PubMed

J Genet Genomics. 2025 Mar 8:S1673-8527(25)00061-X. doi: 10.1016/j.jgg.2025.03.002. Online ahead of print.NO ABSTRACTPMID:40064438 | DOI:10.1016/j.jgg.2025.03.002

J Steroid Biochem Mol Biol. 2025 Mar 8:106720. doi: 10.1016/j.jsbmb.2025.106720. Online ahead of print.ABSTRACTVitamin D deficiency (VDD) is prevalent globally and in pediatric intensive care units, where it represents a modifiable risk factor that may impact patient recovery during hospitalization. Herein, we performed a retrospective analysis of serum samples from a phase-II randomized placebo-controlled trial involving a single large bolus of 10,000 IU/kg vitamin D3 ingested by critically ill children with VDD (25-OH-D < 50 nmol/L). Targeted and untargeted methods were used to comprehensively measure 6 vitamin D metabolites, 239 lipids, 68 polar metabolites, and 4 electrolytes using a multi-step data workflow for compound authentication. Complementary statistical methods classified circulating metabolites/lipids associated with vitamin D repletion following high-dose vitamin D3 intake (n=20) versus placebo (n=11) comprising a standard of care maintenance dose (< 1000 IU/day). There was a striking increase in median serum concentrations of 25-OH-D3 (4.7-fold), 3-epi-25-OH-D3 (24-fold) and their C3-epimer ratio (6.7-fold) in treated patients on day 3, whereas serum vitamin D3 peaked on day 1 (128-fold) unlike placebo. Treatment response differences were attributed to D3 bioavailability and C3-epimerase activity without evidence of hypercalcemia. For the first time, we report the detection of circulating 3-epi-D3 that was strongly correlated with vitamin D3 uptake (r = 0.898). Metabolomic studies revealed that vitamin D sufficiency (serum 25-OH-D >75 nmol/L) coincided with lower circulating levels of 3-methylhistidine, cystine, S-methylcysteine, uric acid, and two lysophosphatidylcholines 7 days after treatment. Rapid correction of VDD was associated with indicators of lower oxidative stress, inflammation, and muscle protein turn-over that may contribute clinical benefits in high-risk critically ill children.PMID:40064426 | DOI:10.1016/j.jsbmb.2025.106720

Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Mar 8:159607. doi: 10.1016/j.bbalip.2025.159607. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Walnut oil (WO) and peanut oil (PO) are common vegetable oils rich in unsaturated fatty acids, known to alleviate atherosclerosis (AS) and reduce the risk of cardiovascular diseases (CVD). WO contains a higher proportion of polyunsaturated fatty acids (PUFAs) compared to PO. This study aimed to explore the influence of WO on AS and elucidate its potential mechanisms, providing a theoretical basis for enhancing the application of WO in functional foods and pharmaceuticals.METHODS: AS was established in rats using a high-fat diet and vitamin D3 injections. Rats with AS were administered WO or PO via gavage at a dose of 1.2 g/kg for 4 weeks. Serum lipid levels and arterial injury were assessed, and transcriptomic and metabolomic analyses of the rat vasculature were performed.RESULTS: Both WO and PO significantly lowered serum lipid levels and the atherogenic index (AI) in rats, reducing arterial wall injury and plaque formation. WO exhibited a more pronounced effect, particularly in decreasing serum levels of TG, TC, HDLC, and LDL-C. Transcriptomic analysis indicated that fatty acid, amino acid metabolism were crucial in AS development due to a high-fat diet. Metabolomic analysis indicated significant changes in the metabolism of arginine, proline, cysteine, methionine, glycine, serine and threonine in rats treated with WO.CONCLUSION: WO and PO help alleviate AS by regulating lipid metabolism and influencing pivotal metabolic pathways like TCA cycle and cysteine-methionine metabolism. The more significant impact of WO indicates its potential as a dietary supplement for preventing and treating AS.PMID:40064415 | DOI:10.1016/j.bbalip.2025.159607

