PubMed

FASEB J. 2024 Jan;38(1):e23366. doi: 10.1096/fj.202301936RR.ABSTRACTCytokinins (CKs) are a class of growth-promoting signaling molecules that affect multiple cellular and developmental processes. These phytohormones are well studied in plants, but their presence continues to be uncovered in organisms spanning all kingdoms, which poses new questions about their roles and functions outside of plant systems. Cytokinin production can be initiated by one of two different biosynthetic enzymes, adenylate isopentenyltransfases (IPTs) or tRNA isopentenyltransferases (tRNA-IPTs). In this study, the social amoeba, Dictyostelium discoideum, was used to study the role of CKs by generating deletion and overexpression strains of its single adenylate-IPT gene, iptA. The life cycle of D. discoideum is unique and possesses both single- and multicellular stages. Vegetative amoebae grow and divide while food resources are plentiful, and multicellular development is initiated upon starvation, which includes distinct life cycle stages. CKs are produced in D. discoideum throughout its life cycle and their functions have been well studied during the later stages of multicellular development of D. discoideum. To investigate potential expanded roles of CKs, this study focused on vegetative growth and early developmental stages. We found that iptA-deficiency results in cytokinesis defects, and both iptA-deficiency and overexpression results in dysregulated tricarboxylic acid (TCA) cycle and amino acid metabolism, as well as increased levels of adenosine monophosphate (AMP). Collectively, these findings extend our understanding of CK function in amoebae, indicating that iptA loss and overexpression alter biological processes during vegetative growth that are distinct from those reported during later development.PMID:38102957 | DOI:10.1096/fj.202301936RR

J Biochem. 2023 Dec 15:mvad109. doi: 10.1093/jb/mvad109. Online ahead of print.ABSTRACTProtein lipidation is a common co- or post-translational modification that plays a crucial role in regulating the localization, interaction, and function of cellular proteins. Dysregulation of lipid modifications can lead to various diseases, including cancer, neurodegenerative diseases, and infectious diseases. Therefore, the identification of proteins undergoing lipidation and their lipidation sites should provide insights into many aspects of lipid biology, as well as providing potential targets for therapeutic strategies. Bottom-up proteomics using liquid chromatography/tandem mass spectrometry is a powerful technique for the global analysis of protein lipidation. Here, we review proteomic methods for profiling protein lipidation, focusing on the two major approaches: the use of chemical probes, such as lipid alkyne probes, and the use of enrichment techniques for endogenous lipid-modified peptides. The challenges facing these methods and the prospects for developing them further to achieve a comprehensive analysis of lipid modifications are discussed.PMID:38102731 | DOI:10.1093/jb/mvad109

Arthritis Res Ther. 2023 Dec 15;25(1):246. doi: 10.1186/s13075-023-03208-2.ABSTRACTOBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disease with complex causes and recurrent attacks that can easily develop into chronic arthritis and eventually lead to joint deformity. Our study aims to elucidate potential mechanism among control, new-onset RA (NORA) and chronic RA (CRA) with multi-omics analysis.METHODS: A total of 113 RA patients and 75 controls were included in our study. Plasma and stool samples were obtained for 16S rRNA sequencing, internally transcribed spacer (ITS) sequencing and metabolomics analysis. And PBMCs were obtained for RNA sequencing. We used three models, logistic regression, least absolute shrinkage and selection operator (LASSO), and random forest, respectively, to distinguish NORA from CRA, and finally we validated model performance using an external cohort of 26 subjects.RESULTS: Our results demonstrated intestinal flora disturbance in RA development, with significantly increased abundance of Escherichia-Shigella and Proteobacteria in NORA. We also found that the diversity was significantly reduced in CRA compared to NORA through fungi analysis. Moreover, we identified 29 differential metabolites between NORA and CRA. Pathway enrichment analysis revealed significant dysregulation of glycerophospholipid metabolism and phenylalanine metabolism pathways in RA patients. Next, we identified 40 differentially expressed genes between NORA and CRA, which acetylcholinesterase (ACHE) was the core gene and significantly enriched in glycerophospholipid metabolism pathway. Correlation analysis showed a strong negatively correlation between glycerophosphocholine and inflammatory characteristics. Additionally, we applied three approaches to develop disease classifier models that were based on plasma metabolites and gut microbiota, which effectively distinguished between new-onset and chronic RA patients in both discovery cohort and external validation cohort.CONCLUSIONS: These findings revealed that glycerophospholipid metabolism plays a crucial role in the development and progression of RA, providing new ideas for early clinical diagnosis and optimizing treatment strategies.PMID:38102690 | DOI:10.1186/s13075-023-03208-2

