PubMed

ACS Nano. 2025 Apr 18. doi: 10.1021/acsnano.5c01564. Online ahead of print.ABSTRACTThe serum prostate-specific antigen (PSA) testing is widely used for prostate cancer (PCa) screening but suffers from poor specificity, leading to unnecessary biopsies and overtreatment. The significant potential of extracellular vesicles (EVs) in cancer diagnosis has driven the development of efficient methods to isolate and identify EV biomarkers from large-scale clinical samples. Here, we systematically evaluate five commonly used EV isolation techniques through proteomic profiling of plasma-derived EVs, endorsing TiO2-based chemical affinity capture as a superior approach for analyzing EVs from complex clinical samples. This method demonstrates exceptional advantages in speed, throughput, reproducibility, and protein coverage. Using this optimized workflow, we analyzed plasma EVs from 80 patients with PCa and benign prostatic hyperplasia (BPH), identifying growth differentiation factor 15 (GDF15) as a compelling biomarker with a predictive power (AUC) of 0.908 for PCa. Extensive validation across independent cohorts comprising 457 samples, including plasma EVs and prostate tissues, confirmed GDF15's ability to distinguish PCa from BPH and stratify PCa stages. Notably, the combination of GDF15 with PSA further enhanced diagnostic efficiency, particularly for patients in the PSA diagnostic gray zone. This study establishes a robust workflow for EV protein analysis in large clinical cohorts and highlights EV-GDF15 as a promising biomarker for noninvasive PCa diagnosis.PMID:40248970 | DOI:10.1021/acsnano.5c01564

Transl Lung Cancer Res. 2025 Mar 31;14(3):878-896. doi: 10.21037/tlcr-2025-105. Epub 2025 Mar 27.ABSTRACTBACKGROUND: As an approved targeting drug, crizotinib has been widely used in the treatment of patients with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements or c-ros oncogene 1 (ROS1) fusions and has demonstrated remarkable therapeutic effects. However, crizotinib-treated patients frequently experience drug resistance, and there are still some underlying mechanisms, which remain unclear. Autophagy, a cellular process that involves the degradation and recycling of cellular components, has been implicated in the development of drug resistance. In this study, we aim to elucidate the mechanisms of crizotinib resistance involving autophagy dysregulation and identify novel therapeutic targets to overcome this resistance.METHODS: We first established a model for crizotinib resistance in HCC78 and H3122 cells. Next, the level of proliferation, apoptosis, autophagy flux, and reactive oxygen species (ROS) of these cells were measured. Subsequently, we analyzed the published single-cell RNA sequencing data from three ALK-rearranged lung cancer organoid samples and performed a metabolomics assay on crizotinib-resistant HCC78 cells. Finally, the therapeutic effects were confirmed in vitro by targeting autophagy flux.RESULTS: Crizotinib induced cell apoptosis and growth arrest by promoting the accumulation of autophagosomes through the inhibition of autophagy flux in ROS1 + or ALK + NSCLC. In contrast, crizotinib-resistant NSCLC cells showed inactivation of signal transducer and activator of transcription 3 (STAT3) phosphorylation and downregulation of prostaglandin endoperoxide synthase 2 (PTGS2), leading to an increase in the metabolite arachidonic acid (AA). AA further promoted autophagy flux and reduced autophagosome accumulation, driving crizotinib resistance under conditions of drug stress. Moreover, chloroquine (CQ), anti-malaria drug and lysosome inhibitor developed in 1940, could induce cell death in crizotinib-resistant NSCLC by blocking AA-mediated autophagy flux and facilitating autophagosome accumulation, significantly enhancing the treatment efficacy of crizotinib in drug-resistant NSCLC.CONCLUSIONS: We discovered a new mechanism of first generation ALK- and ROS1-TKIs resistance, which points to the role of the metabolite AA in resistance to tyrosine kinase inhibitors. It may potentially provide an alternative strategy to overcoming crizotinib resistance in NSCLC treatment by reversing AA-mediated autophagy.PMID:40248722 | PMC:PMC12000944 | DOI:10.21037/tlcr-2025-105

