PubMed

J Environ Manage. 2025 Jan 21;375:124215. doi: 10.1016/j.jenvman.2025.124215. Online ahead of print.ABSTRACTAcetaminophen (APAP) is an extensively consumed over-the-counter and prescribed medication and a constituent of many active pharmaceutical compounds as well as personal care products. Its wide-scale prevalence in the environment due to inefficient treatment technologies has classified APAP as a contaminant of emerging concern. Thus, it is imperative to explore efficient and sustainable methods for remediation of contaminated environments. Considering the need for potent microbial resources, the present study deals with the evaluation of Enterobacter sp. APAP_BS8, degrading ∼88% of APAP (300 mg kg-1) in 16 days in microcosms, and accomplishes the mechanistic perspectives of degradation through in-depth insights into genomics, proteomics, and metabolomics. Whole genome analysis of the 4.9 Mbp genome sequence revealed deaminated glutathione amidase, glucosamine-6-phosphate deaminase, LLM class flavin-dependent oxidoreductase, and oxidoreductase genes can mediate the degradation. Increased expression of proteins corresponding to these genes was observed in proteome analysis. Molecular docking and simulations presented operative interaction and binding of the degradation pathway intermediates at the catalytic site of the identified enzymes. Analysis of the metabolome identified hydroxyquinol, 4-aminophenol, and 3-hydroxy-cis, cis-muconate as intermediates. The outcomes revealed that Enterobacter sp. APAP_BS8 exhibits potential enzymatic machinery for APAP degradation, thus providing scope for formulating sustainable bioremediation technologies.PMID:39842351 | DOI:10.1016/j.jenvman.2025.124215

Comp Biochem Physiol Part D Genomics Proteomics. 2025 Jan 17;54:101422. doi: 10.1016/j.cbd.2025.101422. Online ahead of print.ABSTRACTThe liver-gut axis is an important regulatory axis for the host's metabolic functions. The study of liver gene expression, changes in metabolic products and the regulation of gut microbial communities in plateau animals under harsh environments can reveal the mechanisms by which Tibetan goats adapt to the plateau environment. This study employs transcriptome, metabolome and metagenomic analyses to reveal the differences in genes, metabolism, and gut microbiota between Jianzhou big-eared goats (JBG) and Xizang cashmere goats (TCG), which is of significant importance for improving survival models of high-altitude ruminants. The results showed that there were 553 DEGs in the liver of JBG and TCG. Hepatic metabolomic analysis revealed significant differences in metabolic activity between the JBG and TCG groups, with notable increases in glycerophospholipid and retinol metabolic pathways. The gut microbiota, including Andreesenia, Dielma, Oscillibacter, Agrobacterium, Hyella and Thermosinus, interact with liver metabolites and can regulate the high-altitude adaptability of goats. This study reveals that TCG enhance immune regulation and energy utilization efficiency by regulating liver gene expression, modulating metabolic pathways, and improving gut microbiota, thereby helping TCG maintain healthy survival capabilities in hypoxic and high-radiation environments.PMID:39842302 | DOI:10.1016/j.cbd.2025.101422

