PubMed

Phytomedicine. 2025 Mar 22;141:156676. doi: 10.1016/j.phymed.2025.156676. Online ahead of print.ABSTRACTBACKGROUND: Ticagrelor (TG), a first-line treatment for myocardial infarction (MI), is limited in its clinical application due to the risk of elevated uric acid (UA) levels. Salvianolate injection (SAL), an adjunctive therapy for MI, has been reported to have potential for UA reduction. Although the combined use of TG and SAL has been reported in clinical practice, no studies have focused on the optimal ratio for the combination or the mechanisms underlying their synergistic effects on MI and UA reduction.OBJECTIVE: This study follows the principle of enhancing efficacy and reducing toxicity through combination therapy. It aims to explore the optimal combination ratio (low-dose combination group: 10 mg/kg TG + 10 mg/kg SAL; medium-dose combination group: 10 mg/kg TG + 20 mg/kg SAL; high-dose combination group: 20 mg/kg TG + 20 mg/kg SAL) by evaluating both UA-lowering and anti-MI activities. Additionally, the study investigates the underlying mechanisms of anti-hyperuricemia and anti-MI through metabolomics and transcriptomics, in hopes of providing insights into rational clinical use of these drugs.METHODS: Kidney H&E staining, biochemical assays (UA, BUN, XOD, CRE), in vitro XOD detection, UA transporter protein analysis (GLUT9, OAT1, ABCG2, URAT1), and bioinformatics (PI3K/AKT) were used to assess anti-hyperuricemic activity under different combination ratios. ECG, echocardiography, biochemical assays (CK, LDH), ELISA (cTnT), and H&E staining were employed to evaluate anti-MI activity. The optimal combination ratio was determined based on both anti-hyperuricemic and anti-MI effects, and metabolomics and transcriptomics were used to explore the mechanisms of anti-hyperuricemia and anti-MI for this ratio.RESULTS: The TG-SAL combination reduced TG-induced hyperuricemia by enhancing renal function, UA excretion, and PI3K-AKT expression, as well as inhibiting UA reabsorption and production. Simultaneously, the combination alleviated cardiac injury and restored abnormal cardiac function, demonstrating anti-MI activity. Among the groups, the medium-dose combination showed the best synergistic effect. Further, metabolomics indicated that the anti-hyperuricemic mechanism of the medium-dose combination was related to the positive regulation of selenium compound metabolic pathways. Transcriptomics revealed that the anti-MI activity of the medium-dose combination was associated with the inhibition of cardiac muscle contraction pathways.CONCLUSION: The TG-SAL combination exhibited ideal synergistic effects in enhancing anti-MI activity and reducing TG-induced hyperuricemia, with the medium-dose combination demonstrating the best results. Mechanistically, the medium-dose combination exerted anti-hyperuricemic effects by positively regulating selenium compound metabolic pathways and anti-MI activity by inhibiting cardiac muscle contraction pathways. These findings provide a reference for the rational use of TG and SAL in clinical settings.PMID:40209643 | DOI:10.1016/j.phymed.2025.156676

Water Res. 2025 Apr 5;280:123599. doi: 10.1016/j.watres.2025.123599. Online ahead of print.ABSTRACTMost studies on the biological effects of exogenous pollutants have focused on whole samples or cell populations, and lack spatial heterogeneity consideration due to technical limitations. Microcystin-LR (MC-LR) from cyanobacterial blooms threatens ecosystems and human health, while microcystin-LR disinfection by-products (MCLR-DBPs) in drinking water remain a concern for their toxin-like structure. This study introduces spatial multi-omics to investigate the disruptions caused by ingestion of MC-LR and MCLR-DBPs in zebrafish. The method integrates metabolomics, spatial metabolomics, and spatial transcriptomics to characterize the overall metabolic changes in whole zebrafish caused by MC-LR and MCLR-DBPs, then provides further insight into the variation of spatial distribution of metabolites and genes in MC-LR and MCLR-DBPs targeted organ. The results showed that MC-LR and MCLR-DBPs induced oxidative stress and metabolic imbalance, and disrupted the physiological homeostasis of zebrafish. Spatial multi-omics analysis further revealed that MC-LR and MCLR-DBPs exacerbate disruptions in energy and lipid metabolism, methylation processes, and immune pathways by modulating the expression of genes such as gatm, gnmt, cyp2p9, and tdo2b. In conclusion, this study developed a spatial multi-omics approach that not only enhances the understanding of the biological effects of MC-LR and MCLR-DBPs but also provides robust technical support for investigating other environmental pollutants.PMID:40209558 | DOI:10.1016/j.watres.2025.123599

