from the OPLS-DA model. These significant differential metabolites were predominantly enriched into the metabolic pathways, including purine metabolism and tyrosine metabolism and so. Spearman correlation analysis and the Sankey diagram established the relationship between microbe and metabolites, and some genera may play crucial and pleiotropic functions in the interaction between microbiome and host. These findings indicated that nSiO2 exposure could impact the dysregulation of genes related to xenobiotics metabolism, gut dysbiosis, and metabolic pathways and provided a valuable reference for assessing nSiO2 toxicity from a multi-dimensional perspective.PMID:36868417 | DOI:10.1016/j.chemosphere.2023.138257

Environ Int. 2023 Feb 26;173:107856. doi: 10.1016/j.envint.2023.107856. Online ahead of print.ABSTRACTBACKGROUND: Individuals are exposed to environmental pollutants with endocrine disrupting activity (endocrine disruptors, EDCs) and the early stages of life are particularly susceptible to these exposures. Previous studies have focused on identifying molecular signatures associated with EDCs, but none have used repeated sampling strategy and integrated multiple omics. We aimed to identify multi-omic signatures associated with childhood exposure to non-persistent EDCs.METHODS: We used data from the HELIX Child Panel Study, which included 156 children aged 6 to 11. Children were followed for one week, in two time periods. Twenty-two non-persistent EDCs (10 phthalate, 7 phenol, and 5 organophosphate pesticide metabolites) were measured in two weekly pools of 15 urine samples each. Multi-omic profiles (methylome, serum and urinary metabolome, proteome) were measured in blood and in a pool urine samples. We developed visit-specific Gaussian Graphical Models based on pairwise partial correlations. The visit-specific networks were then merged to identify reproducible associations. Independent biological evidence was systematically sought to confirm some of these associations and assess their potential health implications.RESULTS: 950 reproducible associations were found among which 23 were direct associations between EDCs and omics. For 9 of them, we were able to find corroborating evidence from previous literature: DEP - serotonin, OXBE - cg27466129, OXBE - dimethylamine, triclosan - leptin, triclosan - serotonin, MBzP - Neu5AC, MEHP - cg20080548, oh-MiNP - kynurenine, oxo-MiNP - 5-oxoproline. We used these associations to explore possible mechanisms between EDCs and health outcomes, and found links to health outcomes for 3 analytes: serotonin and kynurenine in relation to neuro-behavioural development, and leptin in relation to obesity and insulin resistance.CONCLUSIONS: This multi-omics network analysis at two time points identified biologically relevant molecular signatures related to non-persistent EDC exposure in childhood, suggesting pathways related to neurological and metabolic outcomes.PMID:36867994 | DOI:10.1016/j.envint.2023.107856

Talanta. 2023 Feb 23;258:124389. doi: 10.1016/j.talanta.2023.124389. Online ahead of print.ABSTRACTThe present study is focused on the determination of low-volatile chemosignals excreted or secreted by mouse pups in their early days of life involved in maternal care induction in mice adult females. Untargeted metabolomics was employed to differentiate between samples collected with swabs from facial and anogenital area from neonatal mouse pups receiving maternal care (first two weeks of life) and the elder mouse pups in the weaning period (4th week old). The sample extracts were analysed by ultra-high pressure liquid chromatography (UHPLC) coupled to ion mobility separation (IMS) in combination with high resolution mass spectrometry (HRMS). After data processing with Progenesis QI and multivariate statistical analysis, five markers present in the first two weeks of mouse pups life and putatively involved in materno-filial chemical communication were tentatively identified: arginine, urocanic acid, erythro-sphingosine (d17:1), sphingosine (d18:1) and sphinganine. The four-dimensional data and the tools associated to the additional structural descriptor obtained by IMS separation were of great help in the compound identification. The results demonstrated the great potential of UHPLC-IMS-HRMS based untargeted metabolomics to identity putative pheromones in mammals.PMID:36867958 | DOI:10.1016/j.talanta.2023.124389

Can J Microbiol. 2023 Mar 3. doi: 10.1139/cjm-2022-0205. Online ahead of print.ABSTRACTSpecialized metabolites produced by microorganisms found in ocean sediments display a wide range of clinically relevant bioactivities, including antimicrobial, anticancer, antiviral, and anti-inflammatory. Due to limitations in our ability to culture many benthic microorganisms under laboratory conditions, their potential to produce bioactive compounds remains underexplored. However, the advent of modern mass spectrometry technologies and data analysis methods for chemical structure prediction has aided in the discovery of such metabolites from complex mixtures. In the present study, ocean sediments were collected from Baffin Bay (Canadian Arctic) and the Gulf of Maine for untargeted metabolomics using mass spectrometry. A direct examination of prepared organic extracts identified 1468 spectra, of which ~45% could be annotated using in silico analysis methods. A comparable number of spectral features were detected in sediments collected from both locations, but 16S rRNA gene sequencing revealed a significantly more diverse bacterial community in samples from Baffin Bay. Based on spectral abundance, 12 specialized metabolites known to be associated with bacteria were selected for discussion. The application of metabolomics directly on marine sediments provides an avenue for culture-independent detection of metabolites produced under natural settings. The strategy can help prioritize samples for novel bioactive metabolite discovery using traditional workflows.PMID:36867856 | DOI:10.1139/cjm-2022-0205

