PubMed

Open Biol. 2025 Mar;15(3):240285. doi: 10.1098/rsob.240285. Epub 2025 Mar 5.ABSTRACTMetabolic processes in fetuses can significantly influence piglet weight at birth. Understanding the genetic determinants of systemic metabolism is crucial for uncovering how genetic and molecular pathways impact biological mechanisms, particularly during the fetal phase. We present data on 1112 plasma metabolites using untargeted ultra-high performance liquid chromatography-tandem mass spectrometry methods, of 260 backcross (BC) fetuses from two sires' breeds at 63 days post-conception. Eight chemical superclasses have been identified, with lipids accounting for the majority of metabolites. Genomic heritability (h²) was estimated for each metabolite, revealing that 50% had h² values below 0.2, with a higher average in the amino acid class compared with the lipid. We annotated 448 significant metabolite quantitative trait loci associated with 10 metabolites, primarily lipids, indicating strong genetic regulation. Additionally, metabolite associations with sex, fetal weight and sire's breed were explored, revealing significant associations for 354 metabolites. Fetal weight influenced the largest number of metabolites, particularly glycerophospholipids and sphingolipids, emphasizing the genetic and metabolic complexity underlying fetal development. These findings enhance our understanding of the genetic regulation of metabolite levels and their associations with key phenotypic traits in fetuses, providing insights into metabolic pathways, potential biomarkers and serving as a baseline dataset for metabolomics studies of fetuses.PMID:40037532 | DOI:10.1098/rsob.240285

J Clin Endocrinol Metab. 2025 Mar 3:dgaf131. doi: 10.1210/clinem/dgaf131. Online ahead of print.ABSTRACTCONTEXT: Tangier disease (TD) is a rare, autosomal recessive genetic disorder associated with a deficiency in cellular cholesterol export leading to cholesterol accumulation in peripheral tissues. With approximately 150 described cases, the disease is significantly understudied, and the clinical presentation appears to be heterogenous.OBJECTIVE: To investigate the phenotype and lipid metabolism in TD.DESIGN: Multicenter cohort study.PATIENTS: Four patients with TD.MAIN OUTCOME MEASURES: Nuclear magnetic resonance (NMR)-based lipidomic and metabolomic analyses were performed in patients with TD and healthy controls.RESULTS: While showing similar laboratory patterns with respect to high-density lipoprotein depletion, the clinical phenotypes of four TD patients were heterogenous with two patients diagnosed at 47 and 72 years having predominantly gastrointestinal and neurological phenotypes. Two previously undescribed variants (c.2418G>A, c.5055.del) were reported.Apart from pathognomonic changes in HDL composition, NMR spectroscopy revealed an increased abundance of VLDL with higher total lipid and cholesterol concentrations, pointing towards an impaired clearance of triglyceride-rich lipoproteins. Increased triglyceride-rich IDL supports impaired hepatic lipase activity, together with a CETP-mediated increase in LDL-triglycerides at higher abundance of large LDL subtypes and decreased small dense LDL.The lipid composition of HDL particles and LDL-1/LDL-4 remained the strongest differentiating factors as compared to healthy controls.CONCLUSIONS: Clinical phenotypes of TD can be heterogeneous including gastrointestinal and neurological manifestations. Impaired triglyceride-rich lipoprotein clearance and hepatic lipase activity could be a pathophysiological hallmark of TD.PMID:40037526 | DOI:10.1210/clinem/dgaf131

Fish Shellfish Immunol. 2025 Mar 2:110246. doi: 10.1016/j.fsi.2025.110246. Online ahead of print.ABSTRACTMytilus live in water as sessile filter feeders, and the mantle tissue plays an important role in their immune defense. However, the overall knowledge of the immunity of this tissue remains limited. Peptidoglycan (PGN) and lipopolysaccharide (LPS) are the most representative microbe-associated molecular patterns (MAMPs) that play roles in the immune stimulation of host cells. In the present study, ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based metabolomic analysis was performed to understand the precise regulatory mechanism at the molecular level in the Mytilus mantle in response to PGN and LPS stress. Moreover, the antioxidant ability and free amino acid composition of the mantle, and the antimicrobial activities of mantle mucus were evaluated. Our results revealed that LPS and PGN stresses had different effects on the mantle's free amino acid composition and antioxidant ability, and the mantle mucus' antimicrobial activity. Both PGN and LPS stress-induced alterations in amino acids, phospholipids, fatty acids, nucleotides, and their derivatives in the mantle. PGN injection activated the amino acid-related metabolism, and inhibited the lipid-related metabolisms in the mantle, while LPS injection activated the amino acid-related metabolisms and inhibited the arachidonic acid metabolism in the mantle compared to that in the control group. In addition, activation of the mTOR and FoxO signaling pathways and inhibition of lipid-related metabolism were observed in PGN vs. LPS. In addition, PGN injection induced the upregulation of fosfomycin and deoxynojirimycin in the mantle compared to LPS injection. Our study highlights the different responses at the metabolomic level of the mussel mantle to different MAMPs and the potential application of metabolites that specifically respond to PGN and LPS challenges in mussels as biomarkers.PMID:40037495 | DOI:10.1016/j.fsi.2025.110246

