PubMed

Front Bioinform. 2025 Mar 10;5:1513790. doi: 10.3389/fbinf.2025.1513790. eCollection 2025.ABSTRACTBACKGROUND: Parkinson's disease is a complex, age-related, neurodegenerative disease associated with dopamine deficiency and both motor and nonmotor deficits. Therapeutic pathways remain challenging in Parkinson's disease due to the low accuracy of early diagnosis, the difficulty in monitoring disease progression, and the limited availability of treatment options.OBJECTIVES: Few data are present to identify urinary biomarkers for various ailments, potentially aiding in the diagnosis and tracking of illness progression in individuals with Parkinson's disease. Thus, the analysis of urinary metabolomic biomarkers (UMB) for early and mid-stage idiopathic Parkinson's disease (IPD) is the main goal of this systematic review.METHODS: For this study, six electronic databases were searched for articles published up to 23 February 2024: PubMed, Ovid Medline, Embase, Scopus, Science Direct, and Cochrane. 5,377 articles were found and 40 articles were screened as per the eligibility criteria. Out of these, 7 controlled studies were selected for this review. Genetic profiling for gene function and biomarker interactions between urinary biomarkers was conducted using the STRING and Cytoscape database.RESULTS: A total of 40 metabolites were identified to be related to the early and mid-stage of the disease pathology out of which three metabolites, acetyl phenylalanine (a subtype of phenylalanine), tyrosine and kynurenine were common and most significant in three studies. These metabolites cause impaired dopamine synthesis along with mitochondrial disturbances and brain energy metabolic disturbances which are considered responsible for neurodegenerative disorders. Furoglycine, Cortisol, Hydroxyphenylacetic acid, Glycine, Tiglyglycine, Aminobutyric acid, Hydroxyprogesterone, Phenylacetylglutamine, and Dihydrocortisol were also found commonly dysregulated in two of the total 7 studies. 158 genes were found which are responsible for the occurrence of PD and metabolic regulation of the corresponding biomarkers from our study.CONCLUSION: The current review identified acetyl phenylalanine (a subtype of phenylalanine), tyrosine and kynurenine as potential urinary metabolomic biomarkers for diagnosing PD and identifying disease progression.PMID:40130009 | PMC:PMC11931117 | DOI:10.3389/fbinf.2025.1513790

Food Sci Nutr. 2025 Mar 24;13(4):e70075. doi: 10.1002/fsn3.70075. eCollection 2025 Apr.ABSTRACTAlthough Psidium cattleianum (strawberry guava, Myrtaceae) is known for its anti-inflammatory, antioxidant, antimicrobial, and antidiabetic properties, its phytochemical profile and associated bioactivities remain largely underexplored. This study employed UHPLC-QTOF-HRMS for untargeted phenolic profiling of leaf and fruit extracts from P. cattleianum, followed by semi-quantification of phenolic subclasses and multivariate data analysis. Four hundred sixty-nine metabolites, including various phenolic subclasses-predominantly flavonoids and phenolic acids were- identified and annotated. Using HEK-293 cells stably transfected with TRPA1 or TRPV1 cation channels, it was found that both leaf and fruit extracts activate and rapidly desensitize TRPA1 in a concentration-dependent manner (EC50 18 and 30 μg/mL; IC50 60 and 47 μg/mL, respectively). Additionally, molecular docking analysis provided deeper insights into the interactions between P. cattleianum phytochemicals and the TRPA1 cation channel, identifying theaflavin 3,3'-O-digallate as the phenolic compound with the highest affinity (S score of -9.27 Kcal/mol). Interestingly, except for theaflavin 3,3'-O-digallate, compounds enriched in the leaf extract exhibited weaker binding interactions and lower S scores (approximately -7 Kcal/mol) compared to those enriched in the fruit extract. Also, a 100 ns molecular dynamics study of theaflavin 3,3'-O-digallate with TRAP1 demonstrated high binding stability of the complex. Overall, this study offers valuable insights into the phytochemical characteristics of P. cattleianum extracts and reveals their mechanism of action through affinity for the TRPA1 cation channel-receptors.PMID:40129993 | PMC:PMC11931593 | DOI:10.1002/fsn3.70075