J Ethnopharmacol. 2025 Mar 8:119590. doi: 10.1016/j.jep.2025.119590. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Changpu San (CPS) is a traditional Chinese medicine (TCM) formula historically used to treat symptoms resembling depression. However, its antidepressant effects and underlying mechanisms remain unclear.AIM OF THE STUDY: This study aims to evaluate CPS's antidepressant effects and elucidate its mechanisms by combining network pharmacology with untargeted metabolomics.MATERIALS AND METHODS: A chronic unpredictable mild stress (CUMS) mouse model was used to assess CPS's antidepressant effects via behavioral tests and body weight monitoring. By integrating network pharmacology and untargeted metabolomics, both based on UPLC-Q-Exactive-Orbitrap-MS for CPS chemical profiling and serum metabolite analysis, a key pathway was identified. This pathway was validated through UPLC-QQQ-MS/MS and ELISA by measuring relevant biomarkers, while its association with colonic microbiota was further investigated using 16S rDNA sequencing.RESULTS: CPS alleviated depression-like behaviors in CUMS mice. A total of 140 compounds were identified in CPS, revealing 140 core targets related to depression. Metabolomics analysis identified 42 serum metabolites significantly altered in CUMS mice, with tryptophan metabolism emerging as a shared pathway across both approaches. Experimental validation showed CPS partially reversed tryptophan metabolism dysregulation, significantly increasing tryptophan levels and reducing kynurenine levels in the brain. Moreover, CPS modulated the colonic microbiota, with key genera such as Prevotella and Bacillus showing correlations with tryptophan metabolism and inflammation.CONCLUSION: CPS shows promise as an effective antidepressant, potentially through modulating tryptophan metabolism and reshaping colonic microbiota. This study provides valuable insights into its mechanisms and offers a methodological reference for researching other TCM formulas.PMID:40064322 | DOI:10.1016/j.jep.2025.119590

J Ethnopharmacol. 2025 Mar 8:119593. doi: 10.1016/j.jep.2025.119593. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Placenta is a kind of traditional Chinese medicine, known as "Ziheche". The role of cow placental peptides (CPP) in delaying liver aging has been reported, and in-depth exploration of the specific regulatory mechanisms is of great significance for the recycling and utilization of CPP and the development of natural anti-aging drugs.AIM OF THE STUDY: To investigate the protective effects and mechanisms of CPP on liver aging induced by D-galactose (D-gal) in mice from the perspective of mitochondrial energy metabolism.METHODS: An aging model was induced in mice using D-gal. The body weight and liver index of mice were measured, followed by staining and electron microscopy to observe liver morphology and aging markers. Reactive oxygen species (ROS) levels and antioxidant-related indicators were assessed, and mitochondrial function was evaluated. Finally, changes and mechanisms in liver transcriptomics and targeted mitochondrial energy metabolomics were analyzed and integrated to elucidate the regulatory pathways through which CPP delays liver aging.RESULTS: CPP improved liver structural damage, oxidative stress, and mitochondrial dysfunction induced by D-galactose in aging mice. It increased the final body weight and liver index, alleviated hepatocyte swelling and degeneration, enhanced liver antioxidant capacity, and restored normal mitochondrial morphology and function. The combined analysis of targeted mitochondrial energy metabolomics and liver transcriptomics revealed that CPP directly or indirectly regulated mitochondrial energy metabolism and delayed aging by influencing the cAMP signaling pathway, PI3K-Akt signaling pathway, oxidative phosphorylation, and other pathways, thereby modulating related genes and metabolites.PMID:40064320 | DOI:10.1016/j.jep.2025.119593