J Chromatogr B Analyt Technol Biomed Life Sci. 2025 Mar 19;1257:124564. doi: 10.1016/j.jchromb.2025.124564. Online ahead of print.ABSTRACTAlthough untargeted metabolomics holds promise for study of metabolites in human health and disease, robust method development and optimization are needed to reduce potential analytical biases and to ensure comprehensive, high-throughput results. In this study, the effect of mass spectrometer (MS) ion source parameters on the signal reproducibility and number of metabolite annotations during untargeted metabolomics is shown. Furthermore, different mobile phase gradients and columns (five reversed phase (RP)-C18 and two hydrophilic interaction liquid chromatography (HILIC) columns) were evaluated for untargeted metabolomics of blood plasma extracts. Positioning the electrospray needle at the farthest on the Z-direction and the closest tested position on the Y-direction with respect to the mass spectrometry inlet produced the best signal reproducibility and the greatest number of metabolite annotations. Moreover, optimal ion source conditions included a positive spray voltage between 2.5 and 3.5 kV, a negative spray voltage between 2.5 and 3.0 kV, vaporization and ion transfer tube (ITT) temperature between 250 and 350 °C, 30 to 50 arbitrary units of sheath gas, and at least 10 auxiliary gas units. Despite the differences in chromatographic characteristics, the different RP columns assessed showed comparable performance in terms of number of metabolites annotated. For HILIC columns, a zwitterionic column demonstrated better performance than an amide column. Finally, as compared with use of a RP column alone, use of both the optimal RP and HILIC approaches expanded metabolome coverage: the number of metabolites annotated increased by 60 %. This study highlights the significance of fine-tuning the MS ion source parameters and optimizing chromatographic conditions on metabolome coverage during untargeted metabolomics of plasma samples.PMID:40209549 | DOI:10.1016/j.jchromb.2025.124564

J Pharm Biomed Anal. 2025 Apr 5;262:116870. doi: 10.1016/j.jpba.2025.116870. Online ahead of print.ABSTRACTPlasma cell mastitis (PCM), a chronic breast inflammatory disease, is characterized by ductal dilatation and plasma cell infiltration. Traditional Chinese Medicine (TCM) Yanghe decoction is used to relieve mastitis symptoms clinically. However, its efficacy and mechanism on PCM remain undefined. The PCM patients receiving dexamethasone and metronidazole tablets, served as control group, with the other group receiving combination of Yanghe decoction, 15 cases each. Main symptom indicators included mass size, skin colour, skin temperature, breast pain, blood cell count (WBC), C reactive protein (CRP), interleukin (IL)-6, IL-4, serum prolactin (PRL), erythrocyte sedimentation rate (ESR), immunoglobulin A (IgA), IgM, and IgG levels. Secondary indicators included TCM syndrome and anxiety/depression scores. Breast differential flora (DF) and metabolites (DAMs) post-treatment between two groups were detected by 16S rRNA sequencing and metabolomics, with further correlation analysis. Post-treatment symptom scores exhibited lower than pre-treatment in both groups, with greater decline on WBC, CRP, IL-6, IL-4, PRL, and ESR, and enhanced IgA, IgM, and IgG levels in Yanghe decoction group than in control group. Notably, Yanghe decoction group demonstrated no significant DF, with decreased Corynebacterium and Rhodococcus, and elevated Staphylococcus, which correlated significantly with the above indicators. Moreover, 43 DAMs were detected between these two groups, with Glycerophosphocholine, 9,10-Epoxyoctadecenoic acid, Arachidic acid, and 4,5-Dihydroorotic acid showing strong correlations with the above flora. Based on the clarification of PCM improvement with Yanghe decoction, we preliminarily explored potential roles of breast tissue microorganisms and DAMs, providing scientific basis for its clinical application and potential clinical biomarkers in PCM.PMID:40209500 | DOI:10.1016/j.jpba.2025.116870

J Pharm Biomed Anal. 2025 Mar 29;262:116830. doi: 10.1016/j.jpba.2025.116830. Online ahead of print.ABSTRACTThis study was aimed to explore the alleviating effect of black rice (BR), black peeled rice (BPR), and black rice bran (BRB) on lipid metabolism disorders in hyperlipidemia mice caused by high fat and cholesterol diet (HFCD). Combined untargeted metabolomics and RNA-seq transcriptomics analysis was used to demonstrate the potential mechanism regulated by BR, BPR and BRB. The untargeted metabolomics analysis indicated that BR especially BRB significantly increased Deoxycholic acid, 5-Dehydroavenasterol, scyllo-Inositol, Phloretin, 5-KETE, Lipoxin B4, 3,4-Dihydroxybenzeneacetic acid levels, while BRB significantly regulated PPAR signaling pathway, Arachidonic acid metabolism, Regulation of lipolysis in adipocytes, Steroid biosynthesis, and Sphingolipid signaling pathway, which closely linked to lipid metabolism. Furthermore, RNA-seq transcriptomics analysis showed that BRB obviously regulated Steroid hormone biosynthesis (Cyp2b9, Cyp2b13 and Cyp2c38) and PPAR signaling pathway (Pparg, Fabp4, Cd36 and Plin4), which were closely associated with inflammation and lipid metabolism. Moreover, quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) analysis validated this. The obtaining results were hoping to reveal the detailed mechanism of BRB in alleviating hyperlipidemia and provide some insights for developing a new kind of natural anti-hyperlipidemia drug.PMID:40209499 | DOI:10.1016/j.jpba.2025.116830

