PubMed

Food Chem X. 2024 Jul 18;23:101668. doi: 10.1016/j.fochx.2024.101668. eCollection 2024 Oct 30.ABSTRACTYuling paste, a traditional Chinese health food derived from longan pulp and American ginseng, undergoes a unique processing method involving nine cycles of steaming and sun-drying. Ultra-high-performance liquid chromatography tandem mass spectrometry combined with widely targeted metabolomics has been used to examine the dynamic change in metabolite profiles through the processing. A total of 758 metabolites were identified. Processing significantly affects metabolite changes, and network pharmacology is subsequently used to explore potential pharmacological ingredients. After processing, the contents of active ingredients such as ginsenoside rh2, oleanolic acid, choline, d-glucose, and D-galacturonic acid were found to increase significantly. These increases can be correlated to the enhancement of five distinct pathways, and the contents of naringenin-7-O-glucoside, adenosine, pantothenic acid, and D-sucrose decreased after the processing, correlating with decreases in two different pathways. This study provides a comprehensive reference and scientific basis for understanding the health benefits associated with this traditional health food.PMID:39139487 | PMC:PMC11321412 | DOI:10.1016/j.fochx.2024.101668

Food Chem X. 2024 Jul 14;23:101646. doi: 10.1016/j.fochx.2024.101646. eCollection 2024 Oct 30.ABSTRACTThe quality of strong-flavor Baijiu, a prominent Chinese liquor, is intricately tied to the choice of sorghum variety used in fermentation. However, a significant gap remains in our understanding of how glutinous and non-glutinous sorghum varieties comprehensively impact Baijiu flavor formation through fermentation metabolites. This study employed untargeted metabolomics combined with feature-based molecular networking (FBMN) to explore the unique metabolic characteristics of these two sorghum varieties during fermentation. FBMN analysis revealed 267 metabolites within both types of fermented sorghum (Zaopei) in the cellar. Further multidimensional statistical analyses highlighted sphingolipids, 2,5-diketopiperazines, and methionine derivatives as critical markers for quality control. These findings represent a significant advancement in our understanding and provide valuable insights for regulating the quality of Baijiu flavors.PMID:39139485 | PMC:PMC11321435 | DOI:10.1016/j.fochx.2024.101646

JHEP Rep. 2024 May 15;6(8):101119. doi: 10.1016/j.jhepr.2024.101119. eCollection 2024 Aug.ABSTRACTBACKGROUND & AIMS: The effectiveness of surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is limited, due to inadequate risk stratification and suboptimal performance of current screening modalities.METHODS: We developed a multicenter prospective cohort of patients with cirrhosis undergoing surveillance with MRI and applied global untargeted metabolomics to 612 longitudinal serum samples from 203 patients. Among them, 37 developed HCC during follow-up.RESULTS: We identified 150 metabolites with significant abundance changes in samples collected prior to HCC (Cases) compared to samples from patients who did not develop HCC (Controls). Tauro-conjugated bile acids and gamma-glutamyl amino acids were increased, while acyl-cholines and deoxycholate derivatives were decreased. Seven amino acids including serine and alanine had strong associations with HCC risk, while strong protective effects were observed for N-acetylglycine and glycerophosphorylcholine. Machine learning using the 150 metabolites, age, gender, and PNPLA3 and TMS6SF2 single nucleotide polymorphisms, identified 15 variables giving optimal performance. Among them, N-acetylglycine had the highest AUC in discriminating Cases and Controls. When restricting Cases to samples collected within 1 year prior to HCC (Cases-12M), additional metabolites including microbiota-derived metabolites were identified. The combination of the top six variables identified by machine learning (alpha-fetoprotein, 6-bromotryptophan, N-acetylglycine, salicyluric glucuronide, testosterone sulfate and age) had good performance in discriminating Cases-12M from Controls (AUC 0.88, 95% CI 0.83-0.93). Finally, 23 metabolites distinguished Cases with LI-RADS-3 lesions from Controls with LI-RADS-3 lesions, with reduced abundance of acyl-cholines and glycerophosphorylcholine-related lysophospholipids in Cases.CONCLUSIONS: This study identified N-acetylglycine, amino acids, bile acids and choline-derived metabolites as biomarkers of HCC risk, and microbiota-derived metabolites as contributors to HCC development.IMPACT AND IMPLICATIONS: The effectiveness of surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is limited. There is an urgent need for improvement in risk stratification and new screening modalities, particularly blood biomarkers. Longitudinal collection of paired blood samples and MRI images from patients with cirrhosis is particularly valuable in assessing how early blood and imaging markers become positive during the period when lesions are observed to obtain a diagnosis of HCC. We generated a multicenter prospective cohort of patients with cirrhosis under surveillance with contrast MRI, applied untargeted metabolomics on 612 serum samples from 203 patients and identified metabolites associated with risk of HCC development. Such biomarkers may significantly improve early-stage HCC detection for patients with cirrhosis undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality.PMID:39139459 | PMC:PMC11321296 | DOI:10.1016/j.jhepr.2024.101119