Eur J Pharmacol. 2025 Mar 8:177466. doi: 10.1016/j.ejphar.2025.177466. Online ahead of print.ABSTRACTOral squamous cell carcinoma (OSCC) is expected to rise ca. 40 % by 2040. Rosmarinic acid (RA) has been recognized for its anticancer properties, although its role in OSCC has been neglected. This work exploits the activity of RA in 2D and 3D models of OSCC cells to compel a roadmap for its anticancer properties. The results demonstrated that RA significantly reduced cell mass and metabolic activity in a dose, time, and cell-type-dependent manner, predominantly in highly-invasive OSCC, without compromising normal mucosa in therapeutic doses. RA decreased mitochondria membrane potential and increased redox state, which was corroborated by pioneering observations on the metabolome landscape of OSCC cells (glutathione reduction and acetate and fumarate release). RA triggered autophagy, upregulating BNIP3 and BCNL1 and downregulating BIRC5. The upregulation of CADM1 and downregulation of VIM, CADM2, SNAIL1, and SOX9 highlighted the modulation of epithelial-mesenchymal transition and the remodeling of the extracellular matrix by the downregulation of MMP-2 and MMP-9. RA interacts with P-glycoprotein with the highest docking score of -6.4 Kcal/mol. The cell surface charge decreased after RA treatment (-22.6±0.3mV vs. -26.3± 0.3mV, p<0.0001), suggesting a reversion of cell polarity and the impairment of invasion. RA also shrank the growth and the metabolic activity of multicellular tumor spheroids. Its modest protein binding with human saliva sheds light on its administration by the oromucosal route. Overall, this work supports the need for further research on the anticancer potential of RA in OSCC, either in monotherapy, combined with conventional treatments, or conveyed in nanosystems.PMID:40064225 | DOI:10.1016/j.ejphar.2025.177466

Bol Med Hosp Infant Mex. 2025;82(1):7-14. doi: 10.24875/BMHIM.24000058.ABSTRACTAt the balance between human health and disease (from the very first moments to the end of life), the mitochondrion is central players because of its metabolic role in adenosine triphosphate synthesis, cell signaling, immune response, and other processes of clinical interest. On the other hand, impairments at the optimal mitochondria function have important consequences in complex diseases, such as heart disease, diabetes, and cancer, among others. These mitochondrial impairments can occur at any age damaging multiple body systems, which have prompted the mitochondrial medicine development. Since mitochondrial diseases have great variability in their clinical manifestations, early studies were centered on mitochondriopathies, however nowadays, this focus has broadened to understand and encompass the mitochondrial role of in diseases development of both pediatric and adult age. The mitochondria potential to improve diagnostic, prognostic, and treatment response strategies has been revealed by experimental approaches using proteomics, genomics, and metabolomics to identify clinical biomarkers showing disease development. Thus, the perspective of mitochondria-based medicine recognizes the importance of generating scientific evidence related to mitochondria and their role in pathological conditions from a comprehensive approach.PMID:40064175 | DOI:10.24875/BMHIM.24000058

Redox Biol. 2025 Mar 5;81:103585. doi: 10.1016/j.redox.2025.103585. Online ahead of print.ABSTRACTMetabolic malnutrition and inflammation-key mechanism links to redox imbalance-are fundamental pathologies that accelerate aging and disease progression, ultimately leading to death. The recently proposed metabolic vulnerability index (MVX) integrates multiple circulatory biomarkers closely linked to both metabolic and inflammatory factors. This study aims to assess MVX's potential to predict mortality in community-based population. In this large community-based prospective study, we included UK Biobank participants who underwent plasma metabolomics analysis. Gender-specific MVX scores were calculated based on six established biomarkers of mortality. Linear and non-linear associations between MVX and mortality were assessed using Cox proportional hazards models and restricted cubic spline models, respectively. Among the 274,092 UKB participants, 24,241 all-cause deaths occurred during a median follow-up period of 13.7 years. A significant, graded positive association was observed between MVX quartiles and all-cause mortality risk (P for trend <0.05), with the highest MVX quartile exhibiting the greatest risk (HR = 1.21 and 95 % CI = 1.16-1.25 after full adjustment). Females had higher MVX score than males (P < 0.05), but males with the same MVX score faced a greater mortality risk. Baseline age and comorbidities interacted (P for interaction <0.05 and synergy index >1) with MVX on mortality risk. Longitudinal analyses showed that females with persistently high MVX score had a significantly increased risk of mortality (HR = 1.39 in fully adjusted model). Collectively, these findings highlight MVX as a novel tool that captures metabolic and potential redox vulnerabilities in community residents, and serves as a valuable resource for identifying high-risk individuals of mortality. Further research is warranted to investigate the underlying mechanisms and establish causal relationships.PMID:40064119 | DOI:10.1016/j.redox.2025.103585

