PubMed

Lupus Sci Med. 2025 Mar 12;12(1):e001197. doi: 10.1136/lupus-2024-001197.ABSTRACTOBJECTIVE: The objective of this research is to identify metabolic markers associated with successful treatment by evaluating the effect of mesenchymal stem cell transplantation (MSCT) on the metabolic profiles of patients with SLE.METHODS: Plasma samples were collected from 20 patients with SLE before and after MSCT. Principal component analysis (PCA) was used to distinguish pretreatment and post-treatment groups and pathway analysis for identifying involved metabolic pathways. Clinical variables were monitored with a median follow-up time of 180 days. Pearson correlation and receiver operating characteristics (ROC) analysis were employed to associate metabolite changes with clinical outcomes and to predict treatment success.RESULTS: We detected 18 121 metabolites, with 1152 showing significant changes post-treatment, which could be clearly distinguished between pretreatment and post-treatment groups through PCA. Pathway analysis indicated involvement in riboflavin and thiamine metabolism. Clinical improvements were observed at a median follow-up time of 180 days after MSCT, including decreased SLE Disease Activity Index scores, urine protein/creatinine ratios, and erythrocyte sedimentation rates, along with increased levels of complement C3 and C4, haemoglobin, and platelets. Pearson correlation indicated that specific metabolite changes were associated with clinical improvements, particularly increases in thiamine monophosphate (TMP) and asiaticoside levels. ROC analysis identified TMP level changes as the most predictive of treatment success, with a 35% increase indicating a good response to MSCT.CONCLUSION: This study concludes that TMP is a potential biomarker that can predict the efficacy of MSCT in treating SLE, providing valuable insights for clinical practice and further research.PMID:40074250 | DOI:10.1136/lupus-2024-001197

J Phycol. 2025 Mar 12. doi: 10.1111/jpy.70001. Online ahead of print.ABSTRACTThe interdependence between microalgae and bacteria has sparked scientific interest over years, primarily driven by the practical applications of microalgal-bacteria consortia in wastewater treatment and algal biofuel production. Although adequate studies have focused on the broad interactions and general behavior between the two entities, there remains a scarcity of study on the metabolic role of symbiotic bacteria in promoting microalgal growth. Here, we use the KEIO Knockout Collection, an Escherichia coli gene knockout mutant library, to systematically screen for genes involved in the interdependence of Chlorella sorokiniana and E. coli. By co-cultivating C. sorokiniana and E. coli knockout mutants in 96-well microplates (200 μL medium per well) under white light at 25°C, 31 potential algal growth-promoting and 56 growth-inhibiting genes out of 3985 genes were identified that enhanced (≥1.25-fold) and diminished (≤0.8-fold) the production of algal chlorophyll-a content, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) mapping of these growth-regulating genes suggested a metabolic symbiosis involving bacteria-derived cobalamin (cobU, cobC), biotin (bioB, bioF, bioC, bioD, fabF, fabH), riboflavin (fbp, guaB, gnd, guaA, zwf, purA), and 2,3-butanediol (fumB, adhE, mdh, frdB, pta, sdhC). The effects of these metabolites were further validated by supplementing the agents into the axenic algal cultures; Dose-dependent trends were observed for each metabolite, with a maximum four-fold increase in algal biomass productivity over the control. The specific growth rate of algae was increased by ≥1.27-fold and doubling time was shortened by ≥22.5%. The present results, obtained through genome-wide analyses of interdependence between microalgae and bacteria, reveals multiple interactions between organisms via metabolites.PMID:40074247 | DOI:10.1111/jpy.70001