Ecotoxicol Environ Saf. 2025 Jan 21;290:117734. doi: 10.1016/j.ecoenv.2025.117734. Online ahead of print.ABSTRACTCo-contamination with organic/inorganic compounds is common in industrial area and poses a great risk to local soil ecological environment. In this study, an operating ink factory site co-contaminated with polycyclic aromatic hydrocarbons (PAHs, mild to moderate pollution level) and heavy metals (HMs, heavy pollution level) was selected and screened for native vegetation, Carmona microphylla. High-throughput sequencing and metabolomics were mainly used to investigate the responses of soil bacteria and metabolites to the composite pollution and rhizosphere effect. As the results showed, among three pollution levels, a medium level of pollution was favorable to increase the richness and diversity of soil bacterial community, while high level of pollution greatly decreased special OTUs number. In addition, HMs were the most significant factors driving bacterial community structure, especially for Cd. The influence of medium molecular weight PAHs with 4 rings (MMW-PAHs) on dominant bacteria was greater than low molecular weight PAHs with 2-3 rings (LMW-PAHs) and high molecular weight PAHs with 5-6 rings (HMW-PAHs). Soil bacterial function was affected mainly by pollution level, but not rhizosphere effect, in which high pollution level changed α diversity and structure and composition of C- and N-cycling bacteria. Rhizosphere promoted network complexity by increasing the connection densities among bacterial communities, metabolites, soil properties and the involved number of metabolites. Compared to HMs, PAHs played a more important role in shaping bacterial community through affecting metabolites in non-rhizosphere soil, which was different from rhizosphere soil with a more significant effect of HMs than PAHs. Some key bacterial taxa have established resistance to HMs in rhizosphere soils, whereas they were sensitive to compound contamination in non-rhizosphere soils. Some key bacterial taxa are resistant to HMs in rhizosphere soils, whereas they are susceptible to complex contamination in non-rhizosphere soils, which could be a consequence of the rhizosphere by regulating soil metabolism. It also provides a valuable reference for how co-contaminants and rhizosphere effect shape together soil bacterial community through the changes of soil metabolites.PMID:39842173 | DOI:10.1016/j.ecoenv.2025.117734

Environ Int. 2025 Jan 16;196:109281. doi: 10.1016/j.envint.2025.109281. Online ahead of print.ABSTRACTE-waste contains hazardous chemicals that may be a direct health risk for workers involved in recycling. We conducted an untargeted metabolomics analysis of urine samples collected from male e-waste processing workers to explore metabolic changes associated with chemical exposures in e-waste recycling in Belgium, Finland, Latvia, Luxembourg, the Netherlands, Poland, and Portugal. Questionnaire data and urine samples were obtained from workers involved in the processing of e-waste (sorting, dismantling, shredding, pre-processing, metal, and non-metal processing), as well as from controls with no known occupational exposure. Pre- and post-shift urine samples were collected and analysed using ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS). A total of 32 endogenous urinary metabolites were annotated with a Variable Importance in Projection (VIP) above 2, indicating that e-waste recycling is mainly associated with changes in steroid hormone and neurotransmitter metabolism, energy metabolism, bile acid biosynthesis, and inflammation. The highest VIP was observed for dopamine-o-quinone, which is linked to Parkinson's disease. These and other changes in metabolism in workers employed in the processing of e-waste need further verification in targeted studies.PMID:39842165 | DOI:10.1016/j.envint.2025.109281

J Hazard Mater. 2025 Jan 16;487:137262. doi: 10.1016/j.jhazmat.2025.137262. Online ahead of print.ABSTRACTMicroplastics have evolved as widespread contaminants in terrestrial and aquatic environments, raising significant environmental concerns due to their persistence and bioaccumulation. In this study, we investigated the toxicity of polyethylene microplastics (PE-MPs) on the agricultural insect, Spodoptera frugiperda. Maize leaves containing three sizes (0.5 μm, 5 μm, and 50 μm) of PE-MPs were fed to fall armyworm larvae for 12 days at concentrations of 1.25 g/ L, 5 g/L, and 20 g/L. The results showed that smaller size and higher concentration of microplastics led to increased toxicity. Furthermore, different sizes and maximum concentrations of PE-MPs were selected for subsequent experiments to observe changes in histological and enzymatic biomarkers, midgut microbiome, and metabolic responses. Following PE-MPs exposure, inflammation signs and oxidative stress were detected in the midgut. Significant changes were also observed in midgut microbiota and metabolomes, most related with oxidative stress, inflammatory disorders, and energy metabolism. These results provide evidence of midgut damage and alterations in the microbiota and metabolome of S. frugiperda because of PE-MPs exposure, highlighting the harm that microplastics can inflict on agricultural insects. Additionally, the study lays a theoretical foundation for future research on the transmission of microplastics through the food chain in agricultural ecosystems.PMID:39842122 | DOI:10.1016/j.jhazmat.2025.137262