BMJ Neurol Open. 2025 Apr 16;7(1):e001026. doi: 10.1136/bmjno-2025-001026. eCollection 2025.ABSTRACTBACKGROUND: Predicting disease progression in multiple sclerosis (MS) remains challenging. PET imaging with 18 kDa translocator protein (TSPO) radioligands can detect microglial and astrocyte activation beyond MRI-visible lesions, which has been shown to be highly predictive of disease progression. We previously demonstrated that nuclear magnetic resonance (NMR)-based metabolomics could accurately distinguish between relapsing-remitting (RRMS) and secondary progressive MS (SPMS). This study investigates whether combining TSPO imaging with metabolomics enhances predictive accuracy in a similar setting.METHODS: Blood samples were collected from 87 MS patients undergoing PET imaging with the TSPO-binding radioligand 11C-PK11195 in Finland. Patient disability was assessed using the expanded disability status scale (EDSS) at baseline and 1 year later. Serum metabolomics was performed to identify biomarkers associated with TSPO binding and disease progression.RESULTS: Greater TSPO availability in the normal-appearing white matter and perilesional regions correlated with higher EDSS. Serum metabolites glutamate (p=0.02), glutamine (p=0.006), and glucose (p=0.008), detected by NMR, effectively distinguished future progressors. These three metabolites alone predicted progression with the same accuracy as TSPO-PET imaging (AUC 0.78; p=0.0001), validated in an independent cohort. Combining serum metabolite data with PET imaging significantly improved predictive power, achieving an AUC of 0.98 (p<0.0001).CONCLUSION: Measuring three specific serum metabolites is as effective as TSPO imaging in predicting MS progression. However, integrating TSPO imaging with serum metabolite analysis substantially enhances predictive accuracy. Given the simplicity and affordability of NMR analysis, this approach could lead to more personalised, accessible treatment strategies and serve as a valuable tool for clinical trial stratification.PMID:40248672 | PMC:PMC12004482 | DOI:10.1136/bmjno-2025-001026

Front Pharmacol. 2025 Apr 3;16:1548491. doi: 10.3389/fphar.2025.1548491. eCollection 2025.ABSTRACTBACKGROUND: Astragaloside IV (AS-IV) is one of the most potent components of Astragalus. It has been reported to promote bone formation and inhibit osteoclastogenesis, suggesting its potential as a candidate for the prevention and treatment of postmenopausal osteoporosis (PMOP). The gut microbiota may play a crucial role in mediating the effects of AS-IV.OBJECTIVE: To investigate the impact of gut microbiota on the efficacy of AS-IV in treating PMOP.METHODS: Mice were randomly divided into three groups: Sham, ovariectomy (OVX), and AS-IV-treated OVX group (80 mg/kg). Bone loss was evaluated using Micro-CT and histopathology. Immunohistochemistry assessed specific bone markers. Inflammatory levels were measured by enzyme-linked immunosorbent assay (ELISA). Intestinal barrier function was examined via colonic histopathology and immunohistochemistry. Gut microbiota composition was analyzed by 16S rDNA sequencing, while metabolomic profiling identified key metabolites. Correlation analysis was performed to explore relationships between differential bacteria, key metabolites, and bone loss.RESULTS: AS-IV improved the femur microarchitecture and modulated bone turnover in OVX mice. AS-IV treatment strengthened the intestinal barrier function and decreased gut permeability. This compound reduced colonic oxidative stress and serum and bone marrow inflammatory cytokine production. 16S rDNA sequencing revealed that AS-IV modulated the gut microbiota composition, while metabolomic analysis showed its effects on pathways related to hormone biosynthesis, D-amino acid metabolism, and galactose metabolism.CONCLUSION: This study provides new insights into the use of AS-IV for treating PMOP, highlighting the gut microbiota and its metabolites as key regulatory factors in AS-IV's therapeutic effects.PMID:40248089 | PMC:PMC12003300 | DOI:10.3389/fphar.2025.1548491