Vet Res. 2023 Dec 14;54(1):120. doi: 10.1186/s13567-023-01247-w.ABSTRACTStaphylococcus aureus modulates the host immune response directly by interacting with the immune cells or indirectly by secreting molecules (secretome). Relevant differences in virulence mechanisms have been reported for the secretome produced by different S. aureus strains. The present study investigated the S. aureus secretome impact on peripheral bovine mononuclear cells (PBMCs) by comparing two S. aureus strains with opposite epidemiological behavior, the genotype B (GTB)/sequence type (ST) 8, associated with a high within-herd prevalence, and GTS/ST398, associated with a low within-herd prevalence. PBMCs were incubated with different concentrations (0%, 0.5%, 1%, and 2.5%) of GTB/ST8 and GTS/ST398 secretome for 18 and 48 h, and the viability was assessed. The mRNA levels of pro- (IL1-β and STAT1) and anti-inflammatory (IL-10, STAT6, and TGF-β) genes, and the amount of pro- (miR-155-5p and miR-125b-5p) and anti-inflammatory (miR-146a and miR-145) miRNAs were quantified by RT-qPCR. Results showed that incubation with 2.5% of GTB/ST8 secretome increased the viability of cells. In contrast, incubation with the GTS/ST398 secretome strongly decreased cell viability, preventing any further assays. The GTB/ST8 secretome promoted PBMC polarization towards the pro-inflammatory phenotype inducing the overexpression of IL1-β, STAT1 and miR-155-5p, while the expression of genes involved in the anti-inflammatory response was not affected. In conclusion, the challenge of PBMC to the GTS/ST398 secretome strongly impaired cell viability, while exposure to the GTB/ST8 secretome increased cell viability and enhanced a pro-inflammatory response, further highlighting the different effects exerted on host cells by S. aureus strains with epidemiologically divergent behaviors.PMID:38098120 | PMC:PMC10720180 | DOI:10.1186/s13567-023-01247-w

BMC Cancer. 2023 Dec 15;23(1):1238. doi: 10.1186/s12885-023-11744-y.ABSTRACTBACKGROUND: Previous metabolic studies in upper digestive cancer have mostly been limited to cross-sectional study designs, which hinders the ability to effectively predict outcomes in the early stage of cancer. This study aims to identify key metabolites and metabolic pathways associated with the multistage progression of epithelial cancer and to explore their predictive value for gastroesophageal cancer (GEC) formation and for the early screening of esophageal squamous cell carcinoma (ESCC).METHODS: A case-cohort study within the 7-year prospective Esophageal Cancer Screening Cohort of Shandong Province included 77 GEC cases and 77 sub-cohort individuals. Untargeted metabolic analysis was performed in serum samples. Metabolites, with FDR q value < 0.05 and variable importance in projection (VIP) > 1, were selected as differential metabolites to predict GEC formation using Random Forest (RF) models. Subsequently, we evaluated the predictive performance of these differential metabolites for the early screening of ESCC.RESULTS: We found a distinct metabolic profile alteration in GEC cases compared to the sub-cohort, and identified eight differential metabolites. Pathway analyses showed dysregulation in D-glutamine and D-glutamate metabolism, nitrogen metabolism, primary bile acid biosynthesis, and steroid hormone biosynthesis in GEC patients. A panel of eight differential metabolites showed good predictive performance for GEC formation, with an area under the receiver operating characteristic curve (AUC) of 0.893 (95% CI = 0.816-0.951). Furthermore, four of the GEC pathological progression-related metabolites were validated in the early screening of ESCC, with an AUC of 0.761 (95% CI = 0.716-0.805).CONCLUSIONS: These findings indicated a panel of metabolites might be an alternative approach to predict GEC formation, and therefore have the potential to mitigate the risk of cancer progression at the early stage of GEC.PMID:38102546 | DOI:10.1186/s12885-023-11744-y