J Hazard Mater. 2025 Jan 19;487:137296. doi: 10.1016/j.jhazmat.2025.137296. Online ahead of print.ABSTRACTPolychlorinated biphenyls (PCBs) are persistent organic pollutants known for their environmental persistence and bioaccumulation, posing significant health risks. This study examines the toxic effects of a representative PCBs (Aroclor 1254) on yellowfin seabream (Acanthopagrus latus) exposured for 30 days through a multi-omics approach. Histopathological examinations revealed structural damage to the intestinal structure and hepatic steatosis, along with elevated serum lipopolysaccharide levels, indicating compromised intestinal barrier integrity and liver inflammation. Metabolomic profiling showed significant alterations in lipid metabolites, including elevated lysophosphatidylcholines and arachidonic acid derivatives. Transcriptomic analysis unveiled 2272 differentially expressed genes in the liver, with notable changes in immune response and metabolic pathways. Gut microbiome analysis showed dysbiosis characterized by an increase in Proteobacteria and a decrease in Firmicutes and Actinobacteria. Remarkably, Tetranor-12S-HETE and LPC 15:1 emerged as key biomarkers for the disruption of the gut-liver axis, correlating with immune gene expression and gut microbiota composition. The integration of transcriptomic, metabolomic, and microbiome data highlighted the complex interplay between A1254 exposure and the gut-liver axis, emphasizing the central role played by PPAR signaling in mediating these effects. Collectively, these results indicate that exposure to A1254 results in bioaccumulation in the liver and gut, leading to severe tissue injury, microbiota dysbiosis, and dysregulation of the gut-liver axis, ultimately disrupting lipid metabolism. These findings underscore the metabolic health risks posed by PCBs exposure in aquatic environments.PMID:39842118 | DOI:10.1016/j.jhazmat.2025.137296

J Pharm Biomed Anal. 2025 Jan 20;256:116684. doi: 10.1016/j.jpba.2025.116684. Online ahead of print.ABSTRACTAlkaptonuria (AKU) is a rare autosomal-recessive disease which is characterized through black urine and ochronosis. It is caused by deficiency of the enzyme Homogentisate 1,2-dioxygenase in the Phenylalanine/Tyrosine degradation pathway which leads to the accumulation of Homogentisic acid (HGA). Urine was provided by AKU patients and healthy controls. Several different methods were developed in this study each with a specific goal. Firstly, a simple and inexpensive RP-UHPLC-UV method for routine monitoring of HGA as a key metabolite employing a Phenylhexyl stationary phase chemistry. Validation was performed in accordance to FDA guidelines and method selectivity was further evaluated via on-line high-resolution sampling 2D-LC-QToF-MS, coupling the Phenylhexyl phase in the first dimension with a C18 phase in the second dimension. Secondly, a targeted and accurate RP-UHPLC-MRM-QTRAP assay, providing quantitative analysis of the relevant pathway metabolites based on a Phenylhexyl stationary phase, and lastly an untargeted HILIC-UHPLC-QToF-MS/MS method with SWATH (sequential window acquisition of all theoretical mass spectra) acquisition employing a sulfobetaine-type HILIC-Z superficially porous particle column, with the aim of uncovering more details about the metabolic profile of this genetic disorder. By untargeted analysis 204 metabolites could be detected and annotated in positive and negative ESI mode in total. Two separate LC methods were employed, differing in their conditions depending on the ionization mode (20 mM ammonium formate as buffer additive adjusted to a pH = 3.5 with formic acid in ESI+ mode and 20 mM ammonium acetate adjusted to a pH = 7.5 with acetic acid in ESI- mode). By effectively combining the aforementioned methods, a comprehensive workflow was developed, allowing the effective analysis of both patient and control urine samples.PMID:39842076 | DOI:10.1016/j.jpba.2025.116684