J Environ Manage. 2025 Mar 9;379:124882. doi: 10.1016/j.jenvman.2025.124882. Online ahead of print.ABSTRACTBiodiversity is threatened particularly in perennial crop cultivation such as fruit trees or grapevines. If established, agroforestry has the potential to increase biodiversity by providing a higher habitat heterogeneity at the example of grapevine (Vitis vinifera L. cv. Riesling) cultivated together with oak or poplar trees for 12 years. Together with the rhizosphere microbiome, the root metabolome was quantified as an indicator of root exudation. Since the root metabolome does not fully align with the exudate metabolome, we are using the root metabolome as a proxy for the exudate metabolome. The results reveal that co-cultivation of grapevine with trees reduces the nutrient availability in the soil and changes the root metabolome of both, grapevine and trees with a more distinct effect of trees on grapevine than vice versa, particularly for oak. Apparently, root-to-root signalling takes place between trees and grapevine. Co-cultivation of grapevine and oak trees also enhanced the alpha diversity of the microbiome. Correlation analysis revealed strong positive correlations between distinct microbial families and metabolites enriched in the roots of Riesling. Thus, microbiome analyses support the view that root-to-root interaction in mixed cultivation of grapevine with trees is mediated by root exudation.PMID:40064088 | DOI:10.1016/j.jenvman.2025.124882

ESC Heart Fail. 2025 Mar 10. doi: 10.1002/ehf2.15215. Online ahead of print.ABSTRACTAIMS: Plasma metabolites are prognostic in heart failure with reduced ejection fraction (HFrEF), with citric acid cycle metabolites linked to ejection fraction (EF) changes. We investigated these mechanisms in a canine chronic HFrEF model. We tested associations between changes in plasma metabolites, left ventricular (LV) end-diastolic volume and cardiomyocyte mitochondrial function.METHODS: Eighteen dogs underwent microembolization to induce moderate HFrEF (target LVEF 35%-40%). Plasma metabolites, LV size and mitochondrial function were assessed over 12 months.RESULTS: Plasma metabolite heatmap showed acylcarnitine changes, with early alterations in organic acids and amino acids predicting later adverse LV remodelling. Using either baseline or change over time, 13 metabolites correlated with 12 month LV enlargement. This is mostly often at 3 months (11 of 13), notably C18:2 (r = -0.58, P = 0.003) and cardiac anaplerotic substrates like glutamine (r = -0.52, P = 0.009) and 3-HBA (r = -0.43, P = 0.035). Impaired cardiomyocyte mitochondrial function correlated with LV enlargement (max ATP synthesis 12.7 vs. 19.9 nmol/min/mg, P = 0.0036; ADP-stimulated respiration 224 vs. 308 nAtom O/min/mg protein; P = 0.0064). Plasma metabolites correlated with mitochondrial parameters at 12 month, particularly with MAX ATP: malate (r = -0.75, P < 0.001), fumarate (r = -0.6, P = 0.008) and glutamine (r = 0.51, P = 0.031).CONCLUSIONS: In canine HFrEF, plasma acylcarnitines, citric acid cycle or anaplerotic metabolites predicted adverse LV remodelling. LV enlargement correlated with reduced cardiomyocyte mitochondrial function, which in turn was also associated with increased citric acid cycle metabolites. Together, these data suggest impaired cardiac energetic function drives plasma metabolite associations in HFrEF progression.PMID:40064034 | DOI:10.1002/ehf2.15215