Environ Pollut. 2025 Mar 2:125964. doi: 10.1016/j.envpol.2025.125964. Online ahead of print.ABSTRACTThe association of individual metals in PM2.5 with cardiovascular damage has been established in previous studies, but there are fewer studies on co-exposure to multiple metals and potential metabolic alterations in cardiovascular damage. To investigate the early cardiovascular effects of multiple metals and the mediating effects of metabolites, we conducted a panel study on young adults from 2017 Winter to 2018 Autumn in Caofeidian, China. A total of 180 serum samples were analyzed for metabolomic profiles using liquid chromatography-mass spectrometry. The associations between personal metal exposure, metabolite levels, and indicators of cardiovascular injury were analyzed by linear mixed-effects modeling (LEM) and Bayesian kernel machine regression (BKMR). Metabolomic analyses showed 79 metabolites in the serum of healthy adults changed significantly between seasons and all metabolites were strongly associated with toxic metals. Additionally, differential metabolites were enriched in seven metabolic pathways and activated by metal exposure, such as Butanoate metabolism and Linoleic acid metabolism. BKMR model interpreted that the overall effect of metals mixture was negatively associated with Capryloyl glycine and Sphinganine and Sb mainly contributed to the effect. The results of mediation analysis revealed that the association between V and VEGF was mediated by Diethylhexyl with a partial proportion of 13.4%. Furthermore, the result also found the association between CerP(d18:1/26:1(17Z)) and ET-1 was mediated by TGFβ1 with a proportion of 53.4%. Our findings suggested that multiple metal exposure was associated with metabolomic changes of cardiovascular damage in young adults, and may simultaneously affect the metabolomic changes by inducing oxidative stress and inflammation.PMID:40037427 | DOI:10.1016/j.envpol.2025.125964

Cell Metab. 2025 Feb 28:S1550-4131(25)00021-X. doi: 10.1016/j.cmet.2025.01.021. Online ahead of print.ABSTRACTBRAF V600E-inhibition effectively treats melanoma, but acquired resistance rapidly develops. Protein expression profiles, mitochondrial energetics, metabolomics and fluxomics data in cell line, xenograft, and patient-derived xenograft systems revealed that concerted reprogramming of metabolic pathways (including glutaminolysis, glycolysis, TCA cycle, electron transport chain [ETC], and transsulfuration), along with an immediate cytoprotective response to drug-induced oxidative stress, underpins drug-tolerant persister cancer cell survival. Realignment of cysteine (Cys) metabolism, in particular an immediate upregulation of cystathionine-γ-lyase (CSE), was vital in persister cells. The oxidative cellular environment, drug-induced elevated cystine uptake and oxidative Cys catabolism, increased intracellular cystine/Cys ratios, thereby favoring cystine as a CSE substrate. This produces persulfides and hydrogen sulfide to protect protein thiols and support elevated energy demand in persister cells. Combining BRAF V600E inhibitors with CSE inhibitors effectively diminished proliferative relapse in culture models and increased progression-free survival of xenografted mice. This, together with induced CSE expression in patient samples under BRAF-V600E-inhibition, reveals an approach to increase BRAF-V600E-targeted therapeutic efficacy.PMID:40037361 | DOI:10.1016/j.cmet.2025.01.021

