PubMed

Metabolomics. 2025 Mar 23;21(2):42. doi: 10.1007/s11306-025-02236-0.ABSTRACTINTRODUCTION: Pyridoxal 5'-phosphate (PLP), the biologically active form of vitamin B6 is involved in 4% of cellular enzymatic activities and its deficiency is responsible for or contributes to several human diseases. The study of underlying mechanisms is still in its infancy and requires suitable model organisms. In Drosophila the deficiency of vitamin B6 produces chromosome aberrations and hallmarks of human diseases including diabetes and cancer. However, the effects of vitamin B6 deficiency have never been examined at a metabolic level.OBJECTIVES: This study evaluates the metabolic changes in vitamin B6 deficient Drosophila larvae with the aim of validating flies as a suitable model for diseases associated to vitamin B6 deficiency.METHODS: To induce vitamin B6 deficiency we fed Drosophila wild type larvae with 4-deoxypyridoxine (4DP), a PLP antagonist. By HPLC analysis we verified that the 4DP treatment was effective in inducing vitamin B6 deficiency. Using an NMR-based metabolomic approach we compared the metabolites in larval extracts from untreated and 4DP-fed larvae.RESULTS: The NMR spectra analysis identified quantitative differences for sixteen metabolites out of forty, including branched chain and aromatic amino acids, glucose, and lipids, thus revealing interesting possible associations with the phenotypes showed by vitamin B6 deficient flies.CONCLUSIONS: Our results validate Drosophila as a suitable model to study in depth the molecular mechanisms underlying human diseases associated with vitamin B6 deficiency and confirmed that 4DP treatment is effective in inducing vitamin B6 deficiency.PMID:40123014 | DOI:10.1007/s11306-025-02236-0

Metabolomics. 2025 Mar 23;21(2):43. doi: 10.1007/s11306-025-02239-x.ABSTRACTINTRODUCTION: Based on distinct triggers, bacterial and allergen-induced inflammatory reactions have different pathophysiology. Metabolomic analysis is high-throughput technique that can provide potential biomarkers to distinguish between these responses.OBJECTIVES: In order to find out the metabolic profiles of two types of inflammation, metabolites were analysed in blood plasma and bronchoalveolar lavage fluid (BALF) of guinea pigs subjected to bacterial lipopolysaccharide (LPS) or allergen ovalbumin (OVA).METHODS: Hydrogen-1 nuclear magnetic resonance (1H NMR) spectroscopy for metabolite analysis was performed in samples of blood plasma and BALF of guinea pigs.RESULTS: Random forest algorithm built on combination of levels of circulating and BALF metabolites resulted in almost ideal discrimination between acute allergic and bacterial inflammation. The differences between inflammation triggered by LPS and OVA were manifested in shift in energy metabolism, metabolism of branched-chain amino acids (BCAAs)/branched-chain keto acids (BCKAs) with alterations in alanine and glutamine, which are linked with both, ammonia homeostasis as well as gluconeogenesis.CONCLUSION: Distinct molecule nutrients are to be utilized during acute bacterial and allergic inflammatory response.PMID:40123009 | DOI:10.1007/s11306-025-02239-x

