PubMed

Int J Mol Sci. 2023 Jul 27;24(15):12059. doi: 10.3390/ijms241512059.ABSTRACTImpaired redox homeostasis in the endoplasmic reticulum (ER) may contribute to proinsulin misfolding and thus to activate the unfolded protein response (UPR) and apoptotic pathways, culminating in pancreatic β-cell loss and type 2 diabetes (T2D). The present study was designed to identify differentially expressed genes (DEGs) encoding enzymes for glutathione metabolism and their impact on the expression levels of genes regulating protein folding and UPR in β-cells of T2D patients. The GEO transcriptome datasets of β-cells of diabetics and non-diabetics, GSE20966 and GSE81608, were analyzed for 142 genes of interest using limma and GREIN software, respectively. Diabetic β-cells showed dataset-specific patterns of DEGs (FDR ≤ 0.05) implicated in the regulation of glutathione metabolism (ANPEP, PGD, IDH2, and CTH), protein-folding (HSP90AB1, HSP90AA1, HSPA1B, HSPA8, BAG3, NDC1, NUP160, RLN1, and RPS19BP1), and unfolded protein response (CREB3L4, ERP27, and BID). The GCLC gene, encoding the catalytic subunit of glutamate-cysteine ligase, the first rate-limiting enzyme of glutathione biosynthesis, was moderately down-regulated in diabetic β-cells from both datasets (p ≤ 0.05). Regression analysis established that genes involved in the de novo synthesis of glutathione, GCLC, GCLM, and GSS affect the expression levels of genes encoding molecular chaperones and those involved in the UPR pathway. This study showed for the first time that diabetic β-cells exhibit alterations in the expression of genes regulating glutathione metabolism, protein-folding, and UPR and provided evidence for the molecular crosstalk between impaired redox homeostasis and abnormal protein folding, underlying ER stress in type 2 diabetes.PMID:37569434 | DOI:10.3390/ijms241512059

Int J Mol Sci. 2023 Jul 27;24(15):12053. doi: 10.3390/ijms241512053.ABSTRACTDiabetic retinopathy (DR) is a microvascular complication of diabetes mellitus (DM) which is the main cause of vision loss in the working-age population. Currently known risk factors such as age, disease duration, and hemoglobin A1c lack sufficient efficiency to distinguish patients with early stages of DR. A total of 194 plasma samples were collected from patients with type 2 DM and DR (moderate to proliferative (PDR) or control (no or mild DR) matched for age, gender, diabetes duration, HbA1c, and hypertension. Untargeted lipidomic and metabolomic approaches were performed. Partial-least square methods were used to analyze the datasets. Levels of 69 metabolites and 85 lipid species were found to be significantly different in the plasma of DR patients versus controls. Metabolite set enrichment analysis indicated that pathways such as metabolism of branched-chain amino acids (methylglutaryl carnitine p = 0.004), the kynurenine pathway (tryptophan p < 0.001), and microbiota metabolism (p-Cresol sulfate p = 0.004) were among the most enriched deregulated pathways in the DR group. Moreover, Glucose-6-phosphate (p = 0.001) and N-methyl-glutamate (p < 0.001) were upregulated in DR. Subgroup analyses identified a specific signature associated with PDR, macular oedema, and DR associated with chronic kidney disease. Phosphatidylcholines (PCs) were dysregulated, with an increase of alkyl-PCs (PC O-42:5 p < 0.001) in DR, while non-ether PCs (PC 14:0-16:1, p < 0.001; PC 18:2-14:0, p < 0.001) were decreased in the DR group. Through an unbiased multiomics approach, we identified metabolites and lipid species that interestingly discriminate patients with or without DR. These features could be a research basis to identify new potential plasma biomarkers to promote 3P medicine.PMID:37569425 | DOI:10.3390/ijms241512053

