PubMed
Recent developments in spatial proteomics with MALDI mass spectrometry imaging: a journey toward clinical adoption
Expert Rev Proteomics. 2025 Jul 19. doi: 10.1080/14789450.2025.2537212. Online ahead of print.NO ABSTRACTPMID:40682383 | DOI:10.1080/14789450.2025.2537212
Metabolomic profile in preschool children with transient wheezing and early onset asthma
Allergol Immunopathol (Madr). 2025 Jul 1;53(4):153-156. doi: 10.15586/aei.v53i4.1327. eCollection 2025.ABSTRACTINTRODUCTION: Early diagnosis of childhood asthma is a challenge; so we questioned whether metabolomic analysis could differentiate persistent recurrent wheezing from transient wheezing in preschoolers.METHODS: Case-control study with individuals aged 4-6 years and 11 months with three or more episodes of wheezing due to bronchospasm was carried out in an allergy outpatient clinic and metabolomics laboratory from July 2021 to February 2023. Two groups were formed: persistent wheezers with multiple trigger attacks after the fourth year of life; and transient wheezers without wheezing for at least 12 months after the third year of life. Those with other wheezing disorders were excluded.RESULTS: This study was carried out on 29 children with a mean age of 4.9 (±0.6) years-19 (65%) persistent wheezers and 10 (35%) transient wheezers. Sensitization to aeroallergens and the positive asthma predictive index were significantly higher among persistent wheezers. From the plasma hydrogen-1 NMR (1H NMR) spectra, five best subsets were selected to discriminate between the two groups with an accuracy rate of 93.1%. Among the metabolites, valine and citrate showed higher signals and lipids and lipoproteins were higher in persistent wheezers.PMID:40682243 | DOI:10.15586/aei.v53i4.1327
Early prediction of gestational diabetes mellitus based on systematically selected multi-panel biomarkers and clinical accessibility-a longitudinal study of a multi-racial pregnant cohort
BMC Med. 2025 Jul 18;23(1):430. doi: 10.1186/s12916-025-04258-w.ABSTRACTBACKGROUND: Early identification of high-risk women is critical for preventing gestational diabetes mellitus (GDM). We aimed to improve early prediction of GDM using multiple panels of cardiometabolic biomarkers assessed in early and mid-pregnancy, considering clinical accessibility.METHODS: In a US study of 2802 pregnant individuals, we assessed 91 cardiometabolic biomarkers at 10-14 (random blood) and 15-26 (fasting) gestational weeks (GW) in 107 GDM cases and 214 controls. Candidate biomarkers were categorized by clinical accessibility from high to low: group I (clinically accessible tests like HbA1c, lipids), group II (clinically accessible biomarkers upon request like insulin-like growth factor (IGF) axis markers, adipokines), and group III (specialty lab-required targeted metabolomics: amino acids (AAs) and phospholipid fatty acids (FAs)). At each visit, we constructed a full model incorporating all candidate biomarkers and conventional predictors. We built alternative models utilizing different groups of biomarkers considering clinical accessibility. Variable selection was performed to retain variables with a p value < 0.10 for a parsimonious model. Model performance was evaluated by area under receiver operating characteristics curve (AUC), proportion of cases followed (PCF, %) and proportion needed to follow (PNF, %), and decision curve analysis.RESULTS: A full model comprising conventional predictors, clinical and non-clinical cardiometabolic biomarkers, and metabolomic markers achieved the highest discriminative accuracy (AUC: 0.842 at 10-14 GW, 0.829 at 15-26 GW). The addition of novel biomarkers increased PCF and decreased PNF, suggesting increased clinical utility. For example, at 10-14 GW, 69.5% of GDM cases are expected to be detected from women whose risk is above the 80% percentile estimated by the full model vs. 49.1% by the conventional model. Additionally, 46.1% of women identified as being at the highest risk by the full model are expected to account for 90.0% of GDM cases vs. 71.1% by the conventional model. Decision curve analysis showed that models incorporating novel biomarkers performed better than the conventional model including glucose, and the full model at 10-14 GW had the highest net benefit, overall.CONCLUSIONS: This study suggested that a selected panel of cardiometabolic biomarkers using early-pregnancy random plasma samples predicted GDM comparably to those using mid-pregnancy fasting samples.PMID:40682053 | DOI:10.1186/s12916-025-04258-w