Front Med (Lausanne). 2025 Apr 3;12:1539467. doi: 10.3389/fmed.2025.1539467. eCollection 2025.ABSTRACTINTRODUCTION: Drug abuse is becoming a global public health crisis. According to the United Nations, the number of drug users worldwide has increased dramatically over the past decade, with a surge in the number of drug abusers. The problem was exacerbated by the expanding market for illicit drugs and the increasing availability of synthetic drugs such as fentanyl. Clinical drug abuse is a problem that requires particular attention, and the potential addictive properties of some drugs and their mechanisms of action are currently unknown, which limits the development and implementation of drug addiction intervention strategies.METHODS: Eight-week-old C57BL/6J mice were used as study subjects. A mental dependence model was established using the conditional position preference experiment (CPP), and the hippocampal tissues of the model mice were subjected to RNA-seq transcriptome sequencing, LC-MS non-targeted metabolome sequencing, and intestinal macro-genome sequencing in order to discover propofol mental dependence signature genes. Correlation analyses of transcriptomics and metabolomics were performed using the Spearman method, and gene-metabolite networks were mapped using Cytoscape software. Real-time fluorescence quantitative PCR and immunoprotein blotting (Western blotting) methods were used to validate the characterized genes.RESULTS: After the conditioned position preference experiment, the conditioned preference scores of the 75 mg/kg propofol and 2 g/kg alcohol groups were significantly higher than those of the control saline group. 152 differential genes and 214 differential metabolites were identified in the 75 mg/kg group. Cluster analysis revealed that changes in the neuroactive ligand receptor pathway were most pronounced. Gut microbiomics assays revealed significant changes in five differential enterobacterial phyla (Campylobacter phylum, Thick-walled phylum, Anaplasma phylum, Actinobacteria phylum, and Chlorella verticillata phylum) in the 75 mg/kg propofol group, which may be related to changes in the differential expression of dopamine.DISCUSSION: These findings suggest that 75 mg/kg propofol has a significant mind-dependent effect on the biology of drug addiction through neuroactive ligand-receptor interaction pathways in conjunction with the tricarboxylic acid cycle, and the metabolic pathways of alanine, aspartate, and glutamate that may influence intestinal microbial changes through bidirectional signaling.PMID:40248078 | PMC:PMC12005058 | DOI:10.3389/fmed.2025.1539467

New Phytol. 2025 Apr 18. doi: 10.1111/nph.70155. Online ahead of print.ABSTRACTHolo-omics provide a novel opportunity to study the interactions among fungi from different functional guilds in host plants in field conditions. We address the entangled responses of plant pathogenic and endophytic fungi associated with sorghum when droughted through the assembly of the most abundant fungal, endophyte genome from rhizospheric metagenomic sequences followed by a comparison of its metatranscriptome with the host plant metabolome and transcriptome. The rise in relative abundance of endophytic Acremonium persicinum (operational taxonomic unit 5 (OTU5)) in drought co-occurs with a rise in fungal membrane dynamics and plant metabolites, led by ethanolamine, a key phospholipid membrane component. The negative association between endophytic A. persicinum (OTU5) and plant pathogenic fungi co-occurs with a rise in expression of the endophyte's biosynthetic gene clusters coding for secondary compounds. Endophytic A. persicinum (OTU5) and plant pathogenic fungi are negatively associated under preflowering drought but not under postflowering drought, likely a consequence of variation in fungal fitness responses to changes in the availability of water and niche space caused by plant maturation over the growing season. Our findings suggest that the dynamic biotic interactions among host, beneficial and harmful microbiota in a changing environment can be disentangled by a blending of field observation, laboratory validation, holo-omics and ecological modelling.PMID:40247824 | DOI:10.1111/nph.70155

New Phytol. 2025 Apr 18. doi: 10.1111/nph.70146. Online ahead of print.ABSTRACTPlant interactions with abiotic and biotic environments are mediated by diverse metabolites, which are crucial for stress response and defense. These metabolites can not only support diversity by shaping species niche differences but also display heritable and plastic intraspecific variation, which few studies have quantified in terms of their relative contributions. To address this shortcoming, we used untargeted metabolomics to annotate and quantify foliar metabolites and restriction-site associated DNA (RAD) sequencing to assess genetic distances among 300 individuals of 10 locally abundant species from a diverse tropical community in Southwest China. We quantified the relative contributions of relatedness and the abiotic and biotic environment to intraspecific metabolite variation, considering different biosynthetic pathways. Intraspecific variation contributed most to community-level metabolite diversity, followed by species-level variation. Biotic factors had the largest effect on total and secondary metabolites, while abiotic factors strongly influenced primary metabolites, particularly carbohydrates. The relative importance of these factors varied widely across different biosynthetic pathways and different species. Our findings highlight that intraspecific variation is an essential component of community-level metabolite diversity. Furthermore, species rely on distinct classes of metabolites to adapt to environmental pressures, with genetic, abiotic, and biotic factors playing pathway-specific roles in driving intraspecific variation.PMID:40247823 | DOI:10.1111/nph.70146