Front Microbiol. 2024 Jul 30;15:1435834. doi: 10.3389/fmicb.2024.1435834. eCollection 2024.ABSTRACTBACKGROUND: Douzhi, a traditional Chinese fermented beverage, features microbial communities primarily composed of lactic acid bacteria (LAB). As fermented foods continue to gain recognition and popularity, douzhi is attracting growing interest. However, investigation of the critical aspects of douzhi's fermentation processes, including fermentation characteristics and microbial community dynamics, remains vital for enhancing food safety and quality for douzhi, as well as for similar fermented food products.METHOD: In this study, we collected douzhi microbial communities from four chain stores, using them as fermentation starter cultures. The microbial dynamics of the fermentation were analyzed, focusing on the inoculation of LAB strains and the transition from a mung bean-based matrix to skimmed milk. The metabolomic profiles of the fermented mung bean matrices were also studied.RESULTS: Douzhi samples obtained from representative chain stores were found to be overwhelmingly dominated by LAB. When inoculated along with the douzhi community, both LAB strains exhibited notable and substantial reductions in the pH value of the designated mung bean matrices compared to those inoculated indigenous microbiota. Specifically, Lactiplantibacillus plantarum CGMCC 1.1856 retained its population, whereas Pediococcus pentosaceus CGMCC 1.2695 exhibited a decrease in relative abundance. Using skimmed milk as a fermentation substrate instead of the mung bean matrix resulted in significant shifts in microbial communities, particularly leading to an increase in Escherichia sp. The metagenomic analyses and functional predictions illustrated that various metabolic functions were enhanced during the fermentation process due to LAB inoculation. The liquid chromatography-mass spectrometry based metabolomic analysis revealed that the inoculation of Lactiplantibacillus plantarum and Pediococcus pentosaceus in mung bean matrix did not introduce new metabolites but significantly altered the concentration and profile of existing metabolites, especially increased low molecular carbohydrates, which may enhance the nutritional potential of the fermented product.DISCUSSION: This study examines the microbial dynamics of douzhi microbiota fermentation, emphasizing the role of lactic acid bacteria in enhancing fermentation activity and metabolite profiles. These insights contribute to improving manufacturing processes and ensuring the safety and quality of douzhi and similar fermented foods.PMID:39139380 | PMC:PMC11319256 | DOI:10.3389/fmicb.2024.1435834

Adv Healthc Mater. 2024 Aug 13:e2402266. doi: 10.1002/adhm.202402266. Online ahead of print.ABSTRACTMicrowave (MW) therapy is an emerging therapy with high efficiency and deep penetration to combat the crisis of bacterial resistance. However, as the energy of MW is too low to induce electron transition, the mechanism of MW catalytic effect remains ambiguous. Herein, a cerium-based metal-organic framework (MOF) is fabricated and used in MW therapy. The MW-catalytic performance of CeTCPP is largely dependent on the ions in the liquid environment, and the electron transition is achieved through a "tribovoltaic effect" between water molecules and CeTCPP. By this way, CeTCPP can generate reactive oxygen species (ROS) in saline under pulsed MW irradiation, showing 99.9995 ± 0.0002% antibacterial ratio against Staphylococcus aureus (S. aureus) upon two cycles of MW irradiation. Bacterial metabolomics further demonstrates that the diffusion of ROS into bacteria led to the bacterial metabolic disorders. The bacteria are finally killed due to "amino acid starvation". In order to improve the applicability of CeTCPP, It is incorporated into alginate-based hydrogel, which maintains good MW catalytic antibacterial efficiency and also good biocompatibility. Therefore, this work provides a comprehensive instruction of using CeTCPP in MW therapy, from mechanism to application. This work also provides new perspectives for the design of antibacterial composite hydrogel.PMID:39138999 | DOI:10.1002/adhm.202402266