Front Immunol. 2025 Mar 10;16:1530098. doi: 10.3389/fimmu.2025.1530098. eCollection 2025.ABSTRACTINTRODUCTION: Cordyceps militaris extract (CME) and cordycepin (CPN) are biomolecules with a wide range of biological activities, including anti-inflammatory, antioxidant and anti-tumour effects. The research objective wasto investigate the influences of CME and cordycepin CPN on colonic morphology, microbiota composition and colonic metabolomics in lipopolysaccharide (LPS)-challenged piglets.METHODS: Twenty-four weaned castrated piglets were randomly divided into four groups: control group (fed basal diets), LPS group (fed basal diets), CPN-LPS group (basal diets + 60 mg/kg cordycepin), and CME-LPS group (basal diets + 60 mg/kg C. militarisextract). On the 21st day, the LPS, CPN-LPS, and CME-LPS groups received an injection of 100 μg/kg BW LPS, while the control group was given sterile saline.RESULTS: The findings demonstrated that CPN or CME attenuated intestinal morphology damage with LPS-challenged piglets. CPN and CME alleviated intestinal microbiota dysbiosis and metabolic disorders under LPS-challenged by enriching serum protein levels, regulating of inflammatory cytokine secretion and altering colonic microbial composition. Colonic microbiota analysis that the CPN improved the relative abundance of Acidobacteriota and inhibited Faecalibacterium, CME promoted the relative abundance of Prevotella and Lachnospiraceae NK4A136group. Meanwhile, the alleviation of colonic damage is achieved through modulation of metabolic pathways linked to tryptophan metabolism, biosynthesis of amino acids and butanoate metabolism.DISCUSSION: Conclusively, our preliminary findings reveal that CPN or CME could serve as a beneficial dietary supplement to alleviate gut diseases in weaning piglets.PMID:40129987 | PMC:PMC11931037 | DOI:10.3389/fimmu.2025.1530098

Front Immunol. 2025 Mar 10;16:1475160. doi: 10.3389/fimmu.2025.1475160. eCollection 2025.ABSTRACTINTRODUCTION: Lipid profiles change in human immunodeficiency virus (HIV) infection and correlate with inflammation. Lipidomic alterations are impacted by multiple non-HIV-related behavioral risk factors; thus, use of animal models in which these behavioral factors are controlled may inform on the specific lipid changes induced by simian immunodeficiency virus (SIV) infection and/or antiretroviral therapy (ART).METHODS: Using ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy, we assessed and compared (ANOVA) longitudinal lipid changes in naïve and ART-treated SIV-infected pigtailed macaques (PTMs). Key parameters of infection (IL-6, TNFa, D-dimer, CRP and CD4+ T cell counts) were correlated (Spearman) with lipid concentrations at critical time points of infection and treatment.RESULTS: Sphingomyelins (SM) and lactosylceramides (LCER) increased during acute infection, returning to baseline during chronic infection; Hexosylceramides (HCER) increased throughout infection, being normalized with prolonged ART; Phosphatidylinositols (PI) and lysophosphatidylcholines (LPC) decreased with SIV infection and did not return to normal with ART; Phosphatidylethanolamines (PE), lysophosphatidylethanolamines (LPE) and phosphatidylcholines (PC) were unchanged by SIV infection, yet significantly decreased throughout ART. Specific lipid species (SLS) were also substantially modified by SIV and/or ART in most lipid classes. In conclusion, using a metabolically controlled model, we identified specific lipidomics signatures of SIV infection and/or ART, some of which were similar to people living with HIV (PWH). Many SLS were identical to those involved in development of organ dysfunctions encountered in virally suppressed individuals. Lipid changes also correlated with markers of disease progression, inflammation and coagulation.DISCUSSION: Our data suggest that lipidomic profile alterations contribute to residual systemic inflammation and comorbidities seen in HIV/SIV infections and therefore may be used as biomarkers of SIV/HIV comorbidities. Further exploration into the benefits of interventions targeting dyslipidemia is needed for the prevention HIV-related comorbidities.PMID:40129985 | PMC:PMC11931036 | DOI:10.3389/fimmu.2025.1475160

