PubMed

Toxicon. 2025 Apr 9:108338. doi: 10.1016/j.toxicon.2025.108338. Online ahead of print.ABSTRACTArecoline is one of the primary constituents of the areca nut. Its pharmacological effects include analgesia, anti-inflammation, and anti-allergy. Current researches on the toxicity of arecoline mainly focuse on oral carcinogenesis and immunotoxicity, so there are relatively little systematic study on its hepatotoxicity and underlying mechanisms. Therefore, this study aims to explore the mechanisms of hepatotoxicity induced by different doses of arecoline in mice by integrating metabolomics and proteomics. In our pathological results, we found that the medium and high dose groups of arecoline can cause fatty degeneration in the livers of mice. Additionally, the different doses of arecoline increased the levels of ALT and AST in the serum of mice. Proteomics research identified that exposure to different doses of arecoline primarily affected the PPARs signaling pathway, thereby influencing fatty acid metabolism, amino acid metabolism, and arachidonic acid metabolism pathways. Metabolomics research identified differential metabolites in each group after arecoline exposure. We observed that with increasing doses of arecoline, the metabolites of lipids and lipid-like molecules in mice gradually increased. The results suggested arecoline may induce fatty degeneration in the liver of mice through the PPARα/Acox-1 mediated pathways of oxidative stress, inflammatory response, energy, and lipid metabolism.PMID:40216365 | DOI:10.1016/j.toxicon.2025.108338

J Dairy Sci. 2025 Apr 9:S0022-0302(25)00204-8. doi: 10.3168/jds.2024-26006. Online ahead of print.ABSTRACTThis study investigated the effects of incorporating tributyrin (TB) and tricaproin (TC) in MR on the liver metabolome of dairy calves. Forty-five male dairy calves (46.1 ± 4.6 kg BW; 2.1 ± 0.63 d of age; mean ± SD) were blocked in order of arrival at the research facility. Within each block, calves were randomly assigned to 3 MR treatments (n = 15 per group): (1) an MR containing milk fat serving as biolical reference for fat composition (MF), (2) a control MR (CON) containing a blend of vegetable fats, and (3) an MR (TRI) containing the same mixture of vegetable fats as CON, to which TB and TC were incorporated. All MR were isoenergetic with 36% lactose, 27% fat, and 24% protein on a DM basis. Calves were housed individually and received MR (13.5% solids) via nipple buckets twice daily at 0630 and 1730 h. Daily milk allowance was 6.0 L from d 1-5, 7.0 L on d 6-9, and 8.0 L from d 10-35. Calves had ad libitum access to water and chopped straw but no starter feed was fed. On d 35 after arrival, the calves were euthanized and liver tissue samples were collected and analyzed using a targeted metabolomics approach. Liquid chromatography and flow injection with electrospray ionization triple quadrupole mass spectrometry using an MxP® Quant 500 kit was used. Distinct metabolic profiles emerged, with principal component analysis (PCA) indicating differences between calves fed MF and those on other treatments, collectively accounting for almost 50% of the total variation. Partial Least Squares Discriminant Analysis (PLS-DA) confirmed significant differences between the liver metabolomes of calves fed MF and other treatments. Volcano plot analysis showed that compared with calves fed NC, 51 metabolites were higher in calves fed MF, including 34 phosphatidylcholines, 8 sphingomyelins, 3 lysophosphatidylcholines, 1 ceramide, 3 hexosylceramides, eicosapentaenoic acid (EPA) and glycochenodeoxycholic acid (GUDCA), while 8 metabolites were lower, including 2 phosphatidylcholines, 1 sphingomyelin (SM C22:3), 1 diacylglycerol (DG 16:0_18:2), 1 lysophosphatidylcholine (lysoPC a C18:2), 2 nitrogen-containing compounds (putrescine and serine) and C5 acylcarnitine. In addition, when comparing calves fed MF to calves fed TRI, 51 metabolites were higher in calves fed MF, including 37 phosphatidylcholines, 8 sphingomyelins, 4 lysophosphatidylcholines, 3 ceramides, 3 hexosylceramides, EPA and GUDCA, while 7 metabolites were lower, including 2 phosphatidylcholines, 1 sphingomyelin (SM C22:3), 1 diacylglycerol (DG 16:0_18:2), 1 lysophosphatidylcholine (lysoPC a C18:2), putrescine and valerylcarnitine (C5). Importantly, no significant differences in metabolites were found between calves fed CON and TRI, suggesting that TB and TC in MR had no effect on the liver metabolome. These results demonstrate that differences in MR fat composition between MF and MR with vegetable fats (CON and TRI) significantly modulate the liver metabolome of calves and underscore the importance of addressing fat composition in MR formulations to optimize metabolic outcomes.PMID:40216240 | DOI:10.3168/jds.2024-26006