BMC Genom Data. 2023 Dec 15;24(1):79. doi: 10.1186/s12863-023-01180-z.ABSTRACTHypertension, commonly referred to as high blood pressure, is a chronic medical condition characterized by persistently elevated blood pressure levels. It is a prevalent global health issue, affecting a significant portion of the population worldwide. Hypertension is often asymptomatic, making it a silent but potentially dangerous condition if left untreated. Genetic instruments for 1,091 were from a recent comprehensive metabolome genome-wide association study (GWAS). Summary statistics of diastolic blood pressure (DBP) and systolic blood pressure (SBP) involving 757,601 sample size were analyzed. Two-sample Mendelian Randomization (MR) was conducted to assess causal effect of metabolites on DBP and SBP risk, and reverse MR analysis was performed to identify the DBP/SBP causal effect on blood metabolites. Twelve and twenty-two metabolites were identified to be associated with DBP and SBP, respectively. Sensitive analysis showed four metabolites had robustness association on BP. Reverse MR demonstrated DBP and SBP could decrease the tricosanoyl sphingomyelin (d18:1/23:0)* level and increase the 2-hydroxyhippurate (salicylurate) level in blood, respectively. Our findings reveal an association between blood metabolites and blood pressure (DBP and SBP), suggesting potential therapeutic targets for hypertension intervention.PMID:38102541 | DOI:10.1186/s12863-023-01180-z

Sci Rep. 2023 Dec 15;13(1):22309. doi: 10.1038/s41598-023-49695-w.ABSTRACTThis study explores the influence of extraction solvents on the composition and bioactivity of Salvia fruticosa extracts. Ultrasound-assisted extraction with water, ethanol and their mixtures in variable proportions was used to produce four different extracts. An untargeted UPLC/MS‑based metabolomics was performed to discover metabolites profile variation between the extracts. In the analyzed samples, 2704 features had been detected, of which 95 were tentatively identified. The concentrations of the important metabolites, namely, caffeic acid, carnosic acid, carnosol, rosmarinic acid, salvianolic acid B and scutellarin, were determined, using UPLC-PDA methods. Rosmarinic acid was the dominant metabolite and antioxidant in all tested extracts, except the aqueous extract, in which scutellarin was the most abundant compound. The extracts and standards were examined for antioxidant activity and xanthine oxidase (XO) inhibitory activity. The most diverse in terms of chemical composition and rich in antioxidant compounds was 70% ethanolic extract and the strongest antioxidant was caffeic acid. All analyzed extracts showed the ability to inhibit XO activity, but the highest value was recorded for 30% ethanolic extract. Among tested standards, the most potent XO inhibitor was caffeic acid. The results suggest that the leaves of Greek sage are a source of natural XO inhibitors and may be an alternative to drugs produced by chemical synthesis.PMID:38102229 | DOI:10.1038/s41598-023-49695-w

Nat Commun. 2023 Dec 15;14(1):8372. doi: 10.1038/s41467-023-44081-6.ABSTRACTATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.PMID:38102116 | DOI:10.1038/s41467-023-44081-6

Brief Bioinform. 2023 Nov 22;25(1):bbad463. doi: 10.1093/bib/bbad463.ABSTRACTMass spectrometry imaging (MSI) is commonly used to map the spatial distribution of small molecules within complex biological matrices. One of the major challenges in imaging MS-based spatial metabolomics is molecular identification and metabolite annotation, to address this limitation, annotation is often complemented with parallel bulk LC-MS2-based metabolomics to confirm and validate identifications. Here we applied MSI method, utilizing data-dependent acquisition, to visualize and identify unknown molecules in a single instrument run. To reach this aim we developed MSIpixel, a fully automated pipeline for compound annotation and quantitation in MSI experiments. It overcomes challenges in molecular identification, and improving reliability and comprehensiveness in MSI-based spatial metabolomics.PMID:38102070 | DOI:10.1093/bib/bbad463