J Pharm Biomed Anal. 2025 Apr 4;262:116869. doi: 10.1016/j.jpba.2025.116869. Online ahead of print.ABSTRACTKnee osteoarthritis (KOA)is an age-related degenerative whole-joint disease characterized by poor outcomes. Wenjing Tongluo Decoction (WJTLD), a Chinese herbal remedy, has demonstrated favorable clinical effects on KOA. However, the precise mechanisms therein remain poorly defined. In this study, we employed the method of anterior cruciate ligament transection (ACLT) method to establish a rat model of KOA. Following 8 weeks of oral administration of WJTLD, the morphology of knee joint cartilage was evaluated using Safranin-O/Fast green staining, H&E staining, and micro-CT imaging. Utilizing GC-MS based untargeted metabolomics and nano-LC-QE-MS based proteomics, we identified altered metabolites and proteins associated with knee cartilage in different rat groups, which were further validated through western blotting and real-time PCR. Our findings indicate that WJTLD alleviates damage to knee joint cartilage and inhibits cartilage degradation. Proteomics data revealed that the altered proteins in OA and WJTLD treated group were related to the biological process including amoebiasis, platelet activation, ECM-receptor interaction, protein digestion and absorption, and ribosome function. Western blotting results confirmed that the expression levels of MMP8 and LDHA were significantly upregulated in the KOA group but were rescued by WJTLD treatment. According to untargeted metabolomics, the intensities of lactic acid, isoleucine, lysine, glutamate, myo-inositol, adenosine, and β-alanine were significantly elevated in the KOA group, however, these metabolites experienced a dramatic following WJTLD treatment. These results suggest that WJTLD exerts a therapeutic effect on KOA by suppressing inflammation and cartilage degradation, as well as regulating multiple pathways related to ECM degradation, amino acid metabolism, and energy metabolism, including glycolysis.PMID:40209497 | DOI:10.1016/j.jpba.2025.116869

Poult Sci. 2025 Mar 15;104(5):105043. doi: 10.1016/j.psj.2025.105043. Online ahead of print.ABSTRACTWenchang chicken, renowned for its high-quality meat, is the economic meat breed in Hainan Province, China. This study compared cage-rearing (CR) and free-range (FR) groups in terms of growth performance, slaughter performance, meat quality, IMP (inosine monophosphate) content, AAs, FAs, serum lipid metabolites, and transcriptomic and metabolomic analyses. The CR group showed increased body weight, live weight, and abdominal fat but lower leg muscle percentage and breast muscle redness, suggesting flavor differences. CR chickens had higher IMP, threonine (Thr), and pentadecanoic, oleic, and linoleic acids, while glutamate (Glu) and alpha-linolenic acid were lower compared to FR. Glycine was elevated, but histidine, myristic, and tricosanoic acids were lower in CR leg muscle. Serum analysis revealed higher total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), fatty acid synthase (FAS), thyroid-stimulating hormone (TSH), leptin (LEP), and adiponectin (ADP) in the CR group. Transcriptomic and metabolomic studies identified 252 differentially expressed genes and 34 metabolites linked to metabolic pathways. In summary, CR system can improve production performance, FR system is considered more flavorful. The results can act as a theoretical basis for selecting a suitable rearing method for this unique breed.PMID:40209466 | DOI:10.1016/j.psj.2025.105043