J Dairy Sci. 2025 Apr 9:S0022-0302(25)00210-3. doi: 10.3168/jds.2025-26323. Online ahead of print.ABSTRACTIn this study, the effect of luxS, a key gene involved in quorum sensing, on the characteristic flavor of yogurt and its molecular mechanisms during the cofermentation of yogurt with engineered probiotics was investigated. The luxS gene overexpression strain was constructed by the homologous recombination technique, and its effect on the expression of population sensing signaling molecules and luxS gene was determined by bioluminescence and quantitative real-time PCR, and finally, headspace solid-phase micro extraction-GC-MS (HS-SPME-GC-MS) and metabolomics were used to determine the mechanism of its effect on the characteristic flavor of yogurt. The results demonstrated that the overexpression strains of Lactobacillus acidophilus CICC 6074-pMG36e-luxS and Lactobacillus helveticus R0052-pMG36e-luxS were successfully constructed. The expression of the luxS gene was upregulated by 2.25-fold and 3.16-fold, respectively. Compared with the wild-type strains, yogurt fermented by the overexpression strains showed a significant increase in AI-2 content, acidity, viable bacterial count, and protein hydrolysis, whereas pH, water-holding capacity, and hardness were significantly reduced. The HS-SPME-GC-MS results revealed the presence of 31 volatile flavor substances in yogurt. Among them, benzaldehyde (almond and burned sugar flavors), 2,4-dimethyl- (almond, cherry, and naphthalene flavors), dibutyl phthalate (a faint aromatic odor), and n-decanoic acid (rancid and fatty notes) were identified as the key differential flavor substances mediated by the luxS gene. Metabolomics results showed that the luxS gene mediates the production of organic acids in yogurt through arginine and proline metabolism, phenylalanine metabolism, and tryptophan metabolism. This study provides a theoretical basis for a deeper understanding of the molecular mechanisms underlying yogurt flavor formation.PMID:40216233 | DOI:10.3168/jds.2025-26323

Biochim Biophys Acta Mol Cell Res. 2025 Apr 9:119954. doi: 10.1016/j.bbamcr.2025.119954. Online ahead of print.ABSTRACTMembrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca2+ signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca2+, reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca2+-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.PMID:40216201 | DOI:10.1016/j.bbamcr.2025.119954

Eur J Pharmacol. 2025 Apr 9:177614. doi: 10.1016/j.ejphar.2025.177614. Online ahead of print.ABSTRACTLiver fibrosis is a reversible pathophysiological condition characterized by excessive extracellular matrix deposition that can progress to cirrhosis and liver failure if left untreated. Taurine, a sulfur-containing amino acid, protects the liver from damage. However, the effects of taurine on liver fibrogenesis have not been completely elucidated. In this study, we used amino acid metabolomics, gene expression microanalysis, and single-cell RNA sequencing (scRNA-seq) to investigate the roles of taurine, formyl peptide receptor 2 (Fpr2), and proinflammatory macrophages in liver fibrosis in human fibrotic sections and two distinct mouse models of liver fibrosis. Taurine transporter SLC6A6 wild-type and knockout littermate models and critical element inhibitors were also used. We found that taurine levels were significantly reduced in both human and murine fibrotic sections and that exogenous taurine supplementation alleviated fibrosis via SLC6A6. Furthermore, gene expression microarray analysis and scRNA-seq analyses demonstrated that exogenous taurine mitigated liver fibrosis, mainly by regulating Fpr2-related macrophage status. WRW4-mediated inhibition of Fpr2 ameliorated M1 macrophage polarization and alleviated liver fibrosis. Additionally, exogenous taurine suppressed Fpr2-modulated macrophage M1 polarization and the production of associated proinflammatory cytokines by repressing NF-κBp65 phosphorylation; moreover, SLC6A6 deficiency or treatment of liver fibrosis mouse models with an NF-κB inhibitor, BAY, impaired this protective effect of taurine. Therefore, taurine exerts a protective effect against liver fibrosis by repressing Fpr2/NF-κBp65-regulated macrophage M1 polarization, highlighting its potential therapeutic agent.PMID:40216178 | DOI:10.1016/j.ejphar.2025.177614