Biotechnol Bioeng. 2024 Sep;121(9):2848-2867. doi: 10.1002/bit.28777. Epub 2024 Jun 22.ABSTRACTThe fast-growing Chinese hamster lung (CHL)-YN cell line was recently developed for monoclonal antibody production. In this study, we applied a serum-free fed-batch cultivation process to immunoglobulin (Ig)G1-producing CHL-YN cells, which were then used to design a dynamic glucose supply system to stabilize the extracellular glucose concentration based on glucose consumption. Glucose consumption of the cultures rapidly oscillated following three phases of glutamine metabolism: consumption, production, and re-consumption. Use of the dynamic glucose supply prolonged the viability of the CHL-YN-IgG1 cell cultures and increased IgG1 production. Liquid chromatography with tandem mass spectrometry-based target metabolomics analysis of the extracellular metabolites during the first glutamine shift was conducted to search for depleted compounds. The results suggest that the levels of four amino acids, namely arginine, aspartate, methionine, and serine, were sharply decreased in CHL-YN cells during glutamine production. Supporting evidence from metabolic and gene expression analyses also suggest that CHL-YN cells acquired ornithine- and cystathionine-production abilities that differed from those in Chinese hamster ovary-K1 cells, potentially leading to proline and cysteine biosynthesis.PMID:39138873 | DOI:10.1002/bit.28777

Biomed Chromatogr. 2024 Aug 13:e5985. doi: 10.1002/bmc.5985. Online ahead of print.ABSTRACTThe aim is to investigate the potential allergens and mechanisms underlying allergic-like reactions induced by Danshen injection (DSI). Utilizing ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS), metabolomics, and bioinformatics, we identified the key allergens, targets, and metabolic pathways involved in DSI-induced allergic-like reactions, validating binding efficiency through molecular docking and molecular dynamics. A total of 45 compounds were identified within DSI, with 24 compounds exhibiting strong binding activity to the MrgprX2 activation site. DSI was found to cause changes in 89 endogenous metabolites, including arachidonic acid, prostaglandins, and leukotrienes, primarily affecting pathways such as phenylalanine metabolism and arachidonic acid metabolism. The key allergens identified were Cryptotanshinone, Miltipolone, Neocryptotanshinone, Salvianolic acid B, and Isosalvianolic acid C, which primarily trigger allergic-like reactions by regulating upstream signaling targets such as ALOX5, PTGS1, PPARD, and LTB4R. Validation confirmed the high binding affinity and stability between key allergens and targets. These findings indicate that the allergic components in DSI primarily induce allergic-like reactions by modulating the aforementioned signaling targets, activating the AA metabolic pathway, promoting mast cell degranulation, and releasing downstream endogenous inflammatory mediators, subsequently eliciting allergic-like reactions.PMID:39138643 | DOI:10.1002/bmc.5985

Clin Epigenetics. 2024 Aug 13;16(1):104. doi: 10.1186/s13148-024-01718-7.ABSTRACTBACKGROUND: The plasma metabolome reflects the physiological state of various biological processes and can serve as a proxy for disease risk. Plasma metabolite variation, influenced by genetic and epigenetic mechanisms, can also affect the cellular microenvironment and blood cell epigenetics. The interplay between the plasma metabolome and the blood cell epigenome remains elusive. In this study, we performed an epigenome-wide association study (EWAS) of 1183 plasma metabolites in 693 participants from the LifeLines-DEEP cohort and investigated the causal relationships in DNA methylation-metabolite associations using bidirectional Mendelian randomization and mediation analysis.RESULTS: After rigorously adjusting for potential confounders, including genetics, we identified five robust associations between two plasma metabolites (L-serine and glycine) and three CpG sites located in two independent genomic regions (cg14476101 and cg16246545 in PHGDH and cg02711608 in SLC1A5) at a false discovery rate of less than 0.05. Further analysis revealed a complex bidirectional relationship between plasma glycine/serine levels and DNA methylation. Moreover, we observed a strong mediating role of DNA methylation in the effect of glycine/serine on the expression of their metabolism/transport genes, with the proportion of the mediated effect ranging from 11.8 to 54.3%. This result was also replicated in an independent population-based cohort, the Rotterdam Study. To validate our findings, we conducted in vitro cell studies which confirmed the mediating role of DNA methylation in the regulation of PHGDH gene expression.CONCLUSIONS: Our findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.PMID:39138531 | DOI:10.1186/s13148-024-01718-7