Plant Physiol Biochem. 2025 Feb 26;222:109677. doi: 10.1016/j.plaphy.2025.109677. Online ahead of print.ABSTRACTThe genus Isodon is recognized as a primary source for the production of ent-kaurane-type diterpenes and previous studies predominantly focused on ent-kaurene and miltiradiene as the most extensively investigated diterpenes in Isodon. The diversity of diterpene synthases within this genus has recently been acknowledged, while such studies have been largely restricted to single species. In this study, we systematically mined and functionally validated diterpene synthases from three Isodon species using transcriptomic and metabolomic analyses. We identified the expression profiles of genes associated with diterpene biosynthesis and integrated these data with metabolomic results to elucidate their roles within the diterpene biosynthetic pathway. By reconstructing the metabolic pathways in Escherichia coli, we functionally characterized 11 diterpene synthases and elucidated the biosynthetic pathways of several diterpene skeletons originated from nor or ent-CPP, including the previously reported skeletons like ent-kaurene and miltiradiene, as well as four skeletons (ent-13-epi-sandaracopimaradiene, ent-neoabietadiene, abieta-8(14)-en-13-ol synthase and sandaracopimaradiene) whose biogenesis was reported in Isodon genus for the first time. This study provides novel insights into the molecular basis underlying diterpene diversity in Isodon and establishes a valuable resource for the development of new bioactive molecules and potential drug lead compounds.PMID:40037178 | DOI:10.1016/j.plaphy.2025.109677

Ecotoxicol Environ Saf. 2025 Mar 3;292:117967. doi: 10.1016/j.ecoenv.2025.117967. Online ahead of print.ABSTRACTExcessive intake of essential and toxic metals affects the pathological process of osteoporosis. At present, the effects of single forms of iron (Fe), lead (Pb) and other metals on bone injury have been widely studied. However, these metal elements usually do not exist in the environment in a separate form. They are ingested in various ways and are often found together in the human body. However, the mechanism of bone damage caused by Fe and Pb mixed exposure is still unclear at this stage. At present, the combined analysis of multi-omics is the conventional method to explore the molecular mechanism behind the disease. Therefore, we attempted to combine proteomics and metabolomics to explain the mechanism of bone damage caused by mixed Fe and Pb exposure. Differential proteins and metabolites were found to be predominantly enriched in the JAK-STAT signalling pathway, inflammatory bowel disease (IBD), and osteoclast differentiation. Combined analysis showed that Fpr2, Lifr, Lisofylline, 7-Ketocholesterol, LacCer (d18: 1/14:0) and other substances may be involved in the process of bone injury mediated by mixed metal exposure. In summary, we hypothesise that mixed exposure to Fe and Pb leads to osteoclast activation via the JAK-STAT signalling pathway in situ and indirectly via the gut-bone axis, resulting in bone damage. In general, our study potentially suggests that bone injury induced by mixed exposure of Fe and Pb may be related to osteoclast proliferation mediated by changes in inflammatory levels in vivo.PMID:40037083 | DOI:10.1016/j.ecoenv.2025.117967

Food Chem. 2025 Feb 26;477:143526. doi: 10.1016/j.foodchem.2025.143526. Online ahead of print.ABSTRACTThis study integrated non-targeted metabolomics with chemometric analyses to dissect the impact of varying shell ratios on the distribution of free (FP) and base-bound (BP) polyphenols from C. oleifera seeds during pressing. We quantified a comprehensive 209-parameter set, encompassing 177 individual polyphenols, via UPLC Q-TOF MS, and analyzed the data using multivariate statistical techniques. PCA model exposed intrinsic variability, while OPLS-DA model effectively distinguished the pairwise comparison samples, revealing 23 differential polyphenols with VIP scores >1 and P-value <0.05. OPLS model further revealed pronounced disparities in the polyphenol transfer from kernels to oils, indicating that FP were the primary drivers at lower shell ratios, while BP emerged as key contributors at higher ratios. These insights establish a scientific foundation for understanding the natural polyphenol transfer mechanisms in C. oleifera seeds, and contribute guidance for developing strategies for polyphenol retention and modulation during processing.PMID:40037042 | DOI:10.1016/j.foodchem.2025.143526