Cancer Lett. 2025 Apr 9:217694. doi: 10.1016/j.canlet.2025.217694. Online ahead of print.ABSTRACTThe castration-resistant prostate cancer (CRPC) remains an incurable disease. Metformin has demonstrated a potential therapeutic effect on CRPC. However, the poor clinical performance of metformin against cancer may be due to its clinical dose being much lower than the anticancer concentration used in pre-clinical experiments. The challenge is to determine a way to enhance sensitivity to metformin at an appropriate concentration on CRPC. In this study, a mouse model of low-dose metformin treatment for CRPC cells were established. Metabolomic-seq and transcriptomic-seq was used to investigate changes in CRPC xenografts. We discovered that low-dose metformin inhibits the progression of CRPC by regulating PDE6D, which induces alterations in purine metabolism and activates the cGMP/PKG pathway. Furthermore, we found that cells with high expression of PDE6D were more resistant to metformin. When combined with the PDE6D inhibitor TMX-4100, the inhibitory effect on tumors was enhanced, and TMX-4100 demonstrated favorable biosafety in animal models. In conclusion, we found that low-dose metformin inhibits the progression of CRPC by regulating PDE6D-induced alterations in purine metabolism and activating the cGMP/PKG pathway. Moreover, patients with high PDE6D expression may exhibit greater resistance to metformin. Combining metformin with TMX-4100 could further improve the inhibitory effects on tumors.PMID:40216151 | DOI:10.1016/j.canlet.2025.217694

Int J Biol Macromol. 2025 Apr 9:143026. doi: 10.1016/j.ijbiomac.2025.143026. Online ahead of print.ABSTRACTFucoidan has great potential for the prevention and treatment of obesity. This study aimed to determine the detailed structure of two fucoidan fractions (LF3-1 and LF4-1) from Saccharina japonica (S. japonica) and its mechanism for treating obesity. LF3-1 and LF4-1, with a molecular weight of 305.3 kDa and 182.1 kDa, respectively, were obtained from S. japonica. The backbone of LF3-1 consisted of →1,3)-α-L-Fucp4S-(1 → and →1,3)-β-D-Galp6S-(1→, branched with α-L-Fucp, β-D-Galp, and β-D-Manp. LF4-1's backbone consisted of →1,3)-α-L-Fucp4S-(1 → and →1,6)-β-D-Galp3S-(1→, branched with α-L-Fucp, β-D-Galp, and β-D-Manp. Over 24 weeks in high-fat-diet-fed C57BL/6 J mice, a mixture of LF3-1 and LF4-1 (100 and 300 mg/kg/d FUC) effectively reduced body weight and insulin resistance, ameliorated dyslipidemia, protected the intestinal barrier integrity, up-regulated Ucp-1, Prdm16 and Pgc-1α expression to inhibit fat accumulation, up-regulated Ppar-α, Ppar-γ, and Cpt-1 expression and down-regulation Fas, Lxr, and Srebp-1c expression to regulate lipid metabolism, and down-regulated expression of Tnf-α, Il-6, Il-1β, and Mcp-1 to ameliorate inflammation. In addition, FUC increased the abundance of Bacteroidetes and Lactobacillus. Lipid metabolomics analysis showed that Erysipelatoclostridium, Lachnoclostridium, Ruminococcaceae_UCG-014, and Staphylococcus may be involved in regulating sphingosine (SPH). This study revealed the structure properties and the potential of the application of FUC in the amelioration of obesity.PMID:40216141 | DOI:10.1016/j.ijbiomac.2025.143026

Exp Eye Res. 2025 Apr 9:110386. doi: 10.1016/j.exer.2025.110386. Online ahead of print.ABSTRACTPrimary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide, driven by elevated intraocular pressure (IOP) due to trabecular meshwork (TM) fibrosis, extracellular matrix (ECM) accumulation, and increased aqueous humor outflow resistance. Transforming growth factor-beta 2 (TGF-β2) promotes the expression of fibrosis-related genes, exacerbating these effects. Salidroside, a bioactive compound, has been shown to inhibit TGF-β2-induced ECM expression and alleviate ocular hypertension. However, its underlying molecular mechanisms remain unclear. This study explores the transcriptional, proteomic, and metabolic changes in human TM cells treated with TGF-β2 and salidroside. Human TM cells were treated with TGF-β2 (5 ng/mL) for 48 hours, followed by salidroside (30 μM) for 24 hours. Multi-omics analyses, including transcriptomics, label-free proteomics, and non-targeted metabolomics, were performed to identify differentially expressed genes (DEGs), proteins (DEPs), and metabolites. The results revealed that TGF-β2 inhibited HTM cell metabolism, affecting pathways like the TCA cycle. Salidroside restores balance by regulating 15 key biomolecules, including MELTF and SLC25A10, through dual-level and post-translation mechanisms. ROC and docking analyses highlight salidroside's role in enhancing metabolic transport and energy activity, with SLC25A10 also linked to RNA processing, showcasing its therapeutic potential. These findings provide valuable insights into POAG pathogenesis and the therapeutic potential of salidroside, offering a foundation for the future development of novel treatment strategies targeting transcriptional, translational, and metabolic dysregulation in POAG.PMID:40216062 | DOI:10.1016/j.exer.2025.110386