Int J Mol Sci. 2023 Jul 27;24(15):12021. doi: 10.3390/ijms241512021.ABSTRACTGraviola (Annona muricata) is a tropical plant with many traditional ethnobotanic uses and pharmacologic applications. A metabolomic study of both aqueous and DMSO extracts from Annona muricata leaves recently allowed us to identify dozens of bioactive compounds. In the present study, we use a proteomic approach to detect altered patterns in proteins on both conditioned media and extracts of HT-1080 fibrosarcoma cells under treatment conditions, revealing new potential bioactivities of Annona muricata extracts. Our results reveal the complete sets of deregulated proteins after treatment with aqueous and DMSO extracts from Annona muricata leaves. Functional enrichment analysis of proteomic data suggests deregulation of cell cycle and iron metabolism, which are experimentally validated in vitro. Additional experimental data reveal that DMSO extracts protect HT-1080 fibrosarcoma cells and HMEC-1 endothelial cells from ferroptosis. Data from our proteomic study are available via ProteomeXchange with identifier PXD042354.PMID:37569395 | DOI:10.3390/ijms241512021

Int J Mol Sci. 2023 Jul 26;24(15):12000. doi: 10.3390/ijms241512000.ABSTRACTCardiac complications are frequently found following a stroke in humans whose pathophysiological mechanism remains poorly understood. We used machine learning to analyse a large set of data from a metabolipidomic study assaying 630 metabolites in a rat stroke model to investigate metabolic changes affecting the heart within 72 h after a stroke. Twelve rats undergoing a stroke and 28 rats undergoing the sham procedure were investigated. A plasmatic signature consistent with the literature with notable lipid metabolism remodelling was identified. The post-stroke heart showed a discriminant metabolic signature, in comparison to the sham controls, involving increased collagen turnover, increased arginase activity with decreased nitric oxide synthase activity as well as an altered amino acid metabolism (including serine, asparagine, lysine and glycine). In conclusion, these results demonstrate that brain injury induces a metabolic remodelling in the heart potentially involved in the pathophysiology of stroke heart syndrome.PMID:37569376 | DOI:10.3390/ijms241512000

Foods. 2023 Jul 28;12(15):2878. doi: 10.3390/foods12152878.ABSTRACTThis study aimed to compare the in vitro fermentation characteristics of polysaccharides from Bergamot and Laoxianghuang (fermented 1, 3, and 5 years from bergamot) using the stable in vitro human gut fermentation model. Results showed that bergamot polysaccharide (BP) and Laoxianghuang polysaccharides (LPs) with different surface topographies were characterized as mannorhamnan (comprising Mannose and Rhamnose) and polygalacturonic acid (comprising Galacturonic acid and Galactose), respectively. The distinct effects on the gut microbiota and metabolome of BP and LPs may be due to their different monosaccharide compositions and surface morphologies. BP decreased harmful Fusobacterium and promoted beneficial Bifidobacterium, which was positively correlated with health-enhancing metabolites such as acetic acid, propionic acid, and pyridoxamine. Lactobacillus, increased by LPs, was positively correlated with 4-Hydroxybenzaldehyde, acetic acid, and butyric acid. Overall, this study elucidated gut microbiota and the metabolome regulatory discrepancies of BP and LPs, potentially contributing to their development as prebiotics in healthy foods.PMID:37569146 | DOI:10.3390/foods12152878

Cancers (Basel). 2023 Aug 7;15(15):4002. doi: 10.3390/cancers15154002.ABSTRACTBACKGROUND: Glioblastoma (GB) is a malignant brain tumour that is challenging to treat, often relapsing even after aggressive therapy. Evaluating therapy response relies on magnetic resonance imaging (MRI) following the Response Assessment in Neuro-Oncology (RANO) criteria. However, early assessment is hindered by phenomena such as pseudoprogression and pseudoresponse. Magnetic resonance spectroscopy (MRS/MRSI) provides metabolomics information but is underutilised due to a lack of familiarity and standardisation.METHODS: This study explores the potential of spectroscopic imaging (MRSI) in combination with several machine learning approaches, including one-dimensional convolutional neural networks (1D-CNNs), to improve therapy response assessment. Preclinical GB (GL261-bearing mice) were studied for method optimisation and validation.RESULTS: The proposed 1D-CNN models successfully identify different regions of tumours sampled by MRSI, i.e., normal brain (N), control/unresponsive tumour (T), and tumour responding to treatment (R). Class activation maps using Grad-CAM enabled the study of the key areas relevant to the models, providing model explainability. The generated colour-coded maps showing the N, T and R regions were highly accurate (according to Dice scores) when compared against ground truth and outperformed our previous method.CONCLUSIONS: The proposed methodology may provide new and better opportunities for therapy response assessment, potentially providing earlier hints of tumour relapsing stages.PMID:37568818 | DOI:10.3390/cancers15154002