Pediatr Res. 2024 Aug 13. doi: 10.1038/s41390-024-03440-9. Online ahead of print.ABSTRACTBACKGROUND: Human milk is unquestionably beneficial for preterm infants. We investigated how the transition from tube to oral/breastfeeding impacts the preterm infants' oral and gut microbiome and metabolome.METHODS: We analyzed stool, saliva, and milk samples collected from a cohort of preterm infants enrolled in the MAP Study, a prospective observational trial. The microbiome and metabolome of the samples were analyzed from 4 longitudinal sample time points, 2 during tube feeds only and 2 after the initiation of oral/breastfeeding.RESULTS: We enrolled 11 mother-infant dyads (gestational age = 27.9 (23.4-32.2)) and analyzed a total of 39 stool, 44 saliva, and 43 milk samples over 4 timepoints. In saliva samples, there was a shift towards increased Streptococcus and decreased Staphylococcus after oral feeding/breastfeeding initiation (p < 0.05). Milk sample metabolites were strongly influenced by the route of feeding and milk type (p < 0.05) and represented the pathways of Vitamin E metabolism, Vitamin B12 metabolism, and Tryptophan metabolism.CONCLUSION: Our analysis demonstrated that the milk and preterm infant's saliva microbiome and metabolome changed over the course of the first four to 5 months of life, coinciding with the initiation of oral/breastfeeds.IMPACT: The microbiome and metabolome is altered in the infant's saliva but not their stool, and in mother's milk when feeds are transitioned from tube to oral/breastfeeding. We assessed the relationship between the gut and oral microbiome/metabolome with the milk microbiome/metabolome over a longitudinal period of time in preterm babies. Metabolites that changed in the infants saliva after the initiation of oral feeds have the potential to be used as biomarkers for disease risk.PMID:39138352 | DOI:10.1038/s41390-024-03440-9

Nat Metab. 2024 Aug 13. doi: 10.1038/s42255-024-01109-5. Online ahead of print.ABSTRACTDietary haem iron intake is linked to an increased risk of type 2 diabetes (T2D), but the underlying plasma biomarkers are not well understood. We analysed data from 204,615 participants (79% females) in three large US cohorts over up to 36 years, examining the associations between iron intake and T2D risk. We also assessed plasma metabolic biomarkers and metabolomic profiles in subsets of 37,544 (82% females) and 9,024 (84% females) participants, respectively. Here we show that haem iron intake but not non-haem iron is associated with a higher T2D risk, with a multivariable-adjusted hazard ratio of 1.26 (95% confidence interval 1.20-1.33; P for trend <0.001) comparing the highest to the lowest quintiles. Haem iron accounts for significant proportions of the T2D risk linked to unprocessed red meat and specific dietary patterns. Increased haem iron intake correlates with unfavourable plasma profiles of insulinaemia, lipids, inflammation and T2D-linked metabolites. We also identify metabolites, including L-valine and uric acid, potentially mediating the haem iron-T2D relationship, highlighting their pivotal role in T2D pathogenesis.PMID:39138340 | DOI:10.1038/s42255-024-01109-5

Leukemia. 2024 Aug 13. doi: 10.1038/s41375-024-02367-8. Online ahead of print.ABSTRACTMutations in the DNAJC21 gene were recently described in Shwachman-Diamond syndrome (SDS), a bone marrow failure syndrome with high predisposition for myeloid malignancies. To study the underlying biology in hematopoiesis regulation and disease, we generated the first in vivo model of Dnajc21 deficiency using the zebrafish. Zebrafish dnajc21 mutants phenocopy key SDS patient phenotypes such as cytopenia, reduced growth, and defective protein synthesis. We show that cytopenia results from impaired hematopoietic differentiation, accumulation of DNA damage, and reduced cell proliferation. The introduction of a biallelic tp53 mutation in the dnajc21 mutants leads to the development of myelodysplastic neoplasia-like features defined by abnormal erythroid morphology and expansion of hematopoietic progenitors. Using transcriptomic and metabolomic analyses, we uncover a novel role for Dnajc21 in nucleotide metabolism. Exogenous nucleoside supplementation restores neutrophil counts, revealing an association between nucleotide imbalance and neutrophil differentiation, suggesting a novel mechanism in dnajc21-mutant SDS biology.PMID:39138265 | DOI:10.1038/s41375-024-02367-8