New Phytol. 2025 Apr 18. doi: 10.1111/nph.70152. Online ahead of print.ABSTRACTWhile specific environments are known to shape plant metabolomes and the makeup of their associated microbiome, it is as yet unclear whether carposphere microbiota contribute to the characteristics of grape fruit flavor of a particular wine region. Here, carposphere microbiomes and berry transcriptomes and metabolomes of three grape cultivars growing at six geographic sites were analyzed. The composition of the carposphere microbiome was determined mainly by environmental conditions, rather than grape genotype. Bacterial microbiota likely contributed to grape volatile profiles. Particularly, candidate operational taxonomic units (OTUs) in genus Sphingomonas were highly correlated with grape C6 aldehyde volatiles (also called green leaf volatiles, GLVs), which contribute to a fresh taste. Furthermore, a core set of expressed genes was enriched in lipid metabolism, which is responsible for bacterial colonization and C6 aldehyde volatile synthesis activation. Finally, a similar grape volatile profile was observed after inoculating the berry skin of two grape cultivars with Sphingomonas sp., thus providing evidence for the hypothetical microbe-metabolite relationship. These results provide novel insight into how the environment-microbiome-plant quality (E × Mi × Q) interaction may shape berry flavor and thereby typicality, serving as a foundation for decision-making in vineyard microbial management.PMID:40247820 | DOI:10.1111/nph.70152

ISME J. 2025 Apr 18:wraf073. doi: 10.1093/ismejo/wraf073. Online ahead of print.ABSTRACTThe susceptibility of corals to environmental stress is determined by complex interactions between host genetic variation and the Symbiodiniaceae family community. We exposed genotypes of Montipora capitata hosting primarily Cladocopium or Durusdinium symbionts to ambient conditions and an eight-day heat stress. Symbionts' cell surface glycan composition differed between genera and was significantly affected by temperature and oxidative stress. The metabolic profile of coral holobionts was primarily shaped by symbionts identity, but was also strongly responsive to oxidative stress. At peak temperature stress, betaine lipids in Cladocopium were remodeled to more closely resemble the abundance and saturation state of Durusdinium symbionts, which paralleled a larger metabolic shift in Cladocopium. Exploring how Symbiodiniaceae members regulate stress and host-symbiont affinity helps identify the traits contributing to coral resilience under climate change.PMID:40247696 | DOI:10.1093/ismejo/wraf073

Stem Cell Res Ther. 2025 Apr 17;16(1):183. doi: 10.1186/s13287-025-04315-4.ABSTRACTBACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are a major global health challenge, affecting millions of people and often lacking effective treatments. The mesenchymal stromal cell (MSC)-derived secretome has emerged as a promising therapeutic approach owing to its potent immunomodulatory properties. However, progress has been hindered by the lack of standardized protocols for inducing a robust immunomodulatory MSC phenotype.METHODS: In this study, we focused on optimizing the MSC-derived secretome to enhance its ability to suppress activated immune cells. Specifically, we examined (1) the effects of IFN-γ and TNF-α, individually and in combination, to uncover potential synergy; (2) the ideal cytokine ratio and (3) concentration; (4) the best production time for the secretome; and (5) the impact of cellular confluence. These factors were systematically evaluated to assess their influence on cell behavior, viability, cytosolic content release, and the secretion of key immunomodulatory and regenerative factors.RESULTS: Our results demonstrate that overnight licensing with a 1:1 ratio of IFN-γ and TNF-α at 60 ng/mL, followed by 48 h of incubation at 90% confluence, yields an optimized conditioned media (CM) with significantly enhanced immunomodulatory properties. Functional assays showed that this CM can inhibit human peripheral blood mononuclear cell (PBMC) activation with more than twice the effectiveness of suboptimal protocols. Additionally, we found that direct cell-cell contact was critical for inducing regulatory T cells (Tregs), highlighting the complex dynamics of immune regulation.CONCLUSIONS: These findings establish a robust and standardized MSC licensing protocol, paving the way for the development of innovative and effective therapies to combat IMIDs.CLINICAL TRIAL NUMBER: Not applicable.PMID:40247371 | DOI:10.1186/s13287-025-04315-4