Int J Biol Macromol. 2025 Mar 10:141933. doi: 10.1016/j.ijbiomac.2025.141933. Online ahead of print.ABSTRACTType 3 resistant starch (RS3) regulates diet-related metabolic diseases by promoting intestinal short-chain fatty acids (SCFAs) and lactate production, and facilitating microbial lactate-to-butyrate fermentation. However, its precise in vivo mechanism remains unclear. Therefore, we studied the effects of type 3 lotus seed resistant starch (LRS3) and sodium lactate (SL) on colonic microbiota composition, metabolism, and lipid parameters. This study aimed to elucidate the mechanism by which LRS3 and SL modulate colonic microbiota and metabolism to mitigate hyperlipidemia in rats induced by a high-fat diet. Results showed LRS3 increased colonic microbial diversity, shifting the composition towards that of healthy rats. LRS3 intake reduced lactic acid-producing bacteria such as Allobaculum, Collinsella, and Blautia in the colon while promoting SCFAs-producing Ruminococcaceae. SL alone stimulated Lachnospiraceae growth. When both were administered, there was a significant increase in Treponema and Ruminococcaceae. The co-intervention of LRS3 and SL significantly affected lipid metabolism-related metabolites, up-regulating palmitic acid while down-regulating androsterone and phosphatidylcholine (PC) substances PC (14:0/20:4(8Z,11Z,14Z,17Z)), influencing unsaturated fatty acid biosynthesis pathways and inhibiting steroid hormone biosynthesis. Finally, via the microbial-metabolism-lipid correlation network, we identified that LRS3 and SL increased SCFAs production through Treponema and Ruminococcaceae metabolism, influencing organic acid and lipid composition in the colon. This indirectly reduced blood lipid levels in hyperlipidemic rats by modulating intestinal microecology.PMID:40074132 | DOI:10.1016/j.ijbiomac.2025.141933

J Ethnopharmacol. 2025 Mar 10:119616. doi: 10.1016/j.jep.2025.119616. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: 5-Fluorouracil (5-FU) commonly induces severe mucositis, causing pain, inflammation, and gastrointestinal dysfunction, which significantly increases patient morbidity and reduces quality of life. In Ayurveda, Traditional Chinese Medicine, and other ethnopharmacological practices, dried ginger has been widely used to alleviate symptoms such as nausea, vomiting, diarrhea, and inflammation, highlighting its important role in traditional medicine.AIM OF THE STUDY: This study explored the potential of dried ginger essential oil (DGEO) in mitigating intestinal epithelial barrier damage in mice with mucositis induced by 5-FU.METHODS: The therapeutic effects of DGEO were evaluated by measurements of weight changes, diarrhea scores, ELISA, and H&E. Further investigations included 16S rRNA sequencing, untargeted metabolomics, molecular docking, and HPLC-MS/MS to explore its underlying mechanisms, with validation performed using western blotting and ELISA.RESULTS: The results demonstrated that DGEO was effective in alleviating mucositis symptoms.It also improved the gut microbiota, enhanced the biotransformation of tryptophan to indole-3-acetic acid (IAA), and elevated the protein expressions of the AHR, CYP1A1, and p-STAT3, as well as levels of IL-22. Moreover, DGEO improved the expression of tight junction(TJ) proteins and anti-apoptotic proteins, enhancing intestinal barrier integrity.CONCLUSION: These findings indicated that DGEO ameliorated 5-FU-induced mucositis by modulating gut microbiota and the tryptophan metabolite IAA-AHR/IL-22/STAT3 signaling axis, providing new insights into its therapeutic applications, particularly its ability to regulate gut microbiota and related signaling pathways.PMID:40074099 | DOI:10.1016/j.jep.2025.119616

J Biol Chem. 2025 Mar 10:108398. doi: 10.1016/j.jbc.2025.108398. Online ahead of print.ABSTRACTPyruvate dehydrogenase kinase (PDK) 1 is one of four isozymes that inhibit the oxidative decarboxylation of pyruvate to acetyl-CoA via pyruvate dehydrogenase. PDK activity is elevated in fasting or starvation conditions to conserve carbohydrate reserves. PDK has also been shown to increase mitochondrial fatty acid utilization. In cardiomyocytes, metabolic flexibility is crucial for the fulfillment of high energy requirements. The PDK1 isoform is abundant in cardiomyocytes, but its specific contribution to cardiomyocyte metabolism is unclear. Here we show that PDK1 regulates cardiomyocyte fuel preference by mediating triacylglycerol turnover in differentiated H9c2 myoblasts using lentiviral shRNA to knockdown Pdk1. Somewhat surprisingly, PDK1 loss did not affect overall PDH activity, basal glycolysis, or glucose oxidation revealed by oxygen consumption rate experiments and 13C6 glucose labelling. On the other hand, we observed decreased triacylglycerol turnover in H9c2 cells with PDK1 knockdown, which was accompanied by decreased mitochondrial fatty acid utilization following nutrient deprivation. 13C16 palmitate tracing of uniformly labelled acyl chains revealed minimal acyl chain shuffling within triacylglycerol, indicating that the triacylglycerol hydrolysis, and not re-esterification, was dysfunctional in PDK1 suppressed cells. Importantly, PDK1 loss did not significantly impact the cellular lipidome or triacylglycerol accumulation following palmitic acid treatment, suggesting that effects of PDK1 on lipid metabolism were specific to the nutrient-deprived state. We validated that PDK1 loss decreased triacylglycerol turnover in Pdk1 knockout mice. Together, these findings implicate a novel role for PDK1 in lipid metabolism in cardiomyocytes, independent of its canonical roles in glucose metabolism.PMID:40074083 | DOI:10.1016/j.jbc.2025.108398