Sci Rep. 2025 Mar 23;15(1):10012. doi: 10.1038/s41598-025-94759-8.ABSTRACTDiabetic macular edema (DME), a sight-threatening retinopathy, is a leading cause of vision loss in persons with diabetes mellitus. Despite strict control of systemic risk factors, a fraction of patients with diabetes developed DME, suggesting the existence of other potential pathogenic factors underlying DME. This study aimed to investigate the plasma metabotype of patients with DME and to identify novel metabolite markers for DME. Biomarkers identified from this study will provide scientific insight and new strategies for the early diagnosis and intervention of DME. To match clinical parameters between case and control subjects, patients with DME (DME, n = 30) or those with diabetes but without DME (Control, n = 30) were assigned to the present case-control study. Distinct metabolite profiles of serum were examined using liquid chromatography-mass spectrometry (LC-MS). A total of 190 distinct metabolites between DME and Control groups were identified (VIP > 1, Fold Change > 1.5 or < 0.667, and P < 0.05). The distinct metabolites between DME and Control groups were enriched in 4 KEGG pathways, namely, Glutamate Metabolism, Carnitine Synthesis, Oxidation of Branched Chain Fatty Acids, and Phytanic Acid Peroxisomal Oxidation. Finally, 4 metabolites were selected as candidate biomarkers for DME, namely, 5-Phospho-beta-D-ribosylamine, Succinic acid, Ascorbyl glucoside, and Glutathione disulfide. The area under the curve for these biomarkers were 0.693, 0.772, 0.762, and 0.771, respectively. This study suggested that impairment in the metabolism and 4 potential metabolites were identified as metabolic dysregulation associated with DME, which might provide insights into potential new pathogenic pathways for DME. 5-Phospho-beta-D-ribosylamine was first identified as a novel metabolite marker, with no previous reports linking it to diabetes or DME. This discovery may offer valuable insights into potential new pathogenic pathways associated with DME.PMID:40122941 | DOI:10.1038/s41598-025-94759-8

BMC Plant Biol. 2025 Mar 24;25(1):375. doi: 10.1186/s12870-025-06410-3.ABSTRACTBACKGROUND: Methyl jasmonate (MeJA) is an effective plant elicitor that enhances secondary metabolism. Chinese chives are prized for their pungent flavor, yet the biosynthetic pathways and regulatory mechanisms of flavor compounds induced by MeJA remain unclear.METHODOLOGY: This study integrated metabolomic and transcriptomic analyses to elucidate how MeJA modulates the biosynthesis of flavor substance precursors in soilless-cultivated Chinese chives.RESULTS: MeJA treatment improved the dry matter content and nutritional quality of Chinese chives. We identified 36 volatile and 183 nonvolatile differentially abundant metabolites between the MeJA-treated and control groups. Gene expression analysis revealed 193 candidate genes associated with flavor formation. Among all the genes, a total of 2,667 DEGs were enriched primarily in metabolic pathways, including secondary metabolite biosynthesis, linoleic acid metabolism, and phenylpropanoid biosynthesis. Furthermore, exogenous MeJA inhibited the synthesis of endogenous jasmonic acid as well as enzyme activity and gene expression related to metabolic pathways. It also promoted the conversion of S-alkyl-L-cysteine to S-alk(en)ylcysteine sulfoxides (CSOs), increasing the accumulation of the flavor precursor CSOs and increasing the levels of S-methyl-L-cysteine. This led to increased concentrations of the key garlic flavor compounds methiin and alliin, intensifying the pungent flavor of Chinese chives. Notably, MeJA-induced AtuFMO1 was associated with enhanced pungent flavor and may be regulated by AtuPHL7 and AP2/ERF-ERF transcription factors.CONCLUSION: In conclusion, exogenous MeJA activates key enzyme-encoding genes involved in the biosynthesis of garlic flavor precursor CSOs, leading to increased accumulation of the spicy compounds Methiin and Alliin. These findings establish AtuFMO1 as a central hub linking hormonal signaling to flavor biosynthesis and provide molecular targets for improving Allium crop flavor and quality through precision horticulture.PMID:40122824 | DOI:10.1186/s12870-025-06410-3

Am J Pathol. 2025 Mar 21:S0002-9440(25)00079-3. doi: 10.1016/j.ajpath.2025.02.007. Online ahead of print.ABSTRACTMetabolic processes within gut microbes generate bioactive metabolites that impact intestinal epithelial barrier function. Using gnotobiotic mice and mass spectrometry-based metabolomics, we identified novel metabolites in host tissues that are of microbial origin. Of those detected, we showed that the gut microbe generated metabolite δ-valerobetaine (δ-VB) is a potent inhibitor of L-carnitine biosynthesis and a modulator of fatty acid oxidation by mitochondria in liver cells. In the current study, we assessed the bioactivity of δ-VB towards gut epithelial barrier function. Germ-free mice are devoid of δ-VB, and we show that administration of δ-VB to germ-free mice also induces the enrichment of transcript sets associated with gut mitochondrial respiration and fatty acid oxidation in colonic tissue. Furthermore, we detected that δ-VB induces the differential expression of genes that function in barrier function in germ-free and conventionally raised mice. Functionally, δ-VB decreased gut barrier permeability and augmented wound healing in cultured gut epithelial cells, and elicited cytoprotective and pro-restitutive effects in a mouse model of colonic injury. We conclude that the microbial derived metabolite δ-VB is a modulator of gut epithelium function, and thus is a molecular target to potentially manage microbiome-host dysbiosis in intestinal health and disease.PMID:40122460 | DOI:10.1016/j.ajpath.2025.02.007