Cancer Prev Res (Phila). 2023 Mar 3:CAPR-22-0384. doi: 10.1158/1940-6207.CAPR-22-0384. Online ahead of print.ABSTRACTSuberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor with anticancer effects via epigenetic and non-epigenetic mechanisms. The role of SAHA in metabolic rewiring and epigenomic reprogramming to inhibit pro-tumorigenic cascades in lung cancer remains unknown. In this study, we aimed to investigate the regulation of mitochondrial metabolism, DNA methylome reprogramming, and transcriptomic gene expression by SAHA in lipopolysaccharide (LPS)-induced inflammatory model of lung epithelial BEAS-2B cells. Liquid chromatography-mass spectrometry was used for metabolomic analysis, while next-generation sequencing was done to study epigenetic changes. The metabolomic study reveals that SAHA treatment significantly regulated methionine, glutathione, and nicotinamide metabolism with alteration of the metabolite levels of methionine, S-adenosylmethionine, S-adenosylhomocysteine, glutathione, nicotinamide, 1-methylnicotinamide, and nicotinamide adenine dinucleotide in BEAS-2B cells. Epigenomic CpG methyl-seq shows SAHA revoked a list of differentially methylated regions in the promoter region of the genes, such as HDAC11, miR4509-1, and miR3191. Transcriptomic RNA-seq reveals SAHA abrogated LPS-induced differentially expressed genes encoding proinflammatory cytokines, including interleukin 1α (IL-1α), IL-1β, IL-2, IL-6, IL-24, and IL-32. Integrative analysis of DNA methylome-RNA transcriptome displays a list of genes, of which CpG methylation correlated with changes in gene expression. qPCR validation of transcriptomic RNA-seq data shows that SAHA treatment significantly reduced the LPS-induced mRNA levels of IL-1β, IL-6, DNMT1, and DNMT3A in BEAS-2B cells. Altogether, SAHA treatment alters the mitochondrial metabolism, epigenetic CpG methylation, and transcriptomic gene expression to inhibit LPS-induced inflammatory responses in lung epithelial cells, which may provide novel molecular targets to inhibit the inflammation component of lung carcinogenesis.PMID:36867722 | DOI:10.1158/1940-6207.CAPR-22-0384

J Proteome Res. 2023 Mar 3. doi: 10.1021/acs.jproteome.3c00076. Online ahead of print.ABSTRACTWe have used household consumables to facilitate electrochemical etching of stainless-steel hypodermic tubing to produce tapered-tip emitters suitable for electrospray ionization for use in mass spectrometry. The process involves the use of 1% oxalic acid and a 5 W USB power adapter, commonly known as a phone charger. Further, our method avoids the otherwise commonly used strong acids that entail chemical hazards: concentrated HNO3 for etching stainless steel, or concentrated HF for etching fused silica. Hence, we here provide a convenient and self-inhibiting procedure with minimal chemical hazards to manufacture tapered-tip stainless-steel emitters. We show its performance in metabolomic analysis with CE-MS of a tissue homogenate where the metabolites acetylcarnitine, arginine, carnitine, creatine, homocarnosine, and valerylcarnitine were identified, all with basepeak separated electropherograms, within <6 min of separation. The mass spectrometry data are freely available through the MetaboLight public data repository via access number MTBLS7230.PMID:36866861 | DOI:10.1021/acs.jproteome.3c00076

J Mol Cell Biol. 2023 Mar 2:mjad014. doi: 10.1093/jmcb/mjad014. Online ahead of print.ABSTRACTBeyond glycemic control, applications of glucagon-like peptide-1 receptor (GLP-1r) agonists (GLP-1 RAs) inhibit inflammation and plaque development in murine atherosclerotic models. However, whether they modulate hematopoietic stem/progenitor cells (HSPCs) to prohibit skewed myelopoiesis in hypercholesteremia remains unknown. In this study, GLP-1r expression in fluorescence-activated cell sorting (FACS)-sorted wild-type HSPCs was determined by capillary western blotting. Bone marrow cells (BMCs) of wild-type or GLP-1r-/- mice were transplanted to lethally irradiated low-density lipoprotein receptor deficient (LDLr-/-) recipients followed by high-fat diet (HFD) for chimerism analysis by FACS. In parallel, LDLr-/- mice were placed on HFD for 6 weeks and then treated with saline or Exendin-4 (Ex-4) for another 6 weeks. HSPC frequency and cell cycle were analyzed by FACS and intracellular metabolite levels were assessed by targeted metabolomics. The results demonstrated that HSPCs expressed GLP-1r and transplantation of GLP-1r-/- BMCs resulted in skewed myelopoiesis in hypercholesterolemic LDLr-/- recipients. In vitro, Ex-4 treatment on FACS-purified HSPCs suppressed cell expansion and granulocyte production induced by LDL. In vivo, Ex-4 treatment inhibited plaque progression, suppressed HSPC proliferation, and modified glycolytic and lipid metabolism in HSPCs of hypercholesteremic LDLr-/- mice. In conclusion, Ex-4 could directly inhibit HSPC proliferation induced by hypercholesteremia.PMID:36866528 | DOI:10.1093/jmcb/mjad014

Cardiovasc Res. 2023 Mar 2:cvad038. doi: 10.1093/cvr/cvad038. Online ahead of print.ABSTRACTAIMS: Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified major metabolic step regulating inflammation. Whether the PDK/PDH axis plays role in vascular inflammation and atherosclerotic cardiovascular disease has never been studied.METHODS AND RESULTS: Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe-/- mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque.CONCLUSIONS: We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans, and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe-/- mice. These results point toward a promising treatment to combat atherosclerosis.PMID:36866436 | DOI:10.1093/cvr/cvad038