Front Pharmacol. 2025 Mar 10;16:1503785. doi: 10.3389/fphar.2025.1503785. eCollection 2025.ABSTRACTIntroduction: Polygonatum cyrtonema Hua (PC) is an essential herbal medicine in China, known for improving muscle quality and enhancing physical function; its active ingredients are polysaccharides (PCPs). A previous study revealed the anti-atrophy effects of PCPs in cachectic mice. However, whether the effects of PCPs on anti-atrophy are associated with gut microenvironment remain elusive. This research endeavored to assess the medicinal efficacy of PCPs in alleviating muscle atrophy and fat lipolysis and explore the potential mechanisms. Methods: A cancer cachexia model was induced by male C57BL/6 mice bearing Lewis lung tumor cells and chemotherapy. The pharmacodynamics of PCPs (32 and 64 mg/kg/day) was investigated through measurements of tumor-free body weight, gastrocnemius muscle weight, soleus muscle weight, epididymal fat weight, tissue histology analysis, and pro-inflammatory cytokines. Immunohistochemistry and Western blotting assays were further used to confirm the effects of PCPs. 16S rRNA sequencing, LC-MS and GC-MS-based metabolomics were used to analyze the gut microbiota composition and metabolite alterations. Additionally, the agonist of free fatty acid receptor 2 (FFAR2)-a crucial short-chain fatty acid (SCFA) signaling molecule-was used to investigate the role of gut microbiota metabolites, specifically SCFAs, in the treatment of cancer cachexia, with comparisons to PCPs. Results: This study demonstrated that PCPs significantly mitigated body weight loss, restored muscle fiber atrophy and mitochondrial disorder, alleviated adipose tissue wasting, strengthened the intestinal barrier integrity, and decreased the intestinal inflammation in chemotherapy-induced cachexia. Furthermore, the reversal of specific bacterial taxa including Klebsiella, Akkermansia, norank_f__Desulfovibrionaceae, Enterococcus, NK4A214_group, Eubacterium_fissicatena_group, Eubacterium_nodatum_group, Erysipelatoclostridium, Lactobacillus, Monoglobus, Ruminococcus, Odoribacter, and Enterorhabdus, along with alterations in metabolites such as amino acids (AAs), eicosanoids, lactic acid and (SCFAs), contributed to the therapeutic effects of PCPs. Conclusion: Our findings suggest that PCPs can be used as prebiotic drugs targeting the microbiome-metabolomics axis in cancer patients undergoing chemotherapy.PMID:40129936 | PMC:PMC11931129 | DOI:10.3389/fphar.2025.1503785

Front Neurol. 2025 Mar 10;16:1535136. doi: 10.3389/fneur.2025.1535136. eCollection 2025.ABSTRACTPostherpetic neuralgia (PHN), a representative type of neuropathic pain, has attracted much research on its diagnosis and therapy at the molecular level. Interestingly, this study based on the brain-gut axis provided a novel point of view to interpret the mechanism of PHN. Past neuroanatomical and neuroimaging studies of pain suggest that the prefrontal cortex, anterior cingulate cortex, amygdala, and other regions of the brain may play crucial roles in the descending inhibition of PHN. Dominant bacterial species in patients with PHN, such as Lactobacillus, generate short-chain fatty acids, including butyrate. Evidence indicates that disturbance of some metabolites (such as butyrate) is closely related to the development of hyperalgesia. In addition, tryptophan and 5-HT in the intestinal tract act as neurotransmitters that regulate the descending transmission of neuropathic pain signals. Concurrently, the enteric nervous system establishes close connections with the central nervous system through the vagus nerve and other pathways. This review aims to investigate and elucidate the molecular mechanisms associated with PHN, focusing on the interplay among PHN, the gut microbiota, and relevant metabolites while scrutinizing its pathogenesis.PMID:40129863 | PMC:PMC11932021 | DOI:10.3389/fneur.2025.1535136