Complement Ther Med. 2025 Mar 21:103165. doi: 10.1016/j.ctim.2025.103165. Online ahead of print.ABSTRACTINTRODUCTION: Fruit juice-antihypertensive drug interactions can lead to subtherapeutic or supratherapeutic outcomes. This systematic review and meta-analysis assess such interactions and their potential clinical relevance.METHODS: PubMed, Scopus, and Science Direct databases were searched from their inception through June 2024. Eligible studies were those that investigated the effects of fruit juice on the pharmacokinetics of antihypertensive drugs. I2 was used to determine heterogeneity among studies and a random effect model was employed for meta-analysis. This review adhered to PRISMA guidelines and was registered in PROSPERO (CRD42022340159).RESULTS: Fifty-one studies were included. Most of them were open-label crossover trials. Grapefruit juice (GFJ), an inhibitor of organic-anion-transporting polypeptide (OATP) transporters and cytochrome P450 (CYP) 3A4, significantly decreased the AUC and Cmax of aliskiren and celiprolol by approximately 80-90%. Conversely, the AUC and Cmax of calcium channel blockers decreased with variable degrees when co-administered with GFJ. Apple and orange juices have comparable effects on certain medications. Most studies had small sample sizes and were of moderate quality. Hemodynamic effects were not assessed in most studies; thus, the clinical significance of these interactions remains uncertain and should be further investigated.CONCLUSION: Co-administration of fruit juice with antihypertensive drugs can result in an increase or decrease in drugs' bioavailability, depending on the drugs' metabolism route and involvement of transporters. Though further studies are needed to confirm clinical relevance in hypertensive patients, it is advised to avoid co-consumption of fruit juice with drugs showing significant changes in pharmacokinetic parameters to prevent subtherapeutic or supratherapeutic effects.PMID:40122403 | DOI:10.1016/j.ctim.2025.103165

J Nutr. 2025 Mar 21:S0022-3166(25)00176-2. doi: 10.1016/j.tjnut.2025.03.024. Online ahead of print.ABSTRACTBACKGROUND: Consuming healthful dietary patterns reduces the risk of developing metabolic diseases and nourishes the intestinal microbiota. Thus, investigating the microbial underpinnings of dietary influences on metabolic health is of clinical interest.OBJECTIVE: To determine the unique contributions of fecal taxa and metabolites in predicting metabolic health markers in adults across various dietary patterns.METHODS: Dietary, metabolic, and fecal microbiota and metabolome data from 118 adults (25-45y) were used for these cross-sectional analyses. The Diet History Questionnaire II assessed adherence to the Dietary Approaches to Stop Hypertension (DASH), Mediterranean diet, Mediterranean-DASH Intervention for Neurocognitive Delay (MIND), and the Healthy Eating Index-2020 (HEI-2020). Metabolic features included waist circumference, blood pressure, and circulating triglyceride (TG), high-density lipoprotein cholesterol (HDL), and glucose concentrations. Microbiota composition was assessed via 16S amplicon sequencing and volatile fatty acid and bile acid concentrations were measured by targeted metabolomics. ANCOM-BC2 and correlation analyses were used to screen for microbiota features independently associated with dietary patterns and metabolic health markers. Then, hierarchical linear regression models were used to evaluate the unique contributions of select microbial features on metabolic markers beyond adherence to dietary patterns.RESULTS: HEI-2020 positively associated with microbiota richness (p = 0.02). Beta diversity varied across all dietary patterns (p < 0.05). DASH diet scores, [Eubacterium] xylanophilum abundance, and deoxycholic acid (DCA) concentration explained the most variance in systolic (R2 = 0.32) and diastolic (R2 = 0.26) blood pressure compared to other dietary patterns and microbial features. TG concentrations were best predicted by MIND diet scores, [E]. eligens abundance, and isobutyrate concentrations (R2 = 0.24).CONCLUSIONS: Integrating fecal taxa and metabolites alongside dietary indices improved metabolic health marker prediction. These results point to a potential role of the intestinal microbiota in underpinning physiological responses to diet and highlight potential microbial biomarkers of metabolic health.PMID:40122388 | DOI:10.1016/j.tjnut.2025.03.024