Integrated volatile metabolomic and transcriptomic analysis provides insights into the regulation of odor components between two Ferula species
BMC Plant Biol. 2025 Jul 19;25(1):928. doi: 10.1186/s12870-025-06969-x.ABSTRACTBACKGROUND: Ferula (Apiaceae), a genus of perennial herbs with significant medicinal and culinary value, derives its characteristic odor primarily from volatile organic compounds (VOCs), particularly volatile sulfur compounds (VSCs) and terpenoids. Despite their economic importance, two critical gaps hinder targeted utilization: Ferula species-specific VOCs remains undocumented, and the metabolic pathways and key genes of VSCs and terpenoids in Ferula are still unclear.RESULTS: Volatile metabolomic and transcriptomic analyses were performed on two species of Ferula-viz., Ferula sinkiangensis K. M. Shen (XJ, strong odor) and Ferula ferulaeoides (Steud.) Korov (DS, bland odor). A total of 561 VOCs were annotated, with VSCs dominating XJ (45.98%) and terpenoids prevailing in DS (44.01%). The results VSCs were the primary source of the strong odor in XJ. In total, 42,817 differentially expressed genes (DEGs) were identified between XJ and DS in this study. KEGG pathway enrichment analysis of DEGs revealed significant divergence in the biosynthetic pathways of VSCs and terpenoids between the two Ferula species. Integrative multi-omics analysis identified 87 genes linked to VSC biosynthesis and 54 regulatory genes governing terpenoid production. In XJ, elevated accumulation of VSCs was mechanistically associated with the synergistic upregulation of glutamate-cysteine ligase (GSH), γ-glutamyltransferase (GGT), and flavin monooxygenase (FMO). High levels of VSCs precursors (e.g., S-allyl-L-cysteine sulfoxide) and transcriptional activation of these genes strongly correlated with the species-specific pungent odor profile. In DS, geranylgeranyl diphosphate synthase (GGPS) and farnesyl pyrophosphate synthase (FDPS) were identified as key regulators of terpenoid biosynthesis.CONCLUSIONS: The present study expands our knowledge of the volatile metabolic profiles of the two Ferula species and lays the foundation for further studies on the regulatory mechanisms of Ferula quality.PMID:40682024 | DOI:10.1186/s12870-025-06969-x
Associations between circulating metabolites and pca: a bidirectional two-sample Mendelian randomization study
Discov Oncol. 2025 Jul 18;16(1):1370. doi: 10.1007/s12672-025-03204-9.ABSTRACTBACKGROUND: Prostate cancer (PCa) remains the most prevalent cancer among male globally. Despite the critical role of genetic factors in PCa pathogenesis, recent advances in metabolomics have highlighted the significant contributions of circulating metabolites to genetic risk profiles for PCa. However, the causal relationship between metabolites and PCa is not yet unclear.METHODS: We utilized a bidirectional two-sample Mendelian randomization (MR) approach, analyzing metabolite datasets from the Canadian Longitudinal Study of Aging (CLSA), the Cooperative Health Research in the Region of Augsburg (KORA) study, and the TwinsUK study and PCa dataset from the Oncoarray. Replication analyses were performed with the UK Biobank. Instrumental variables (IVs) were selected based on established MR criteria and analyzed using methods including the Wald ratio, inverse-variance weighted (IVW), MR-Egger, and weighted median. To ensure robustness, sensitivity analyses were performed using Cochrane's Q, Egger's intercept, MR-PRESSO, and leave-one-out (LOO) methods.RESULTS: We identified causal relationships between circulating metabolites and PCa risk. After removing high influential SNPs and outliers and reanalysis, we obtained the levels of N6-carbamoylthreonyladenosine (OR 0.61, 95% CI 0.37-1.01, p = 0.054) and 4-ethylphenylsulfate (OR 0.66, 95% CI 0.47-0.92, p = 0.015) causally associated with PCa. All results passed FDR correction; 4-ethylphenylsulfate also remained significant after Bonferroni adjustment. Reverse MR analysis highlighted robust causal relationships of PCa to homovanillate (OR 1.07, 95% CI 1.03-1.10, p = 5.49 × 10 - 5) and X-12,627 (OR 1.03, 95% CI 1.01-1.04, p = 7.54 × 10-5) levels.CONCLUSION: These insights underscore the etiology and risk factors of PCa, providing genetic evidence for the development of therapeutic targets and contributing to elucidating disease mechanisms, suggesting potential diagnostic biomarkers.PMID:40681942 | DOI:10.1007/s12672-025-03204-9