Cancers (Basel). 2023 Jul 25;15(15):3764. doi: 10.3390/cancers15153764.ABSTRACTMultiple myeloma (MM) is an incurable haematological malignancy of plasma cells in the bone marrow. In rare cases, an aggressive form of MM called extramedullary multiple myeloma (EMM) develops, where myeloma cells enter the bloodstream and colonise distal organs or soft tissues. This variant is associated with refractoriness to conventional therapies and a short overall survival. The molecular mechanisms associated with EMM are not yet fully understood. Here, we analysed the proteome of bone marrow mononuclear cells and blood plasma from eight patients (one serial sample) with EMM and eight patients without extramedullary spread. The patients with EMM had a significantly reduced overall survival with a median survival of 19 months. Label-free mass spectrometry revealed 225 proteins with a significant differential abundance between bone marrow mononuclear cells (BMNCs) isolated from patients with MM and EMM. This plasma proteomics analysis identified 22 proteins with a significant differential abundance. Three proteins, namely vascular cell adhesion molecule 1 (VCAM1), pigment epithelium derived factor (PEDF), and hepatocyte growth factor activator (HGFA), were verified as the promising markers of EMM, with the combined protein panel showing excellent accuracy in distinguishing EMM patients from MM patients. Metabolomic analysis revealed a distinct metabolite signature in EMM patient plasma compared to MM patient plasma. The results provide much needed insight into the phenotypic profile of EMM and in identifying promising plasma-derived markers of EMM that may inform novel drug development strategies.PMID:37568580 | DOI:10.3390/cancers15153764

J Clin Med. 2023 Jul 28;12(15):4978. doi: 10.3390/jcm12154978.ABSTRACTBACKGROUND: Preoperative fasting and surgery cause metabolic stress, insulin resistance with ketosis, and postoperative nausea and vomiting (PONV). Oral carbohydrate loading strategy (CHO) improves outcomes in labor and general surgery. We aimed to compare the effectiveness of CHO with standard fasting in patients undergoing elective cesarean delivery (CD) under spinal anesthesia.METHODS: A single-center, parallel, prospective randomized controlled trial (RCT) was conducted in a tertiary university obstetrics department at Pomeranian Medical University in Szczecin, Poland. Patients were randomly assigned (1:1 ratio) to the CHO group (oral carbohydrate 2 h before elective CD, n = 75) or the SF group (control-standard fasting, n = 73). The main outcome measures were incidence and severity of PONV at 6 and 24 h after CD, time to the first peristalsis, time to first bowel movement, and biochemical parameters indicating ketosis in mothers and their children.RESULTS: A total of 148 adult females with singleton pregnancies undergoing elective CD under spinal anesthesia (ASA I and II) were included in the final analysis. At 24 h after CD, 8.0% from the CHO group vs. 20.55% reported three or more episodes of vomiting or dry retching as compared to patients in the SF group (p = 0.041). Preoperative CHO supplementation decreased preoperative feelings of hunger (p < 0.001) and thirst (p < 0.001). Laboratory results in the CHO group showed higher plasma pH (p = 0.001) and glucose (p < 0.001), lower F2-isoprostane in plasma (p = 0.049) and urine (p = 0.018), lower urine F2-isoprostane/creatinine ratio (p = 0.045) than in the SF group. HOMA-IR (p < 0.001) and lactate (p < 0.001) were higher in the CHO group than in the control group.CONCLUSIONS: There was no significant difference in the incidence or severity of early PONV at 6 h. The incidence of vomiting or dry retching at 24 h after cesarean delivery was lower in the CHO group as compared to standard starvation, but the combined results of PONV frequency and severity on the Wengritzky scale did not differ between the two study groups. Preoperative CHO supplementation decreased preoperative feelings of hunger and thirst, enhancing the comfort of pregnant women.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04069806.PMID:37568381 | DOI:10.3390/jcm12154978