J Hazard Mater. 2025 Apr 7;492:138204. doi: 10.1016/j.jhazmat.2025.138204. Online ahead of print.ABSTRACTZinc (Zn) is an essential micronutrient for plants, but excessive concentrations induce cytotoxicity. As one of the world's primary crops, rice's response mechanisms to Zn toxicity remain poorly understood. In this study, we characterized a rice mutant, NG3-6, which exhibited enhanced sensitivity to Zn toxicity compared to the wild type (WT). At Zn concentrations of 40 μM and above, NG3-6 displayed severe toxicity symptoms, including reduced primary root length, plant height, and dry weight, whereas the WT plants maintained normal growth until Zn concentrations exceeded 400 μM. The mutant demonstrated a higher Zn uptake capacity in roots, leading to increased Zn accumulation across all tissues. This higher Zn accumulation was correlated with elevated reactive oxygen species (ROS) production. Zn toxicity induced the accumulation of oxidative stress-related metabolites, such as L-proline, glutathione, and water-soluble sugars, in both the mutant and WT. However, NG3-6 showed distinct metabolic alterations in response to high Zn treatment, including significant accumulation of certain metabolites associated with the pentose phosphate pathway, amine biosynthesis, and benzoic acid-related pathways, concurrent with reduced flavonoid biosynthesis. These findings advance our understanding of the molecular mechanisms underlying root adaptive strategies to Zn toxicity in plants.PMID:40209416 | DOI:10.1016/j.jhazmat.2025.138204

Environ Int. 2025 Apr 6;198:109441. doi: 10.1016/j.envint.2025.109441. Online ahead of print.ABSTRACTNanoplastics (NPs) have been widely detected in freshwater environments and photodegradation, as well as physical and chemical breakdown, lead to different surface charges on the plastics. Although evidence in the literature highlights the importance of NPs surface charge to neurotoxicity, substantial gaps in mechanistic understanding remain. In the current study, zebrafish (Danio rerio) were exposed to differentially charged NPs (PS, PS-NH2, PS-COOH) at environmentally relevant concentration (10 μg/L). After full life cycle exposure, the potential neurotoxicity, brain damage, and the altered brain metabolism was investigated through light sheet microscopy 3-dimensional imaging, histopathology, Evans blue dye (EBD) extravasation, gene expression, and untargeted and targeted metabolomics of brain tissue in zebrafish. Exposure to PS, PS-NH2, PS-COOH caused adverse effects on the performance of neurobehaviors, blood-brain-barrier (BBB) permeability, amino acid metabolism, damage to the BBB and mitochondria, and overt inflammatory response. PS-NH2 (4.56-fold) and PS-COOH (3.59-fold) accumulated in the reticular formation (RF) of the male brain, while only PS-NH2 was detected in the RF (6.57-fold) and ventral hypothalamus (Hv) (3.08-fold) of female brains. Several important biological pathways were negatively impacted in a charge- and gender-specific fashion. This study provides novel insights into the underlying toxicity mechanisms of differentially charged NPs in a model aquatic species, as well as the associated environmental risks of this important group of emerging contaminants.PMID:40209392 | DOI:10.1016/j.envint.2025.109441

Food Chem. 2025 Apr 5;482:144198. doi: 10.1016/j.foodchem.2025.144198. Online ahead of print.ABSTRACTDriven by the need for sustainable agriculture, using Lycium barbarum (goji) sawdust as a substrate for mushroom cultivation increases productivity while reducing environmental impact. This study evaluates the effects of different proportions of goji sawdust on the growth, yield, and metabolic profiles of pink A. cornea. Six substrate formulations were tested, with 16 % goji sawdust supporting optimal yield and quality. LC-MS/MS-based metabolomics identified 1335 metabolites, mainly organic acids and derivatives, lipids and lipid-like molecules, organoheterocyclic compounds, and benzenoids. Biomarker analysis revealed twenty to thirty-five metabolites associated with substrate variations. KEGG enrichment highlighted key metabolic pathways, including ABC transporters, amino acid biosynthesis, D-amino acid metabolism, and aminoacyl-tRNA biosynthesis, contributing to substrate adaptation. While this study offers insights into the metabolic responses of pink A. cornea to goji sawdust, future research should incorporate absolute biomarkers quantification to further validate these results and optimize substrate compositions.PMID:40209374 | DOI:10.1016/j.foodchem.2025.144198

Food Chem. 2025 Apr 1;482:144178. doi: 10.1016/j.foodchem.2025.144178. Online ahead of print.ABSTRACTGut bacteria have a significant impact on modern genetics and contribute to the improvement of aquatic germplasm, which is a key focus for breeders. However, the effects of complex interactions between gut bacteria community and phenotypic trait of aquatic products remain largely unknown. Here, we unravel the association between phenotypic trait, gut microbiota and host metabolic variables of 216 sea cucumbers (Apostichopus japonicus) by Metagenome-wide association studies (MWAS) and Weighted correlation network analysis (WGCNA) methods. Our findings reveal that a total of 14 microbial biomarkers and 201 metabolic markers considered being associated with polysaccharide and collagen content. Among them, Desulfobacterota has the capacity to facilitate the synthesis of octopamine within the neuroactive ligand-receptor metabolic pathway, subsequently influencing polysaccharide content. Additionally, the Lachnospiraceae_NK4A136_group was shown to enhance collagen content through the facilitation of glycine synthesis. In conclusion, this research indicating that precision microbiome management could be a strategy for develop strategies for cultivating high-quality aquatic germplasm.PMID:40209373 | DOI:10.1016/j.foodchem.2025.144178