J Ethnopharmacol. 2025 Apr 9:119741. doi: 10.1016/j.jep.2025.119741. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Xin-shu-bao tablets (XSB), a traditional Chinese medicine widely prescribed in China, have received approval for its role in enhancing cardiac function in coronary heart disease patients. Lipid metabolism plays a critical role in the onset and progression of ventricular remodeling in heart failure with reduced ejection fraction (HFrEF). However, the pharmacological mechanisms through which XSB influences lipid metabolism in the context of ventricular remodeling with HFrEF have yet to be elucidated.AIM OF THE STUDY: The aim of the present study was to explore the potential of XSB as an inhibitor of ventricular remodeling in patients with HFrEF and to uncover the mechanisms by which XSB exerts myocardial protection via lipid metabolism.MATERIALS AND METHODS: To investigate the cardioprotective effects of XSB on HFrEF following myocardial infarction (MI), a murine model of MI generated by ligating the left anterior descending artery. The myocardial protective effects of XSB were evaluated through histological analysis of cardiac tissue and quantification of serum biomarkers associated with myocardial injury. Cardiac fibrosis was assessed using Masson's trichrome staining and Western blot analysis. Apoptosis, efferocytosis, and inflammation were measured through TUNEL staining, WB, and q-PCR in myocardial tissues. Differentially expressed metabolites in the myocardium were identified using MALDI-MSI and lipidomics analysis. Additionally, the involvement of the PPARγ/MFGE8 pathway in the cardioprotective effects of XSB was explored using Western blot validation in heart tissues. These approaches collectively aimed to elucidate the underlying mechanisms by which XSB exerts its cardioprotective effects, particularly through lipid metabolism.RESULTS: Our findings demonstrated that treatment with XSB significantly attenuated structural and functional cardiac impairments, as indicated by improvements in cardiac function and reductions in apoptosis, efferocytosis, inflammation, and cardiac fibrosis in myocardial tissues. Specifically, XSB markedly decreased the levels of pro-inflammatory cytokines, such as IL-6, IL-10, and TNF-α. Additionally, XSB downregulated the expression of apoptosis-related proteins BAX and Caspase-3, while increasing the expression of the anti-apoptotic protein Bcl-2. Metabolomic analyses using MALDI-MSI and lipidomics revealed that XSB suppressed the elevated levels of glycerol phospholipids, such as PC(16:1e_22:5), PI(18:0_20:4), PI(18:2_20:4), PC(16:0e_22:4), LPS(18:0), PI(16:0_18:2), PC(19:0_22:6), and PS(18:1_22:6) in myocardial tissues. Furthermore, XSB modulated the expression of key proteins associated with lipid metabolism, including upregulation of PPARγ and SLC27A1, and downregulation of MFGE8, MERTK, and GSN. These results suggest that XSB exerts its cardioprotective effects through modulation of lipid metabolism and related signaling pathways.CONCLUSIONS: XSB demonstrate cardioprotective effects by improving cardiac function and modulating ventricular remodeling processes in mice with HFrEF. These processes involve attenuation of inflammation, apoptosis, efferocytosis, and cardiac fibrosis. The cardioprotective mechanisms of XSB are mediated through the regulation of lipid metabolism via the PPARγ/MFGE8 signaling pathway.PMID:40216048 | DOI:10.1016/j.jep.2025.119741

J Ethnopharmacol. 2025 Apr 9:119797. doi: 10.1016/j.jep.2025.119797. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is characterized by progressive cognitive dysfunction and memory loss. Tenuifoliside A (TFSA) is a constituent of RADIX POLYGALAE, a medicinal herb traditionally used in the clinical treatment of AD in China. However, the therapeutic mechanism of this compound is unknown.AIM OF THE STUDY: To investigate the effects and pharmacological mechanisms of TFSA in ameliorating AD symptoms in APP/PS1 mice.MATERIALS AND METHODS: The neuroprotective effects of TFSA were assessed using behavioral tests, transmission electron microscopy, and immunofluorescence staining. The differential metabolites in the feces of model mice were obtained from non-targeted metabolomics analysis. Differential abundances of microbiota in the gut were investigated by 16S rRNA sequencing, and correlations among differential metabolites and microbiota were investigated using an integrated approach.RESULTS: Cognitive impairment and Aβ burden were mitigated in APP/PS1 mice treated with TFSA. TFSA intervention led to an increase in the diversity of gut microbiota and a reduction in the relative abundance of Firmicutes, Bacteroidetes, and Proteobacteria. There were 71 differential metabolites in mice given high dose of TFSA. In comparison to the AD group, the mice treated with TFSA exhibited a notable enrichment in various pathways including glucose and lipid metabolism, tryptophan metabolism. Based on integrated metabolomics and 16S rRNA sequencing, 23 metabolite-microbiota pairs were different between the TFSA and AD groups, and there was an especially strong correlation between Alistipes and 2,3-dinor-8-epi-prostaglandin F2α. Validation experiment demonstrated TFSA ameliorates AD by regulating metabolism pathways and inhibiting neuroinflammation.CONCLUSIONS: This study offers a theoretical basis for elucidating the molecular mechanism of TFSA's amelioration of AD. Although the potential pharmacological mechanisms of TFSA are still unknown, we have demonstrated that TFSA inhibits neuroinflammation and improves AD symptoms in APP/PS1 mice by remodeling the microbiota and its metabolites.PMID:40216042 | DOI:10.1016/j.jep.2025.119797