Metabolomic Profiling for Predicting Coronary Artery Aneurysms and IVIG Resistance in Kawasaki Disease- An Exploratory Study
J Cardiovasc Transl Res. 2025 Jul 18. doi: 10.1007/s12265-025-10648-5. Online ahead of print.ABSTRACTWe investigated the metabolomic profile of Kawasaki disease(KD) and its association with the development of coronary artery aneurysms (CAA) and resistance to intravenous immunoglobulin(IVIG) therapy. Metabolomic profiling was performed on 26 patients with KD. A total of 44 metabolites-including 12 amino acids, L-carnitine, and 31 acylcarnitines-were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) after IVIG administration. Methylglutarylcarnitine, a medium-chain acylcarnitine, was identified as a differentially expressed metabolite in KD patients with CAA. Additionally, C2, C3, C14, C16, C16OH, C18:2, and C18:2OH were differentially expressed between IVIG-resistant and IVIG-responsive patients. Pathway analysis using the KEGG database revealed that arginine biosynthesis and alanine, aspartate, and glutamate metabolism were among the most affected pathways in KD patients with CAA. This study demonstrated several differentially expressed metabolites in KD patients with CAA and IVIG resistance. These findings provide new insights into the metabolic pathways underlying KD complications.PMID:40681906 | DOI:10.1007/s12265-025-10648-5
PNPLA7 mediates Parkin-mitochondrial recruitment in adipose tissue for mitophagy and inhibits browning
Nat Commun. 2025 Jul 19;16(1):6651. doi: 10.1038/s41467-025-61904-w.ABSTRACTPINK1/Parkin-mediated ubiquitin-dependent mitophagy is a critical negative regulatory machinery for browning in the inguinal white adipose tissue (iWAT). However, the precise regulatory mechanism underlying PINK1/Parkin-mediated mitophagy during browning of iWAT remains largely unknown. Here we report that PNPLA7, an Endoplasmic Reticulum and mitochondria-associated membrane (MAM) protein, inhibits browning of iWAT by promoting PINK1/Parkin-mediated mitophagy upon cold challenge or β3-adrenergic receptor agonist treatment. With genetic manipulation in mice, we show that adipose tissue overexpressing PNPLA7 induces mitophagy, abolishes iWAT browning and interrupts adaptive thermogenesis. Conversely, conditional ablation of PNPLA7 in adipose tissue promotes browning of iWAT, resulting in enhanced adaptive thermogenesis. Mechanistically, PNPLA7 interacts with Parkin to promote mitochondrial recruitment of Parkin for mitophagy activation and mitochondria degradation by disrupting PKA-induced phosphorylation of Parkin under cold challenge. Taken together, our findings suggest that PNPLA7 is a critical regulator of mitophagy that resists cold-induced browning of iWAT, thus providing a direct mechanistic link between mitophagy and browning of iWAT.PMID:40681495 | DOI:10.1038/s41467-025-61904-w
PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease
Clin Transl Med. 2025 Jul;15(7):e70404. doi: 10.1002/ctm2.70404.ABSTRACTBACKGROUND: Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual-extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles-respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.METHODS: We used a mouse model for mitochondrial myopathy ("deletor"), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.RESULTS: In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.CONCLUSIONS: Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.PMID:40681476 | DOI:10.1002/ctm2.70404
Letter: Differentiating Between Atopic Dermatitis and Non-Atopic Eczema Using Metabolomics
Dermatitis. 2025 Jul 18. doi: 10.1177/17103568251360263. Online ahead of print.NO ABSTRACTPMID:40681327 | DOI:10.1177/17103568251360263
Multi-omics reveals manure-borne doxycycline and fragmented oversized microplastics co-disrupt pak choi growth and amplify antibiotic resistance in agroecosystems