J Clin Endocrinol Metab. 2025 Mar 1:dgaf142. doi: 10.1210/clinem/dgaf142. Online ahead of print.ABSTRACTCONTEXT: While increased fiber intake may benefit appetite and metabolism in the general population, its effects in individuals with Prader-Willi Syndrome (PWS), a condition characterized by hyperphagia, obesity and metabolic dysregulation, remain to be explored.OBJECTIVES: This study assessed the effects of a fiber intervention on hyperphagia, metabolic health, and gut microbiota in individuals with PWS, and explored associations between changes in health markers and shifts in microbiota.METHODS: Participants received either a high-dose fiber intervention (35g/day) or a control for 3 weeks. Following a washout period of 4 to 8 weeks, participants switched treatments for another 3 weeks. Fecal (bacterial 16S ribosomal RNA) and blood (immunometabolic markers, targeted metabolomics) samples were collected before and after each treatment.RESULTS: Fourteen participants (with a median age of 13.6 years, 8 [57.1%] were female) reported high tolerance to the fiber intervention. While it did not significantly alter hyperphagia or key metabolic markers, the fiber intervention led to shifts in gut microbiota diversity and increased the abundance of beneficial bacteria, such as Bifidobacterium longum and Faecalibacterium prausnitzii. Additionally, it altered fecal and serum metabolites, including a decrease in branched-chain fatty acids and an increase in serum C4-OH acylcarnitine.CONCLUSION: While this study did not observe significant changes in primary or secondary endpoints, it suggests that a short-term high-fiber intervention may induce beneficial shifts in gut microbiota and microbial metabolites in individuals with PWS. Further research is warranted to investigate the long-term effects and potential therapeutic applications of fiber interventions in PWS.PMID:40036959 | DOI:10.1210/clinem/dgaf142

Nutr Rev. 2025 Mar 2:nuaf027. doi: 10.1093/nutrit/nuaf027. Online ahead of print.ABSTRACTThe dynamic balance between pro- and anti-inflammatory networks decreases as individuals age, and intestinal dysbiosis can initiate and maintain low-grade systemic inflammation. Interactions between the microbiota and humans occur from the beginning of life and, in general, the diversity of microbiota decreases with aging. The microbiome produces different metabolites with systemic effects, including immune system regulation. This understanding will be useful in controlling inflammation and preventing metabolic changes. Therefore, this review aims to identify the main metabolites synthesized by the intestinal microbiota to be used as biomarkers associated with longevity. This is a narrative review using scientific articles published in the last 10 years in the following databases: PubMed, Scielo, and Lilacs, using the Boolean operators "and" or "or." For this review, we identified 5 articles. The main metabolites described in the literature to date are organic acids, bile acids (BAs), short-chain fatty acids, branched-chain amino acids, trimethylamine N-oxide (TMAO), and derivatives of tryptophan and indole. Among these, the only ones not yet well characterized in studies on longevity were BAs and TMAO. Glutamate and p-cresol were also highlighted in the literature, with a negative association with longevity. The others showed an association, mostly positive, and can be used as potential biomarkers correlated with healthy aging and, if better studied, as targets for intervention to promote health and well-being.PMID:40036950 | DOI:10.1093/nutrit/nuaf027

Environ Toxicol Chem. 2025 Mar 1:vgaf056. doi: 10.1093/etojnl/vgaf056. Online ahead of print.ABSTRACTThe experimental design of New Approach Methodologies (NAMs) might deviate from common ecotoxicological studies, often requiring tailored statistical approaches. For instance, in NAMs developed for the detection of endocrine activity using aquatic vertebrate eleutheroembryos (Xenopus Eleutheroembryonic Thyroid Assay (XETA), Rapid Androgen Disruption Activity Reporter (RADAR) assay and Rapid Estrogen Activity In Vivo (REACTIV) assay), all concentration groups are nested within three independent study repeats, named 'runs' in the relevant Test Guidelines. Here, runs are referred to as replicates to emphasize their role as the repeated, independent entity. By contrast, for most other ecotoxicological studies the replicates are nested in the concentration groups. This leads to a different dependency structure for the XETA, RADAR and REACTIV assays. Disregarding this violates the basic statistical requirement for independence of observations potentially leading to incorrect conclusions. Unfortunately, in the statistical sections of the Test Guidelines of the XETA, RADAR and REACTIV assay, it is not clearly recommended to regard this dependency structure as statistical recommendations using a mixed ANOVA are provided only in the annexes. Here, we present "xeredar", an open-source R-package allowing automated statistical analysis of XETA, RADAR and REACTIV assays where the dependency structure of the data is correctly regarded through a mixed ANOVA. xeredar was validated on 36 XETA ring test studies and further tested on 41 RADAR ring test studies. A power analysis was carried out for the REACTIV assay, demonstrating that ignoring the dependency structure potentially leads to lower power and an increased false positive rate in comparison to the mixed ANOVA approach. The open-source R-package "xeredar" also comes with a Shiny app, making it accessible to everyone and thereby enhancing standardization and reproducibility for the statistical analyses of XETA, RADAR, and REACTIV assays.PMID:40036949 | DOI:10.1093/etojnl/vgaf056