J Hazard Mater. 2025 Apr 9;492:138207. doi: 10.1016/j.jhazmat.2025.138207. Online ahead of print.ABSTRACTThe global prevalence of antibiotic resistance genes (ARGs) has aroused increasing concern due to its threat to ecological security and human health. Although biochar has been widely used for pollution remediation including ARGs, little is known its regulation on antibiotics and ARGs propagation under riparian zones, where undergo frequent occurrence of dry and wet alternations (DWA) caused by water-level fluctuation. Therefore, this study investigated the regulative effects of biochar through different addition approaches on ARGs spread in riparian zone sediments. Under DWA, the presence of biochar (2 % w/w) inhibited microbial diversity and function expression, especially for tiled biochar. In addition, compared with DWA, the tiled biochar decreased ARGs abundance by 45.36 %, while the well-mixed increased that by 269.02 %. The ARGs abundance in sediments was positively correlated with mobile genetic element abundance (R2=0.996, p < 0.05), indicative of high horizontal gene transfer potential of ARGs. Metabolomics revealed that both DWA and biochar significantly altered microbial metabolism pathways in sediments, involving sulfur metabolism and histidine metabolism. Furthermore, ARGs propagation in riparian zones may be dominantly driven by MGEs, especially by transposases and integrase. These findings highlight the tiled biochar remediation effects on ARGs in riparian zones under DWA caused by global warming.PMID:40215939 | DOI:10.1016/j.jhazmat.2025.138207

J Hazard Mater. 2025 Apr 5;492:138192. doi: 10.1016/j.jhazmat.2025.138192. Online ahead of print.ABSTRACTToxicity assessments based on transcriptomics and metabolomics at target organs are magnitude difference due to the tremendous variations in the sensitivity of receptor binding sites (subunits), which often require expensive instrumentation using quantitative whole-body autoradiography. In this study, zebrafish embryos combined with toxicity identification evaluation (TIE) and ECOSAR toxicity prediction were applied to monitor comprehensive toxicity changes of fermentation pharmaceutical wastewater (FPW) in the expanded granular sludge bed (EGSB) and the modified simultaneous nitrification-denitrification (SND) process. FPW with high toxicity (30.93 TU) was predominately detoxified (to 4.04 TU) in anaerobic EGSB process, in which chlortetracycline (CTC) was degraded via demethylation, dechlorination and ring-cleaving. TIE results showed that non-polar pollutants contributed to the major toxicity and existed in the whole process. The pH adjustment significantly influenced the toxicities of CTC and its mixture with NH4+-N (MCTC+NH4+) or NO2--N (MCTC+NO2-) due to the hydrolysis and chelation. Noticeably, nearly no nitrite/nitrate were accumulated in SND treatment process, which greatly alleviated the toxicities of MCTC+NH4+ and MCTC+NO2- due to no generation of free ammonia and free nitrous acid. MCTC+NH4+ exhibited antagonistic toxicity in all test pH, but MCTC+NO2- converted from synergistic (pH i) to antagonistic (pH 7.5). This study deepened the detoxification mechanistic interpretations of FPW in the modified EGSB-SND process as well as related toxicity variation information.PMID:40215933 | DOI:10.1016/j.jhazmat.2025.138192