Environ Pollut. 2025 Jul 16:126832. doi: 10.1016/j.envpol.2025.126832. Online ahead of print.ABSTRACTThe intensification of livestock farming and plastic consumption has led to widespread co-contamination of agricultural soils with veterinary antibiotics (e.g., doxycycline, DOX) and microplastics (MPs). This study employed an integrative multi-omics approach (transcriptomics, metabolomics, microbiome analysis, qPCR) to investigate the synergistic effects of fragmented oversized microplastics (OMPs; 5-20 mm) and manure-borne DOX on pak choi growth and antibiotic resistance gene (ARG) dissemination in a realistic rhizobox system simulating manure-amended soil. We observed that co-exposure to DOX and OMPs significantly reduced pak choi biomass by approximately 29% compared to controls. This co-exposure induced synergistic stress responses, altering root transcriptomes and causing metabolic disturbances in both plants and rhizosphere soil. Crucially, OMPs acted as "dual carriers", not only concentrating DOX but also facilitating ARG dissemination. Co-exposure amplified total ARG abundance in rhizosphere soil by 2.8-fold and implicated key hosts like Lysobacter for tetracycline ARGs. Furthermore, microbial community restructuring occurred, marked by a decline in beneficial taxa like Pseudomonas and an increase in potentially detrimental genera like Brevundimonas. These findings demonstrate intricate synergistic interactions where OMPs enhance DOX bioavailability, exacerbating phytotoxicity and ARG spread. This poses significant risks to crop productivity and environmental health. Our results underscore the critical need for long-term monitoring, pre-treatment of manure to remove plastics/antibiotics and adoption of biodegradable mulches, among other measures, to ensure sustainable agriculture and mitigate public health risks.PMID:40681073 | DOI:10.1016/j.envpol.2025.126832
The synergistic regulatory mechanism of SmPAL1 and its interacting protein SmRCA in promoting the accumulation of phenolic compounds and inhibiting the synthesis of terpenoids
Int J Biol Macromol. 2025 Jul 16:146108. doi: 10.1016/j.ijbiomac.2025.146108. Online ahead of print.ABSTRACTThis study investigates the synergistic regulatory mechanisms of SmPAL1 and its interacting protein SmRCA in Salvia miltiorrhiza, a medicinal plant known for its phenolic acid and terpenoid compounds. SmPAL1, identified as a "valve" key regulatory gene, plays a key role in phenolic acid biosynthesis. Using gene editing, metabolomic, and transcriptomic analyses, we explored the impact of SmPAL1 on metabolic pathways in transgenic hairy roots. The results revealed that overexpression of SmPAL1 significantly enhances the accumulation of phenolic compounds while inhibiting terpenoid synthesis. Additionally, we identified SmRCA, an interacting protein with SmPAL1, which negatively regulates its activity. This interaction was confirmed through yeast two-hybrid, BiFC, and GST pull-down assays. Our findings demonstrate that SmPAL1 and SmRCA jointly regulate primary and secondary metabolism in S. miltiorrhiza. The study provides a foundation for metabolic engineering aimed at increasing the production of valuable phenolic compounds in this medicinal plant, highlighting the potential for improving its medicinal properties through targeted genetic modifications.PMID:40680965 | DOI:10.1016/j.ijbiomac.2025.146108
Pinto bean supplementation modulates gut microbiota and improves markers of gut integrity in a mouse model of estrogen deficiency
J Nutr. 2025 Jul 16:S0022-3166(25)00431-6. doi: 10.1016/j.tjnut.2025.07.008. Online ahead of print.ABSTRACTBACKGROUND: Emerging research suggests that changes in gut microbiota play a key role in menopause-related diseases by modulating gut health.OBJECTIVE: This study investigated the effects of pinto bean (PB) supplementation on gut integrity in an estrogen-deficient mouse model.METHODS: Sixty 3-m-old female C57BL/6J mice were injected with either sesame oil (vehicle) or vinylcyclohexene diepoxide (VCD, 160 mg/kg) for 30 d to induce estrogen deficiency. Mice were then randomly assigned to two dietary groups (n=15/group): control (AIN-93M) or AIN-93M + 10% (wt/wt) PB for 16 wks. Ovarian failure was confirmed by uterine weight and serum FSH. Gut health was assessed by measuring tight junction proteins, β-glucuronidase activity, short-chain fatty acids (SCFAs), and 16S microbiota composition. PB was evaluated for its estrogenic effects by molecular docking analysis of the identified polyphenols against ER-α and ER-β. Data were analyzed by 2-way ANOVA, with estrogen status (VCD) and diet as factors followed by post hoc tests when significant (P<0.05) interaction effect was observed.RESULTS: VCD significantly (PVCD< 0.05) reduced relative uterine weight (∼35%) and increased serum FSH (∼60%), confirming estrogen reduction. PB restored jejunal Cldn1 (Pdiet x