Explore the vast range of titles available.

Metabolomics enables the comprehensive profiling of cellular metabolites at the systems level, thereby providing a direct readout of biochemical activity that can be correlated with phenotype and used to identify therapeutic targets. Although several challenges remain to be addressed, emerging mass spectrometric and bioinformatic technologies have already proven to be effective tools for diagnostics and for providing insights into cell metabolism. Metabolites, the chemical entities that are transformed during metabolism, provide a functional readout of cellular biochemistry. With emerging technologies in mass spectrometry, thousands of metabolites can now be quantitatively measured from minimal amounts of biological material, which has thereby enabled systems-level analyses. By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanism are being revealed and are shaping our understanding of cell biology, physiology and medicine.

Background Pathway enrichment techniques are useful for understanding experimental metabolomics data. Their purpose is to give context to the affected metabolites in terms of the prior knowledge contained in metabolic pathways. However, the interpretation of a prioritized pathway list is still challenging, as pathways show overlap and cross talk effects. Results We introduce FELLA, an R package to perform a network-based enrichment of a list of affected metabolites. FELLA builds a hierarchical representation of an organism biochemistry from the Kyoto Encyclopedia of Genes and Genomes (KEGG), containing pathways, modules, enzymes, reactions and metabolites. In addition to providing a list of pathways, FELLA reports intermediate entities (modules, enzymes, reactions) that link the input metabolites to them. This sheds light on pathway cross talk and potential enzymes or metabolites as targets for the condition under study. FELLA has been applied to six public datasets –three from Homo sapiens , two from Danio rerio and one from Mus musculus – and has reproduced findings from the original studies and from independent literature. Conclusions The R package FELLA offers an innovative enrichment concept starting from a list of metabolites, based on a knowledge graph representation of the KEGG database that focuses on interpretability. Besides reporting a list of pathways, FELLA suggests intermediate entities that are of interest per se. Its usefulness has been shown at several molecular levels on six public datasets, including human and animal models. The user can run the enrichment analysis through a simple interactive graphical interface or programmatically. FELLA is publicly available in Bioconductor under the GPL-3 license.

NAD + is a vital redox cofactor and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Supplementation with NAD + precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), protects against metabolic disease, neurodegenerative disorders and age-related physiological decline in mammals. Here we show that nicotinamide riboside kinase 1 (NRK1) is necessary and rate-limiting for the use of exogenous NR and NMN for NAD + synthesis. Using genetic gain- and loss-of-function models, we further demonstrate that the role of NRK1 in driving NAD + synthesis from other NAD + precursors, such as nicotinamide or nicotinic acid, is dispensable. Using stable isotope-labelled compounds, we confirm NMN is metabolized extracellularly to NR that is then taken up by the cell and converted into NAD + . Our results indicate that mammalian cells require conversion of extracellular NMN to NR for cellular uptake and NAD + synthesis, explaining the overlapping metabolic effects observed with the two compounds. Raising cellular levels of the metabolic cofactor NAD + reverses key indicators of aging. Here, Ratajczak et al . show that cellular levels of NAD + depend on the extracellular catalytic activity of NRK1, which processes two NAD + precursors, nicotinamide mononucleotide and nicotinamide riboside, in mice.

Matrix‐assisted laser desorption/ionisation mass spectrometry imaging (MALDI–MSI) has become a pivotal tool in biomedical research, enabling untargeted, spatially resolved analysis of molecular species in complex biological tissues. Among the critical steps in MALDI–MSI workflows, matrix deposition significantly influences sensitivity, spatial resolution and reproducibility by affecting crystal morphology and analyte extraction efficiency. While wet deposition techniques, such as manual spray‐coating, electrospray deposition and automated systems, have been widely adopted, they often suffer from limitations related to solvent‐induced analyte delocalisation. These challenges have driven increasing interest in dry matrix deposition methods, which aim to eliminate or minimise solvent use to enhance spatial fidelity and image quality. This review summarises the main dry deposition strategies used in MALDI–MSI, covering their principles, instrumentation, benefits and limitations. It also discusses recent comparative studies (2023–2025) between wet and dry approaches, examining their impact on analytical performance and the increasing importance of dry deposition in high‐resolution spatial omics.

Metabolism is vital to every aspect of cell function, yet the metabolome of induced pluripotent stem cells （iPSCs） remains largely unexplored. Here we report, using an untargeted metabolomics approach, that human iPSCs share a pluripotent metabolomic signature with embryonic stem cells （ESCs） that is distinct from their parental cells, and that is characterized by changes in metabolites involved in cellular respiration. Examination of cellular bioenergetics corroborated with our metabolomic analysis, and demonstrated that somatic cells convert from an oxidative state to a glycolytic state in pluripotency. Interestingly, the bioenergetics of various somatic cells correlated with their repro- gramming efficiencies. We further identified metabolites that differ between iPSCs and ESCs, which revealed novel metabolic pathways that play a critical role in regulating somatic cell reprogramming. Our findings are the first to globally analyze the metabolome of iPSCs, and provide mechanistic insight into a new layer of regulation involved in inducing pluripotency, and in evaluating iPSC and ESC equivalence.