Genome Biol. 2025 Apr 17;26(1):100. doi: 10.1186/s13059-025-03556-z.ABSTRACTBACKGROUND: Direct conversion of reactive glial cells to neurons is a promising avenue for neuronal replacement therapies after brain injury or neurodegeneration. The overexpression of neurogenic fate determinants in glial cells results in conversion to neurons. For repair purposes, the conversion should ideally be induced in the pathology-induced neuroinflammatory environment. However, very little is known regarding the influence of the injury-induced neuroinflammatory environment and released growth factors on the direct conversion process.RESULTS: We establish a new in vitro culture system of postnatal astrocytes without epidermal growth factor that reflects the direct conversion rate in the injured, neuroinflammatory environment in vivo. We demonstrate that the growth factor combination corresponding to the injured environment defines the ability of glia to be directly converted to neurons. Using this culture system, we show that chromatin structural protein high mobility group box 2 (HMGB2) regulates the direct conversion rate downstream of the growth factor combination. We further demonstrate that Hmgb2 cooperates with neurogenic fate determinants, such as Neurog2, in opening chromatin at the loci of genes regulating neuronal maturation and synapse formation. Consequently, early chromatin rearrangements occur during direct fate conversion and are necessary for full fate conversion.CONCLUSIONS: Our data demonstrate novel growth factor-controlled regulation of gene expression during direct fate conversion. This regulation is crucial for proper maturation of induced neurons and could be targeted to improve the repair process.PMID:40247387 | DOI:10.1186/s13059-025-03556-z

Nutr J. 2025 Apr 17;24(1):62. doi: 10.1186/s12937-025-01125-5.ABSTRACTBACKGROUND: Ultra-processed food (UPF) consumption has been linked to adverse metabolic outcomes, potentially mediated by alterations in gut microbiota and metabolite production.OBJECTIVE: This study aims to explore the cross-sectional and longitudinal associations between NOVA-classified UPF consumption, fecal microbiota, and fecal metabolome in a population of Mediterranean older adults at high cardiovascular risk.METHODS: A total of 385 individuals, aged between 55 and 75 years, were included in the study. Dietary and lifestyle information, anthropometric measurements, and stool samples were collected at baseline and after 1-year follow-up. Fecal microbiota and metabolome were assessed using 16 S rRNA sequencing and liquid chromatography-tandem mass spectrometry, respectively.RESULTS: At baseline, higher UPF consumption was associated with lower abundance of Ruminococcaceae incertae sedis (β = - 0.275, P = 0.047) and lower concentrations of the metabolites propionylcarnitine (β = - 0.0003, P = 0.013) and pipecolic acid (β = - 0.0003, P = 0.040) in feces. Longitudinally, increased UPF consumption was linked to reduced abundance of Parabacteroides spp. after a 1-year follow-up (β = - 0.278, P = 0.002).CONCLUSIONS: High UPF consumption was associated with less favorable gut microbiota and metabolite profiles, suggesting a possible link to reduced short-chain fatty acid (SCFA) production, altered mitochondrial energy metabolism, and impaired amino acid metabolism. These findings support the reduction of UPF consumption and the promotion of dietary patterns rich in fiber for better gut health. Further research is needed to confirm these associations and clarify the underlying mechanisms.TRIAL REGISTRATION: ISRCTN89898870 ( https://doi.org/10.1186/ISRCTN89898870 ).PMID:40247349 | DOI:10.1186/s12937-025-01125-5