Plant Physiol. 2023 Dec 15:kiad643. doi: 10.1093/plphys/kiad643. Online ahead of print.ABSTRACTTriterpenes are a class of bioactive compounds with diverse biological functions, playing pivotal roles in plant defense against biotic stressors. Oxidosqualene cyclases (OSCs) serve as gatekeepers in the biosynthesis of triterpenes. In this study, we utilized a Nicotiana benthamiana heterologous expression system to characterize NaOSC1 from Nicotiana attenuata as a multifunctional enzyme capable of synthesizing lupeol, dammarenediol II, 3-alpha,20-lupanediol, and 7 other triterpene scaffolds. We also demonstrated that NaOSC2 is, in contrast, a selective enzyme, producing only the β-amyrin scaffold. Through virus-induced gene silencing and in vitro toxicity assays, we elucidated the roles of NaOSC1 and NaOSC2 in the defense of N. attenuata against Manduca sexta larvae. Metabolomic and feature-based molecular network analyses of leaves with silenced NaOSC1 and NaOSC2 unveiled 3 potential triterpene glycoside metabolite clusters. Interestingly, features identified as triterpenes within these clusters displayed a significant negative correlation with larval mass. Our study highlights the pivotal roles of NaOSC1 and NaOSC2 from N. attenuata in the initial steps of triterpene biosynthesis, subsequently influencing defense against M. sexta through the modulation of downstream triterpene glycoside compounds.PMID:38101922 | DOI:10.1093/plphys/kiad643

Int J Cardiol. 2023 Dec 13:131657. doi: 10.1016/j.ijcard.2023.131657. Online ahead of print.ABSTRACTBACKGROUND: Understanding the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF) continues to be challenging. Several inflammatory and metabolic biomarkers have recently been suggested to be involved in HFpEF.OBJECTIVES: The purpose of this review was to synthesize the evidence on non-traditional biomarkers from metabolomic studies that may distinguish HFpEF from heart failure with reduced ejection fraction (HFrEF) and controls without HF.METHODS: A systematic search was conducted using Medline and PubMed with search terms such as "HFpEF" and "metabolomics", and a meta-analysis was conducted.RESULTS: Myeloperoxidase (MPO) levels were significantly (p < 0.001) higher in HFpEF than controls without HF, but comparable (p = 0.838) between HFpEF and HFrEF. Carnitine levels were significantly (p < 0.0001) higher in HFrEF than HFpEF, but comparable (p = 0.443) between HFpEF and controls without HF. Derivatives of reactive oxidative metabolites (DROMs) were not significantly (p = 0.575) higher in HFpEF than controls without HF.CONCLUSION: These data suggest that MPO is operative in HFpEF and HFrEF and may be a biomarker for HF. Furthermore, circulating carnitine levels may distinguish HFrEF from HFpEF.PMID:38101703 | DOI:10.1016/j.ijcard.2023.131657

Sci Total Environ. 2023 Dec 13:169172. doi: 10.1016/j.scitotenv.2023.169172. Online ahead of print.ABSTRACTChronic exposure to endocrine-disrupting chemicals through foods of aquatic origin, at levels that are commonly found in the environment, can affect metabolic health and lead to metabolic diseases. One such chemical is 2-phenylphenol (2-PP), a suspected endocrine disruptor that is used extensively in agriculture and industry, and has become a widespread pollutant in aquatic environments. This study evaluated the risk of exposure to 2-PP through foods of aquatic origin from Vembanad Lake, using a Target Hazard Quotient (THQ) and an untargeted metabolomics approach. The study found that 2-PP content was higher in samples from areas with intense industrial, tourism, and agricultural activities. The average concentration of 2-PP in fish, crustaceans, and mollusks from the Vembanad estuary ranged from 0.012 to 0.017 mg/kg. The mean concentration of 2-PP was used to assess the THQ of exposure to the coastal population. The results showed that the THQ value was <1, indicating a low to moderate health risk for both adults and children. Furthermore, an untargeted metabolomics approach using HPLC-Q-Orbitrap MS was used to study the metabolome changes associated with chronic exposure to 2-PP (at the environmentally relevant concentration) over 60 days in the Wistar albino rat model. The findings indicated significant alterations in the phospholipid, fatty acid, sterol lipid, and amino acid profiles, suggesting that chronic exposure to 2-PP at environmentally relevant concentrations could affect purine, phenylalanine, tyrosine, and cholesterol metabolism.PMID:38101641 | DOI:10.1016/j.scitotenv.2023.169172