VCD<0.05) in VCD-treated mice and significantly increased (Pdiet=0.010) β-glucuronidase activity (∼25%). PB enriched some beneficial bacteria genera (i.e., Bifidobacterium, Bacteroides, Dubosiella and Lactobacillus) and increased fecal acetic, propionic, n-butyric and total SCFAs by 2-fold compared to those on the control diet. Molecular docking analysis identified sinapic and ferulic acid as phytoestrogens in PB with high binding affinity for estrogen receptors.CONCLUSIONS: PB supplementation improves gut microbial diversity and integrity in estrogen deficiency, offering potential benefits for menopause-related gut health.PMID:40680856 | DOI:10.1016/j.tjnut.2025.07.008
Mitochondrial cardiovascular diseases: molecular mechanisms, multi-omics exploration and therapeutic strategies
J Adv Res. 2025 Jul 16:S2090-1232(25)00546-6. doi: 10.1016/j.jare.2025.07.021. Online ahead of print.ABSTRACTBACKGROUND: Recent research highlights that abnormal mitochondrial function is a key feature in several cardiovascular diseases (CVDs), including aortic dissection, aortic aneurysm, atherosclerosis, pulmonary hypertension, and heart failure. We propose a novel concept termed mitochondrial cardiovascular diseases (Mito-CVDs) to define these conditions, which involve heart and vascular disorders directly driven by mitochondrial impairments, with the aim of highlighting the critical role of mitochondria in CVDs.AIM OF REVIEW: This review aims to explore the complex relationship between mitochondrial impairments and Mito-CVDs, offering insights into potential molecular mechanisms and therapeutic strategies to address these diseases.KEY SCIENTIFIC CONCEPTS OF REVIEW: The role of mitochondrial impairments in CVDs is expounded upon in detail, encompassing aspects such as excessive production of Reactive Oxygen Species (ROS), diminished Oxidative Phosphorylation (OXPHOS) capacity, and perturbations in Ca2+ transport. We also recapitulate the application of mitochondrial multi-omics, incorporating genomics, transcriptomics, proteomics, and metabolomics, within the realm of CVDs research. Additionally, single-cell mtDNA sequencing technology unfolds novel vistas for disclosing mitochondrial heterogeneity and status functional in Mito-CVDs. To enhance the understanding of Mito-CVDs, we present advanced diagnostic tools and categorize specific subtypes within each class of these disorders. Additionally, we propose Predictive, Preventive, and Personalized Medicine (PPPM) strategies designed to address mitochondrial impairments. Emerging therapeutic approaches are also discussed, including small-molecule modulators targeting key metabolic pathways, precision-based mtDNA editing technologies, and mitochondrial transplantation. A profound and exhaustive analysis of the mechanisms and therapeutic avenues associated with Mito-CVDs holds the potential to engender novel perspectives and opportunities for the prevention and treatment of CVDs.PMID:40680831 | DOI:10.1016/j.jare.2025.07.021
Synthetic microbial community mimicking kefir for investigating community dynamics and interspecies interactions
Int J Food Microbiol. 2025 Jul 15;442:111345. doi: 10.1016/j.ijfoodmicro.2025.111345. Online ahead of print.ABSTRACTKefir grains serve as natural dairy starter cultures, surviving in high-altitude environments with low temperatures and limited oxygen, while maintaining robust fermentation capabilities. In this study, we reconstructed a synthetic microbial community (SMC) within the kefir microbial ecosystem and explored the strategies that keep this SMC stable and functioning within the complex environment. We investigated the interactions among kefir species by comparing their symbiotic capabilities, milk acidification properties, and fermentation profiles during growth in both individual cultures and co-cultures across various media. Additionally, to deepen our understanding of system-level responses within the SMC, we integrated metabolomics with pure culture techniques to elucidate the mechanisms that enable coexistence among SMC members. The composition of the SMC in fermented milk was determined through co-cultivation assessments and flavor profile analysis, which identified the key members as Lactobacillus kefiranofaciens CZ22, Lactococcus lactis CZ19, and Saccharomyces cerevisiae Y8. The fermented milk produced by SMC shared identical volatile compound profiles with traditional kefir milk, including