J Proteome Res. 2025 Mar 4. doi: 10.1021/acs.jproteome.4c00795. Online ahead of print.ABSTRACTA nanosheath-flow capillary electrophoresis mass spectrometry (CE-MS) system with electrospray ionization was used to profile cationic metabolite cargo in exosomes secreted by nontumorigenic MCF-10A and tumorigenic MDA-MB-231 breast epithelial cells. An in-house-produced sheath liquid interface was developed and machined from PEEK to enable nanoflow volumes. Normalization of CE-MS peak areas to the total UV signal was employed to enhance quantitative accuracy and reduce variability. CE-MS-based metabolomics revealed increased purine synthesis intermediates and increased carnitine synthesis metabolites in MDA-MB-231-derived exosomes, with pathway enrichment indicating the activation of de novo purine pathways and upregulation of carnitine metabolism. In addition, nano-LC-MS-based proteomics revealed differential expression of ecto-5'-nucleotidase (NT5E) and mitochondrial aldehyde dehydrogenase (ALDH9A1), demonstrating metabolic alterations in related enzymatic steps. This study demonstrates the application of nanosheath-flow CE-MS for comprehensive and quantitative exosome metabolomics, uncovering metabolic reprogramming in purine and carnitine pathways between normal and cancerous breast cell lines and providing insight into exosome-mediated signaling of breast cancer metabolism.PMID:40036676 | DOI:10.1021/acs.jproteome.4c00795

Br J Dermatol. 2025 Feb 27:ljaf001. doi: 10.1093/bjd/ljaf001. Online ahead of print.ABSTRACTBACKGROUND: Prognosis and quality of life of advanced cutaneous T cell lymphoma (CTCL) patients, in particular those with Sézary syndrome (SS) and advanced-stage mycosis fungoides (MF), are poor. Monoclonal antibodies or antibody-drug conjugates (ADCs) have been implemented into CTCL therapy algorithms, but the spectrum of antibody-targetable cell-surface antigens on T cell non-Hodgkin lymphomas (T-NHL) is limited.OBJECTIVES: To evaluate expression of the MHC-II chaperone CD74 across common subtypes of CTCL by various methods, and to explore the efficacy of CD74-targeting of CTCL cells by anti-CD74 antibody-drug conjugate (ADC) in vitro and in vivo.METHODS: We comprehensively investigate expression of CD74 in well-defined CTCL cell lines by PCR analyses, immunoblotting and flow cytometry. More than 140 primary CTCL samples of all common entities are analyzed by immunohistochemistry, flow cytometry, immunofluorescence and 'co-detection by indexing' (CODEX) multiplexed tissue imaging as well as single-cell RNAseq analyses. DNA methylation of CTCL cell lines is interrogated by generation of genome-wide methylation profiling. The effect of a maytansinoid-conjugated humanized ADC against CD74 is investigated on CTCL cell lines in vitro, alone or in combination with gemcitabine, and in vivo after xenotransplantation of CTCL cell lines in NOD-scid Il2rgnull (NSG) mice.RESULTS: We demonstrate by different experimental approaches in CTCL cell lines and a broad collection of primary CTCL samples that CD74 is widely and robustly expressed in CTCL cells. Additionally, CD74 expression in SS and MF is confirmed by analyses of single cell (sc)RNA-seq data, and correlates in CTCL cell lines with CD74 gene DNA hypomethylation. CD74 is rapidly internalized in CTCL cells, and CD74 targeting by the ADC STRO-001 efficiently kills CTCL-derived cell lines. Finally, CD74 targeting synergizes with conventional chemotherapy in vitro, and eradicates murine xenotransplants of CTCL cell lines in vivo.CONCLUSIONS: CD74 is expressed across common CTCL subtypes, and CD74-targeting efficiently kills CTCL cells in vitro and in vivo. Our data thus identify CD74-targeting as highly promising treatment strategy for CTCL.PMID:40036608 | DOI:10.1093/bjd/ljaf001