Phytomedicine. 2025 Mar 20;141:156675. doi: 10.1016/j.phymed.2025.156675. Online ahead of print.ABSTRACTBACKGROUND: Liver injury and uveitis pose severe threats to human health. Owing to the close relationship of physiology and pathology between the liver and the eyes, cases in which both conditions occur simultaneously are not uncommon in clinical settings, significantly complicating treatment. However, no suitable comorbid animal model has been reported, and research on the pathological mechanisms of this comorbidity is lacking. Prunella vulgaris L., a well-known traditional Chinese medicine renowned for its liver-clearing and eye-brightening properties. Prunella vulgaris polyphenols (PVPs) hold promise for improving liver injury and uveitis. However, research exploring their dual therapeutic effects within a single organism remains lacking, leaving the key active components and mechanisms of action largely uninvestigated.PURPOSE: This exploratory study aimed to establish a rat model of liver injury combined with uveitis and investigated its pathological mechanisms, evaluating the therapeutic efficacy of PVPs in alleviating liver injury combined with uveitis in rats. Additionally, it explored the mechanism of action and identified key active ingredients of PVPs, offering potential new directions for the development of clinical therapeutic drugs.METHODS: A rat model of liver injury with uveitis was established through intraperitoneal d-GalN/LPS injection. Metabolomics and proteomics were applied to investigate pathological mechanisms, followed by validation using acylcarnitine and S100A9 inhibitors. PVPs were administered to evaluate therapeutic effects and explore mechanisms involved in alleviating liver injury and uveitis. Network pharmacology combined with molecular docking identified critical active components in PVPs. Subsequent animal experiments verified the efficacy of the representative component in improving liver injury and uveitis.RESULTS: d-GalN/LPS (150 mg/kg : 1 mg/kg) induced significant liver injury and uveitis in rats. Metabolomics analysis pointed to acylcarnitine as a key metabolite, and its inhibition reduced inflammation. Proteomics analysis implicated S100A9 in inflammation and immunity. Then, we intervened with S100A9 inhibitors in the model rats. The results suggested that the pathological mechanism of liver injury and uveitis caused by d-GalN/LPS involved the upregulation of S100A9 expression, an increase in PP2A activity, the inhibition of AMPK phosphorylation, and the downregulation of CPT1A, leading to the accumulation of acylcarnitine and promoting the inflammatory response in the liver and retina. Further, experiments involving PVPs demonstrated dose-dependent improvements in liver injury and uveitis caused by d-GalN/LPS. The underlying mechanism of action involved suppression of S100A9 expression, reduction of PP2A activity, activation of AMPK, upregulation of CPT1A, and subsequent reduction in acylcarnitine accumulation in both the liver and retina. This mechanism effectively alleviated the inflammatory effects induced by d-GalN/LPS. Network pharmacology and molecular docking analyses pinpointed several key active components of PVPs-namely, rosmarinic acid, salviaflaside, esculetin, 2-hydroxycinnamic acid, 3,4-dihydroxybenzaldehyde, and 7,8-dihydroxycoumarin-that play significant roles in mitigating liver injury and uveitis. Follow-up experiments using the representative active component rosmarinic acid in rats confirmed its efficacy in improving symptoms of d-GalN/LPS-induced liver injury and uveitis, further validating the therapeutic potential of these key active components.CONCLUSIONS: This study successfully established a rat model of liver injury combined with uveitis and confirmed the efficacy of PVPs in alleviating this condition. Furthermore, it determined that the underlying mechanism involves regulation of the S100A9-PP2A-AMPK pathway, with rosmarinic acid identified as a key active compound. These findings provide a basis for clinical studies on liver-eye comorbidities and offer critical evidence for further research and drug development of PVPs in liver-clearing and eye-brightening.PMID:40215815 | DOI:10.1016/j.phymed.2025.156675

Ultrason Sonochem. 2025 Apr 3;117:107338. doi: 10.1016/j.ultsonch.2025.107338. Online ahead of print.ABSTRACTThis study systematically investigates the effects of different drying methods-Hot Air Drying (HAD), Microwave Drying (MWD), and Ultrasound-Microwave Combined Drying (UMWD)-on the drying kinetics, total phenolic content (TPC), antioxidant activity, and metabolome of Camellia oils (COs). UMWD significantly reduced drying time and increased TPC by 102.20 % and 395.94 % compared to MWD and HAD, respectively. The antioxidant capacity, as measured by FRAP, DPPH, and ABTS assays, was enhanced to 8.51, 11.35, and 37.68 µg VC/mL under UMWD conditions, showing marked improvements over MWD and HAD. Metabolomic analysis identified 1,350 metabolites, with 447 differential metabolites specific to UMWD. A total of 47 antioxidant-related metabolites (ACCMs) were identified, most of which exhibited up to a 10-fold increase in UMWD/HAD comparisons. These findings demonstrate that UMWD effectively enhances both the bioactive components and antioxidant capacity of COs, making a significant contribution to the preparation of high-quality camellia oil. Additionally, the study offers new insights into how ultrasound-assisted drying methods can enhance the bioactive components of food products.PMID:40215790 | DOI:10.1016/j.ultsonch.2025.107338