J Food Prot. 2025 Mar 21:100494. doi: 10.1016/j.jfp.2025.100494. Online ahead of print.ABSTRACTIn food science, fungi demonstrate a paradoxical role: some species contribute positively by improving food's flavor, aroma, and texture, while others undermine food safety and quality, leading to spoilage or contamination through the production of harmful mycotoxins. When fungi colonize food materials, they produce distinct chemical profiles consisting of both primary and secondary metabolites. Metabolomics, a field dedicated to the analysis of small molecular compounds within biological entities, offers valuable insights into fungal metabolic activities and their impact on food safety and quality. This paper explores recent progress in applying metabolomics to investigate fungi within food systems, focusing on the complex interactions between fungi and their environments. Additionally, it identifies promising directions for advancing research in this rapidly evolving domain.PMID:40122345 | DOI:10.1016/j.jfp.2025.100494

Diabetes Res Clin Pract. 2025 Mar 21:112108. doi: 10.1016/j.diabres.2025.112108. Online ahead of print.ABSTRACTAIM: The aims of this study were to compare the metabolic profiles of type 2 diabetes mellitus patients with metformin and insulin monotherapy, to assess the associations of metabolites with major adverse cardiovascular events (MACE) distinctly for metformin-only and insulin-only users, and to test for effect modification by the glucose-lowering treatment.METHODS: We included 3,058 metformin-only and 558 insulin-only users from the UK Biobank. Mean concentrations of 249 metabolites of metformin and insulin users were compared with Cohen's d, their associations with MACE were assessed with Cox regression and interaction terms were tested.RESULTS: Mean VLDL size, HDL size, and concentrations of large and very large HDL molecules differed between insulin-only and metformin-only users. Overall, 75 metabolomic biomarkers were significantly associated with MACE in insulin-only users and 57 in metformin-only users. Significant interaction terms were observed between treatment group and albumin (protective in metformin users only) and 86 lipids/fatty acids, which were all statistically significantly associated with MACE among insulin users only.CONCLUSION: Metformin and insulin users have different metabolic profiles and a consistent pattern emerged that the metabolic profile of metformin users is favorable compared to the one of insulin users due to a lower associated MACE risk.PMID:40122179 | DOI:10.1016/j.diabres.2025.112108

Virulence. 2025 Mar 23:2482158. doi: 10.1080/21505594.2025.2482158. Online ahead of print.ABSTRACTOBJECTIVE: Metabolic Associated Fatty Liver Disease (MAFLD) impacts approximately 25% of the global population. The objective of our study was to elucidate the characteristics of the gut microbiome and alterations in plasma metabolites among MAFLD patients.METHODS: Between April 2023 and July 2023, 60 patients with MAFLD, along with 60 age, ethnicity, and sex-matched healthy controls (HCs), were enrolled from Inner Mongolia Autonomous Region, China. Analysis of gut microbiota composition and plasma metabolic profiles was conducted using metagenome sequencing and LC-MS.RESULTS: LEfSe analysis identified five pivotal species: Eubacterium rectale, Dialister invisus, Pseudoruminococcus massiliensis, GGB3278 SGB4328, and Ruminococcaceae bacteria. In subgroup analysis, Eubacterium rectale tended to be increased by more than 2 times and more than double in the non-obese MAFLD group, and MAFLD with moderate hepatic steatosis（HS）respectively. Combinations of phenomics and metabolomics yielded the highest accuracy (AUC = 0.97) in the MAFLD diagnosis. Combinations of phenomics and metagenomics yielded the highest accuracy (AUC = 0.94) in the prediction of the MAFLD HS progress. Plasma samples identified 172 metabolites mainly composed of fatty acid metabolites such as propionic acid and butyric acid analogues. Ruminococcaceae bacteria have a strong positive correlation with β-Alanine, Uric acid and L-Valine. Pseudoruminococcus massiliensis have a strong positive correlation with β-Alanine.CONCLUSION: Increases in Eubacterium rectale and decreases in Dialister invisus seem to be indicative of MAFLD patients. Eubacterium rectale may predicts HS degree of MAFLD and play an important role in the development of non-obese MAFLD. Eubacterium rectale can generate more propionic acid and butyric acid analogues to absorb energy and increase lipid synthesis, and ultimately cause MAFLD. The observed association between Ruminococcaceae bacteria and β-Alanine or Uric acid in these patients could offer fresh insights into the disease mechanism.PMID:40122128 | DOI:10.1080/21505594.2025.2482158