Anal Chem. 2025 Mar 4. doi: 10.1021/acs.analchem.4c06682. Online ahead of print.ABSTRACTAchyrocline satureioides have good therapeutic effects on nonsmall cell lung cancer (NSCLC). Nevertheless, it is still challenging to elucidate the active ingredients and mechanism of action due to their complex chemical composition. To address this, we innovatively combined network pharmacology with spatial metabolomics to comprehensively investigate the active components and the action mechanism in the present study. First, metabolomics of cells treated with the methanol extract of A. satureioides (ASM) utilizing high-resolution ultrahigh-performance liquid chromatography tandem mass spectrometry (HR-UHPLC-MS/MS) revealed 32 changed metabolites and 7 enriched metabolic pathways, confirming the anti-NSCLC effect of ASM and its impact on endogenous metabolites at the cellular level. Then, 69 chemical components in the ASM were identified using HR-UHPLC-MS/MS, followed by the screening of 6 core components and 10 core targets of anti-NSCLC with the help of network pharmacology and molecular docking. Lastly, quercetin, the most abundant compound among the six core active ingredients, was chosen for evaluating its anti-NSCLC effect and the potential mechanism using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). 51 altered endogenous metabolites were screened, and pathway enrichment analysis results were consistent with cell metabolomics, corroborating our network pharmacology predictions. In addition, we also observed the accumulation of three metabolites of quercetin in the tumor tissues. Network pharmacology combined with MSI elucidated the metabolic mechanisms by which A. satureioides treats NSCLC, offering new insights into herbal cancer therapies.PMID:40036484 | DOI:10.1021/acs.analchem.4c06682

J Chem Inf Model. 2025 Mar 4. doi: 10.1021/acs.jcim.4c02212. Online ahead of print.ABSTRACTPredicting blood-brain barrier (BBB) penetration is crucial for developing central nervous system (CNS) drugs, representing a significant hurdle in successful clinical phase I studies. One of the most valuable properties for this prediction is the polar surface area (PSA). However, molecular structures are missing geometric optimization, which, together with lack of standardization, leads to variations in calculation. Additionally, prediction rules have been established by combining different molecular properties such as the BBB score or CNS multiparameter optimization (CNS MPO). This study aims to create an approach for 3D PSA calculation, to directly apply this value in combination with a set of 23 other parameters in a novel machine learning (ML)-based scoring, and to further evaluate existing prediction models using a standardized database. We developed and analyzed a standardized data set derived from the same laboratory, encompassing 24 calculated and experimentally determined molecular parameters such as PSA from various models, HPLC log P values, and hydrogen bond characteristics for 154 radiolabeled molecules and licensed or well-characterized drugs. These molecules were classified into categories based on BBB penetration, nonpenetration, and interactions with efflux transporters. We supplemented these with a novel in silico 3D calculation of nonclassical PSA. Additionally, we have calculated published prediction rules based on this standardized and transparent database. Using these data, we trained various ML models within a 100-fold Monte Carlo cross-validation framework to derive a novel ML-based prediction score for BBB penetration and validated the three most used existing predictive rules. To interpret the influence of individual molecular parameters and different existing predictive rules, we employed explainable artificial intelligence methods including Shapley additive explanations (SHAP) and surrogate modeling. The ML approach outperformed existing scores for BBB penetration by applying a complex nonlinear integration of molecular properties, with the random forest model achieving the best performance for predicting binary BBB penetration (area under the receiver operating characteristic curve (AUC) 0.88, 95% confidence intervals: 0.87-0.90), and multiclass efflux transporter versus CNS-positive and CNS-negative prediction (AUC 0.82, 95% CI: 0.81-0.82). SHAP analysis revealed the multifactorial nature of the problem, highlighting the advantage of multivariate models over single predictive parameters. The ML model's superior predictive capability was demonstrated in comparison with existing scoring systems, like the CNS MPO (AUC 0.53), the CNS MPO Positron emission tomography (PET) (AUC 0.51), and BBB score (AUC 0.68) while also enabling the identification of efflux transporter substrates and inhibitors. Our integrated ML approach, combining experimental and in silico measurements with novel in silico methods based on a standardized database including a plethora of different substance groups (licensed drugs and in vivo evaluated PET tracers), enhances the prediction of BBB penetration. This approach may reduce the reliance on extensive experimental measurements and animal testing, accelerating CNS drug development.PMID:40036481 | DOI:10.1021/acs.jcim.4c02212