Comp Biochem Physiol Part D Genomics Proteomics. 2025 Apr 3;55:101499. doi: 10.1016/j.cbd.2025.101499. Online ahead of print.ABSTRACTGlobal climate change has subjected freshwater organisms to environmental stressors, such as heat and drought; however, little remains known about their metabolic response to these stressors. Herein we performed quasi-targeted metabolomic analysis to investigate the metabolic response of Sinosolenaia oleivora gills under heat and drought stress. The survival rate of S. oleivora under 48-h heat stress did not significantly differ from that in the control group; however, in the drought group, the mortality rate was >50 % at 24 h, and complete mortality occurred within 48 h, with significantly lower survival rates than the conventional and heat groups. Overall, 747 metabolites were identified across the three groups. Orthogonal partial least squares discriminant and clustering heatmap analyses indicated that both heat and drought stress significantly impacted the gill metabolome of S. oleivora. In the heat group (sc), compared to the conventional group (s), 17 metabolites were significantly upregulated and 46 were significantly downregulated. Eight metabolic pathways were significantly affected: pyruvate metabolism, propanoate metabolism, adrenergic signaling in cardiomyocytes, tyrosine metabolism, butanoate metabolism, nicotinate and nicotinamide metabolism, citrate cycle (tricarboxylic acid cycle), and oxidative phosphorylation. In the drought group (sd), compared to the heat group (sc), 26 metabolites were significantly upregulated and four were significantly downregulated. Three metabolic pathways showed significant differences: longevity regulating pathway-worm, GABAergic synapse, estrogen signaling pathway. We believe that succinic acid and fumaric acid can serve as indicators of heat stress, while nicotinamide and 4-aminobutyric acid can serve as biomarkers of drought stress in S. oleivora.PMID:40215765 | DOI:10.1016/j.cbd.2025.101499

Food Chem. 2025 Apr 10;483:144239. doi: 10.1016/j.foodchem.2025.144239. Online ahead of print.ABSTRACTPlant proteins are emerging as alternatives to animal proteins. This study compared the physicochemical properties and nutritional characteristics of soybean protein isolate (SPI) and sheep whey protein (SWP), which is gaining recognition for its nutritional benefits. SWP exhibited higher amino acid content, larger particle size, increased turbidity, and superior foaming and emulsification capacities compared to SPI (p < 0.05). In contrast, SPI demonstrated better emulsification stability. In vitro, gastrointestinal digestion showed that SPI achieved a higher degree of hydrolysis in both gastric and intestinal phases, although SWP had a faster initial hydrolysis rate. During gut microbiota fermentation, SWP produced significantly higher levels of short-chain fatty acids (SCFAs) than SPI (p < 0.05). Non-targeted metabolomics revealed distinct metabolic differences, particularly in amino acid metabolism, bile acid synthesis, and hormone biosynthesis. These findings suggest SWP is suitable for nutritional supplementation, while SPI is better for dairy-based alternatives.PMID:40215742 | DOI:10.1016/j.foodchem.2025.144239

Plant Physiol Biochem. 2025 Apr 6;223:109891. doi: 10.1016/j.plaphy.2025.109891. Online ahead of print.ABSTRACTThe black poplar, the predominant poplar cultivars in China, has substantial economic and ecological importance. However, there were differences in phenotypic traits, such as growth, wood properties, resistance, tolerance and so on, between different black poplar cultivars. So, this study examined the effects of genetic background on the metabolite and volatile compound compositions of black poplar via metabolomics and gas chromatography‒mass spectrometry (GC‒MS). In total, 699 metabolites and 146 volatile compounds were identified. Multivariate statistical analysis revealed that 19-Hydroxy-Pge2, Isopropyl Apiosylglucoside, 3-Hydroxyisoheptanoic Acid, Capsianoside V, 3-(3,4-Dihydroxybenzyl)-7-Hydroxy-5-Methoxy-4-Chromanone, Lysope (0:0/20:0), N-(3-Methylbutyl) Acetamide, and 1,4-Benzothiazine-O-Quinonimine serve as biomarkers for differentiating various black poplar cultivars. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that galactose metabolism, alpha-linolenic acid metabolism, sphingolipid metabolism, and alanine, aspartate, and glutamate metabolism were key metabolic pathways impacting the physiological functions of black poplar. Volatile compound analysis indicated significant variability among the black poplar types; however, all shared (+)-cedrol as the primary odor contributor, which has a cedarwood-like aroma that is woody, dry, sweet, and soft. Most of biomarkers and volatile compounds are the physiological or ecological benefits, can be used to predict complex phenotypic traits of black poplar, offering a solid basis for breeding fine varieties of poplar. The screening approach used here may also be applied to the identification and improvement of other tree cultivars.PMID:40215732 | DOI:10.1016/j.plaphy.2025.109891