PLoS One. 2025 Mar 10;20(3):e0319461. doi: 10.1371/journal.pone.0319461. eCollection 2025.ABSTRACTHolstein Friesian is the most popular breed of dairy cows worldwide due to its exceptional milk production capabilities. In dairy cow management, the body condition score (BCS) is a useful tool, serving as a reliable indicator of a cow's nutritional status and overall health. It is determined via a subjective visual and tactile assessment of fat cover and muscle mass. A low BCS is associated with decreased milk production and fertility. While genetic and nutritional factors have previously been associated with BCS, their effects are often moderate. In this study, we compared the fecal microbiome and the untargeted fecal metabolome of normal (BCS ≥ 3, n = 16) and thin (BCS < 3, n = 16) Holstein Friesian dairy cows. The 16S rRNA gene-based metagenomic analysis revealed that thin cows had significantly higher levels of Clostridiaceae, Erysipelotrichales, Erysipelotrichaceae, and Turicibacter, while normal cows had higher levels of Clostridiales_vadinBB60_group, UCG-010, Bacteroidaceae, Ruminococcaceae, Paludibacteraceae, Alistipes, and Bacteroides. The fecal metabolomic analysis showed that key signaling pathways, including the mechanistic target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K)-Akt, and AMP-activated protein kinase (AMPK) pathways, were enriched in thin cows. In addition, a significant correlation was observed between differential microbial taxa and metabolites. Notably, Clostridiaceae and Erysipelotrichaceae species are linked to inflammation, infectious diseases, and conditions such as ruminal acidosis. Additionally, the mTOR, PI3K-Akt, and AMPK pathways are known to be activated by both nutrient deficiencies and inflammation. We propose that, in addition to genetic and nutritional factors, gut microbiome dysbiosis may contribute to subclinical health conditions, such as chronic inflammation and acidosis, which indirectly affect the cow's BCS. These findings are guiding our ongoing research on the underlying health conditions in thin cows to better understand the role that the gut microbiome plays in the regulation of the body condition.PMID:40063888 | DOI:10.1371/journal.pone.0319461

Proc Natl Acad Sci U S A. 2025 Mar 18;122(11):e2322440122. doi: 10.1073/pnas.2322440122. Epub 2025 Mar 10.ABSTRACTThe long-term success of introduced populations depends on both their initial size and ability to compete against existing residents, but it remains unclear how these factors collectively shape colonization dynamics. Here, we investigate how initial population (propagule) size shapes the outcome of community coalescence by systematically mixing eight pairs of in vitro microbial communities at ratios that vary over six orders of magnitude, and we compare our results to neutral ecological theory. Although the composition of the resulting cocultures deviated substantially from neutral expectations, each coculture contained species whose relative abundance depended on propagule size even after ~40 generations of growth. Using a consumer-resource model, we show that this dose-dependent colonization can arise when resident and introduced species have high niche overlap and consume shared resources at similar rates. Strain isolates displayed longer-lasting dose dependence when introduced into diverse communities than in pairwise cocultures, consistent with our model's prediction that propagule size should have larger, more persistent effects in diverse communities. Our model also successfully predicted that species with similar resource-utilization profiles, as inferred from growth in spent media and untargeted metabolomics, would show stronger dose dependence in pairwise coculture. This work demonstrates that transient, dose-dependent colonization dynamics can emerge from resource competition and exert long-term effects on the outcomes of community coalescence.PMID:40063808 | DOI:10.1073/pnas.2322440122

Annu Rev Plant Biol. 2025 Mar 10. doi: 10.1146/annurev-arplant-083123-082752. Online ahead of print.ABSTRACTRoot exudation is the process by which plants release organic and inorganic metabolites from their roots into the surrounding soil. Root exudation is a dynamic process and shapes plant-environment interactions at the root-soil interface. Little is known about the biological and environmental factors that shape the exuded metabolome, hereafter referred to as the exudome, despite its importance in structuring soil processes. Here, we emphasize plant physiological and morphological traits that modulate the exudome in a species- and developmental stage-specific manner. We further discuss how environmental factors drive exudation processes. We highlight evidence of a potential circadian exudation rhythm and further illustrate how the physical (temperature, structure), chemical (moisture, pH, nutrients, pollutants), and biological (micro- and macrofauna) properties of soil alter the root exudome composition and release patterns. Exploring the factors that directly or indirectly modulate exudation will enhance our understanding of how this dynamic process mediates plant-environment interactions.PMID:40063678 | DOI:10.1146/annurev-arplant-083123-082752