Metabolism. 2025 Mar 10:156189. doi: 10.1016/j.metabol.2025.156189. Online ahead of print.ABSTRACTBACKGROUND: Triacylglycerol (TAG) plasma excursions after a high-fat meal are blunted after Roux-en-Y gastric bypass (RYGB), but underlying mechanisms are poorly understood. We studied TAG absorption and metabolism in 12 RYGB-operated individuals and 12 unoperated controls (CON) matched on sex, age, and BMI.METHODS: Participants followed a 7-day controlled diet and on day 4 underwent 1H-MR Spectroscopy of liver TAG and a high-fat liquid meal with oral and intravenous labeled stable isotope metabolites, subcutaneous abdominal fat biopsies, and indirect calorimetry. Subsequently, participants collected stool for 96 h.RESULTS: Overall fat absorption from the controlled diet was moderately lower in RYGB than CON (88 % versus 93 %, P < 0.01), without indication of greater specific malabsorption of fat from the high-fat test meal (recovery of TAG and labeled TAG in 96-hour stool samples). After an overnight fast, plasma TAG concentrations and incorporation of plasma fatty acids (IV tracer) into TAG did not differ between groups. The postprandial 6-hour iAUC of plasma TAG plasma concentrations was markedly lower in RYGB than CON (15 versus 70 mmol/L × min, P = 0.03). The postprandial chylomicron (CM) particle response (plasma ApoB48) was initially higher in RYGB, but with lower CM-TAG plasma concentrations and appearance of labeled palmitate from the oral tripalmitin tracer over the 6 h.CONCLUSION: Fat absorption is only moderately lower after RYGB compared with unoperated matched controls. Nevertheless, postprandial TAG and CM plasma kinetics after a high-fat meal are markedly altered after RYGB with substantially lower TAG and CM-TAG concentrations despite a faster CM particle release.PMID:40074057 | DOI:10.1016/j.metabol.2025.156189

Phytomedicine. 2025 Mar 6;140:156622. doi: 10.1016/j.phymed.2025.156622. Online ahead of print.ABSTRACTBACKGROUND: Hyperuricemia (HUA) is a metabolic disease disturbing human health caused by the overproduction or underexcretion of uric acid (UA). Astragalus is the root of Astragalus membranaceus (Fisch.) Bunge, has notable regulatory effect on chronic nephritis, proteinuria and spontaneous sweating, suggesting it could be a potential anti-HUA agent. However, limited research has been conducted on its anti-HUA effect and mechanism.METHODS: The present study performed untargeted and plasma metabolomics of Astragalus extract to identify the main constituents that can be absorbed and exert effect in mice, and further investigated the underlying mechanism by enzyme activity assay, Western Blotting and molecular docking.RESULTS: The results showed that Astragalus flavone extract inhibited UA synthesis by binding to XOD to hinder substrate binding and inhibiting xanthine oxidase (XOD) protein expression, inhibited JNK/AP-1/NLRP3/IL-1β signaling pathway to alleviate prolonged HUA-induced inflammation and abnormal UA metabolism, and protected the kidney by reducing serum renal function index and improving renal tissue atrophy, fibrosis and tubular dilatation both in vitro and in vivo. Besides, glycitein and isoformononet were identified as the main flavones in Astragalus extract absorbed into the bloodstream of mice, isoformononetin was found to inhibit UA synthesis by direct binding to XOD, and glycitein was found to interact with c-Jun to facilitate UA excretion and inhibit inflammation.CONCLUSION: This paper represents the pioneering investigation that firstly identifying two flavonoids of Astragalus extract that can be absorbed to fight against HUA, and elucidating their diverse molecular mechanism by targeting JNK/AP-1/NLRP3/IL-1β signaling pathway, UA metabolism and kidney protection.PMID:40073779 | DOI:10.1016/j.phymed.2025.156622