seven alcohols, seven aldehydes, six ketones, five esters, two carboxylic acids, two ethers, one acyl compound, and five miscellaneous volatile compounds. Our findings revealed that the coexistence mechanism among these three species is based on cross-feeding interactions. Lc. lactis CZ19 provides L. kefiranofaciens CZ22 with amino acids such as tyrosine, proline, and arginine, promoting its growth. Moreover, S. cerevisiae Y8 supplies primary metabolic products, including purines, pyrimidines, and nucleotides, to L. kefiranofaciens CZ22, facilitating the coexistence of all three species. During the fermentation process of the SMC, L. kefiranofaciens CZ22 maintained high abundance and accelerated acidification and enhanced flavor volatiles in milk. The SMC we constructed effectively maintained the core kefir species and fermentation performance of kefir starter cultures, simplified the complex fermentation system and laid the groundwork for the modernization and improvement of the production process. This study systematically elucidates the coexistence strategies employed by synthetic microbial systems in fermented milk production, while enhancing our understanding of microbial interactions in traditional fermented foods.PMID:40680682 | DOI:10.1016/j.ijfoodmicro.2025.111345
Mitochondrial metabolism reprogramming-mediated cardiomyocyte senescence involved in arsenic stress-evoked heart failure
Environ Int. 2025 Jul 14;202:109686. doi: 10.1016/j.envint.2025.109686. Online ahead of print.ABSTRACTChronic exposure to environmental inorganic arsenic is associated with cardiotoxicity, but the underlying mechanisms remain poorly understood. This study investigated how arsenite disrupts mitochondrial metabolism, focusing on the tricarboxylic acid (TCA) cycle, and its role in cardiomyocyte senescence and dysfunction. Proteomics and metabolomics analysis revealed that environmental arsenic exposure altered mitochondrial electron transport chain (ETC) proteins and impaired key enzymes in the TCA cycle, including citrate synthase and succinate dehydrogenase. In vivo drinking exposure to environmental arsenite for six months significantly downregulated mitochondrial metabolic enzymes, leading to disruptions in energy metabolism and cardiac aging. In vitro experiments using AC16 human cardiomyocytes confirmed that environmental arsenite exposure induced early senescence, characterized by increased expression of the aging-related marker CDKN1A and the cardiac injury marker NPPB. Even sub-cytotoxic doses of arsenite impaired mitochondrial TCA cycle function before inducing senescence and injury. Dietary supplementation with nicotinamide mononucleotide (NMN) in vivo and administration with NMN in vitro mitigated cardiomyocyte senescence-associated secretory phenotype and heart failure, suggesting that cardiac aging plays a central role in arsenic-induced functional impairment. Treatment with the mitochondrial antioxidant Mito-TEMPO alleviated these effects, restoring TCA cycle enzyme activity, reducing senescence, and improving cardiomyocyte function across multiple cell generations. These findings suggest that mitochondrial metabolic reprogramming plays a central role in environmental stressor arsenite-induced cardiomyocyte aging and identify mitochondrial metabolism as a potential target to mitigate arsenic-induced cardiac dysfunction.PMID:40680680 | DOI:10.1016/j.envint.2025.109686
Oxymatrine for treating atopic dermatitis: Network pharmacology, bioinformatics, metabolomics, and experimental validation
Int Immunopharmacol. 2025 Jul 17;163:115243. doi: 10.1016/j.intimp.2025.115243. Online ahead of print.ABSTRACTBACKGROUND: Sophora flavescens Aiton is among the most used herbs for atopic dermatitis (AD). However, the therapeutic effect of oxymatrine (OMT), one of the main active components of Sophora flavescens Aiton, on AD and its mechanism of action remain unclear.METHODS: To investigate the anti-AD effects of OMT, we used a Cavia porcellus model of AD induced by 2,4-Dinitrochlorobenzene (DNCB) or Ovalbumin (OVA). In both DNCB- and OVA-induced Cavia porcellus, we assessed the total dermatitis score and performed histopathology and evaluated immune cell factors to gauge the anti-AD activity. To further explore the mechanism of action of OMT in AD treatment, we combined bioinformatics and network pharmacology with plasma metabolomics analysis.RESULTS: In DNCB-induced and OVA-induced