J Exp Bot. 2025 Mar 10:eraf094. doi: 10.1093/jxb/eraf094. Online ahead of print.ABSTRACTAdenosine undergoes ATP-dependent phosphorylation catalyzed by adenosine kinase (ADK). In plants, ADK also phosphorylates cytokinin ribosides, transport forms of the hormone. Here, we investigated the substrate preferences, oligomeric states and structures of ADKs from moss (Physcomitrella patens) and maize (Zea mays) alongside metabolomic and phenotypic analyses. We showed that dexamethasone-inducible ZmADK overexpressor lines in Arabidopsis can benefit from a higher number of lateral roots and larger root areas under nitrogen starvation. We discovered that maize and moss enzymes can form dimers upon increasing protein concentration, setting them apart from the monomeric human and protozoal ADKs. Structural and kinetic analyses revealed a catalytically inactive unique dimer. Within the dimer, both active sites are mutually blocked. The activity of moss ADKs, exhibiting a higher propensity to dimerize, was tenfold lower compared to maize ADKs. Two monomeric structures in a ternary complex highlight the characteristic transition from an open to a closed state upon substrate binding. This suggests that the oligomeric state switch can modulate the activity of moss ADKs and likely other plant ADKs. Moreover, dimer association represents a novel negative feedback mechanism, helping to maintain steady levels of adenosine and AMP.PMID:40063605 | DOI:10.1093/jxb/eraf094

Aging Cell. 2025 Mar 10:e70033. doi: 10.1111/acel.70033. Online ahead of print.ABSTRACTPhysical activity (PA) may delay the onset of age-related diseases by decelerating biological aging. We investigated the association between leisure-time physical activity (LTPA) and metabolomics-based aging markers (MetaboAge and MetaboHealth) in late midlife and during 16 years of follow-up. At the 16-year follow-up, we also investigated the association between device-based PA and MetaboAge and MetaboHealth. We included 1816 individuals (mean age 61.6 years) from the Helsinki Birth Cohort Study at baseline and followed them up for 5 (n = 982) and 16 years (n = 744), respectively. LTPA was assessed via questionnaire at baseline and 16 years later and device-based PA with ActiGraph accelerometer at the 16-year follow-up. Fasting blood samples were applied to calculate MetaboAge acceleration (ΔmetaboAge) and MetaboHealth at baseline and at both follow-ups. Covariate-adjusted multiple regression analyses and linear mixed models were applied to study the associations. A higher volume of LTPA at baseline was associated with a lower MetaboHealth score at the 5-year follow-up (p < 0.0001 for time × LTPA interaction). No associations were detected at the 16-year follow-up. An increase in LTPA over 16 years was associated with a decrease in MetaboHealth score (p < 0.001) and a decrease in LTPA with an increase in MetaboHealth score. Higher device-based PA was associated with a lower MetaboHealth score, but not with ΔmetaboAge. In conclusion, higher LTPA in late midlife and device-based PA in old age were associated with improved MetaboHealth. Increasing LTPA with age may protect against MetaboHealth-based aging. The results support the importance of PA for biological aging in later life.PMID:40063409 | DOI:10.1111/acel.70033

Gut Microbes. 2025 Dec;17(1):2476570. doi: 10.1080/19490976.2025.2476570. Epub 2025 Mar 10.ABSTRACTNumerous studies have accelerated the knowledge expansion on the role of gut microbiota in inflammatory bowel disease (IBD). However, the precise mechanisms behind host-microbe cross-talk remain largely undefined, due to the complexity of the human intestinal ecosystem and multiple external factors. In this review, we introduce the interactome concept to systematically summarize how intestinal dysbiosis is involved in IBD pathogenesis in terms of microbial composition, functionality, genomic structure, transcriptional activity, and downstream proteins and metabolites. Meanwhile, this review also aims to present an updated overview of the relevant mechanisms, high-throughput multi-omics methodologies, different types of multi-omics cohort resources, and computational methods used to understand host-microbiota interactions in the context of IBD. Finally, we discuss the challenges pertaining to the integration of multi-omics data in order to reveal host-microbiota cross-talk and offer insights into relevant future research directions.PMID:40063366 | DOI:10.1080/19490976.2025.2476570