Nat Prod Res. 2025 Mar 23:1-20. doi: 10.1080/14786419.2025.2481615. Online ahead of print.ABSTRACTAesculus indica (Wall. ex Cambess.) Hook. is a deciduous tree species native to the temperate regions of the Himalayas. A member of the Sapindaceae family holds notable importance in traditional medicinal systems for its diverse applications. Different parts of A. indica are traditionally employed to treat a range of ailments such as rheumatism, digestive disorders, skin diseases, fever, arthritis, joint pain, and inflammation. These traditional practices are supported by recent pharmacological findings, which validate the plant's bioactive potential. This review compiles evidence highlighting A. indica's anti-inflammatory, antioxidant, antimicrobial, antidiabetic, and cytotoxic properties. The Aescin, a key ingredient of its seed, is particularly recognised for its potent anti-inflammatory and venotonic activities; however, improper seed processing can lead to toxicity concerns, underscoring the need for careful evaluation in medicinal applications. This review presents an in-depth overview of the botany, traditional uses, phytochemistry, pharmacology, and toxicology of A. indica, emphasizing its commercial viability. Additionally, it explores advanced metabolomic tools/techniques to identify untapped bioactive compounds and aims to support further research and application of A. indica in nutraceutical and medicinal formulations.PMID:40122095 | DOI:10.1080/14786419.2025.2481615

Drug Dev Ind Pharm. 2025 Mar 23:1-16. doi: 10.1080/03639045.2025.2484326. Online ahead of print.ABSTRACTOBJECTIVE: This research is focused on the metabolomics and cytotoxic effects of the anticancer drug erlotinib encapsulated in poly(lactide-co-glycolide) nanoparticles on non-small cell lung cancer (NSCLC) cell lines.METHODS: Uniform-sized nanoparticles (0.325 and 0.068 PDI) with mean diameters of 264.5 and 268.4 nm for blank and erlotinib-PLGA nanoparticles (nanodrugs-NDs) were formulated, respectively. The encapsulation efficiency of prepared nanoparticles was found to be 90.1%. 36% of erlotinib was released from PLGA nanoparticles within 24 hours, and the maximum sustained release was 43% at 72 hours. The metabolomic and cytotoxic effects of ND were evaluated.RESULTS: The Bax/Bcl-2 ratio was the lowest in the nanodrug group at 72 hours, showing increased apoptosis, indicating that the most effective drug formulation is the combined nanoparticle at 72 hours. The metabolomic studies revealed changing amino acids, antioxidant molecules, and carbohydrate profiles. The most significant changes were obtained in pathways related to the synthesis of p-glycoprotein, which is the principal protein for drug efflux and causes drug resistance. The lowest levels of amino acids and polyamines like serine, threonine, spermine, and spermidine were obtained at 72 hours with erlotinib encapsulated in poly(lactide-co-glycolide) (PLGA) nanoparticles, showing that the drug resistance may in part be overcome with this nanoparticles.CONCLUSION: The encapsulation of erlotinib with PLGA showed effects and influenced critical metabolic pathways, especially pointing out the need to lower drug resistance and signifying it's potential use as an effective treatment strategy for NSCLC.PMID:40122082 | DOI:10.1080/03639045.2025.2484326