Cavia porcellus, OMT showed potent anti-atopic activity, including reduction of AD-like skin lesions and inhibition of inflammatory cytokine expression. Metabolic profiles revealed significant changes in lipid, histidine, and glutathione metabolism, which are related to inflammation, during OMT treatment in AD. Through bioinformatics analysis and network pharmacology, we identified 12 common targets among the potential 489 CE-related genes, 2513 immunity-related genes, and 477 OMT targets. The enrichment analysis of GO and KEGG pathways for the common targets revealed that they were mainly enriched in the IL-2, IL-17, IL-10, IL-4, and IL-13 signaling pathways as well as pathways related to neutrophil degranulation and Th1 and Th2 cell differentiation. These signaling pathways are closely linked to mast cell degranulation. In the RBL-2H3 cell degranulation model, OMT inhibited the levels of inflammatory cytokines, β-hexosaminidase, histamine, and Ca2+levels in a dose-dependent manner.CONCLUSIONS: OMT inhibits mast cell degranulation and decreases the release of inflammatory factors, including histamine, LTB4, β-aminohexylglucosidase, IL-2, IL-4, and IL-13, for treating AD.PMID:40680609 | DOI:10.1016/j.intimp.2025.115243
Mapping the metabolic perturbations associated with palmitate-induced oxidative stress and development of insulin resistance in skeletal muscle cells
Biophys Chem. 2025 Jul 9;326:107490. doi: 10.1016/j.bpc.2025.107490. Online ahead of print.ABSTRACTThe development of insulin resistance (IR) in the skeletal muscle has been identified as one of the hallmarks of Type 2 diabetes mellitus (T2DM). Studies have shown that palmitic acid (PA), a saturated free fatty acid (FFA), can contribute to the development of IR in various insulin-responsive tissues via the induction of oxidative stress and mitochondrial dysfunction. The specific molecular mechanisms and metabolic changes that lead to IR development are not completely defined, and a better understanding of these mechanisms is needed. Our study aims to identify metabolites linked with the development of IR in skeletal muscles using PA and map the major metabolic pathways involved. Rat-derived L6 myotubes were exposed to PA to establish IR. Cellular and biochemical experiments were performed, and the metabolic perturbations associated with the induction of oxidative stress and IR were identified using 1H NMR-based metabolomics. PA exposure was associated with a loss of cellular viability due to lipid accumulation in the myotubes. This was associated with an induction of oxidative stress, loss of function, and reduced mitochondrial membrane potential. The metabolic fingerprint linked with the development of oxidative stress and IR in skeletal muscles was identified, wherein significant perturbations in the levels of methanol, dimethylamine, serine, lysine, proline, glycerol, and alanine (p < 0.05) were observed. The dysregulated metabolites and pathways identified in this study can be proposed as biomarkers for detecting palmitate-induced oxidative stress and development of IR in the skeletal myotubes - phenotypes associated with T2DM and related metabolic disorders.PMID:40680601 | DOI:10.1016/j.bpc.2025.107490
Diagnostic biomarkers for Sepsis and septic shock: A NMR based serum metabolomics study
Biophys Chem. 2025 Jul 9;326:107491. doi: 10.1016/j.bpc.2025.107491. Online ahead of print.ABSTRACTDespite the availability of advanced treatment, sepsis and septic shock have the highest mortality in the intensive care unit. Theories suggested that targeting hyper inflammation can aid treatment, but oxidative stress plays a major role in disease pathogenesis. The present study aimed to explore the nuclear magnetic resonance (NMR) - based serum biomarkers of sepsis and septic shock resultant of oxidative stress. The serum metabolic profile of n = 41 septic shock, n = 21 sepsis, and n = 16 disease control patients were collected and analyzed using a 1D 1H Carr Purcell Meiboom Gill (CPMG) pulse program. NMR spectroscopy-based quantitative assessment of metabolites was performed to compare the activity of lactate dehydrogenase and phenylalanine hydroxylase between sepsis, septic shock, and disease control in sepsis and septic shock by comparing pyruvate/lactate (Pyr/Lac) and phenylalanine/tyrosine (Phe/Tyr) ratios. These ratios were evaluated for their discriminatory potential, statistical and clinical significance. We found out that Pyr/Lac ratio was lowest in septic shock followed by sepsis and disease control, Phe/Tyr ratio was highest in septic shock, followed by sepsis and disease control. Pyr/Lac ratio and Phe/Tyr were negatively and positively correlated with APACHE II. Both the ratios illustrated high discriminatory potential in AUROC evaluation. The results presented in the study demonstrate that lactate dehydrogenase activity is elevated and phenylalanine hydroxylase declines in septic shock. This could be used as an effective tool for diagnosis, prognosis, evaluation of disease activity, and treatment response.PMID:40680600 | DOI:10.1016/j.bpc.2025.107491