Phytomedicine. 2025 Mar 7;140:156526. doi: 10.1016/j.phymed.2025.156526. Online ahead of print.ABSTRACTBACKGROUND: The coastal wetland mangrove plant Acanthus ilicifolius l. (AI) is used as traditional medicine for liver protection and liver fibrosis treatment, but the pharmacodynamics of the hepatoprotective substance and the mechanisms of liver protection are not clear.PURPOSE: This work aimed to assess the liver-protective ability of AI and elucidate the pharmacodynamics of the hepatoprotective substance of AI responsible for its liver activity.STUDY DESIGN AND METHODS: This study first appraised the hepatoprotective activity of the alcohol extract of AI. To identify the hepatoprotective substance in AI, network topology and the contribution index were comprehensively analyzed and screened. The screened medicinal substances, acteoside (ACT) and isoacteoside (IACT), were tested for hepatoprotective activity using mouse liver damage model and l-02 hepatocyte injury model, and metabolomics was employed to explore the mechanism of liver protection.RESULTS: AI could restore the biochemical indicators of liver damage induced by CCl4 to normal conditions. The phenylethanoid glycoside compounds ACT and IACT, are the hepatoprotective substances of AI. ACT protects the liver tissue by regulating α-linolenic acid metabolism, glycerophospholipid metabolism, and amino acid-related pathway.CONCLUSION: This research provides basic information of the research and development of liver-protective effects of AI and ACT.PMID:40073778 | DOI:10.1016/j.phymed.2025.156526

Redox Biol. 2025 Mar 5;81:103582. doi: 10.1016/j.redox.2025.103582. Online ahead of print.ABSTRACTAnaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma affecting children and young adults. About 30% of patients develop therapy resistance therefore new precision medicine drugs are highly warranted. Multiple rounds of structure-activity optimization of Caffeic Acid Phenethyl Ester have resulted in CM14. CM14 causes upregulation of genes involved in oxidative stress response and downregulation of DNA replication genes leading to G2/M arrest and subsequent apoptosis induction. In accordance with this, an unbiased proteomics approach, confocal microscopy and molecular modeling showed that TUBGCP2, member of the centrosomal γ-TuRC complex, is a direct interaction partner of CM14. CM14 overcomes ALK inhibitor resistance in ALCL and is also active in T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia. Interestingly, CM14 also induced cell death in docetaxel-resistant prostate cancer cells thus suggesting an unexpected role in solid cancers. Thus, we synthesized and thoroughly characterized a novel TUBGCP2 targeting drug that is active in ALCL but has also potential for other malignancies.PMID:40073758 | DOI:10.1016/j.redox.2025.103582

Plant Physiol Biochem. 2025 Mar 5;222:109755. doi: 10.1016/j.plaphy.2025.109755. Online ahead of print.ABSTRACTAlpinia oxyphylla Miq., a well-accepted medicinal and edible plant in south China. The primary ingredients of this medicine vary significantly depending on their origin, which profoundly impacts its quality. In this study, a principal component analysis was performed on 17 different planting areas of A. oxyphylla, with nootkatone and kaempferol identified as representative sesquiterpenoids and flavonoids, respectively. To investigate the genes involved in nootkatone and kaempferol biosynthesis, a combined transcriptome and metabolome profiling was carried out on materials sourced from geo-authentic and non-authentic areas. The transcriptome analysis of these two types of accessions identified 96,691 unigenes, with 13,589 genes showing differential expression in both regions. Metabolome analysis revealed 2859 differentially accumulated metabolites across the four pairwise comparisons. Correlation analysis uncovered a number of genes, that associated with the differential biosynthesis of nootkatone and kaempferol in A. oxyphylla fruits from geo-authentic and non-authentic areas. Further investigation highlighted the candidate gene AoFMO1's ability to heterologously biosynthesize nootkatone in Arabidopsis thaliana leaves. This research lays the groundwork for a deeper understanding of the molecular mechanisms behind the authentication of A. oxyphylla's quality synthesis, and presents a comprehensive list of candidate genes for future functional studies to enhance the development of high-quality A. oxyphylla varieties rich in medicinal ingredients.PMID:40073739 | DOI:10.1016/j.plaphy.2025.109755