Virol J. 2025 Apr 17;22(1):103. doi: 10.1186/s12985-025-02719-5.ABSTRACTUsutu virus (USUV) is an emerging orthoflavivirus, which mainly affects birds but in rare cases can cause severe neuroinvasive disease in humans. The virus relies on a multitude of host cell proteins, molecules and cellular processes for its replication, and must subvert host antiviral responses to establish a successful infection. Studying the complex network of virus-host protein interactions by proteomics approaches can therefore provide new insights in the replication cycle of USUV and its pathogenesis. We have previously shown that the USUV protein NS4A acts as an antagonist of the antiviral interferon response, and here we further map the host interaction partners of USUV NS4A using proximity labeling coupled to mass spectrometry. The resulting NS4A interactome revealed many host proteins involved in the autophagy pathway. We showed that both USUV infection and overexpression of USUV NS4A can indeed induce the autophagy pathway. However, stimulation or inhibition of the autophagy pathway in general did not affect USUV replication. Therefore, we decided to specifically analyze the role of the selective autophagy receptor sequestosome 1 (p62/SQSTM1), since we identified this protein as an important interaction partner of USUV NS4A. We found that p62 is involved in the degradation of USUV NS4A. In agreement with this, the knockdown of p62 enhanced replication of USUV in A549 cells. P62 thus plays an antiviral role during USUV infection, although this antiviral effect might also be related to its functions outside the autophagy pathway, such as modulation of the immune response. In conclusion, this study showed that USUV NS4A induces autophagy and is then targeted by p62 for degradation by the autophagic machinery, uncovering a new role of p62 in the antiviral defense against USUV.PMID:40247289 | DOI:10.1186/s12985-025-02719-5

BMC Cancer. 2025 Apr 17;25(1):719. doi: 10.1186/s12885-025-14133-9.ABSTRACTBACKGROUND: Enhanced glycolytic levels in cancer cells are a common characteristic of many cancer types. Modulation of glycolytic metabolism is crucial for enhancing the efficacy of cancer therapy. The specific role of 6-methoxyflavone in regulating glycolytic metabolism in cancer cells remains unclear. This study aimed to elucidate the impact of 6-methoxyflavone on glycolytic metabolism in cervical cancer cells and its clinical relevance.METHODS: The tandem mass tag (TMT) proteomic analysis was used to identify significantly enriched biological processes and pathways in HeLa cells after treatment with 6-methoxyflavone. Additionally, the differential expression of glycolysis-related proteins was validated using parallel reaction monitoring (PRM) proteomics. Untargeted and targeted metabolomics analyses were used to identify differentially expressed glycolysis-related metabolites. Furthermore, alternative splicing, new transcripts, and domain analyses were used to detect the effects of 6-methoxyflavone on the structures of glycolysis-related genes and proteins. Subcellular localization, molecular docking, and non-covalent interaction analyses were used to detect the subcellular localization, affinity of 6-methoxyflavone for glycolysis-related proteins, and sites of non-covalent interactions. Clinical characteristics and immunological correlation analyses were used to elucidate the relationships between glycolysis-related genes and clinicopathological characteristics, survival, prognosis, and immune-related indicators of patients with cervical cancer. Finally, glycolysis stress tests and enzyme activity assays were used to verify the effect of 6-methoxyflavone on glycolysis in HeLa cells.RESULTS: TMT and PRM proteomics, as well as untargeted and targeted metabolomics results, showed that 6-methoxyflavone downregulated the expression levels of glycolysis-related proteins and metabolites in HeLa cells, and that the structures and functions of glycolysis-related genes and proteins in the cytoplasm underwent changes. 6-Methoxyflavone had a good affinity for nine glycolysis-related proteins, all of which had non-covalent interaction sites. Clinical characteristics and immune correlation analyses showed relationships between 6-methoxyflavone and five clinical characteristics, survival prognosis, and four immune-related indicators in patients with cervical cancer. After treatment with 6-methoxyflavone, the basal glycolytic level, maximum glycolytic capacity, and glycolytic reserve of HeLa cells were downregulated. Additionally, 6-methoxyflavone inhibited the activity of pyruvate kinase.CONCLUSION: 6-Methoxyflavone inhibited energy metabolism in HeLa cells through the glycolysis pathway. 6-Methoxyflavone may be related to five clinical characteristics, prognosis, tumor microenvironment, immune cells, immune checkpoints, and immunotherapy efficacy in patients with cervical cancer.PMID:40247232 | DOI:10.1186/s12885-025-14133-9