Front Neurosci. 2025 Mar 10;19:1498981. doi: 10.3389/fnins.2025.1498981. eCollection 2025.ABSTRACTMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS), and Fibromyalgia (FM) are complex, chronic illnesses with overlapping clinical features. Symptoms that are reported across these conditions include post-exertional malaise (PEM), fatigue, and pain, yet the etiology of these illnesses remains largely unknown. Diagnosis is challenging in patients with these conditions as definitive biomarkers are lacking; patients are required to meet clinical criteria and often undergo lengthy testing to exclude other conditions, a process that is often prolonged, costly, and burdensome for patients. The identification of reliable validated biomarkers could facilitate earlier and more accurate diagnosis and drive the development of targeted pharmacological therapies that might address the underlying pathophysiology of these diseases. Major driving forces for biomarker identification are the advancing fields of metabolomics and proteomics that allow for comprehensive characterization of metabolites and proteins in biological specimens. Recent technological developments in these areas enable high-throughput analysis of thousands of metabolites and proteins from a variety of biological samples and model systems, that provides a powerful approach to unraveling the metabolic phenotypes associated with these complex diseases. Emerging evidence suggests that ME/CFS, GWS, and FM are all characterized by disturbances in metabolic pathways, particularly those related to energy production, lipid metabolism, and oxidative stress. Altered levels of key metabolites in these pathways have been reported in studies highlighting potential common biochemical abnormalities. The precise mechanisms driving altered metabolic pathways in ME/CFS, GWS, and FM remain to be elucidated; however, the elevated oxidative stress observed across these illnesses may contribute to symptoms and offer a potential target for therapeutic intervention. Investigating the mechanisms, and their role in the disease process, could provide insights into disease pathogenesis and reveal novel treatment targets. As such, comprehensive metabolomic and proteomic analyses are crucial for advancing the understanding of these conditions in-order to identify both common, and unique, metabolic alterations that could serve as diagnostic markers or therapeutic targets.PMID:40129725 | PMC:PMC11931034 | DOI:10.3389/fnins.2025.1498981

J Mol Cell Cardiol Plus. 2025 Mar 1;11:100290. doi: 10.1016/j.jmccpl.2025.100290. eCollection 2025 Mar.ABSTRACTHeart failure (HF) remains a major cause of morbidity and mortality worldwide and represents a major challenge for diagnosis, prognosis and treatment due to its heterogeneity. Traditional biomarkers such as BNP and NT-proBNP are valuable but insufficient to capture the complexity of HF, especially phenotypes such as HF with preserved ejection fraction (HFpEF). Recent advances in multi-omics technology and novel biomarkers such as cell-free DNA (cfDNA), microRNAs (miRNAs), ST2 and galectin-3 offer transformative potential for HF management. This review explores the integration of these innovative biomarkers into clinical practice and highlights their benefits, such as improved diagnostic accuracy, enhanced risk stratification and non-invasive monitoring capabilities. By leveraging multi-omics approaches, including lipidomics and metabolomics, clinicians can uncover new pathways, refine the classification of HF phenotypes, and develop personalized therapeutic strategies tailored to individual patient profiles. Remarkable advances in proteomics and metabolomics have identified biomarkers associated with key HF mechanisms such as mitochondrial dysfunction, inflammation and fibrosis, paving the way for targeted therapies and early interventions. Despite the promising results, significant challenges remain in translating these findings into routine care, including high costs, technical limitations and the need for large-scale validation studies. This report argues for an integrative, multi-omics-based model to overcome these obstacles and emphasizes the importance of collaboration between researchers, clinicians and policy makers. By linking innovative science with practical applications, multi-omics approaches have the potential to redefine HF management and lead to better patient outcomes and more sustainable healthcare systems.PMID:40129519 | PMC:PMC11930597 | DOI:10.1016/j.jmccpl.2025.100290