Am J Epidemiol. 2025 Feb 24:kwaf033. doi: 10.1093/aje/kwaf033. Online ahead of print.ABSTRACTEmerging evidence links per- and polyfluoroalkyl substances (PFAS) exposure and metabolic disruptions to fetal growth retardation. However, earlier studies on singletons couldn't fully account for genetic factors. Therefore, we used a co-twin control study design to identify cord metabolomic signatures of PFAS exposure and assess its mediating role in twin birthweight discordance. We analyzed 204 twin neonates born from the Wuhan Twin Birth Cohort (August 2016-January 2018). Cord serum PFAS concentrations and untargeted metabolomic profiles were determined using liquid chromatography-tandem mass spectrometry. Within-twin metabolome-wide association analyses identified 69 metabolites (effect coefficients: 0.09-0.35) positively associated with log2-transformed perfluorooctanoic acid (PFOA) difference and 51 metabolites (effect coefficients: 0.08-0.38) positively associated with log2-transformed perfluoroheptane sulfonate (PFHpS) difference after false discovery rate (FDR) correction. PFAS-associated metabolites were primarily enriched in steroid hormone biosynthesis, arginine and proline metabolism, glycerophospholipid metabolism, and unsaturated fatty acid biosynthesis pathways. Five amino acids, one carbohydrate, one cofactor and vitamin, and five lipids mediated the relationship between PFHpS exposure difference and intra-twin birthweight difference, with mediation proportions ranging from 32.0% to 72.7%. This study is the first to use a within-twin comparison, providing new insights into the underlying mechanisms linking PFAS exposure with twin birthweight discordance.PMID:40036346 | DOI:10.1093/aje/kwaf033

J Anim Sci. 2025 Feb 27:skaf054. doi: 10.1093/jas/skaf054. Online ahead of print.ABSTRACTDespite the rising popularity of plant-based (vegan) diets for dogs, the metabolic effects of plant-based diets in dogs have not been thoroughly investigated. Evaluating the impact of a vegan diet on the fecal metabolome in dogs could offer valuable insight into the effects on gastro-intestinal and overall health. This study evaluated the fecal metabolic signature of an experimental extruded vegan diet (PLANT) compared to a commercial extruded animal-based diet (MEAT) in healthy adult dogs. Sixty-one client-owned healthy adult dogs completed a randomized, double-blinded longitudinal study consisting of a 4-week acclimation period, where all dogs received the MEAT diet, followed by a 12-week experimental period where they either continued with the MEAT diet or switched to the PLANT diet. Fecal collections occurred at baseline (after 4-week acclimation) and exit (after the experimental period). Fecal metabolites were quantified using 1H NMR spectroscopy. Multiple mixed model gamma linear regression was used to evaluate the association of metabolite concentration against age, sex, and body weight (BW), along with an interaction between diet and time. Sixty-six metabolites were quantified. Only 2/66 metabolites differed between groups at baseline and within the MEAT diet group over time. In contrast, 46/66 metabolites differed in concentrations over time in response to feeding the PLANT diet. At the exit time-point, dogs fed the PLANT diet had increased metabolites related to carbohydrate fermentation, such as acetic (p<0.01) and propanoic (p<0.01) acid and increases in sugar metabolites when compared to the MEAT group. These findings indicate that the fecal metabolic signature of dogs fed a plant-based diet is distinct from dogs fed an animal-based diet, even if both diets have a similar nutrient profile and are processed similarly.PMID:40036327 | DOI:10.1093/jas/skaf054