BMC Cardiovasc Disord. 2025 Apr 17;25(1):292. doi: 10.1186/s12872-025-04758-w.ABSTRACTBACKGROUND: The Metabolic Vulnerability Index (MVX) is a novel multi-marker risk score derived from nuclear magnetic resonance (NMR) measures and has shown predictive value for mortality in heart failure. Hence, we aimed to evaluate the distribution of MVX and its clinical correlates within a clinical trial population and a comparable subpopulation of patients with heart failure with reduced ejection fraction and ischemic heart disease within a community cohort.METHODS: We studied a clinical trial (2016-2018) and a community cohort (2003-2012), matched based on ejection fraction category and presence of ischemic heart failure. NMR LipoProfile analyses of plasma from both populations provided measures of valine, leucine, isoleucine, citrate, GlycA, and small high-density lipoprotein particles used to compute sex-specific MVX scores. Univariable and multivariable regression models assessed the relationship between MVX (modeled continuously), and selected demographic and clinical covariates.RESULTS: Clinical trial patients (N = 101, median age: 63, 93% male, median EF: 28%) were younger and predominantly male compared to the cohort (N = 288, median age: 75, 70% male, median EF: 30%). The median MVX score was lower in the clinical trial (50, 42-61) compared to the cohort (66, 58-73). Male sex and hyperlipidemia were linked to higher MVX scores in the clinical trial, while obesity and NT-proBNP were linked to lower and higher MVX scores, respectively, in the cohort (p <.05). After adjusting for significant covariates from univariable analyses and age in multivariable analyses, only the associations between male sex and MVX scores in the clinical trial, and NT-proBNP levels with MVX in the cohort remained significant.CONCLUSION: This study highlights significant differences in MVX distribution and its clinical correlates between a clinical trial and a community cohort despite matched heart failure subtypes. These findings have important implications for interpreting and applying the score in diverse study settings.PMID:40247156 | DOI:10.1186/s12872-025-04758-w

Nat Plants. 2025 Apr 17. doi: 10.1038/s41477-025-01964-4. Online ahead of print.ABSTRACTIn apples, fruit firmness is a crucial quality trait influencing fruit storability, transportability, shelf life and consumer preference. However, the genetic network underlying this trait remains unclear. Therefore, the present study investigated the changes in apple fruit at different stages of postharvest storage using a combination of transcriptomic and metabolomic analyses. With prolonged storage, we detected a significant increase in two metabolites, D-galacturonic acid (D-GalUA) and D-glucuronic acid (D-GlcA), which are associated with a key class 1 non-symbiotic haemoglobin (MdHb1). We innovatively found that MdHb1 regulates fruit softening by catalysing the conversion from protopectin to water-soluble pectin. Biochemical analysis demonstrated that MdMYB2/MdNAC14/MdNTL9 transcription factors directly bind to the MdHb1 promoter to activate its transcriptional expression and promote fruit softening. Further injection experiments in apple fruit and histological as well as transmission electron microscopy analyses of the fruit samples revealed that D-GalUA and D-GlcA reduce the transcription of MdHb1, or through the MdMYB2/MdNAC14/MdNTL9-MdHb1 regulatory module, thereby delaying fruit softening. Our study provides novel insights into the role of two important metabolites, D-GalUA and D-GlcA, in the regulation of MdHb1-mediated fruit softening in apples.PMID:40247144 | DOI:10.1038/s41477-025-01964-4

Pediatr Res. 2025 Apr 17. doi: 10.1038/s41390-025-04038-5. Online ahead of print.ABSTRACTBACKGROUND: We previously examined plasma metabolic changes before and after botulinum toxin-A injections of cerebral palsy (CP) children and showed that the glycine, serine and threonine metabolism may play a key role in neuritogenesis. This study analysed untargeted metabolomics combined with proteomics of plasma to discussed which substances are meaningfully changed, to what extent they affect the effects of action.METHODS: Blood samples were collected from 91 children with spastic CP at 4 time points: pre-injection (T1), 1 month post-injection (T2), 3 months post-injection (T3) and 6 months post-injection (T4). Differentially changed metabolites and proteins were selected, and co-expression pathways were constructed to explore the key molecular processes.RESULTS: A total of 674 proteins and 354 metabolites were identified. The differential metabolites were mainly involved in the linoleic acid metabolism, beta-Alanine metabolism, citrate cycle, pyruvate metabolism and glycolysis or gluconeogenesis. Differential proteins were primarily associated with glucose metabolism, lipid metabolism, immune and inflammation responses. Co-expression pathways showed that ECM-receptor interaction, complement and coagulation cascades, glycolysis or gluconeogenesis, pyruvate metabolism, and linoleic acid metabolism were the main pathways.CONSLUSIONS: Our results indicated the botulinum toxin-A predominantly activated the glucose metabolism, lipid metabolism, and immune and inflammation responses, and energy metabolism changed significantly in this process.TRIAL REGISTRATION DETAILS: ChiCTR2000033800, Research on the mechanism of botulinum toxin relieving spasticity in children with cerebral palsy. Approval No. 202023041. Registered 13 June 2020, http://www.chictr.org.cn/showproj.html?proj=52267 .IMPACT STATEMENT: This is the first study that combined dynamic metabolomics and proteomics analysis to investigate the molecular changes in children with spastic cerebral palsy after botulinum toxin-A injections, which might provide a theoretical reference for the further subsequent study for targets to increase the efficacy and prolong the duration of botulinum toxin-A, and would be a valuable resource for the metabolomics and proteomics field in this group.PMID:40247116 | DOI:10.1038/s41390-025-04038-5