Coupling countercurrent chromatography to mass spectrometry to resolve natural products complex mixtures
J Chromatogr A. 2025 Jul 14;1758:466222. doi: 10.1016/j.chroma.2025.466222. Online ahead of print.ABSTRACTCountercurrent chromatography coupled with mass spectrometry (CCC-MS) has become a powerful tool for analysing complex natural product mixtures. This method provides high resolution, minimal sample loss, and versatility for both preparative and analytical applications. CCC, a liquid-liquid chromatography technique, excels in managing the inherent complexity of metabolomes, while MS offers sensitive detection and structural elucidation. The evolution of CCC-MS has faced early challenges, particularly regarding interfacing and ionisation efficiency. However, its development has propelled advancements such as reduced-pressure ionisation methods (e.g., ESI, APCI) and offline hyphenation strategies. Recent applications have demonstrated its effectiveness in metabolite profiling, isolating target compounds, and bio-guided fractionation, which contribute to the discovery of novel metabolites and their biological activities. Despite ongoing challenges in data analysis, improvements in data processing tools and molecular networking platforms are enhancing compound annotation and discovery. Overall, CCC-MS continues to be a critical asset in natural product research, providing valuable insights into the structural diversity of bioactive compounds.PMID:40680449 | DOI:10.1016/j.chroma.2025.466222
c-Myc promotes metabolic reprogramming in pulmonary hypertension via the stimulation of glutaminolysis and the reductive tricarboxylic acid cycle
Redox Biol. 2025 Jul 9;85:103765. doi: 10.1016/j.redox.2025.103765. Online ahead of print.ABSTRACTEndothelial cell (EC) dysfunction is key in initiating and progressing pulmonary hypertension (PH). EC dysfunction in PH leads to hyperproliferation and vascular remodeling of the pulmonary blood vessels. Increased glutaminolysis and altered cellular metabolism are pivotal in hyperproliferative cancer cells. However, whether a similar enhancement in glutamine metabolism is involved in the EC hyperproliferation and if this contributes to vascular remodeling during PH development is unresolved and was the focus of our study. Metabolic flux analysis showed elevated glutaminolysis and enhanced metabolic flux through the reductive tricarboxylic acid (TCA) cycle in pulmonary arterial ECs isolated from an ovine experimental model of PH (PH-PAECs). PH-PAECs also exhibited increased c-Myc protein levels, a master regulator of glutaminolysis. Therefore, we assessed the effect of increased c-Myc expression on metabolic reprogramming, glutaminolysis, and proliferation in control PAECs. Results from a comprehensive snapshot metabolomics investigation and metabolic flux analysis confirmed the reprogramming of mitochondrial metabolism, enhanced glutamine metabolism, and increased glycolysis in c-Myc overexpressing PAECs. Additionally, c-Myc overexpression impacted the ATP production rate, disrupted mitochondrial respiration, increased reactive oxygen species production, induced cell proliferation, and suppressed apoptosis. Functionally, these metabolic changes suppressed nitric oxide (NO) production. We also demonstrate that a small-molecule c-Myc inhibitor, 10058-F4, attenuates glutaminolysis, suppresses the reverse TCA cycle and glycolysis, and reverses the hyperproliferative phenotype, thereby restoring NO levels in PH-PAECs. We also demonstrate that directly targeting HIF-1α reverses the hyper-proliferative, anti-apoptotic phenotype in PH-PAECs. Thus, targeting c-Myc signaling and suppressing glutaminolysis or glycolysis could be a novel therapy for PH.PMID:40680382 | DOI:10.1016/j.redox.2025.103765