PLoS One. 2025 Mar 4;20(3):e0318557. doi: 10.1371/journal.pone.0318557. eCollection 2025.ABSTRACTMetabolic Dysfunction-Associated Steatohepatitis (MASH) represents the severe condition of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Currently, there is a need to identify non-invasive biomarkers for an accurate diagnosis of MASH. Previously, omics studies identified alterations in lipid metabolites involved in MASLD. However, these studies require validation in other cohorts. In this sense, our aim was to perform lipidomics to identify the circulating lipid metabolite profile of MASH. We assessed a liquid chromatography coupled to a mass spectrometer-based untargeted lipidomic assay in serum samples of 216 women with morbid obesity that were stratified according to their hepatic diagnosis into Normal Liver (NL, n = 44), Simple Steatosis (SS, n = 66) and MASH (n = 106). First, we identified a profile of lipid metabolites that are increased in MASLD, composed of ceramides, triacylglycerols (TAG) and some phospholipids. Then, we identified that patients with SS have a characteristic profile of increased levels of ceramides, diacylglycerols DG (36:2) and DG (36:4), some TAG and a few phospholipids such as PC (32:1), PE (38:3), PE (40:6), PI (32:0) and PI (32:1). Later, in MASH patients, we found increased levels of ceramides, deoxycholic acid, a set of TAG, and some phospholipids such as PC, PE, PI and LPI; while we found decreased levels of the DG (36:0). Finally, we have reported a panel of lipid metabolites that might be used to differentiate patients with MASH from SS patients, made up of increased levels of 9-HODE some PC and PE, the LPI (16:0) and decreased levels of DG (36:0). To conclude, our investigation has suggested a lipid metabolite profile associated with MASLD and MASH. Specifically, a set of lipid metabolites seems to be discriminatory in MASH subjects compared to SS individuals. Thus, this panel of lipid metabolites could be used as a non-invasive diagnostic tool.PMID:40036208 | DOI:10.1371/journal.pone.0318557

J Proteome Res. 2025 Mar 4. doi: 10.1021/acs.jproteome.4c00715. Online ahead of print.ABSTRACTCoal worker's pneumoconiosis (CWP) is characterized by chronic inflammation and pulmonary fibrosis. The key factor contributing to the incurability of CWP is the unclear pathogenesis. This study explored the characteristic changes in proteomics and metabolomics of early and advanced CWP patients through proteomics and metabolomics techniques. Proteomics identified proteins that change with the progression of CWP, with significant enrichment in the TGF-β signaling pathway and autoimmune disease pathways. Metabolomics revealed the metabolic characteristics of CWP at different stages. These metabolites mainly include changes in amino acid metabolism, unsaturated fatty acid synthesis, and related metabolites. Integrated analysis found that ABC transporters are a shared pathway among the three groups, and ABCD2 is involved in the ABC transporter pathway. In the subsequent independent sample verification analysis, consistent with proteomics experiments, compared to the CM group, FMOD expression level was upregulated in the NIC group. TFR expression level was consistently downregulated in both the IC and NIC groups. Additionally, ABCD2 increased in the IC group but decreased in the NIC group. In summary, this study revealed the metabolic characteristics of CWP at different stages. These findings may provide valuable insights for the early prediction, diagnosis, and treatment of CWP.PMID:40036136 | DOI:10.1021/acs.jproteome.4c00715

Eur J Nutr. 2025 Mar 4;64(3):106. doi: 10.1007/s00394-025-03627-8.ABSTRACTPURPOSE: Assessing the health impacts of nutritional interventions in metabolically compromised but otherwise healthy individuals is challenging, necessitating sensitive tools. Phenotypic flexibility offers an innovative way to measure homeostatic capacity during challenge tests. A composite biomarker of inflammatory resilience has proven useful in evaluating the health benefits of whole-grain wheat interventions in overweight and obese individuals. Expanding this method to other dietary interventions to combat low-grade inflammation is essential.METHODS: This study investigated the feasibility of a composite biomarker of inflammatory resilience through secondary analysis of samples from two independent energy restriction (ER) trials, Bellyfat (NCT02194504) and Nutritech (NCT01684917). In these trials, fasting and postprandial inflammation was analysed using a variety of markers. Four composite biomarker models were developed on the basis of postprandial inflammatory marker responses via the 'health space' model method. These models were statistically evaluated for their sensitivity in detecting the effects of 12 weeks of ER.RESULTS: The minimal composite biomarkers, consisting of IL-6, IL-8, IL-10, and TNF-α, lacked the ability to detect postprandial intervention effects in both ER trials. However, in the Nutritech study, the extended, endothelial, and optimized composite biomarkers of inflammatory resilience displayed significant responses to the ER (all P < 0.005). In the latter 3 models, a reduction in the inflammatory score was correlated with a reduction in BMI and body fat percentage.CONCLUSION: This study underscores the feasibility of employing a composite biomarker of inflammatory resilience to evaluate ER interventions. Further validation in additional nutritional intervention studies is necessary. Once validated, this composite biomarker could offer a novel approach for assessing low-grade inflammation and phenotypic flexibility.PMID:40035864 | DOI:10.1007/s00394-025-03627-8