J Sep Sci. 2023 Aug 11:e2300175. doi: 10.1002/jssc.202300175. Online ahead of print.ABSTRACTPrevious clinical studies have found that the efficacy of processed Qixue Shuangbu Prescription has been significantly improved in the treatment of chronic heart failure. However, the absorbed constituents and synergistic mechanisms of processed Qixue Shuangbu Prescription to enhance the therapeutic effect of chronic heart failure remain unclear. In this study, we propose an integrated strategy combining plasma metabolomics, network pharmacology, and molecular docking to study the absorbed constituents and synergistic mechanisms of processed Qixue Shuangbu Prescription. A total of 34 prototype constituents and 24 metabolites were identified in rat plasma after administration of crude and processed Qixue Shuangbu Prescription. As a result, six potential absorbed constituents and six potential targets for the treatment of chronic heart failure were identified. In addition, the result of molecular docking indicated that the key constituents exhibited good affinity to hub targets. This study showed that the multiomics approach could effectively clarify absorbed constituents and synergistic mechanisms of traditional Chinese medicine processing from a new perspective.PMID:37568244 | DOI:10.1002/jssc.202300175

J Assist Reprod Genet. 2023 Aug 12. doi: 10.1007/s10815-023-02904-x. Online ahead of print.ABSTRACTPURPOSE: The purpose of this study was to investigate alterations in serum metabolites during endometrial transformation and possible associations with recurrent implantation failure (RIF) in hormonal replacement therapy (HRT)-frozen embryo transfer (FET) cycles.METHODS: We performed a prospective study involving 100 patients scheduled for HRT-FET cycles during January 2022 to April 2022. Blood serum samples were collected on the day of progesterone administration (dPA) and on the third day of progesterone administration (d3PA). Gas chromatography-mass spectrometry (GC-MS) analysis was performed to identify and quantify serum metabolites. A nested case-control study including 19 RIF patients and 19 matching controls was conducted to explore the predictive value of serum metabolites for RIF. Partial least squares discriminant analysis (PLS-DA) and receiver operating characteristic (ROC) curve analysis were performed to establish prediction models.MAIN RESULTS: We identified 105 serum metabolites, with 76 of them exhibiting significant alterations during the initial 3 days of endometrial transformation. Metabolites involved in amino acid metabolism and tricarboxylic acid (TCA) cycle showed lower levels during endometrial transformation. In the nested case-control study, the prediction model based on the ratio of serum metabolites between d3PA and dPA showed the highest area under the ROC curve (AUC), accuracy, and R2 and Q2 values. Eight metabolites, including indol-3-propionic acid, beta-alanine, myristoleic acid, malic acid, indole, DL-isocitric acid, proline, and itaconic acid, exhibited high predictive values for RIF.CONCLUSION: This study demonstrates alterations in serum metabolites during endometrial transformation, particularly in amino acid metabolism and TCA cycle. The identified metabolites, especially indol-3-propionic acid and malic acid, show potential as predictive markers for RIF. These findings contribute to a better understanding of the metabolic changes associated with endometrial receptivity and provide insights for the development of personalized approaches to improve implantation outcomes in FET cycles.PMID:37568040 | DOI:10.1007/s10815-023-02904-x

Sci Rep. 2023 Aug 11;13(1):13047. doi: 10.1038/s41598-023-39757-4.ABSTRACTThe saltwater hard clam Mercenaria mercenaria (M. mercenaria) as a representative of low-value shellfish, enhancing its flavor quality, is the key to enter the high-end market. Nevertheless, there has not been reported research on the flavor quality of M. mercenaria. This study compared the flavor quality of selective and non-selective saltwater hard clams of M. mercenaria by using various indicators: proximate component, free amino acids, nucleotides, and metabolomic analysis. The results indicated that selective breeding contributed to the significant improvement contents of crude protein, flavor-associated free amino acids (glutamic acid, aspartic acid, proline, etc.), and nucleotides (AMP) (P < 0.05). Then, the metabolome was utilized to assess the metabolite changes in the pre/post-selective breeding of M. mercenaria and further understand the flavor characteristics and metabolic status. In the metabolomics assay, among the 3143 quantified metabolites, a total of 102 peaks were identified as significantly different metabolites (SDMs) between the selective and non-selective varieties of M. mercenaria (VIP > 1 and P < 0.05). These results can provide new insights for future research on improving the quality of saltwater bivalves through selective breeding.PMID:37567877 | DOI:10.1038/s41598-023-39757-4