Aquat Toxicol. 2025 Apr 4;283:107355. doi: 10.1016/j.aquatox.2025.107355. Online ahead of print.ABSTRACTBroflanilide is a novel bisamide insecticide that is extensively used. Previous study reported that broflanilide induced neurotoxicity during zebrafish embryonic development, however, its behavior impact and the involved neural cell heterogeneous mechanism remains largely unknown. Here, we performed a series of neuro-behavior test for adult zebrafish that were exposed to 5 and 25 μg/L broflanilide for 30 days. We found that 25 μg/L broflanilide could induce abnormal locomotion and cognitive defect. These changes were accompanied by synaptic homeostasis inference (decreased number of synaptic knobs), and neuron loss. Simultaneously, a targeted metabolomic assay showed that the glutathione metabolism and GABAergic synapses in brain were significantly altered, indicating an altered synaptic transmission, which is consistent with the synaptic injury. Single-cell RNA sequencing of zebrafish brain showed changed cell composition after exposure, including a decreased ratio of neuron and oligodendrocyte, and an increased proportion of astrocytes. Meanwhile, genes involved in synaptic functional pathways were altered in neuron, astrocyte and oligodendrocytes, which partly explained the disruption of synaptic homeostasis. These findings reveal the long-term risk of broflanilide toward neural health of aquatic organisms and suggest an across-cell types transcriptional regulation in mediating the neurotoxicity.PMID:40209298 | DOI:10.1016/j.aquatox.2025.107355

Aquat Toxicol. 2025 Apr 5;283:107354. doi: 10.1016/j.aquatox.2025.107354. Online ahead of print.ABSTRACTDimethyl sulfoxide (DMSO) is a widely used solvent in biological research due to its ability to enhance membrane permeability, facilitating drug delivery and molecular transport across cellular membranes. However, its effects on cellular metabolism, especially at low concentrations, remain insufficiently understood. This study investigated the metabolic disruptions induced by 0.1-10 % DMSO in the RTgill-W1 fish cell line, focusing on changes in cell viability, oxidative stress, and key metabolic pathways. Results revealed that DMSO exposure caused dose-dependent declines in cell viability at 0.5 % DMSO and increases in reactive oxygen species (ROS) at 4 % and higher, indicating elevated oxidative stress. Metabolomic profiling revealed altered levels of numerous metabolites and significant impacts on 41 metabolic pathways belonging to five major functional groups: amino acid metabolism, carbohydrate metabolism, lipid metabolism, vitamin and co-factor metabolism, and nucleotide metabolism. The effects were observed across all exposure concentrations (0.1, 0.5, 1, 4, and 8 %), with more pronounced impacts at higher concentrations. These findings highlight that DMSO, even at low concentrations (≤ 0.5 %), can have widespread effects on cellular metabolism, impacting experimental outcomes in in vitro studies. This study provides valuable insights into the biochemical impacts of DMSO on fish cell lines and emphasizes a caution in using DMSO in biological research to minimize unintended cellular effects. Additionally, it highlights the critical need to include solvent controls at matching concentrations to accurately distinguish solvent-induced effects from those caused by experimental treatments.PMID:40209297 | DOI:10.1016/j.aquatox.2025.107354

Hepatol Commun. 2025 Feb 3;9(2):e0608. doi: 10.1097/HC9.0000000000000608. eCollection 2025 Feb 1.ABSTRACTBACKGROUND: Hepatitis-E virus (HEV)-induced liver failure during pregnancy leads to maternal and fetal complications. This study investigates the HEV-associated metabolomic and immunological changes to elucidate the worsening of obstetric outcomes in patients with acute liver failure (ALF) due to HEV.METHODS: Pregnant women with (i) acute viral hepatitis, IgM HEV positive (AVH-E, n = 31, Gr.I), (ii) acute liver failure (ALF-E, n = 15, Gr.II), (iii) acute hepatitis but negative for viral infections (non-HEV, n = 30, Gr.III), and healthy (HC, n = 21, Gr.IV) were evaluated at delivery for plasma untargeted metabolomics, cytokine, and immune profiling.RESULTS: AVH-E and ALF-E (Gr.I, II) showed elevated TNF-α, IL-1β, IL-9, IL-22, and IL-33 compared to HC. In addition, in ALF-E, IFN-γ and IL-12p70 were decreased, but MIP-1α, fractalkine, SDF-1α, IL-22, and IL-33 were increased compared to AVH-E. Both AVH-E and ALF-E had decreased choline, sn-glycero-3-phosphocholine, O-palmitoyl-r-carnitine, and increased taurocholic acid. However, patients with ALF-E had a 2-5-fold decline in these metabolites with raised taurochenodeoxycholic acid. ALF-E showed increased naive T/B cells, decreased CD4, CD8 Tcm, Tem, and plasmablasts, compared to AVH-E contributing to higher failed inductions, preterm births, maternal complications like eclampsia, disseminated intravascular coagulation, preterm premature rupture of membranes, small-for-gestational-age infants, higher rates of intrauterine death, abortion, and mortality.CONCLUSIONS: HEV infection reduces choline, phosphocholine, and palmitoyl carnitine, enhancing inflammation in ALF-E, while increasing taurocholic and taurochenodeoxycholic acids impairs the immune response. These factors together likely contribute to severe obstetric complications, including higher failed inductions, intrauterine death, and maternal and fetal mortality in ALF-E.PMID:40209115 | DOI:10.1097/HC9.0000000000000608