Environ Sci Technol. 2025 Mar 25. doi: 10.1021/acs.est.4c10717. Online ahead of print.ABSTRACTPregnancy is a potential critical window to air pollution exposure for long-term maternal metabolic effects. However, little is known about potential early metabolic mechanisms linking air pollution to maternal metabolic health. We included 544 pregnant Mexican women with both ambient PM2.5 levels during pregnancy and untargeted serum metabolomics to examine associations between pregnancy PM2.5 exposure (overall and monthly) and postpartum metabolites, implementing FDR-adjusted robust linear regression controlling for covariates. Pathway enrichment analyses (in Reactome and MetaboAnalyst) and effect modification by fetal sex and folic acid supplementation were also evaluated. Higher PM2.5 exposure levels throughout pregnancy were associated with higher bile acids and amino acids, dysregulated glycerophospholipids, or lower fatty acyl levels (FDR < 0.05), among other metabolites. Potential critical windows of susceptibility to monthly PM2.5 on metabolites were observed in early to midpregnancy (FDR < 0.005). Main findings were consistent by strata of fetal sex and folic acid supplementation. Metabolic pathways corresponding to positive PM2.5-metabolite associations indicated enriched bile acid, dietary lipid, and transmembrane transport metabolism, whereas for negative PM2.5-metabolite associations, we identified altered pathways involving adipogenesis, incretin peptide hormone, GLP-1, PPAR-alpha, and fatty acid receptors (FDR < 0.05). PM2.5 exposures during pregnancy, especially in early gestation, altered maternal postpartum lipids as well as amino acid metabolism.PMID:40129413 | DOI:10.1021/acs.est.4c10717

J Proteome Res. 2025 Mar 25. doi: 10.1021/acs.jproteome.5c00017. Online ahead of print.ABSTRACTHuman cytomegalovirus (HCMV) is the leading cause of congenital infections resulting in severe morbidity and mortality among newborns worldwide. Currently, the most significant prognostic factor of congenital cytomegalovirus (cCMV) infection is the time of maternal infection, with a more severe clinical phenotype if the mother's first outbreak occurs during the first trimester of pregnancy. Nonetheless, the pathogenesis of cCMV infection has still to be completely characterized. In particular, little is known about the metabolic response triggered by HCMV in congenitally infected newborns. As such, urinary metabolic profiling by 1H nuclear magnetic resonance (NMR) might represent a promising tool to be exploited in the context of cCMV. This study aims to investigate the impact of HCMV infection on the urine metabolome in a population of congenitally infected newborns and uninfected controls by 1H NMR spectroscopy combined with multivariate statistical analysis. The 1H NMR spectra of patients (n = 35) and controls (n = 15) allowed the identification of an overall amount of 55 metabolites. Principal Component Analysis (PCA) and clustering correctly assigned 49 out of 50 newborns into the infected and control groups. Partial Least-Squares-Discriminant Analysis (PLS-DA) revealed that newborns with cCMV resulted in having increased betaine, citrate, 3-hydroxybutyrate, 4-hydroxybutyrate, acetoacetate, formate, glycolate, lactate, succinate, and threonine levels in the urine. On the other hand, healthy controls showed increased 4-aminohippurate, creatine, creatinine, fumarate, mannitol, taurine, and dimethylamine levels. These results showed a clear difference in metabolomic fingerprint between newborns with cCMV infection and healthy controls. Thus, metabolomics can be considered a new, promising diagnostic and prognostic tool in the clinical management of cCMV patients.PMID:40129280 | DOI:10.1021/acs.jproteome.5c00017

Biomed Chromatogr. 2025 May;39(5):e70026. doi: 10.1002/bmc.70026.ABSTRACTHoneybran-fried Cimicifuga Rhizoma (HBCR) is often used to treat prolonged diarrhea and prolapse of the anus, uterine prolapse, and gastric ptosis caused by spleen qi deficiency and the inability to elevate qi, and thus the lowering of middle qi. Rats were divided randomly into four groups. Fecal samples of rats in each group were subjected to metabolomics analysis. We identified the chemical components of HBCR using liquid chromatography-tandem mass spectrometry. We predicted the potential active components and key targets of HBCR using network pharmacology to construct a "drug-potential active ingredient-target-disease" network. The key targets screened by network pharmacology and differential metabolites screened by metabolomics analysis were subjected to combined pathway analysis. Pharmacodynamic indices showed that HBCR had a good therapeutic effect upon IBS-D. Metabolomics analysis revealed 26 differential metabolites in the treatment of IBS-D by HBCR. A total of 69 chemical components were identified, and 32 potential active components and 296 key targets were screened. Combination of metabolomics analysis and network pharmacology for joint pathway analysis revealed that the therapeutic effect of HBCR may be affected by the metabolism of linoleic acid, retinol, arachidonic acid, and tryptophan. HBCR had significant therapeutic effects in rats with IBS-D.PMID:40129176 | DOI:10.1002/bmc.70026