Food Microbiol. 2023 Oct;115:104328. doi: 10.1016/j.fm.2023.104328. Epub 2023 Jul 7.ABSTRACTDrug-resistant Salmonella is widely distributed in the meat production chain, endangering food safety and public health. Acidification of meat products during processing can induce acid stress, which may alter antibiotic resistance. Our study investigated the effects of acid stress on the antibiotic resistance and metabolic profile of Salmonella Typhimurium, and explored the underlying mechanisms using metabolomic and transcriptomic analysis. We found that acid-stressed 14028s was more sensitive to small molecule hydrophobic antibiotics (SMHA) while more resistant to meropenem (MERO). Metabolomic analysis revealed that enhanced sensitivity to SMHA was correlated with increased purine metabolism and tricarboxylic acid cycle. Transcriptomic analysis revealed the downregulation of chemotaxis-related genes, which are also associated with SMHA sensitivity. We also found a significant downregulation of the ompF gene, which encodes a major outer membrane protein OmpF of Salmonella. The decreased expression of OmpF porin hindered the influx of MERO, leading to enhanced resistance of the bacteria to the drug. Our findings contribute to greatly improve the understanding of the relationship between Salmonella metabolism, gene expression, and changes in drug resistance after acid stress, while providing a structural framework for exploring the relationship between bacterial stress responses and antibiotic resistance.PMID:37567621 | DOI:10.1016/j.fm.2023.104328

Int J Biol Macromol. 2023 Aug 9:126246. doi: 10.1016/j.ijbiomac.2023.126246. Online ahead of print.ABSTRACTRoot bark (Lycii cortex) of Lycium contains high contents of characteristic bioactive compounds, including kukoamine A (KuA) and kukoamine B (KuB). RIPENING INHIBITOR (RIN) is well known as a master regulator of Solanaceaous fruit ripening. However, the role of RIN in the biosynthetic pathway of KuA in Lycium remains unclear. In this study, integrated transcriptomic, metabolomic analyses and hairy root system are used to characterize the role of RIN in KuA biosynthesis in Lycium. The ultra performance liquid chromatography electrospray ionization tandem mass spectrometry analysis revealed that KuA was significantly induced in LrRIN1 RNAi lines and not detected in overexpression lines. A total of 20,913 differentially expressed genes (DEGs) and 60 differentially accumulated metabolites (DAMs) were detected in LrRIN1 transgenic hairy roots, which were used for weighted gene co-expression network analysis. Our result reveals a high association between KuA and structural genes in the phenolamide pathway, which shows a negative correlation with LrRIN1. In addition, overexpression of the polyamine pathway gene thermospermine synthase LcTSPMS, a potential target gene of Lycium RIN, increased the contents of both KuA and KuB in L. chinense hairy root, indicating that TSPMS is responsible for KuA biosynthesis and is also the common upstream biosynthetic gene for both KuA and KuB. Our results lay a solid foundation for uncovering the biosynthetic pathway of KuA, which will facilitate the molecular breeding and genetic improvement of Lycium species.PMID:37567520 | DOI:10.1016/j.ijbiomac.2023.126246

J Biol Chem. 2023 Aug 9:105147. doi: 10.1016/j.jbc.2023.105147. Online ahead of print.ABSTRACTThe vertebrate host's immune system and resident commensal bacteria deploy a range of highly reactive small molecules that provide a barrier against infections by microbial pathogens. Gut pathogens, such as Vibrio cholerae, sense and respond to these stressors by modulating the expression of exotoxins that are crucial for colonization. Here, we employ mass-spectrometry-based profiling, metabolomics, expression assays and biophysical approaches to show that transcriptional activation of the hemolysin gene hlyA in V. cholerae is regulated by intracellular forms of sulfur with sulfur-sulfur bonds termed reactive sulfur species (RSS). We first present a comprehensive sequence similarity network analysis of the arsenic repressor (ArsR) superfamily of transcriptional regulators where RSS and H2O2 sensors segregate into distinct clusters. We show that HlyU, transcriptional activator of hlyA in V. cholerae, belongs to the RSS-sensing cluster and readily reacts with organic persulfides, showing no reactivity and or DNA-dissociation following treatment with GSSG or H2O2. Surprisingly, in V. cholerae cell cultures, both sulfide and peroxide treatment downregulate HlyU-dependent transcriptional activation of hlyA. However, RSS metabolite profiling shows that both sulfide and peroxide treatment raise the endogenous inorganic sulfide and disulfide levels to a similar extent, accounting for this crosstalk, and confirming that V. cholerae attenuates HlyU-mediated activation of hlyA in a specific response to intracellular RSS. These findings provide new evidence that gut pathogens may harness RSS-sensing as an evolutionary adaptation that allows them to overcome the gut inflammatory response by modulating the expression of exotoxins.PMID:37567478 | DOI:10.1016/j.jbc.2023.105147