Pathol Res Pract. 2025 Apr 7;270:155956. doi: 10.1016/j.prp.2025.155956. Online ahead of print.ABSTRACTColorectal cancer (CRC) is the third most frequently diagnosed cancer, with rectal cancer (RC) accounting for approximately 35 % of cases, posing a significant health burden. The early phase of R progression is characterized by the accumulation of genetic and epigenetic changes that promote cell growth. These rapidly dividing cells form a benign adenoma, which can eventually transform into malignant tumors and metastasize to other organs. Among the key molecular alterations, a mutation in the Wnt/β-catenin signaling pathway plays a crucial role. Additionally, BRAF mutation contributes to 8-10 % of CRC cases, while mutation in PIK3C pathways is responsible for 20-25 % of cases. The RC involves complex biological mechanisms. This review article highlights the pivotal role of mRNA in diagnosing and predicting the prognosis of RC, explores the various functions of non-coding RNAs (ncRNA,s), and examines the impact of RNA editing and modification on the progression of tumor genesis. Furthermore, we discuss the cellular signaling pathways and microenvironment interaction and pathways like PI3K/Akt/mTOR and Wnt/β-catenin. Advancements in molecular, RNA, and genetic research have evolved the treatment of cancer. Techniques like next-generation sequencing have tremendously opened the biological field of research. Along with this, techniques like CRISPR/Cas9 aid in the developing therapeutic strategies. Proteomics and metabolomics approach further contribute to novel research direction in oncology.PMID:40215670 | DOI:10.1016/j.prp.2025.155956

J Agric Food Chem. 2025 Apr 11. doi: 10.1021/acs.jafc.5c01501. Online ahead of print.ABSTRACTThe berries of Piper borbonense (Miq.) C. DC., a wild vine native to Madagascar, are prized for their distinctive aroma and flavor, considered superior to the ones of the domesticated peppers (P. nigrum L., P. longum L.). The scarcity of studies on P. borbonense, locally known as voatsipérifery, makes it difficult to secure the identity of its berries and complement its sensory analysis. This supports the need for a comprehensive phytochemical investigation utilizing complementary analytical techniques. Headspace gas chromatography highlighted differences in the "volatilome" of P. borbonense and P. nigrum, while an untargeted metabolomic analysis, based on the LC-MS2-based feature-based molecular networking tool, annotated different classes of compounds (monoterpenoids, sesquiterpenoids, monolignols, lignans, and piperamides). This analysis next guided the isolation of 40 fully characterized compounds, including two new natural products [the sesquiterpene lactone 4-hydroxyisogelehomanolide (29) and the hydroxycinnamate ester borbonensin (38)]. The phytochemical profile of voatsipérifery is remarkable for the presence of the nonvolatile monoterpene p-menth-5-en-1,2-diol (23), of sesquiterpene lactones, and of large amounts of sesamin (34), a marker trait that clearly distinguishes it from those of the cultivated peppers of commerce and was confirmed with a parallel investigation of P. nigrum. Overall, our study underlines the relevance of advanced metabolomic approaches to characterize the phytochemical profile of spices and identify specific marker compounds.PMID:40215346 | DOI:10.1021/acs.jafc.5c01501

Sci Adv. 2025 Apr 11;11(15):eadp4532. doi: 10.1126/sciadv.adp4532. Epub 2025 Apr 11.ABSTRACTMetabolomic genome-wide association studies (mGWASs), or metabolomic quantitative trait locus (metQTL) analyses, are gaining growing attention. However, robust methods and analysis guidelines, vital to address the complexity of metabolomic data, remain to be established. Here, we use whole-genome sequencing and metabolomic data from two independent studies to compare different approaches. We adopted three popular data transformation methods for metabolite levels-(i) log10 transformation, (ii) rank inverse normal transformation, and (iii) a fully adjusted two-step procedure-and compared population-based versus family-based analysis approaches. For validation, we performed permutation-based testing, Huber regression, and independent replication analysis. Simulation studies were used to illustrate the observed differences between data transformations. We demonstrate the advantages and limitations of popular analytic strategies used in mGWASs where especially low-frequency variants in combination with a skewed metabolite measurement distribution can lead to potentially false-positive metQTL findings. We recommend the rank inverse normal transformation or robust test statistics such as in family-based association tests as reliable approaches for mGWASs.PMID:40215300 | DOI:10.1126/sciadv.adp4532