Biochem Genet. 2025 Mar 10. doi: 10.1007/s10528-025-11070-x. Online ahead of print.ABSTRACTBreast cancer is a heterogeneous tumor with 4 major molecular subtypes. Hormone receptor (HR)-positive and HER2-negative breast cancer accounts for 70% of invasive breast cancers. In our study, we collected 15 original Luminal B breast cancer tissue (LBBC) and paired non-cancerous adjacent tissue (NATs) from patients and performed LC-MS/MS-based label-free quantitative phosphoproteomic analysis. The untargeted metabolomics analysis was also used to determine the differences in metabolic patterns between LBBC and NATs. In addition, an integrative analysis of phosphoproteomics and metabolomics data was performed to investigate regulatory metabolic pathways. The main regulatory proteins were verified by western blot. Phosphoproteomics analysis identified 1385 differentially phosphorylated sites in 785 proteins. The protein kinase A (PKA) and protein kinase C (PKC) families and p70 ribosomal S6 kinase (RPS6K) were strongly activated in LBBC, whereas the cycle-dependent kinases (CDKs) were markedly inhibited. Cancer-specific activation of PI3K-mTORC and Hippo signaling pathways were also highlighted. Metabolomic analysis showed that 223 metabolites were significantly differentially accumulated, including fatty acids (3-hydroxycapric acid; dodecanoic acid; linoleic acid; stearic acid), glycerophospholipids, glycerophosphatidylcholines, and sphingolipids, which were mainly involved in fatty acid oxidation metabolism, sphingolipid metabolism, purine metabolism, and amino acid metabolism pathway. After integrative analysis, we found that the sphingolipid metabolic pathway played the major regulatory role. We also validated 3 phosphorylated proteins (p-YAP, p-SGK1, and p-SGPP2) in the PI3K-mTORC, Hippo signaling pathway, and sphingolipid metabolic pathway, respectively. The present study provides the first integrative phosphoproteome and metabolome profiles of LBBC, mainly involving dysregulation of sphingolipid homeostasis mediated by PI3K-mTORC and Hippo signaling pathways. This study described two phosphorylation pathways and sphingolipid metabolism regulation module for a better understanding of LBBC carcinogenesis and therapy.PMID:40063314 | DOI:10.1007/s10528-025-11070-x

J Med Internet Res. 2025 Mar 10;27:e65563. doi: 10.2196/65563.ABSTRACTBACKGROUND: Traditional risk models for immunoglobulin A nephropathy (IgAN), which primarily rely on renal indicators, lack comprehensive assessment and therapeutic guidance, necessitating more refined and integrative approaches.OBJECTIVE: This study integrated network biomarkers with unsupervised learning clustering (k-means clustering based on network biomarkers [KMN]) to refine risk stratification in IgAN and explore its clinical value.METHODS: Involving a multicenter prospective cohort, we analyzed 1460 patients and validated the approach externally with 200 additional patients. Deeper metabolic and microbiomic insights were gained from 2 distinct cohorts: 63 patients underwent ultraperformance liquid chromatography-mass spectrometry, while another 45 underwent fecal 16S RNA sequencing. Our approach used hierarchical clustering and k-means methods, using 3 sets of indicators: demographic and renal indicators, renal and extrarenal indicators, and network biomarkers derived from all indicators.RESULTS: Among 6 clustering methods tested, the KMN scheme was the most effective, accurately reflecting patient severity and prognosis with a prognostic accuracy area under the curve (AUC) of 0.77, achieved solely through cluster grouping without additional indicators. The KMN stratification significantly outperformed the existing International IgA Nephropathy Prediction Tool (AUC of 0.72) and renal function-renal histology grading schemes (AUC of 0.69). Clinically, this stratification facilitated personalized treatment, recommending angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for lower-risk groups and considering immunosuppressive therapy for higher-risk groups. Preliminary findings also indicated a correlation between IgAN progression and alterations in serum metabolites and gut microbiota, although further research is needed to establish causality.CONCLUSIONS: The effectiveness and applicability of the KMN scheme indicate its substantial potential for clinical application in IgAN management.PMID:40063072 | DOI:10.2196/65563