Neurobiol Aging. 2025 Mar 8;150:69-79. doi: 10.1016/j.neurobiolaging.2025.03.004. Online ahead of print.ABSTRACTIncreasing age and elevated intraocular pressure (IOP) are the two major risk factors for glaucoma, the most common cause of irreversible blindness worldwide. Accumulating evidence is pointing to metabolic failure predisposing to neuronal loss with advancing age and IOP injury. Many neurotransmitters are synthesized from endogenous metabolites and are essential for correct cell to cell signaling along the visual pathways. We performed detailed, small molecule metabolomic profiling of the aging mouse retina and further explored the impact of IOP elevation at different ages. The resultant metabolomic profiles showed clear discrimination between young and middle-aged retinas and these changes are accentuated following eye pressure elevation. Alterations in glutamate and Gamma-aminobutyric acid (GABA) related metabolites were the most apparent changes with advancing age with further reductions in GABA and related pathways after IOP elevation. These changes were further confirmed using immunohistochemistry and patch-clamp electrophysiological recording experiments.PMID:40073716 | DOI:10.1016/j.neurobiolaging.2025.03.004

Food Chem. 2025 Mar 8;479:143788. doi: 10.1016/j.foodchem.2025.143788. Online ahead of print.ABSTRACTIn this study, metabolomics and chemometrics were utilized to comprehensively investigate chemical mechanisms of aroma, taste, and color formation in cold-brewed green tea (4 °C). The results showed that the typical flavor of cold-brewed green tea (tea-to-water ratio: 1:50 g/mL) developed gradually after 1 h. Compared with the hot-brewed (80 °C) condition, volatile alcohols accumulated more under cold-brewing conditions. The extraction rate of bitter compounds such as caffeine decreased by more than 40 %, while the umami compound L-theanine increased about 9.2 % compared to hot-brewed green tea. The low temperatures also reduced flavonoid extraction ratio and retained high level of chlorophyll, resulting in a greener infusion. These differences led to cold-brewed green tea exhibiting a floral aroma, umami, sweet taste, and green color. This study revealed the impact of extraction temperature on the extraction efficiency of compounds from green tea. These findings can provide analysis methods for controlling quality of cold-brewed green tea.PMID:40073559 | DOI:10.1016/j.foodchem.2025.143788

Int J Food Microbiol. 2025 Mar 6;434:111136. doi: 10.1016/j.ijfoodmicro.2025.111136. Online ahead of print.ABSTRACTOptimizing the carbon source to increase biofilm production and thus boost the heat tolerance of strains is a promising strategy. However, related research is scarce. This study investigated the effects of varying glucose and sucrose amounts added to MRS medium on biofilm production and heat tolerance by Lactiplantibacillus plantarum LIP-1. Transcriptomic, proteomic, and metabolomic approaches were combined to analyze the intrinsic mechanism underlying the sucrose-induced increase in biofilm production. We then investigated the protective role of the biofilm for the strain. Compared with the control group (2 % glucose), biofilm production in the experimental group (2 % glucose+2 % sucrose) increased by 27 %, and after heat treatment (75 °C for 40 s), the experimental group demonstrated a 38 % increase in heat tolerance. Multiomic results unveiled that biofilm synthesis-related metabolism pathways were altered in the experimental group compared with the control group. When the expression of key genes and the enzymes they encode(sacA, metC, mccB, and CTH) was upregulated, L-homocysteine was synthesized. According to metabolomics results, the L-homocysteine content in the experimental group increased to twice that in the control group. This resulted in a 37 % increase in the extracellular protein content of biofilms. The biofilm inhibition test confirmed that this increase in extracellular protein content was the primary factor augmenting the strain's heat tolerance. The findings suggested that adding sucrose to MRS medium for boosting biofilm production is a viable technical approach that enhances cell tolerance to heat.PMID:40073550 | DOI:10.1016/j.ijfoodmicro.2025.111136