Int Wound J. 2025 Apr;22(4):e70158. doi: 10.1111/iwj.70158.ABSTRACTMass spectrometry is increasingly utilised in medicine to identify and quantify small biomarkers for diagnostic and prognostic purposes. Conventional mass spectrometry, however, requires time-consuming sample preparation, hindering its clinical application. Direct sampling mass spectrometry, which allows for direct analysis of patient samples with minimal preparation, offers potential for clinical use. This systematic review examines the utility of direct sampling mass spectrometry for the assessment of external wounds and explores its translational applications in wound care. Out of 2 930 screened abstracts, six studies were included employing various direct sampling mass spectrometry technologies. These studies focused on burn wounds (n = 3), pressure ulcers (n = 2), and acute surgical wounds (n = 1). Both targeted and untargeted molecular profiling methods were used to examine biomarkers related to inflammatory and healing processes, including various proteins, lipid species, and other metabolites. Direct sampling mass spectrometry was found to complement conventional methods such as histology, providing additional insights into the spatial localisation and accumulation of metabolites within wounds. Additionally, imaging techniques equipped with this technology can spatially map wound surfaces and reveal dynamic changes in wounds as they age or progress through different healing processes, with specific metabolite and protein accumulations potentially aiding in prognostication.PMID:40129114 | DOI:10.1111/iwj.70158

Aging Cell. 2025 Mar 24:e14465. doi: 10.1111/acel.14465. Online ahead of print.ABSTRACTCaloric restriction is associated with slow aging in model organisms. Additionally, some drugs have also been shown to slow aging in rodents. To better understand metabolic mechanisms that are involved in increased lifespan, we analyzed metabolomic differences in six organs of 12-month-old mice using five interventions leading to extended longevity, specifically caloric restriction, 17-α estradiol, and caloric restriction mimetics rapamycin, canagliflozin, and acarbose. These interventions generally have a stronger effect in males than in females. Using Jonckheere's trend test to associate increased average lifespans with metabolic changes for each sex, we found sexual dimorphism in metabolism of plasma, liver, gastrocnemius muscle, kidney, and inguinal fat. Plasma showed the strongest trend of differentially expressed compounds, highlighting potential benefits of plasma in tracking healthy aging. Using chemical set enrichment analysis, we found that the majority of these affected compounds were lipids, particularly in male tissues, in addition to significant differences in trends for amino acids, which were particularly apparent in the kidney. We also found strong metabolomic effects in adipose tissues. Inguinal fat exhibited surprising increases in neutral lipids with polyunsaturated side chains in male mice. In female mice, gonadal fat showed trends proportional to lifespan extension effect across multiple lipid classes, particularly phospholipids. Interestingly, for most tissues, we found similar changes induced by lifespan-extending interventions to metabolomic differences between untreated 12-month-old mice and 4-month-old mice. This finding implies that lifespan-extending treatments tend to reverse metabolic phenotypes to a biologically younger stage.PMID:40129070 | DOI:10.1111/acel.14465

J Neurochem. 2025 Mar;169(3):e70042. doi: 10.1111/jnc.70042.ABSTRACTUnderstanding the molecular basis of the structural organization of the human brain may shed light on its functional mechanism. We present spatial lipidomics analysis of human brain sections containing neocortical gray matter and two white matter regions representing two axonal tracks: the cingulum bundle and the corpus callosum. Using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) we identify lipid composition differences not only between gray and white matter but also between two axonal tracks. Results, obtained with the MALDI-MSI method, correlated with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis of these brain regions, with Spearman's correlation coefficient equal to 0.48 (the cingulum bundle vs. gray matter), 0.47 (the corpus callosum vs. gray matter), 0.33 (the cingulum bundle vs. the corpos callosum) on 75 lipids annotated in both experiments. Using UPLC-MS/MS analysis, we further identified specific lipid classes that distinguished the two white matter regions (CL, PG, LPE), while gray and white matter comparison yielded well-established differences in lipid composition between myelin-rich and myelin poor regions (CL, DG, Cholesterol). Our findings highlight the significance of in-depth molecular analysis of brain regions and enhance our comprehension of the brain's molecular composition.PMID:40129064 | DOI:10.1111/jnc.70042