J Hazard Mater. 2025 Mar 19;491:137980. doi: 10.1016/j.jhazmat.2025.137980. Online ahead of print.ABSTRACTEpidemiological evidence linking air pollution to children's thyroid function is inconsistent, and the role of metabolites remains unknown. We conducted a panel study with 3 repeated visits among 143 children aged 4-12 years. The outdoor levels of ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, and fine particulate matter were estimated 3 consecutive days preceding blood draw. Exposure to ozone was linearly associated with the reduction of free thyroxine (FT4) only at lag 0 day. Bayesian kernel machine regression and weighted quantile sum regression indicated that exposure to air pollution mixture linked to reduced FT4 at lag 0 day, with ozone being the primary contributor. Untargeted metabolomics were measured in 48 children, revealing that 27 serum metabolites were associated with ozone, primarily involving ether lipid and glycerophospholipid metabolism pathways. Casual inference tests showed that eight glycerophospholipid metabolites were identified as mediators of ozone's effect on FT4, seven of which were involved in ether lipid pathway. The integrated analysis identified a cluster of children with reduced FT4, characterized by increased ozone and decreased phosphatidylethanolamine plasmalogen and alkyl-phosphatidylcholine. Our findings suggested that short-term exposure to outdoor ozone in children may disrupt glycerophospholipid levels within the ether lipid metabolic pathway, leading to reduced FT4.PMID:40122003 | DOI:10.1016/j.jhazmat.2025.137980

Curr Opin Plant Biol. 2025 Mar 22;85:102703. doi: 10.1016/j.pbi.2025.102703. Online ahead of print.ABSTRACTTricin, a flavonoid, is a noncanonical lignin monomer present in grasses and other monocots, but rarely in dicots. This review explores the latest discovery of biosynthesis, transport, and distribution of tricin in plant cell walls, and discusses the missing gaps in this engaging topic. Tricin biosynthesis in grasses involves the phenylpropanoid and flavonoid pathways, with distinct enzymatic processes leading to tricin incorporation into lignin polymers. Methods for characterizing and quantifying tricin in lignin are also highlighted, including NMR spectroscopy and chromatographic techniques with discussion of challenges associated with its low abundance in plant tissues. The stability of tricin during biomass pretreatment processes is discussed, with findings indicating that acidic and alkaline conditions degrade tricin, while milder pretreatments preserve its structure. These insights underscore the potential of tricin in enhancing the functionality of lignin for sustainable bioprocessing, offering promising applications in pharmaceuticals, nutraceuticals, and biorefinery industries.PMID:40121929 | DOI:10.1016/j.pbi.2025.102703

Thromb Res. 2025 Mar 20;249:109309. doi: 10.1016/j.thromres.2025.109309. Online ahead of print.ABSTRACTBACKGROUND: High-throughput metabolomics studies have advanced the identification of novel biomarkers and enhanced the understanding of the pathogenesis of venous thrombosis. This systematic review aims to summarize metabolomics research conducted on venous thromboembolism (VTE), as well as its chronic sequelae, including chronic thromboembolic pulmonary hypertension (CTEPH) and post-thrombotic syndrome (PTS), encompassing both pre-clinical and clinical investigations.METHODS: A systematic search using relevant keywords related to metabolomics profiling and venous thromboembolism was conducted across four databases (PubMed, Embase, Scopus, and Web of Science). Quality assessment for animal studies was performed using SYRCLE, and for human studies, QUADOMICS was used. The study protocol is registered in PROSPERO under registry code CRD42024529490.RESULTS: Multiple metabolic disturbances were identified in various venous thrombotic conditions, including dysregulations in cellular respiration and the metabolism of carbohydrates, amino acids, lipids, and nucleic acids. Notably, altered levels of serum amino acids and their derivatives were frequently reported in patients with venous thrombosis, though findings regarding specific amino acids such as alanine, arginine, and tryptophan were inconsistent. Additionally, disruptions in tricarboxylic acid (TCA) cycle metabolites were commonly observed. Pathway enrichment analysis revealed significant involvement of several metabolic pathways, including valine, leucine, and isoleucine biosynthesis; alanine and aspartate metabolism; d-glutamine and D-glutamate metabolism; and arginine metabolism.CONCLUSIONS: This systematic review offers a comprehensive overview of metabolomics research in venous thromboembolism and its chronic sequelae, identifying the most affected metabolic pathways associated with disease progression.PMID:40121920 | DOI:10.1016/j.thromres.2025.109309