Water Res. 2025 Feb 27;279:123406. doi: 10.1016/j.watres.2025.123406. Online ahead of print.ABSTRACTIron and manganese (Fe/Mn) often lead to aesthetic quality issues in water supply. Strong and problematic black-brown particle formation was persistently observed in an alluvial drinking water well, even though oxygen enrichment probes, intended for in situ i.e., subsurface iron/manganese removal, were installed. To investigate the cause of the problem, a comparative and multiparametric approach was undertaken at the problematic well, seven additional wells (with 0.3 to 70 km distance to the affected well) and all the adjacent surface waters. Via a time-series investigation of up to 2.5 years, microbiological analysis (high-throughput 16S rRNA gene amplicon sequencing, total cell count) and chemical analysis (high-resolution elemental analysis using inductively coupled mass spectrometry and others) of the water samples were performed. Results revealed previously unreported, extremely dynamic, and seasonally recurring patterns of genus Crenothrix (a sheathed, filamentous bacterial population) in water samples obtained from the particle-affected well. Crenothrix spp. dominated the microbial community in summer months (up to 82 % relative abundance), being virtually absent in winter. Explanatory models for the high dynamics and association with bio-geochemical processes were established. These included methane formation and manganese mobilization in relation to riverbank filtration in the summer months, as well as changing aerobic and anaerobic conditions in the aquifer. Dominance of Crenothrix spp. in the affected well, low abundance in weak particle-affected wells, and total absence in non-affected wells was observed. This led to the suggestion of Crenothrix spp. as a technical indicator for Fe/Mn treatment failure for alluvial groundwater (e.g., genetic marker quantification by q/dPCR), to be evaluated in future studies regarding their applicability across a broader geographic context. Despite being first described in association with drinking water deterioration 150 years ago, this is the first study reporting seasonally recurring dominant patterns of Crenothrix spp. in association with operational/aesthetic issues for drinking water production.PMID:40073487 | DOI:10.1016/j.watres.2025.123406

Biomed Chromatogr. 2025 Apr;39(4):e70042. doi: 10.1002/bmc.70042.ABSTRACTIxeris sonchifolia (IS) has been demonstrated to have beneficial effects on clearing heat and detoxifying, promoting blood circulation and removing blood stasis. However, the protective effects of active fractions and the underlying mechanisms of IS against toxic heat and blood stasis syndrome (THBSS) remain unclear. This study aimed to investigate this. In this study, the protective effects of 30%, 50%, and 70% ethanol fractions of IS on rats with THBSS were evaluated by observing myocardial pathology, analyzing blood rheology and blood routine indices, and the general conditions of the rats. Comprehensive metabolomic analysis of plasma and myocardium samples was conducted using ultra-high-performance liquid chromatography linear ion trap quadrupole orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MS/MS). The results showed that IS-30% had a significant protective effect on rats with THBSS, and it could play a protective role by modulating 35 differential metabolites associated with key metabolic pathways, including glycerophospholipid metabolism, sphingosine metabolism, alpha-linolenic acid metabolism, and nicotinate and nicotinamide metabolism. Analysis of different metabolites and pathways showed that they are closely associated with inflammatory responses; therefore, it is hypothesized that IS-30% may protect against THBSS by exerting an anti-inflammatory effect. This study provides valuable data supporting the druggability of IS-30% and offers new insights into its potential therapeutic applications.PMID:40073453 | DOI:10.1002/bmc.70042