Skelet Muscle. 2025 Mar 25;15(1):9. doi: 10.1186/s13395-025-00377-3.ABSTRACTBACKGROUND: Exercising with low muscle glycogen content can improve training adaptation, but the mechanisms underlying the muscular adaptation are still largely unknown. In this study, we measured substrate utilization and cell signaling in different muscle fiber types during exercise and investigated a possible link between these variables.METHODS: Five subjects performed a single leg cycling exercise in the evening (day 1) with the purpose of reducing glycogen stores. The following morning (day 2), they performed two-legged cycling at ∼70% of VO2peak for 1 h. Muscle biopsies were taken from both legs pre- and post-exercise for enzymatic analyses of glycogen, metabolite concentrations using LC-MS/MS-based quantification, and protein signaling using Western blot in pools of type I or type II fibers.RESULTS: Glycogen content was 60-65% lower for both fiber types (P < 0.01) in the leg that exercised on day 1 (low leg) compared to the other leg with normal level of glycogen (normal leg) before the cycling exercise on day 2. Glycogen utilization during exercise was significantly less in both fiber types in the low compared to the normal leg (P < 0.05). In the low leg, there was a 14- and 6-fold increase in long-chain fatty acids conjugated to carnitine in type I and type II fibers, respectively, post-exercise. This increase was 3-4 times larger than in the normal leg (P < 0.05). Post-exercise, mTORSer2448 phosphorylation was increased in both fiber types in the normal leg (P < 0.05) but remained unchanged in both fiber types in the low leg together with an increase in eEF2Thr56 phosphorylation in type I fibers (P < 0.01). Exercise induced a reduction in the autophagy marker LC3B-II in both fiber types and legs, but the post-exercise level was higher in both fiber types in the low leg (P < 0.05). Accordingly, the LC3B-II/I ratio decreased only in the normal leg (75% for type I and 87% for type II, P < 0.01).CONCLUSIONS: Starting an endurance exercise session with low glycogen availability leads to profound changes in substrate utilization in both type I and type II fibers. This may reduce the mTORC1 signaling response, primarily in type I muscle fibers, and attenuate the normally observed reduction in autophagy.PMID:40128889 | DOI:10.1186/s13395-025-00377-3

BMC Biol. 2025 Mar 24;23(1):85. doi: 10.1186/s12915-025-02167-1.ABSTRACTBACKGROUND: Sperm metabolic pathways that generate energy for motility are compartmentalized within the flagellum. Dysfunctions in metabolic compartments, namely mitochondrial respiration and glycolysis, can compromise motility and male fertility. Studying these compartments is thus required for fertility treatment. However, it is very challenging to capture images of metabolic compartments in motile spermatozoa because the fast beating of the flagellum introduces motion blur. Therefore, most approaches immobilize spermatozoa prior to imaging.RESULTS: Our findings indicate that immobilizing sperm alters their metabolic profile, highlighting the necessity for measuring metabolism in spermatozoa during movement. We achieved this by encapsulating mouse epididymis in a hydrogel followed by two-photon fluorescence lifetime imaging microscopy for imaging motile sperm in situ. The autofluorescence of endogenous metabolites-FAD, NADH, and NADPH-enabled us to visualize sperm metabolic compartments without staining. We trained machine learning for automated image segmentation and generated metabolic fingerprints using object-based phasor analysis. We show that metabolic fingerprints of spermatozoa and the mitochondrial compartment (1) can distinguish individual males by genetic background, age, or fecundity status, (2) correlate with fertility, and (3) change with age likely due to increased oxidative metabolism.CONCLUSIONS: Our approach eliminates the need for sperm immobilization and labeling and captures the native state of sperm metabolism. This technique could be adapted for metabolism-based sperm selection for assisted reproduction.PMID:40128804 | DOI:10.1186/s12915-025-02167-1