Brain. 2025 Apr 10:awaf089. doi: 10.1093/brain/awaf089. Online ahead of print.ABSTRACTAutism spectrum disorder is a complex neurodevelopmental disease characterized by altered cortical network excitability. Recent genetic studies have identified deep layer V cortical pyramidal neurons in the frontal cortex as central to autism pathophysiology, yet the cortical circuits, plasticity mechanisms and molecular signalling pathways involved remain poorly understood. Layer V pyramidal neurons consist of two main types with distinct functional roles: intratelencephalic neurons, which respond to low-frequency stimulation and project within the cortex and striatum, and pyramidal tract neurons, which are tuned to theta-frequency inputs and convey information to subcortical structures. Determining which of these two neuron types is more critical to autism pathophysiology and whether disruptions in their synaptic connectivity or intrinsic excitability contribute to autism-related dysfunctions would significantly advance our understanding of the disorder. Integrins, a family of cell adhesion molecules, are vital for neuronal function. The gene encoding β3 integrin (ITGB3) is genetically linked to autism spectrum disorder, with rare mutations identified in affected individuals, while Itgb3 knockout mice exhibit autism-like behaviours, including impaired social memory and increased grooming. However, it remains unclear why loss of β3 integrin is associated with autism spectrum disorder, how it disrupts cortical circuits, and which plasticity mechanisms and molecular pathways are involved. Here, we demonstrate that β3 integrin selectively regulates the excitability of pyramidal tract neurons in the medial prefrontal cortex. Using electrophysiology, proteomics and molecular approaches, we show that β3 integrin regulates the gain, adaptation and precision of action potential discharge by controlling the surface expression of Ca2+-activated SK2 channels. Genetic ablation of Itgb3 impaired intrinsic excitability and SK2 channel function in pyramidal tract neurons, with no effects in intratelencephalic neurons. Furthermore, we identified Tau, a protein traditionally linked to neurodegenerative diseases, as part of the SK2 channel interactome. Proteomic analyses revealed altered protein kinase A-dependent phosphorylation of Tau in Itgb3 knockout mice, while protein kinase A inhibition restored SK2 channel currents, thereby connecting phosphorylation changes to excitability deficits. Our findings expand the current mechanistic framework linking signalling pathway dysfunctions to cortical excitability deficits, highlighting the dysregulation of pyramidal tract neuron excitability as a core feature of autism pathophysiology and demonstrating the involvement of β3 integrin, SK2 channels, Tau and PKA in this process. Because pyramidal tract neurons serve as final integrators of cortical computations before relaying information outside the cortex, their impaired excitability may disrupt communication with subcortical targets, contributing to the complex pathophysiology of autism spectrum disorder.PMID:40209105 | DOI:10.1093/brain/awaf089