J Pharm Biomed Anal. 2025 Jan 16;256:116674. doi: 10.1016/j.jpba.2025.116674. Online ahead of print.ABSTRACTThe incidence of acute liver injury is increasing and poses a significant threat to human health. Ganoderma lucidum spore oil (GLSO), a lipid substance extracted from Ganoderma lucidum spore powder using supercritical CO2 technology, has been investigated for its potential to prevent acute liver injury. However, the specific mechanism underlying the protective effects of GLSO remains incompletely understood. In this study, we investigated the preventive effect of GLSO on acute liver injury in rats, focusing on the gut microbiome and serum metabolomics. GLSO effectively alleviated liver dysfunction and reduced inflammation, leading to the prevention of acute liver injury in rats. Serum metabolomics analysis revealed that GLSO primarily modulated lipid metabolic pathways related to glycerophospholipid metabolism and sphingolipid metabolism. Specifically, GLSO decreased the levels of metabolites such as lysophosphatidylcholine (LPC), glycerophosphatidylcholine (GPC), and sphinganine 1-phosphate (SA1P), while increasing the levels of phosphatidylglycerol (PG) and digalactosylceramide (DGC). Gut microbiomics data indicated that GLSO effectively regulated the composition of the gut microbiota in rats with acute liver injury. Specifically, it increased the abundance of Firmicutes and decreased the abundance of Proteobacteria. Mantel test correlation analysis revealed a close relationship between gut microbial Burkholderiales and lipid metabolites in GLSO-mediated prevention of acute liver injury. GLSO exerts its preventive effects on acute liver injury by remodeling the gut microbiota and regulating lipid metabolism. These findings provide novel insights and potential directions for the development of new drugs targeting acute liver injury.PMID:39842075 | DOI:10.1016/j.jpba.2025.116674

Mol Genet Metab. 2025 Jan 17;144(3):109022. doi: 10.1016/j.ymgme.2025.109022. Online ahead of print.ABSTRACTMucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked lysosomal storage disorder. It results from a deficiency of the enzyme iduronate-2-sulfatase (I2S), leading to the accumulation of glycosaminoglycans (GAGs) in various tissues and organs. Clinical manifestations include skeletal abnormalities, facial coarsening, organ enlargement, and developmental delays. The main objective of this study was to identify neuronopathic MPS II-specific biomarkers for early detection, diagnosis, monitoring, and follow up of affected patients. We thus applied liquid chromatography-high-resolution mass spectrometry (LC-HRMS) based untargeted metabolomic approaches to identify these potential biomarkers which could discriminate patients with the neuronopathic form of MPS II from healthy controls. Secondary aims focused on a better understanding of how the disease may affect the metabolome of patients. Urine and plasma samples from 21 untreated neuronopathic MPS II patients characterized by severe clinical manifestations were compared to 23 age- and gender-matched healthy control samples using a Xevo G2-XS Qtof MS (Waters Corp.). A comprehensive metabolomic workflow and multivariate statistical analyses revealed metabolites consistently elevated in MPS II patients. These include acylaminosugars, dipeptides, amino acids and their derivatives, lipid structures, and various compounds indicating disruptions in metabolic pathways. Development and validation of quantitative methods will be done using tandem mass spectrometry. Furthermore, identifying biomarkers associated with the central nervous system (CNS) in MPS II patients would help detect the neuronopathic form of the disease early, and enable the evaluation of the effectiveness of novel therapeutic strategies.PMID:39842066 | DOI:10.1016/j.ymgme.2025.109022

Sci Adv. 2025 Jan 24;11(4):eadu5787. doi: 10.1126/sciadv.adu5787. Epub 2025 Jan 22.ABSTRACTLysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multiomic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially in NPC1-/- and NPC2-/- mutants, where lysosomes accumulate cholesterol. Autophagic and endocytic cargo delivery failures correlated with elevated lysophosphatidylcholine species and multilamellar structures visualized by cryo-electron tomography. Loss of mitochondrial cristae, MICOS complex components, and OXPHOS components rich in iron-sulfur cluster proteins in NPC2-/- cells was largely alleviated when iron was provided through the transferrin system. This study reveals how lysosomal dysfunction affects mitochondrial homeostasis and underscores nMOST as a valuable discovery tool for identifying molecular phenotypes across LSDs.PMID:39841834 | DOI:10.1126/sciadv.adu5787