Sci Total Environ. 2023 Dec 13:169383. doi: 10.1016/j.scitotenv.2023.169383. Online ahead of print.ABSTRACTThe practical advantages of capillary whole blood collection over venipuncture plasma collection for human exposome research are well known. However, before epidemiologists, clinicians, and public health researchers employ these microvolume sample collections, a rigorous evaluation of pre-analytical storage conditions is needed to develop protocols that maximize sample stability and reliability over time. Therefore, we performed a controlled experiment of dried whole blood collected on 10 μL Mitra microsamplers (DBM), 5-mm punches of whole blood from a dried blood spot (DBS), and 10 μL of plasma, and evaluated the effects of storage conditions at 4 °C, -20 °C, or -80 °C for up to 6 months on the resulting metabolite profiles measured with untargeted liquid chromatography-high resolution mass spectrometry (LC-HRMS). At -80 °C storage conditions, metabolite profiles from DBS, DBM, and plasma showed similar stability. While DBS and DBM metabolite profiles remained similarly stable at -20 °C storage, plasma profiles showed decreased stability at -20 °C compared to -80 °C storage. At refrigerated temperatures (4 °C), metabolite profiles collected on DBM were more stable than plasma or DBS, particularly for lipid classes. These results inform robust capillary blood sample storage protocols for DBM and DBS at potentially warmer temperatures than -80 °C, which may facilitate blood collections for populations outside of a clinical setting.PMID:38101622 | DOI:10.1016/j.scitotenv.2023.169383

J Lipid Res. 2023 Dec 13:100483. doi: 10.1016/j.jlr.2023.100483. Online ahead of print.ABSTRACTApolipoprotein H (APOH) downregulation can cause hepatic steatosis and gut microbiota dysbiosis. However, the mechanism by which APOH-regulated lipid metabolism contributes to metabolic dysfunction associated steatotic liver disease (MASLD) remains undetermined. Herein, we aim to explore the regulatory effect of APOH, mediated through various pathways, on metabolic homeostasis and MASLD pathogenesis. We analyzed serum marker levels, liver histopathology, and cholesterol metabolism-related gene expression in global ApoH-/- C57BL/6 male mice. We used RNA sequencing and metabolomic techniques to investigate the association between liver metabolism and bacterial composition. Fifty-two differentially expressed genes were identified between ApoH-/- and WT mice. The mRNA levels of de novo lipogenesis genes were highly upregulated in ApoH-/- mice than in WT mice. Fatty acid, glycerophospholipid, sterol lipid, and triglyceride levels were elevated, while hyodeoxycholic acid levels were significantly reduced in the liver tissues of ApoH-/- mice than in those of WT mice. Microbial beta diversity was lower in ApoH-/- mice than in WT mice, and gut microbiota metabolic functions were activated in ApoH-/- mice. Moreover, ApoH transcripts were downregulated in patients with MASLD, and APOH-related differential genes were enriched in lipid metabolism. Open-source transcript-level data from human MASH livers reinforced a significant association between MASH and APOH downregulation. In conclusion, our studies demonstrated that APOH downregulation aggravates fatty liver and induces gut microbiota dysbiosis by dysregulating bile acids. Our findings offer a novel perspective on APOH-mediated lipid metabolic dysbiosis and provide a valuable framework for deciphering the role of APOH in fatty liver disease.PMID:38101620 | DOI:10.1016/j.jlr.2023.100483