ACS Chem Neurosci. 2025 Apr 10. doi: 10.1021/acschemneuro.4c00804. Online ahead of print.ABSTRACTDepression is a complex mental disorder. Studies have shown that purine metabolism disorders in depression and regulation of purine metabolites and related purinergic receptors may be an effective way to alleviate depression. Chaigui granules (CG) are a Chinese medicine prescription with antidepressant effects. Its antidepressant effect has been shown to be related to the improvement of purine metabolism disorders in depression. In this study, exogenous purine metabolite adenosine supplementation and adenosine A1 receptor antagonist (DPCPX) were employed to investigate the potential of Chaigui granules to exert an antidepressant effect by examining the behavioral indices of CUMS rats. The aim of this study was to determine whether the antidepressant effect of Chaigui granules is mediated by A1R receptors using DPCPX, an A1R receptor antagonist. Nontargeted metabolomic analysis was employed to compare and analyze the alterations in the metabolic profile of plasma and peripheral blood mononuclear cells (PBMCs) in each experimental group. Subsequently, combining the results from the metabolomics profile, targeted metabolomics was employed to identify key metabolites for purine metabolism. The objective was to investigate the effects of Chaigui granules, exogenous adenosine supplementation, and DPCPX on purine metabolism in depressed rats. Finally, the relevant signal pathways were validated by molecular biological means. The results of the depression-like behavior indicate that the antidepressant efficacy of Chaigui granules was associated with the modulation of adenosine and adenosine A1 receptor. Metabolomic analysis demonstrated that the Chaigui granule and adenosine exerted a pronounced regulatory effect on purine metabolism, and the regulatory effect on peripheral blood mononuclear cells (PBMCs) was markedly superior to that observed in plasma. In addition, targeted quantitative analysis showed that all eight purine metabolites were reversed after the administration of Chaigui granules and adenosine. Concurrently, the administration of an adenosine A1 receptor antagonist may serve to mitigate the regulatory impact of Chaigui granules on purine metabolites. Finally, the molecular biological results indicate that the antidepressant effect of Chaigui granules may be mediated by the A1R receptor, and it can play an antidepressant role by regulating the CAMP-PKA-CREB-BDNF pathway.PMID:40209102 | DOI:10.1021/acschemneuro.4c00804

Endocrinology. 2025 Apr 10:bqaf054. doi: 10.1210/endocr/bqaf054. Online ahead of print.ABSTRACTBioactivity of the hormone and growth factor activin A is central to fertility and health. Dysregulated circulating activin levels occur with medication usage and multiple pathological conditions. The inhibin-alpha knockout mouse (InhaKO) models chronic activin elevation and unopposed activin A bioactivity. In InhaKO fetal testes, lipid droplet, steroid profiles, and seminiferous cords are abnormal; adults develop gonadal and adrenal tumours due to chronic activin A excess exposure. Here we address how this exposure affects lipid, metabolite and steroid composition in whole testes, ovaries and adrenals of adult InhaKO mice using histological, transcriptomic, and mass-spectrometry (MS) methods, including MS imaging (MALDI-MSI). MALDI-MSI delineated spatial lipid profiles within interstitial, inner cord, and outer cord regions containing normal spermatogenesis; these differed between WT and KO samples. In proximity to tumours, lipids showed distinctive distribution patterns both within and adjacent to the tumour. Significantly altered lipids and metabolic profiles in whole InhaKO testes homogenates were linked to energy-related pathways. In gonads and adrenal glands of both sexes, steroidogenic enzyme transcription and steroids are different, as expected. Lipid profiles and steroidogenic enzyme proteins, HSD3B1 and CYP11A1, are affected within and near gonadal tumours. This documents organ-specific effects of chronic activin A elevation on lipid composition and cellular metabolism, in both histologically normal and tumour-affected areas. The potential for activin A to influence numerous steroidogenic processes should be considered in context and with spatial precision, particularly in relationship to pathologies.PMID:40209098 | DOI:10.1210/endocr/bqaf054

Pancreas. 2025 Feb 14. doi: 10.1097/MPA.0000000000002468. Online ahead of print.ABSTRACTOBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage. Although gemcitabine (GEM) is commonly used as the first-line chemotherapy, many patients eventually develop resistance. This study aims to investigate the role of nicotinamide phosphoribosyltransferase (NAMPT) in mediating gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC), with a focus on identifying potential therapeutic targets within the nicotinate and nicotinamide metabolic pathways.METHODS: We established the gemcitabine-resistant pancreatic cancer cell line BxPC-3-GR9 to simulate acquired resistance development. Subsequently, we conducted LC/MS metabolomics assays to identify altered metabolic pathways during gemcitabine resistance development. Additionally, molecular and functional experiments targeting key enzymes in KEGG-enriched metabolic pathways to identify genes exhibiting significant changes. Mechanistically, transcriptome sequencing and molecular assays were employed to elucidate the regulatory mechanisms governing these target genes.RESULTS: Compared to parent BxPC-3 cell lines, significant alterations in the nicotinate and nicotinamide metabolic pathways were found in BxPC-3-GR9. Furthermore, nicotinamide was the only metabolite shared during the enrichment process; higher expression of NAMPT was also detected in gemcitabine-resistant cell lines. NAMPT knockdown increased gemcitabine sensitivity in gemcitabine-resistant cells, which validated in inherently resistant cell lines. Transcriptome analysis and molecular experiments demonstrated that NAMPT regulates the p53 signaling pathway via CCND1/2, contributing to gemcitabine resistance.CONCLUSION: These findings suggest that NAMPT could serve as a promising therapeutic target to overcome gemcitabine resistance in PDAC, laying the groundwork for future clinical investigations aimed at modulating nicotinate and nicotinamide metabolism to improve treatment outcomes.PMID:40209023 | DOI:10.1097/MPA.0000000000002468