Biomed Pharmacother. 2025 Mar 22;186:118006. doi: 10.1016/j.biopha.2025.118006. Online ahead of print.ABSTRACTOBJECTIVE: Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain polyunsaturated fatty acids (PUFAs). Increasing studies suggest that FADS1 is a potential cancer target. Our previous research has demonstrated the significant role of FADS1 in cancer biology and patient survival, especially in kidney cancers. We aim to explore the underlying mechanism in this study.METHOD AND RESULTS: We found that pharmacological inhibition or knockdown of the expression of FADS1 significantly reduced the intracellular conversion of long-chain PUFAs, effectively inhibits renal cancer cell proliferation, and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we showed that while FADS1 inhibition induces endoplasmic reticulum (ER) stress, FADS1 expression is augmented by ER-stress inducer, suggesting a necessary role of PUFA production in response to ER stress. FADS1-inhibition sensitized cellular response to ER stress inducers, leading to cell apoptosis. Also, FADS1 inhibition-induced ER stress leads to activation of the PERK/eIF2α/ATF4/ATF3 pathway. Inhibiting PERK or knockdown of ATF3 rescued FADS1 inhibition-induced ER stress and cell growth suppression, while ATF3-overexpression aggravates the FADS1 inhibition-induced cell growth suppression and leads to cell death. Metabolomic analysis revealed that FADS1 inhibition results in decreased level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response, as well as impaired biosynthesis of nucleotides, possibly accounting for the cell cycle arrest.CONCLUSION: Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.PMID:40121894 | DOI:10.1016/j.biopha.2025.118006

Phytomedicine. 2025 Mar 18;141:156666. doi: 10.1016/j.phymed.2025.156666. Online ahead of print.ABSTRACTBACKGROUND: The pathogenesis of hepatocellular carcinoma (HCC) is characterized by its complexity and diversity, involving processes such as glycolysis, autophagy, and cellular immunity. Notably, the role of ERK/ULK1/NCOA4-mediated inhibition of iron autophagy in HCC pathogenesis has not been previously reported. This study provides a novel elucidation of HCC pathogenesis and identifies the clinical adjuvant therapy drug, Epimedium, as a potential treatment based on this mechanism. The research clarifies the regulatory effects of Epimedium on the ERK/ULK1/NCOA4-mediated inhibition of iron autophagy pathway in the treatment of HCC, thereby offering a scientific foundation for clinical treatment strategies and the development of innovative drugs.PURPOSE: The objective of this study is to uncover a new aspect of HCC pathogenesis, ERK/ULK1/NCOA4-mediated inhibition of iron autophagy, and to screen for clinical targeted adjuvant therapy drugs based on this mechanism.METHODS: A HCC rat model was induced with N-Nitrosodiethylamine (DEN). The physiological status of the HCC rats was assessed through indicators such as body weight and organ index. Liver damage in HCC rats was evaluated using hematoxylin and eosin (HE) staining and biochemical markers. Additionally, untargeted metabolomics was employed to explore the pathogenesis of HCC. UPLC-Q-TOF-MS combined with network pharmacology was employed to elucidate novel mechanisms, predict pathway targets, filtrate active ingredients and analyze the biological processes and signaling pathways modulated by EPME. DEN liver cancer rats were treated with different concentrations of EPME and protein expression levels were assessed by Western blot analysis. Molecular docking techniques were utilized to assess the binding affinity between the core components of EPME and target proteins. A HepG2 liver cancer in vitro model, in combination with inhibitor (SBI-0206965), was employed to verify the modulatory effects of EPME and its active ingredients on the ERK/ULK1/NCOA4 signaling pathway. Microscale thermophoretic (MST) was employed to verify the binding ability of the EPME core components to the ULK1 protein.RESULTS: Metabolomics combined with network pharmacology revealed a novel pathogenesis of HCC, which is ERK/ULK1/NCOA4-mediated iron autophagy inhibition. EPME can activate iron autophagy mediated by ERK/ULK1/NCOA4 through active ingredients such as icaritin, astragalin, and emodin, thereby enhancing the survival conditions of HCC-afflicted rats and mitigating liver damage and carcinogenesis, ultimately achieving therapeutic outcomes in HCC treatment.CONCLUSION: The ERK/ULK1/NCOA4-mediated iron autophagy inhibition represents a novel therapeutic mechanism for HCC. The clinical adjuvant drug EPME may exert therapeutic effects on HCC by activating ERK/ULK1/NCOA4-mediated iron autophagy.PMID:40121885 | DOI:10.1016/j.phymed.2025.156666