Chem Biol Interact. 2023 Dec 13:110833. doi: 10.1016/j.cbi.2023.110833. Online ahead of print.ABSTRACTMany chemotherapeutic drugs suffer from multidrug resistance (MDR). Efflux transporters, namely ATP-binding cassettes (ABCs), that pump the drugs out of the cancer cells comprise one major reason behind MDR. Therefore, ABC inhibitors have been under development for ages, but unfortunately, without clinical success. In the present study, an L-type amino acid transporter 1 (LAT1)-utilizing derivative of probenecid (PRB) was developed as a cancer cell-targeted efflux inhibitor for P-glycoprotein (P-gp), breast cancer resistant protein (BCRP) and/or several multidrug resistant proteins (MRPs), and its ability to increase vinblastine (VBL) cellular accumulation and apoptosis-inducing effects were explored. The novel amino acid derivative of PRB (2) increased the VBL exposure in triple-negative human breast cancer cells (MDA-MB-231) and human glioma cells (U-87MG) by 10-68 -times and 2-5-times, respectively, but not in estrogen receptor-positive human breast cancer cells (MCF-7). However, the combination therapy had greater cytotoxic effects in MCF-7 compared to MDA-MB-231 cells due to the increased oxidative stress recorded in MCF-7 cells. The metabolomic study also revealed that compound 2, together with VBL, decreased the transport of those amino acids essential for the biosynthesis of endogenous anti-oxidant glutathione (GSH). Moreover, the metabolic differences between the outcomes of the studied breast cancer cell lines were explained by the distinct expression profiles of solute carriers (SLCs) that can be concomitantly inhibited. Therefore, attacking several SLCs simultaneously to change the nutrient environment of cancer cells can serve as an adjuvant therapy to other chemotherapeutics, offering an alternative to ABC inhibitors.PMID:38101600 | DOI:10.1016/j.cbi.2023.110833

Environ Pollut. 2023 Dec 13:123146. doi: 10.1016/j.envpol.2023.123146. Online ahead of print.ABSTRACTPhthalic acid esters (PAEs) plasticizers are virulent endocrine disruptors that are mixed into plastics while fabricating and can filter out once they release into the surrounding environments. Plastic surfaces serve as new habitats for microorganisms, referred to as 'plastisphere'. Previous metagenomic investigations of the 'plastisphere' indicated that marine plastic surfaces may harbor microbes that degrade PAEs plasticizers. To our knowledge, the potential of microorganisms in the marine 'plastisphere' to metabolize PAEs is poorly understood. In this study, by screening the natural microbial community on plastic debris that had been deployed in situ for up to 20 months, a novel marine bacterium, Microbacterium esteraromaticum DEHP-1, was successfully isolated, which could degrade and mineralize 10-200 mg/L dibutyl phthalate (DBP) and bis(2-ethylhexyl) phthalate (DEHP). According to the results of gas chromatography-mass spectrometry (GC-MS) and whole genome mining of strain DEHP-1, we found that strain DEHP-1 may metabolize DBP by successive removal of the ester side chain by esterase 2518 to produce mono-butyl phthalate (MBP) and phthalic acid (PA), whereas the degradation of DEHP may take place by the direct action of monooxygenase 0132 on the fatty acid side chain of the DEHP molecule to produce di-n-hexyl phthalate (DnHP) and DBP, and then the subsequent hydrolysis of DBP by de-esterification to PA and finally into the tricarboxylic acid (TCA) cycle. Non-targeted metabolomics results showed that intracellular degradation of PAEs did not happen. However, exposure to PAEs was found to significantly affect pathways such as arginine and proline, riboflavin, glutathione and lysine degradation. Therefore, the intracellular metabolic behavior of strain DEHP-1 exposed to PAEs was proposed for the first time. This study sheds light on the metabolic capacity and strategies of bacteria in the marine 'plastisphere' to effectively degrade PAEs and highlights the importance of marine microbes in mitigating plastic poisonousness.PMID:38101529 | DOI:10.1016/j.envpol.2023.123146