Rev Col Bras Cir. 2025 Jan 17;51:e20243685. doi: 10.1590/0100-6991e-20243685-en. eCollection 2025.ABSTRACTINTRODUCTION: Advances in imaging methods have led to an increasingly frequent diagnosis of adrenal gland lesions as incidental findings. Despite progress in this field, there is still limited information regarding the epidemiology of the clinical and metabolic profile of patients with adrenal incidentaloma (AI). The objective is analyze the epidemiology of adrenal tumors at Gaffrée e Guinle University Hospital (HUGG) and compare it with data from the literature.METHOD: This is a cross-sectional study that included patients of any gender and age who was treated at HUGG for adrenal tumors.RESULTS: The following variables were evaluated: age, gender, functionality, benignity, and size. We also analyzed the metabolic profile of patients with AI, specifically those with mild autonomy cortisol secretion. Out of 31 patients with adrenal tumors, 68% were female. The mean age was 55 years with a standard deviation of ±16.2. 54% of the sample had adrenal incidentalomas. 93.6% of the sample had benign cases. Among the adrenal incidentalomas, 53% were non-functioning. In patients with adrenal tumors, only 10% had metabolic syndrome, while in patients with mild autonomous cortisol secretion, this number rose to 17%.CONCLUSION: The sample of patients with adrenal tumors and incidentaloma at HUGG presented a prevalence of metabolic complications similar to that found in the literature.PMID:39841720 | DOI:10.1590/0100-6991e-20243685-en

PLoS One. 2025 Jan 22;20(1):e0316032. doi: 10.1371/journal.pone.0316032. eCollection 2025.ABSTRACTGinsenosides are the most important secondary metabolites of ginseng. Ginseng has developed certain insect resistance properties during the course of evolutionary environmental adaptation. However, the mechanism underlying the insect resistance of ginseng is poorly understood. To elucidate the insect resistance mechanism of ginseng, we performed stress experiments on ginseng inoculated with black chafer larvae. The contents of ginsenosides in the ginseng roots, stems and leaves were determined at 0, 72, 120 and 168 h after the inoculation of insects. The tandem-mass-tag technology was used to determine the protein phosphorylation sites. Plant hormones were analyzed by multiple reaction monitoring targeted metabolomics. The results showed that ginsenosides present in the stems and leaves were more responsive to insect herbivory treatment than those present in the roots. Through proteomics, we found that the expression of most of the differentially expressed proteins, including GAPC1, GAPC2, and CSD1, was downregulated by insect herbivory treatment, HSP81-3 expression was up-regulated under insect herbivory stress. Regarding plant hormones, abscisic acid (ABA), gibberellic acid, Typhasterol (TY), iopentene adenine (IP), Cytokinin Riboside (czR) and Thiamethasone (tZ) levels were increased by herbivory treatment. With the increase in herbivory treatment time, the levels of trans-Zeatin-riboside (tzR), Isopentenyl adenosine riboside (iPR), and indole-3-acetic acid (IAA) were increased after 168h. The levels of salicylic acid (SA), jasmonates (JA), cis-PODA, and JA-Ile were increased after 120h but decreased thereafter. Under stress conditions, the expression of many antioxidant-related proteins was down-regulated; however, HSP81-3 expression was up-regulated, indicating that the plants exhibited severe oxidative stress. In conclusion, HSP81-3 plays an important role in ABA-dependent regulations involved in response to insect herbivory stress in ginseng. GAPC1 and GAPC2 also participate in the process of anti-herbivory stress response in ginseng.PMID:39841642 | DOI:10.1371/journal.pone.0316032