Food Chem. 2025 Mar 19;480:143954. doi: 10.1016/j.foodchem.2025.143954. Online ahead of print.ABSTRACTThe objectives of this research were to analyze the effects of varying nitrogen application rates on fruit quality and antioxidant properties of blue honeysuckle through widely targeted metabolomics analysis. High nitrogen application resulted in a reduction in fruit size and soluble solid content, along with significant decreases in the levels of total anthocyanins, phenolic compounds, flavonoids, and antioxidant indices. Under low nitrogen, key flavonoids in fruit namely Kaempferol-7-O-glucoside, Morin 3-alpha-L-lyxopyranoside, and Quercetin-3-O-xyloside (Reynoutrin) showed the high peak areas, with SOD, POD, and CAT activities at 1742.19, 45,525.65, and 1065.13 U/g, but decreased under high nitrogen. The molecular docking analysis revealed affinity values of -5.39, -2.72, -4.37, -3.98, -4.04, -4.18, -2.51, -2.31, and - 4.08 kcal/mol for SOD, POD, and CAT. These three flavonoids play a crucial role in the antioxidant defense system by targeting different enzymes, and their reduced concentrations under high nitrogen conditions may impair the fruit's antioxidant capacity.PMID:40121874 | DOI:10.1016/j.foodchem.2025.143954

Chemosphere. 2025 Mar 22;377:144334. doi: 10.1016/j.chemosphere.2025.144334. Online ahead of print.ABSTRACTThe prevalence of polycyclic aromatic hydrocarbons and their oxygenated and nitrogen containing analogs in freshwater ecosystems are of concern due to their reported toxicity to several aquatic species including Daphnia magna. This study explored the molecular-level responses of phenanthrene (PHEN), 9,10-phenanthrenequinone (PHQ), and phenanthridine (PN) as little is known about the impacts of these pollutants on the metabolic profile of D. magna. For this purpose, D. magna was exposed to three sub-lethal concentrations of these pollutants for 24 h. To assess molecular-level responses, 52 polar metabolites were extracted from individual adult daphnids, and analyzed using a mass spectrometry-based targeted metabolomics approach. Exposure to PN resulted in the most statistically significant changes to the metabolic profile of D. magna followed by PHQ, and then PHEN exposures. After PN exposure, the biochemical pathway analysis showed that all exposure concentrations shared 21 perturbed metabolic pathways. However, the number of disrupted metabolic pathways increased with increasing exposure concentrations for PHEN and PHQ. The results suggest that PN and PHQ exposures are more disruptive due to the presence of reactive functional groups when compared to PHEN exposure. For the tested concentration ranges, the findings indicate that exposure to PN resulted in non-monotonic disruptions across exposure concentrations. In contrast, exposure to PHEN and PHQ elicited perturbations that were concentration-dependent. Although the reported median effective concentration (EC50) for PN is higher than PHEN and PHQ, our data shows that metabolomics captures molecular-level changes that may not be detected by traditional toxicity metrics.PMID:40121761 | DOI:10.1016/j.chemosphere.2025.144334

BMC Womens Health. 2025 Mar 22;25(1):135. doi: 10.1186/s12905-025-03676-5.NO ABSTRACTPMID:40121498 | DOI:10.1186/s12905-025-03676-5