Oncotarget. 2025 Mar 12;16:140-162. doi: 10.18632/oncotarget.28703.ABSTRACTThe human genome project ushered in a genomic medicine era that was largely unimaginable three decades ago. Discoveries of druggable cancer drivers enabled biomarker-driven gene- and immune-targeted therapy and transformed cancer treatment. Minimizing treatment not expected to benefit, and toxicity-including financial and time-are important goals of modern oncology. The Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine founded by Drs. John Mendelsohn and Thomas Tursz provided a vision for innovation, collaboration and global impact in precision oncology. Through pursuit of transcriptomic signatures, artificial intelligence (AI) algorithms, global precision cancer medicine clinical trials and input from an international Molecular Tumor Board (MTB), WIN has led the way in demonstrating patient benefit from precision-therapeutics through N-of-1 molecularly-driven studies. WIN Next-Generation Precision Oncology (WINGPO) trials are being developed in the neoadjuvant, adjuvant or metastatic settings, incorporate real-world data, digital pathology, and advanced algorithms to guide MTB prioritization of therapy combinations for a diverse global population. WIN has pursued combinations that target multiple drivers/hallmarks of cancer in individual patients. WIN continues to be impactful through collaboration with industry, government, sponsors, funders, academic and community centers, patient advocates, and other stakeholders to tackle challenges including drug access, costs, regulatory barriers, and patient support. WIN's collaborative next generation of precision oncology trials will guide treatment selection for patients with advanced cancers through MTB and AI algorithms based on serial liquid and tissue biopsies and exploratory omics including transcriptomics, proteomics, metabolomics and functional precision medicine. Our vision is to accelerate the future of precision oncology care.PMID:40073368 | DOI:10.18632/oncotarget.28703

PLoS One. 2025 Mar 12;20(3):e0315708. doi: 10.1371/journal.pone.0315708. eCollection 2025.ABSTRACTPURPOSE: This study aimed to examine the differential expression profiles of plasma metabolites in rat models of post-traumatic osteoarthritis (PTOA) and elucidate the roles of metabolites and their pathways in the progression of PTOA using bioinformatics analysis.METHOD: Plasma samples were collected from 24 SD female rats to model PTOA, and metabolomic assays were conducted. The samples were divided into three groups: the surgically induced mild PTOA group (Group A: 3 weeks postoperative using the modified Hulth model; age 2 months), the surgically induced severe PTOA group (Group B: 5 weeks postoperative using the modified Hulth model; age 2 months), and the normal control group (Group C: healthy rats aged 2 months). Metabolites were structurally identified by comparing the retention times, molecular masses, secondary fragmentation spectra, collision energies, and other metabolite data with a database (provided by Shanghai Applied Protein Technology Co., Ltd.). Target prediction and pathway analysis were subsequently performed using bioinformatics analysis.RESULTS: The experiment revealed that in the mild PTOA group, levels of Alpha-ketoglutarate, Isocitric acid, Dichloroacetate, and other metabolites increased significantly compared with the normal group, whereas Linolenic acid, Lactose, and others decreased significantly. These findings suggest that these metabolites can serve as biomarkers for the diagnosis of early PTOA. In the severe PTOA group, Diosgenin, Indoleacrylic acid, Alpha-ketoglutarate, Isocitric acid, and others were elevated and may also be used as biomarkers for PTOA diagnosis. Adrenosterone, (+)-chlorpheniramine, and Phenanthridine levels were higher in the severe PTOA group compared to the mild PTOA group, while Menadione, Adenosine 5'-monophosphate, and Arg-Gly-Asp levels were lower.CONCLUSIONS: Taurocholate, indoleacrylic acid, alpha-ketoglutarate, and isocitric acid may serve as biomarkers for PTOA joint injury in rats. Menadione, adenosine 5'-monophosphate, and Arg-Gly-Asp exhibited differential expression between severe and mild PTOA groups in rats, potentially reflecting the injury's severity. Further investigation into these molecules in human tissues is warranted to ascertain their utility as biomarkers for PTOA in humans.PMID:40073326 | DOI:10.1371/journal.pone.0315708