Immunobiology. 2023 Jul 27;228(5):152722. doi: 10.1016/j.imbio.2023.152722. Online ahead of print.ABSTRACTThe pathogenesis of primary Sjogren's syndrome (pSS) has not been fully elucidated. We explored differentially expressed proteins and metabolic pathways in pSS using proteomics and metabolomics. 456 named proteins in total were identified, among which 50 were significantly changed in the pSS. Altered proteins were significantly associated with signaling pathways such as antigen processing and presentation, human immunodeficiency virus 1 infection, and FC gamma R-mediated phagocytosis. Meanwhile, 12 proteins, such as SH3BGRL3, TPM4, and CA1, can be used as potential clinical molecular markers. Moreover, 128 metabolites were significantly expressed in the pSS group. A total of 96 pathways were significantly enriched including central carbon metabolism in cancer, taurine and hypotaurine metabolism, and ABC transporters. Notably, both proteomics and metabolomics enriched glycolysis/gluconeogenesis metabolism, pentose phosphate pathway, and glutathione metabolism pathways. In this study, the progression mechanism of pSS was analyzed and novel biomarkers were identified by proteomics and metabolomics.PMID:37567091 | DOI:10.1016/j.imbio.2023.152722

Food Chem. 2023 Jul 29;431:137035. doi: 10.1016/j.foodchem.2023.137035. Online ahead of print.ABSTRACTPostmortem aging is a value-added process for meat. The objective of this study was to evaluate the dynamic changes and metabolic pathways of metabolites in Mongolian sheep during early postmortem chilled aging. Widely targeted metabolomic was used to analyze the metabolites of mutton within five days of chilled aging. A total of 1093 metabolites were identified in Mongolian sheep, covering 16 subclasses. Multivariate statistical analysis showed that 467 metabolites had significant changes during aging, including amino acid and its metabolites, fatty acyl, and glycerophospholipid. In particular, 60 metabolites decreased, while other 407 metabolites increased with aging time. The Kyoto encyclopedia of genes and genomes pathway analysis revealed that protein digestion and absorption, amino acyl-trNA biosynthesis, unsaturated fatty acid biosynthesis, nucleotide metabolism and carbon metabolism were the main enrichment pathways in aging. These findings provide a more comprehensive insight into metabolic profiling and metabolic pathways during chilled aging in mutton.PMID:37567080 | DOI:10.1016/j.foodchem.2023.137035

Nutrition. 2023 Jul 13;116:112160. doi: 10.1016/j.nut.2023.112160. Online ahead of print.ABSTRACTOBJECTIVES: High-resolution metabolomics enables global assessment of metabolites and molecular pathways underlying physiologic processes, including substrate utilization during the fasted state. The clinical index for substrate utilization, respiratory exchange ratio (RER), is measured via indirect calorimetry. The aim of this pilot study was to use metabolomics to identify metabolic pathways and plasma metabolites associated with substrate utilization in healthy, fasted adults.METHODS: This cross-sectional study included 33 adults (mean age 27.7 ± 4.9 y, mean body mass index 24.8 ± 4 kg/m2). Participants underwent indirect calorimetry to determine resting RER after an overnight fast. Untargeted metabolomics was performed on fasted plasma samples using dual-column liquid chromatography and ultra-high-resolution mass spectrometry. Linear regression and pathway enrichment analyses identified pathways and metabolites associated with substrate utilization measured with indirect calorimetry.RESULTS: RER was significantly associated with 1389 metabolites enriched within 13 metabolic pathways (P < 0.05). Lipid-related findings included general pathways, such as fatty acid activation, and specific pathways, such as C21-steroid hormone biosynthesis and metabolism, butyrate metabolism, and carnitine shuttle. Amino acid pathways included those central to metabolism, such as glucogenic amino acids, and pathways needed to maintain reduction-oxidation reactions, such as methionine and cysteine metabolism. Galactose and pyrimidine metabolism were also associated with RER (all P < 0.05).CONCLUSIONS: The fasting plasma metabolome reflects the diverse macronutrient pathways involved in carbohydrate, amino acid, and lipid metabolism during the fasted state in healthy adults. Future studies should consider the utility of metabolomics to profile individual nutrient requirements and compare findings reported here to clinical populations.PMID:37566924 | DOI:10.1016/j.nut.2023.112160