Sci Rep. 2024 Aug 14;14(1):18843. doi: 10.1038/s41598-024-69507-z.ABSTRACTApplication of stable isotopically labelled (SIL) molecules in Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) over a series of time points allows the temporal and spatial dynamics of biochemical reactions to be tracked in a biological system. However, these large kinetic MSI datasets and the inherent variability of biological replicates presents significant challenges to the rapid analysis of the data. In addition, manual annotation of downstream SIL metabolites involves human input to carefully analyse the data based on prior knowledge and personal expertise. To overcome these challenges to the analysis of spatiotemporal MALDI-MSI data and improve the efficiency of SIL metabolite identification, a bioinformatics pipeline has been developed and demonstrated by analysing normal bovine lens glucose metabolism as a model system. The pipeline consists of spatial alignment to mitigate the impact of sample variability and ensure spatial comparability of the temporal data, dimensionality reduction to rapidly map regional metabolic distinctions within the tissue, and metabolite annotation coupled with pathway enrichment modules to summarise and display the metabolic pathways induced by the treatment. This pipeline will be valuable for the spatial metabolomics community to analyse kinetic MALDI-MSI datasets, enabling rapid characterisation of spatio-temporal metabolic patterns from tissues of interest.PMID:39138264 | DOI:10.1038/s41598-024-69507-z

Sci Rep. 2024 Aug 13;14(1):18768. doi: 10.1038/s41598-024-69205-w.ABSTRACTUntargeted metabolomic analysis is a powerful tool used for the discovery of novel biomarkers. Chagas disease (CD), caused by Trypanosoma cruzi, is a neglected tropical disease that affects 6-7 million people with approximately 30% developing cardiac manifestations. The most significant clinical challenge lies in its long latency period after acute infection, and the lack of surrogate markers to predict disease progression or cure. In this cross-sectional study, we analyzed sera from 120 individuals divided into four groups: 31 indeterminate CD, 41 chronic chagasic cardiomyopathy (CCC), 18 Latin Americans with other cardiomyopathies and 30 healthy volunteers. Using a high-throughput panel of 986 metabolites, we identified three distinct profiles among individuals with cardiomyopathy, indeterminate CD and healthy volunteers. After a more stringent analysis, we identified some potential biomarkers. Among peptides, phenylacetylglutamine and fibrinopeptide B (1-13) exhibited an increasing trend from controls to ICD and CCC. Conversely, reduced levels of bilirubin and biliverdin alongside elevated urobilin correlated with disease progression. Finally, elevated levels of cystathionine, phenol glucuronide and vanillactate among amino acids distinguished CCC individuals from ICD and controls. Our novel exploratory study using metabolomics identified potential biomarker candidates, either alone or in combination that if confirmed, can be translated into clinical practice.PMID:39138245 | DOI:10.1038/s41598-024-69205-w

J Agric Food Chem. 2024 Aug 13. doi: 10.1021/acs.jafc.4c03411. Online ahead of print.ABSTRACTPlant cell culture technology helps to obtain natural plant-derived metabolites. The callus of sorghum, a prominent cereal crop, possesses various metabolites with potential health benefits. However, the epigenetic mechanism regulating metabolic biosynthetic capabilities in sorghum remains unknown. Therefore, we conducted N6-methyladenine (6mA) methylome analysis using transcriptome profiling and metabolome analysis to investigate the role of 6mA alterations in two calluses having different biosynthetic capacities, which were derived from immature sorghum embryos. Our findings indicate that the 6mA upregulation within gene bodies is crucial in transcriptional activity potentially mediated by the DNA demethylase SbALKBH1. Furthermore, 6mA was significantly enriched in genes involved in the biosynthesis of flavonoids and isoflavonoids. This could serve as a novel source of bioactive compounds for human health. Thus, 6mA could play an essential role in flavonoid biosynthesis in the sorghum callus.PMID:39138187 | DOI:10.1021/acs.jafc.4c03411