Proc Natl Acad Sci U S A. 2025 Apr 15;122(15):e2427129122. doi: 10.1073/pnas.2427129122. Epub 2025 Apr 10.ABSTRACTThe hepatocyte Ashwell-Morell receptor (AMR) is the prototypical mammalian lectin and the first cell receptor isolated. This recycling endocytic receptor of the plasma membrane determines the concentrations of hundreds of circulating glycoproteins in the blood and plays important roles in host responses to and outcomes of infection. The compositional and topological determinants of a physiological AMR ligand have remained unclear with contradictory findings reported. Previous studies established that the AMR binds multivalent galactose on desialylated triantennary or higher-branched N-glycans with little to no binding to galactose on biantennary forms. However, the vast majority of circulating blood glycoproteins are modified by biantennary N-glycans, rendering them unlikely to be ligands bound and eliminated by the AMR. Separately, other studies reported that AMR ligands include sialylated N-glycans, and specifically α2-6, but not α2-3, sialic acid linkages. Herein, we investigated the composition and topology of AMR ligands using a known physiological AMR ligand, intestinal alkaline phosphatase (IAP). Recombinant active IAP was produced in glycoengineered cells with either biantennary or higher valency triantennary and tetra-antennary N-glycan structures, and further with and without either α2-6 or α2-3 sialic acid linkages. These closely homogenous IAP monomer glycoforms assemble as dimers with similar enzymatic activity and were compared in AMR binding and clearance assays. Our results indicate that the AMR does not significantly bind IAP when its N-glycans are predominantly sialylated with either α2-6 or α2-3 sialic acid linkages. Multivalent desialylated AMR ligands may, however, appear when IAP monomers dimerize, resulting in the close proximation of biantennary N-glycans.PMID:40208943 | DOI:10.1073/pnas.2427129122

PLoS Med. 2025 Apr 10;22(4):e1004454. doi: 10.1371/journal.pmed.1004454. eCollection 2025 Apr.ABSTRACTBACKGROUND: Early life is a critical period for neurodevelopment, where factors such as maternal nutrition and breastfeeding duration significantly impact the growth of head circumference and cognitive development in children. Our study aimed to explore the associations between maternal dietary patterns during pregnancy, duration of breastfeeding, and their impacts on child head circumference and cognitive outcomes.METHODS AND FINDINGS: Our study utilised data from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort, which enrolled 700 mother-child pairs between 2008 and 2010 with 86% clinical follow-up at age 10. Pregnancy dietary patterns, described as 'Varied' and 'Western,' were derived from food frequency questionnaires and used to model quantitative metabolite scores via sparse partial least squares modelling of blood metabolome data. Cognitive development was assessed using the Bayley Scales of Infant Development at 2.5 years and the Wechsler Intelligence Scale for Children at age 10. Head circumference was measured from 20 weeks gestation to 10 years, and calibrated using related anthropometric measures. Growth trajectories were evaluated using linear mixed models and latent class trajectory models. Parental and child genetic influences for cognition and head circumference were controlled by including polygenic risk scores derived from genomic data. We found that a Western dietary pattern during pregnancy was associated with lower cognitive scores at age 2.5 (β -1.24 [-2.16, -0.32], p = 0.008) and reduced head circumference growth (p-interaction < 0.0001). We found that a Varied dietary pattern during pregnancy was associated with higher estimated intelligence quotient (IQ) at age 10 (β 1.29 [0.27, 2.3], p = 0.014). Additionally, head circumference growth was associated with higher cognitive scores at age 10 (β 3.40 [1.21, 5.60], p = 0.002), and it partly mediates the association between the Varied dietary pattern and estimated IQ (proportion mediated 13.5% [0.01, 0.71], p = 0.034). Extended breastfeeding duration was also independently associated with increased head circumference growth (p-interaction < 0.0001). These patterns and correlations were consistent even after adjusting for potential confounders and accounting for genetic influences.CONCLUSIONS: Our findings reveal that a Western dietary pattern during pregnancy is associated with lower cognitive scores at age 2.5 and decreased head circumference growth, suggesting potential adverse impacts on early neurodevelopment. Conversely, a Varied dietary pattern is linked with a higher estimated IQ at age 10, with head circumference growth contributing to this positive outcome. These findings highlight the critical role of maternal nutrition during pregnancy, and duration of breastfeeding, in promoting optimal neurodevelopmental outcomes. Effective public health strategies should therefore focus on enhancing maternal dietary practices to support better cognitive and physical development in children.PMID:40208849 | DOI:10.1371/journal.pmed.1004454