Metabolomics analysis of stem cells and differentiated cells points to chemical unsaturation as a key feature of stem cell metabolites. Manipulation of these metabolites' concentrations directly influences stem cell behavior, highlighting biological oxidation as a driver for differentiation. Metabolites offer an important unexplored complementary approach to understanding the pluripotency of stem cells. Using MS-based metabolomics, we show that embryonic stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. By monitoring the reduced and oxidized glutathione ratio as well as ascorbic acid levels, we demonstrate that the stem cell redox status is regulated during differentiation. On the basis of the oxidative biochemistry of the unsaturated metabolites, we experimentally manipulated specific pathways in embryonic stem cells while monitoring the effects on differentiation. Inhibition of the eicosanoid signaling pathway promoted pluripotency and maintained levels of unsaturated fatty acids. In contrast, downstream oxidized metabolites (for example, neuroprotectin D1) and substrates of pro-oxidative reactions (for example, acyl-carnitines), promoted neuronal and cardiac differentiation. We postulate that the highly unsaturated metabolome sustained by stem cells allows them to differentiate in response to in vivo oxidative processes such as inflammation.

Background Measured exhaled volatile organic compounds (VOCs) in breath also referred to as exhaled volatilome have been long claimed as a potential source of non-invasive and clinically applicable biomarkers. However, the feasibility of using exhaled volatilome in clinical practice remains to be demonstrated, particularly in pediatrics where the need for improved non-invasive diagnostic and monitoring methods is most urgent. This work presents the first formal evidence-based judgment of the clinical potential of breath volatilome in the pediatric population. Methods A rigorous systematic review across Web of Science, SCOPUS, and PubMed databases following the PRISMA statement guidelines. A narrative synthesis of the evidence was conducted and QUADAS-2 was used to assess the quality of selected studies. Results Two independent reviewers deemed 22 out of the 229 records initially found to satisfy inclusion criteria. A summary of breath VOCs found to be relevant for several respiratory, infectious, and metabolic pathologies was conducted. In addition, we assessed their associated metabolism coverage through a functional characterization analysis. Conclusion Our results indicate that current research remains stagnant in a preclinical exploratory setting. Designing exploratory experiments in compliance with metabolomics practice should drive forward the clinical translation of VOCs breath analysis. Impact What is the key message of your article? Metabolomics practice could help to achieve the clinical utility of exhaled volatilome analysis. What does it add to the existing literature? This work is the first systematic review focused on disease status discrimination using analysis of exhaled breath in the pediatric population. A summary of the reported exhaled volatile organic compounds is conducted together with a functional characterization analysis. What is the impact? Having noted challenges preventing the clinical translation, we summary metabolomics practices and the experimental designs that are closer to clinical practice to create a framework to guide future trials.

Background Succinate is produced by both human cells and by gut bacteria and couples metabolism to inflammation as an extracellular signaling transducer. Circulating succinate is elevated in patients with obesity and type 2 diabetes and is linked to numerous complications, yet no studies have specifically addressed the contribution of gut microbiota to systemic succinate or explored the consequences of reducing intestinal succinate levels in this setting. Results Using germ-free and microbiota-depleted mouse models, we show that the gut microbiota is a significant source of circulating succinate, which is elevated in obesity. We also show in vivo that therapeutic treatments with selected bacteria diminish the levels of circulating succinate in obese mice. Specifically, we demonstrate that Odoribacter laneus is a promising probiotic based on its ability to deplete succinate and improve glucose tolerance and the inflammatory profile in two independent models of obesity ( db/db mice and diet-induced obese mice). Mechanistically, this is partly mediated by the succinate receptor 1. Supporting these preclinical findings, we demonstrate an inverse correlation between plasma and fecal levels of succinate in a cohort of patients with severe obesity. We also show that plasma succinate, which is associated with several components of metabolic syndrome including waist circumference, triglycerides, and uric acid, among others, is a primary determinant of insulin sensitivity evaluated by the euglycemic-hyperinsulinemic clamp. Conclusions Overall, our work uncovers O. laneus as a promising next-generation probiotic to deplete succinate and improve glucose tolerance and obesity-related inflammation. 3xBZTCGcPCuPE54e-xtBbB Video Abstract

Untargeted metabolomics reveals a dysregulation of sphingolipid production during neuropathic pain exemplified by N , N -dimethylsphingosine, whose upregulation is involved in the generation of pain. Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its chemical basis. We show by using untargeted metabolomics that sphingomyelin-ceramide metabolism is altered in the dorsal horn of rats with neuropathic pain and that the upregulated, endogenous metabolite N,N -dimethylsphingosine induces mechanical hypersensitivity in vivo. These results demonstrate the utility of metabolomics to implicate unexplored biochemical pathways in disease.

Key nuclear processes in eukaryotes, including DNA replication, repair, and gene regulation, require extensive chromatin remodeling catalyzed by energy-consuming enzymes. It remains unclear how the ATP demands of such processes are met in response to rapid stimuli. We analyzed this question in the context of the massive gene regulation changes induced by progestins in breast cancer cells and found that ATP is generated in the cell nucleus via the hydrolysis of poly(ADP-ribose) to ADP-ribose. In the presence of pyrophosphate, ADP-ribose is used by the pyrophosphatase NUDIX5 to generate nuclear ATP. The nuclear source of ATP is essential for hormone-induced chromatin remodeling, transcriptional regulation, and cell proliferation.