Int J Obes (Lond). 2025 Apr 17. doi: 10.1038/s41366-025-01775-9. Online ahead of print.ABSTRACTOBJECTIVE: This study aims to find maternal and neonatal metabolomic signatures that contribute to the adverse birthweight outcomes including abnormally high and low birth weight. We also investigated the role of metabolomic signatures in the associations of maternal risk factors such as parity and gestational weight gain with adverse birthweight outcomes.METHODS: Ninety-six pregnant women and their newborns from the MADRES prospective cohort were studied. Maternal serum at third trimester and newborn cord blood were assayed for untargeted metabolomics using mass-spectrometry. Metabolome-wide association analysis was conducted to assess maternal and newborn metabolomic features association with birth weight Z-score, followed by network analysis of maternal and newborn metabolomics. Lastly, the contribution of maternal and newborn metabolomics to associations between maternal risk factors and newborn birthweight was assessed.RESULTS: Maternal gestational weight gain and parity were positively associated with newborn birthweight. Maternal glucose and branched-chain amino acid metabolism pathways and newborn's fatty acid, glucose metabolism and C21-steroid hormone biosynthesis were significantly enriched with high birth weight Z-score. Dysregulation in these pathways linked maternal factors such as gestational weight gain and parity with high birth weight Z-score.CONCLUSION: Our findings indicate that altered maternal sugar and energy metabolism, newborn sugar and amino acid metabolism, and newborn C21-steroid hormone biosynthesis were associated with high birth weight. Dysregulated metabolism in pregnant women and newborn may contribute to the pathophysiological mechanisms linking maternal excessive gestational weight gain and multiparity with high birth weight.PMID:40247088 | DOI:10.1038/s41366-025-01775-9

Signal Transduct Target Ther. 2025 Apr 18;10(1):113. doi: 10.1038/s41392-025-02167-1.ABSTRACTAlthough cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.PMID:40246868 | DOI:10.1038/s41392-025-02167-1

J Environ Sci (China). 2025 Sep;155:475-487. doi: 10.1016/j.jes.2024.09.001. Epub 2024 Sep 10.ABSTRACTAtorvastatin (ATV), a commonly prescribed lipid-lowering drug, has been widely detected in various aquatic environments due to its large use and low degradation rate. Since the target gene inhibited by ATV is highly conserved in organisms, many studies have shown that ATV can interfere with lipid metabolism in aquatic non-target organisms. However, studies on mitochondria, energy metabolism, and developmental toxicity of ATV on non-target organisms are limited. In this study, Mugilogobius chulae embryos were exposed to ATV (0.5 and 50 µg/L) until 96 hour post fertilization (hpf). The results confirmed that the environmental concentrations of ATV caused toxic effects including developmental malformations, pathological damage, hepatotoxicity, and oxidative stress in M. chulae larvae. Both transcriptomic and metabolomic analyses showed that ATV exposure interfered the normal processes of oxidative phosphorylation and TCA cycle, resulting in energy metabolic disorder. In addition, ATV exposure also damaged the mitochondrial structure of M. chulae larvae. Thus, M. chulae could regulate PI3K/AMPK/FoxO proteins to promote mitochondrial regeneration, support autophagy, and even initiate apoptosis to maintain metabolism homeostasis. Taken together, our findings suggested that mitochondrial dysfunction and metabolic disorder were involved in ATV-induced toxicity which may cause developmental malformations and abnormalities, providing novel insight into the toxic mechanisms of ATV.PMID:40246482 | DOI:10.1016/j.jes.2024.09.001