J Neurosci. 2024 Aug 13:e2253232024. doi: 10.1523/JNEUROSCI.2253-23.2024. Online ahead of print.ABSTRACTFamilial dysautonomia (FD) is a rare sensory and autonomic neuropathy that results from a mutation in the ELP1 gene. Virtually all patients report gastrointestinal (GI) dysfunction and we have recently shown that FD patients have a dysbiotic gut microbiome and altered metabolome. These findings were recapitulated in an FD mouse model and moreover, the FD mice had reduced intestinal motility, as did patients. To understand the cellular basis for impaired GI function in FD, the enteric nervous system (ENS) (both female and male mice) from FD mouse models was analyzed during embryonic development and adulthood. We show here that not only is Elp1 required for the normal formation of the ENS, but it is also required in adulthood for the regulation of both neuronal and non-neuronal cells and for target innervation in both the mucosa and in intestinal smooth muscle. In particular, CGRP innervation was significantly reduced as was the number of dopaminergic neurons. Examination of an FD patient's gastric biopsy also revealed reduced and disoriented axons in the mucosa. Finally, using an FD mouse model in which Elp1 was deleted exclusively from neurons, we found significant changes to the colon epithelium including reduced E-cadherin expression, perturbed mucus layer organization and infiltration of bacteria into the mucosa. The fact that deletion of Elp1 exclusively in neurons is sufficient to alter the intestinal epithelium and perturb the intestinal epithelial barrier, highlights a critical role for neurons in regulating GI epithelium homeostasis.Significance Statement This study demonstrates the key role that ELP1 plays in ENS development and maintenance. Previously, we showed that patients with the peripheral neuropathy, familial dysautonomia (FD), and a mouse model of FD, have a dysbiotic microbiome and metabolome and impaired gut motility. FD is caused by a mutation in the gene, ELP1, which plays a critical role in modifying tRNAs and hence proteome homeostasis. Using both FD mouse models and an FD patient biopsy, we identify cellular and molecular disruptions in the ENS and intestinal epithelium that may cause the FD intestinal clinical manifestations. In addition to dysregulated neurogenesis, peripheral axons are reduced, which may underlie gut dysmotility and indirectly, lead to breaches in the epithelium barrier integrity.PMID:39138000 | DOI:10.1523/JNEUROSCI.2253-23.2024

Aging Cell. 2024 Aug 13:e14277. doi: 10.1111/acel.14277. Online ahead of print.ABSTRACTNeuronal cells are highly specialized cells and have a specific metabolic profile to support their function. It has been demonstrated that the metabolic profiles of different cells/tissues undergo significant reprogramming with advancing age, which has often been considered a contributing factor towards aging-related diseases including Alzheimer's (AD) and Parkinson's (PD) diseases. However, it is unclear if the metabolic changes associated with normal aging predispose neurons to disease conditions or a distinct set of metabolic alterations happen in neurons in AD or PD which might contribute to disease pathologies. To decipher the changes in neuronal metabolism with age, in AD, or in PD, we performed high-throughput steady-state metabolite profiling on heads in wildtype Drosophila and in Drosophila models relevant to AD and PD. Intriguingly, we found that the spectrum of affected metabolic pathways is dramatically different between normal aging, Tau, or Synuclein overexpressing neurons. Genetic targeting of the purine and glutamate metabolism pathways, which were dysregulated in both old age and disease conditions partially rescued the neurodegenerative phenotype associated with the overexpression of wildtype and mutant tau. Our findings support a "two-hit model" to explain the pathological manifestations associated with AD where both aging- and Tau/Synuclein- driven metabolic reprogramming events cooperate with each other, and targeting both could be a potent therapeutic strategy.PMID:39137949 | DOI:10.1111/acel.14277