Sci Immunol. 2023 Aug 18;8(86):eadg3517. doi: 10.1126/sciimmunol.adg3517. Epub 2023 Aug 11.ABSTRACTThe skin needs to balance tolerance of colonizing microflora with rapid detection of potential pathogens. Flexible response mechanisms would seem most suitable to accommodate the dynamic challenges of effective antimicrobial defense and restoration of tissue homeostasis. Here, we dissected macrophage-intrinsic mechanisms and microenvironmental cues that tune macrophage signaling in localized skin infection with the colonizing and opportunistic pathogen Staphylococcus aureus. Early in skin infection, the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by γδ T cells and hypoxic conditions within the dermal microenvironment diverted macrophages away from a homeostatic M-CSF- and hypoxia-inducible factor 1α (HIF-1α)-dependent program. This allowed macrophages to be metabolically rewired for maximal inflammatory activity, which requires expression of Irg1 and generation of itaconate, but not HIF-1α. This multifactorial macrophage rewiring program was required for both the timely clearance of bacteria and for the provision of local immune memory. These findings indicate that immunometabolic conditioning allows dermal macrophages to cycle between antimicrobial activity and protection against secondary infections.PMID:37566679 | DOI:10.1126/sciimmunol.adg3517

Sci Adv. 2023 Aug 11;9(32):eadh0485. doi: 10.1126/sciadv.adh0485. Epub 2023 Aug 11.ABSTRACTMetabolomics, the study of metabolites (small molecules of <1500 daltons), has been posited as a potential tool to explore the past in a comparable manner to other omics, e.g., genomics or proteomics. Archaeologists have used metabolomic approaches for a decade or so, mainly applied to organic residues adhering to archaeological materials. Because of advances in sensitivity, resolution, and the increased availability of different analytical platforms, combined with the low mass/volume required for analysis, metabolomics is now becoming a more feasible choice in the archaeological sector. Additional approaches, as presented by our group, show the versatility of metabolomics as a source of knowledge about the human past when using human osteoarchaeological remains. There is tremendous potential for metabolomics within archaeology, but further efforts are required to position it as a routine technique.PMID:37566664 | DOI:10.1126/sciadv.adh0485

Sci Adv. 2023 Aug 11;9(32):eadg4017. doi: 10.1126/sciadv.adg4017. Epub 2023 Aug 11.ABSTRACTObesity is associated with cognitive decline. Recent observations in mice propose an adipose tissue (AT)-brain axis. We identified 188 genes from RNA sequencing of AT in three cohorts that were associated with performance in different cognitive domains. These genes were mostly involved in synaptic function, phosphatidylinositol metabolism, the complement cascade, anti-inflammatory signaling, and vitamin metabolism. These findings were translated into the plasma metabolome. The circulating blood expression levels of most of these genes were also associated with several cognitive domains in a cohort of 816 participants. Targeted misexpression of candidate gene ortholog in the Drosophila fat body significantly altered flies memory and learning. Among them, down-regulation of the neurotransmitter release cycle-associated gene SLC18A2 improved cognitive abilities in Drosophila and in mice. Up-regulation of RIMS1 in Drosophila fat body enhanced cognitive abilities. Current results show previously unidentified connections between AT transcriptome and brain function in humans, providing unprecedented diagnostic/therapeutic targets in AT.PMID:37566655 | DOI:10.1126/sciadv.adg4017