Hepatology. 2025 Mar 12. doi: 10.1097/HEP.0000000000001304. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Portal vein tumor thrombosis (PVTT), an indicator of clinical metastasis, significantly shortens hepatocellular carcinoma (HCC) patients' lifespan, and no effective treatment has been established. We aimed to illustrate mechanisms underlying PVTT formation and tumor metastasis, and identified potential targets for clinical intervention.APPROACH AND RESULTS: Multi-omics data of 159 HCC patients (including 37 cases with PVTT) was analyzed to identify contributors to PVTT formation and tumor metastasis. In vitro and in vivo experiments were performed to confirm the critical role of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) in HCC metastasis. Metabolomics and transcriptomics techniques, single-cell RNA sequencing, combined with experimental verification were complemented to illustrate mechanisms underlying CAD induced pro-metastatic efficacy. Analysis of proteogenomic data of HCC cohort identified CAD as the key contributor to PVTT formation and tumor metastasis in HCC. Further experiments confirmed that high CAD expression could significantly promote HCC metastasis, and vice versa. Mechanistically, CAD manipulated de novo pyrimidine anabolism, leading to dihydroorotic acid (DHO) accumulation which directly bound to ubiquitination factor E4B (UBE4B). UBE4B subsequently regulated JAK1 ubiquitination and activated the NF-κB pathway to promote epithelial-mesenchymal transition (EMT) of HCC cells. Additionally, CAD generated an immunosuppressive milieu conducive to HCC metastasis by recruiting and reprogramming macrophages into a "pro-tumor" phenotype. Consequently, the metastatic capability of HCC was remarkably enhanced.CONCLUSION: Therapy targeting CAD may offer a promising approach to curb HCC metastasis by reducing tumor cells' metastatic potential and also shifting the tumor microenvironment towards a less pro-metastatic state.PMID:40073276 | DOI:10.1097/HEP.0000000000001304

J Proteome Res. 2025 Mar 12. doi: 10.1021/acs.jproteome.4c00529. Online ahead of print.ABSTRACTLung cancer stands as the leading cause of cancer-related death worldwide, impacting both men and women in the United States and beyond. Radiation therapy (RT) serves as a key treatment modality for various lung malignancies. Our study aims to systematically assess the prognosis and influence of RT on metabolic reprogramming in patients diagnosed with nonsmall-cell lung cancer (NSCLC) through longitudinal metabolic profiling. A cohort of 54 NSCLC patients underwent thoracic radiotherapy, with 96% receiving a total radiation dose ranging from 40 to 70 Gy, averaging 56.3 Gy. Blood biospecimens were collected before RT, during RT, and at the first follow-up after RT, with a total of 126 serum samples randomized for liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis using a high-performance LC (HPLC)-Q-Exactive mass spectrometry system. Our results indicated that the serum metabolite coumarin derivatives prior to radiotherapy exhibited the strongest unfavorable outcome with overall survival in these NSCLC cases. The metabolites in the blood samples can reflect the responses during RT. Notably, over half of the metabolites (12/23) were found to be fatty acids in the longitudinal analysis. This pilot study indicated that metabolic profiling of biofluids from NSCLC patients undergoing RT has the potential to assess the patient outcomes during and after treatment.PMID:40073233 | DOI:10.1021/acs.jproteome.4c00529

Br Poult Sci. 2025 Mar 12:1-10. doi: 10.1080/00071668.2025.2454960. Online ahead of print.ABSTRACT1. The avian gut hosts a complex and dynamic microbial ecosystem, which is essential for regulating host organ function. However, the relationship between the gut microbiota and the hypothalamic axis in acute stress vulnerability in ducks remains unclear.2. This study investigated how the gut microbiota affects microbial metabolism and the host stress response by comparing hypothalamic neurotransmitter availability, microbial composition and co-metabolites generated by both the microbiota and hypothalamus in ducks exhibiting the lowest active avoidance (LAA) and highest active avoidance (HAA) behaviour.3. The HAA group experienced a significant increase in the availability of arginine, histidine, glutamine, norepinephrine, L-tyrosine and melatonin during acute stress in the hypothalamus, compared to that in the LAA group. The 16S rRNA sequencing revealed significant differences in the gut microbiota composition based on acute stress vulnerabilities.4. Both caecal and hypothalamic metabolomic analyses identified 71 metabolites altered in caecal content and 95 in the hypothalamus. There was significant enrichment in pathways such as the cGMP-PKG signalling, dopaminergic synapse and endocrine resistance.5. Correlation analyses demonstrated that certain co-metabolites, including 1,3-dicyclohexylurea, 1-deoxyvaleric acid, 2-amino-2-methyl-1,3-propanediol, 3-chloroaniline, methenamine, N4-acetylcytidine-triphosphate and traumatin, may play a role in the gut microbiota-hypothalamic axis.6. The results suggested that the gut microbiome influenced acute stress responses. This provided a basis for understanding gut-hypothalamic communication and its impact on behaviour in ducks.PMID:40072466 | DOI:10.1080/00071668.2025.2454960