Mol Metab. 2024 Aug 11:102005. doi: 10.1016/j.molmet.2024.102005. Online ahead of print.ABSTRACTOBJECTIVE: The mitochondrial pyruvate carrier (MPC) occupies a critical node in intermediary metabolism, prompting interest in its utility as a therapeutic target for the treatment of obesity and cardiometabolic disease. Dysregulated nutrient metabolism in adipose tissue is a prominent feature of obesity pathophysiology, yet the functional role of adipose MPC has not been explored. We investigated whether the MPC shapes the adaptation of adipose tissue to dietary stress in female and male mice.METHODS: The impact of pharmacological and genetic disruption of the MPC on mitochondrial pathways of triglyceride assembly (lipogenesis and glyceroneogenesis) was assessed in 3T3L1 adipocytes and murine adipose explants, combined with analyses of adipose MPC expression in metabolically compromised humans. Whole-body and adipose-specific glucose metabolism were subsequently investigated in male and female mice lacking adipocyte MPC1 (Mpc1AD-/-) and fed either standard chow, high-fat western style, or high-sucrose lipid restricted diets for 24 weeks, using a combination of radiolabeled tracers and GC/MS metabolomics.RESULTS: Treatment with UK5099 or siMPC1 impaired the synthesis of lipids and glycerol-3-phosphate from pyruvate and blunted triglyceride accumulation in 3T3L1 adipocytes, whilst MPC expression in human adipose tissue was negatively correlated with indices of whole-body and adipose tissue metabolic dysfunction. Mature adipose explants from Mpc1AD-/- mice were intrinsically incapable of incorporating pyruvate into triglycerides. In vivo, MPC deletion restricted the incorporation of circulating glucose into adipose triglycerides, but only in female mice fed a zero fat diet, and this associated with sex-specific reductions in tricarboxylic acid cycle pool sizes and compensatory transcriptional changes in lipogenic and glycerol metabolism pathways. However, whole-body adiposity and metabolic health were preserved in Mpc1AD-/- mice regardless of sex, even under conditions of zero dietary fat.CONCLUSION: These findings highlight the greater capacity for mitochondrially driven triglyceride assembly in adipose from female versus male mice and expose a reliance upon MPC-gated metabolism for glucose partitioning in female adipose under conditions of dietary lipid restriction.PMID:39137831 | DOI:10.1016/j.molmet.2024.102005

Cell. 2024 Aug 7:S0092-8674(24)00824-9. doi: 10.1016/j.cell.2024.07.030. Online ahead of print.ABSTRACTTumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. Engulfment of cholesterol-rich myelin debris endows subsets of TAMs to acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma.PMID:39137777 | DOI:10.1016/j.cell.2024.07.030

Cancer Cell. 2024 Aug 12;42(8):1386-1400.e8. doi: 10.1016/j.ccell.2024.07.005.ABSTRACTChanges in plasma and fecal metabolomes in colorectal cancer (CRC) progression (normal-adenoma-CRC) remain unclear. Here, plasma and fecal samples were collected from four independent cohorts of 1,251 individuals (422 CRC, 399 colorectal adenoma [CRA], and 430 normal controls [NC]). By metabolomic profiling, signature plasma and fecal metabolites with consistent shift across NC, CRA, and CRC are identified, including CRC-enriched oleic acid and CRC-depleted allocholic acid. Oleic acid exhibits pro-tumorigenic effects in CRC cells, patient-derived organoids, and two murine CRC models, whereas allocholic acid has opposing effects. By integrative analysis, we found that oleic acid or allocholic acid directly binds to α-enolase or farnesoid X receptor-1 in CRC cells, respectively, to modulate cancer-associated pathways. Clinically, we establish a panel of 17 plasma metabolites that accurately diagnoses CRC in a discovery and three validation cohorts (AUC = 0.848-0.987). Overall, we characterize metabolite signatures, mechanistic significance, and diagnostic potential of plasma and fecal metabolomes in CRC.PMID:39137727 | DOI:10.1016/j.ccell.2024.07.005

Stud Hist Philos Sci. 2024 Aug 12;107:54-63. doi: 10.1016/j.shpsa.2024.07.004. Online ahead of print.ABSTRACTEvolution requires selection. Molecular/chemical/preDarwinian evolution is no exception. One molecule must be selected over another for molecular evolution to occur and advance. Evolution, however, has no goal. The laws of physics have no utilitarian desire, intent or proficiency. Laws and constraints are blind to "usefulness." How then were potential multi-step processes anticipated, valued and pursued by inanimate nature? Can orchestration of formal systems be physico-chemically spontaneous? The purely physico-dynamic self-ordering of Chaos Theory and irreversible non-equilibrium thermodynamic "engines of disequilibria conversion" achieve neither orchestration nor formal organization. Natural selection is a passive and after-the-fact-of-life selection. Darwinian selection reduces to the differential survival and reproduction of the fittest already-living organisms. In the case of abiogenesis, selection had to be 1) Active, 2) Pre-Function, and 3) Efficacious. Selection had to take place at the molecular level prior to the existence of non-trivial functional processes. It could not have been passive or secondary. What naturalistic mechanisms might have been at play?PMID:39137534 | DOI:10.1016/j.shpsa.2024.07.004