Physiol Genomics. 2025 Mar 10. doi: 10.1152/physiolgenomics.00115.2024. Online ahead of print.ABSTRACTAging is the primary risk factor for the development of many chronic diseases, including dementia, cardiovascular disease, and diabetes. There is significant interest in identifying novel "geroprotective" agents, including by repurposing existing drugs, but such treatments may affect organ systems differently. One current example is the nucleoside reverse transcriptase inhibitor 3TC, which has been increasingly studied as a potential gerotherapeutic. Recent data suggest 3TC may reduce inflammation and improve cognitive function in older mice; however, the effects of 3TC on other tissues in aged animals are less well characterized. Here, we use transcriptomics (RNA-seq) and targeted metabolomics to investigate the influence of 3TC supplementation on skeletal muscle in older mice. We show that 3TC: (a) does not overtly affect muscle mass or functional/health markers; (b) largely reverses age-related changes in gene expression and metabolite signatures; and (c) is potentially beneficial for mitochondrial function in old animals via increases in antioxidant enzymes and decreases in mitochondrial reactive oxygen species. Collectively, our results suggest that, in addition to its protective effects in other tissues, 3TC supplementation does not have adverse effects in aged muscle, and may even protect muscle/mitochondrial health in this context.PMID:40062980 | DOI:10.1152/physiolgenomics.00115.2024

Microbiol Spectr. 2025 Mar 10:e0263924. doi: 10.1128/spectrum.02639-24. Online ahead of print.ABSTRACTEmerging evidence suggests that altered gut microbiota is linked to community-acquired pneumonia (CAP), but the potential mechanisms by which gut microbiota and its metabolites contribute to the development of CAP remain unclear. Fecal samples from 32 CAP patients and 36 healthy controls were analyzed through metagenomic sequencing and metabolomic profiling. The gut microbiota composition in CAP patients showed significant differences and lower diversity compared to healthy controls. Genera involved in short-chain fatty acid (SCFA) production, such as Faecalibacterium, Ruminococcus, and Eubacterium, as well as species like Faecalibacterium prausnitzii, Bifidobacterium adolescentis, Eubacterium rectale, Prevotella copri, and Ruminococcus bromii, were significantly depleted in CAP patients. Bacterial co-occurrence network analysis revealed an over-representation of pro-inflammatory bacteria, which contributed to the core gut microbiome in CAP patients. Metabolomic analysis of fecal samples identified a distinct metabolic profile, with a notable increase in arachidonic acid, but a decrease in secondary bile acids, such as deoxycholic acid, lithocholic acid, and ursodeoxycholic acid, compared to healthy controls. Spearman correlation analysis between differential microbiota and bile acids showed that Faecalibacterium prausnitzii, Bifidobacterium adolescentis, Eubacterium rectale, and Prevotella copri were positively correlated with ursocholic acid, lithocholic acid, and ursodeoxycholic acid, respectively. Our results suggest that the reduction in secondary bile acids, insufficient production of SCFAs, and an overabundance of pro-inflammatory bacteria may contribute to metabolic inflammation in the body. These factors could play a key role in the pathogenesis of CAP, driven by gut microbiota alterations.IMPORTANCE: This study presents a comprehensive metagenomic and metabolomic analysis of fecal samples from community-acquired pneumonia (CAP) patients, identifying key characteristics, such as decreased secondary bile acids, imbalanced short-chain fatty acid production, and increased pro-inflammatory bacteria. These findings provide valuable insights into the mechanisms linking gut microbiota alterations to CAP pathogenesis and suggest that targeting the gut microbiota could be a promising strategy for intervening in CAP.PMID:40062854 | DOI:10.1128/spectrum.02639-24