Nat Commun. 2025 Mar 24;16(1):2749. doi: 10.1038/s41467-025-57683-z.ABSTRACTRed blood cell development from erythroid progenitors requires profound reshaping of metabolism and gene expression. How these transcriptional and metabolic alterations are coupled is unclear. Nprl3 (an inhibitor of mTORC1) has remained in synteny with the α-globin genes for >500 million years, and harbours most of the a-globin enhancers. However, whether Nprl3 serves an erythroid role is unknown. We found that while haematopoietic progenitors require basal Nprl3 expression, erythroid Nprl3 expression is further boosted by the α-globin enhancers. This lineage-specific upregulation is required for sufficient erythropoiesis. Loss of Nprl3 affects erythroblast metabolism via elevating mTORC1 signalling, suppressing autophagy and disrupting glycolysis. Broadly consistent with these murine findings, human NPRL3-knockout erythroid progenitors produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Therefore, we propose that the anciently conserved linkage of NprI3, α-globin and their associated enhancers has coupled metabolic and developmental control of erythropoiesis.PMID:40128524 | DOI:10.1038/s41467-025-57683-z

Nat Food. 2025 Mar 24. doi: 10.1038/s43016-025-01148-5. Online ahead of print.ABSTRACTAccording to existing food processing classification systems, plant-based protein-rich (PBPR) foods are often considered 'ultra-processed'-and therefore perceived as unhealthy-despite their ability to provide various bioactive compounds beneficial for human health. Here we used a non-targeted metabolomics approach to analyse the impact of processing on the biochemical composition of PBPR foods. Our results show that existing food classification systems may provide questionable categories for PBPR foods without considering their overall biochemical composition, including phytochemicals. An analysis focusing specifically on biochemical compounds of soy-based products manufactured using various technologies showed no clear distinctions between processing groups in the principal component analysis based on the NOVA and Poti classification. However, clear differences were found between soy-based products based on their phytochemical profile. Although food processing classification systems are welcome in their attempt to guide consumers towards healthy choices, they should be improved to more accurately reflect the biochemical composition of PBPR foods.PMID:40128334 | DOI:10.1038/s43016-025-01148-5

J Ethnopharmacol. 2025 Mar 24:119657. doi: 10.1016/j.jep.2025.119657. Online ahead of print.NO ABSTRACTPMID:40128138 | DOI:10.1016/j.jep.2025.119657

J Proteome Res. 2025 Mar 24. doi: 10.1021/acs.jproteome.4c00863. Online ahead of print.ABSTRACTPulmonary embolism (PE) is a life-threatening disease. Our aim was to search for potential biomarkers by using modern high-throughput metabolomics methods to improve diagnostic efficacy. The discovery cohort included 60 participants, including 30 PE patients and 30 healthy individuals. The validation cohort included 40 participants, including 20 PE patients and 20 healthy individuals. Gas chromatography-mass spectrometry (GC-MS) was combined with multivariate data analysis to determine serum metabolic profiles in patients with PE and healthy controls. The distribution of metabolic profiles in the two cohorts was assessed by unsupervised principal component analysis (PCA) and supervised partial least-squares discriminant analysis (PLS-DA). Sixteen metabolites were initially selected from the ranked variable of predictive importance (VIP) scores and applied to the correlation analysis of PE-related clinical indicators. Four metabolites that were correlated with D-dimer levels were selected, including l-tryptophan, N-alpha-acetyl-l-lysine, dopamine, and N2-acetylornithine. Finally, the AUC values were calculated to be 0.958 (95% CI: 0.9072-1) for the combined biomarker panel, including the 4 specific metabolites in the discovery cohort, and 0.963 (95% CI: 0.9122-1) in the validation cohort. The results suggest that these four specific metabolites can be used as diagnostic biomarkers to improve diagnostic efficacy in pulmonary embolism.PMID:40128110 | DOI:10.1021/acs.jproteome.4c00863