Chemosphere. 2023 Dec 13:140940. doi: 10.1016/j.chemosphere.2023.140940. Online ahead of print.ABSTRACTMicroplastic (MP) and nanoplastic (NP) could cause gut microbiota alterations. Although micro/nanoplastic (MNP) degradation is attracting increasing scientific interest, the evaluation of MNP reduction in gut needs to be further investigated. This study aimed to determine whether partial reduction of polystyrene MNP in gut could affect the immunity, gut microbiota and metabolome of mice. Serum eotaxin/CCL11 was at a lower level in the mice exposed to 200 μg and 500 μg NP (i.e., 2NP and 5NP groups, respectively) compared to those exposed to 500 μg MP (i.e., 5 MP group), while serum IL-2 and IL-4 were both greater in the 5NP group compared to the 5 MP group. The gut bacterial alpha diversity, fungal diversity and evenness were all similar among the MNP and control groups. However, the gut fungal richness was greater in both the 5NP and 5 MP groups compared to the control group. The gut bacterial and fungal compositions were both different between the MNP and control groups. Multiple gut bacteria and fungi showed different levels between the 2NP and 5NP groups, as well as between the 2NP and 5 MP groups. Increased Staphylococcus and decreased Glomus were determined in the 2NP group compared to both the 5NP and 5 MP groups. A Lactobacillus phylotype was found as the sole gatekeeper in the bacterial network of the 2NP group, while a Bifidobacterium phylotype contributed most to the stability of the bacterial networks of both the 5NP and 5 MP groups. Multiple differential gut metabolic pathways were found between the 2NP and 5NP/5 MP groups, and mTOR signaling pathway was largely upregulated in the 2NP group compared to both the 5NP and 5 MP groups. The relevant results could help with the evaluation of partial reduction of MNP in gut.PMID:38101478 | DOI:10.1016/j.chemosphere.2023.140940

Cell Metab. 2023 Dec 8:S1550-4131(23)00421-7. doi: 10.1016/j.cmet.2023.11.010. Online ahead of print.ABSTRACTCommon genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.PMID:38101397 | DOI:10.1016/j.cmet.2023.11.010

Food Chem. 2023 Dec 12;440:138188. doi: 10.1016/j.foodchem.2023.138188. Online ahead of print.ABSTRACTTo investigate effects of metabolites and volatile compounds on the quality of Nuodeng ham, gas chromatography-mass spectrometry (GC-MS), ultra-high performance liquid chromatography-Q exactive orbitrap-mass spectrometry (UHPLC-QE-MS), and gas chromatography-ion transfer spectroscopy (GC-IMS) were used to analyze the differences of free fatty acids, small molecule metabolites and volatile compounds of Nuodeng ham at different ripening stages (the first, second and third year sample). 40 free fatty acids were detected. 757 and 300 metabolites were detected in positive and negative ion modes, respectively. 48 differential metabolites (VIP ≥ 1.5, P < 0.05) might important components affecting flavor differences of Nuodeng ham. Metabolic pathways revealed that fermenting-ripening of ham was associated with 31 metabolic pathways, among, 19 pathways were significant (Impact > 0.01, P < 0.05). 58 volatile compounds were identified, combined with PCA and PLS-DA, 15 flavor markers were screened out. These findings provide a scientific basis for further research on the flavor formation mechanism of Nuodeng ham.PMID:38100964 | DOI:10.1016/j.foodchem.2023.138188

Hum Vaccin Immunother. 2023 Dec 15;19(3):2282803. doi: 10.1080/21645515.2023.2282803. Epub 2023 Dec 15.ABSTRACTA significant surge in research endeavors leverages the vast potential of high-throughput omic technology platforms for broad profiling of biological responses to vaccines and cutting-edge immunotherapies and stem-cell therapies under development. These profiles capture different aspects of core regulatory and functional processes at different scales of resolution from molecular and cellular to organismal. Systems approaches capture the complex and intricate interplay between these layers and scales. Here, we summarize experimental data modalities, for characterizing the genome, epigenome, transcriptome, proteome, metabolome, and antibody-ome, that enable us to generate large-scale immune profiles. We also discuss machine learning and network approaches that are commonly used to analyze and integrate these modalities, to gain insights into correlates and mechanisms of natural and vaccine-mediated immunity as well as therapy-induced immunomodulation.PMID:38100557 | DOI:10.1080/21645515.2023.2282803