Intensive Care Med Exp. 2025 Jan 22;13(1):9. doi: 10.1186/s40635-024-00708-6.ABSTRACTPURPOSE: The landiolol and organ failure in patients with septic shock (STRESS-L study) included a pre-planned sub-study to assess the effect of landiolol treatment on inflammatory and metabolomic markers.METHODS: Samples collected from 91 patients randomised to STRESS-L were profiled for immune and metabolomic markers. A panel of pro- and anti-inflammatory cytokines were measured through commercially acquired multiplex Luminex assays and statistically analysed by individual and cluster-level analysis (patient). Metabolite fingerprinting was carried out by flow infusion electrospray ionisation high-resolution mass spectrometry and metabolomic data were analysed using the R-based platform MetaboAnalyst. The metabolites were identified using DIMEdb (dimedb.ibers.aber.ac.uk) from their mass/charge ratios. These metabolomic data were also re-analysed using individual and cluster-level analysis. The individual-level models were adjusted for confounders, such as age, sex, noradrenaline dosage and patient (random effect).RESULTS: Analysis was undertaken at cluster- and individual-level. There were no significant differences in cytokine concentration level between trial arms nor survivors and non-survivors over the duration of the observations from day 1 to day 4. Metabolomic analysis showed some separation in the levels of ceramides and cardiolipins between those who survived and those who died. Following adjusted analysis for confounders, plasma metabolite concentrations remained statistically different between landiolol and standard care arms for succinic acid, L-tryptophan, L-alanine, 2,2,2-trichloroethanol, lactic acid and D-glucose.CONCLUSIONS: In a study of ICU patients with established septic shock and a tachycardia, landiolol treatment used to reduce the heart rate from above 95 to a range between 80 and 94 beats per minute did not induce significant cytokine changes. D-Glucose, lactic acid, succinic acid, L-alanine, L-tryptophan and trichloroethanol were pathways that may merit further investigation.TRIAL REGISTRATION: EU Clinical Trials Register Eudra CT: 2017-001785-14 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001785-14/GB ); ISRCTN registry Identifier: ISRCTN12600919 ( https://www.isrctn.com/ISRCTN12600919 ).PMID:39841388 | DOI:10.1186/s40635-024-00708-6

CA Cancer J Clin. 2025 Jan 22. doi: 10.3322/caac.21880. Online ahead of print.ABSTRACTNext-generation sequencing has revealed the disruptive reality that advanced/metastatic cancers have complex and individually distinct genomic landscapes, necessitating a rethinking of treatment strategies and clinical trial designs. Indeed, the molecular reclassification of cancer suggests that it is the molecular underpinnings of the disease, rather than the tissue of origin, that mostly drives outcomes. Consequently, oncology clinical trials have evolved from standard phase 1, 2, and 3 tissue-specific studies; to tissue-specific, biomarker-driven trials; to tissue-agnostic trials untethered from histology (all drug-centered designs); and, ultimately, to patient-centered, N-of-1 precision medicine studies in which each patient receives a personalized, biomarker-matched therapy/combination of drugs. Innovative technologies beyond genomics, including those that address transcriptomics, immunomics, proteomics, functional impact, epigenetic changes, and metabolomics, are enabling further refinement and customization of therapy. Decentralized studies have the potential to improve access to trials and precision medicine approaches for underserved minorities. Evaluation of real-world data, assessment of patient-reported outcomes, use of registry protocols, interrogation of exceptional responders, and exploitation of synthetic arms have all contributed to personalized therapeutic approaches. With greater than 1 × 1012 potential patterns of genomic alterations and greater than 4.5 million possible three-drug combinations, the deployment of artificial intelligence/machine learning may be necessary for the optimization of individual therapy and, in the near future, also may permit the discovery of new treatments in real time.PMID:39841128 | DOI:10.3322/caac.21880

mSystems. 2025 Jan 22:e0161524. doi: 10.1128/msystems.01615-24. Online ahead of print.ABSTRACTDuring batch fermentation, a variety of compounds are synthesized, as microorganisms undergo distinct growth phases: lag, exponential, growth-no-growth transition, stationary, and decay. A detailed understanding of the metabolic pathways involved in these phases is crucial for optimizing the production of target compounds. Dynamic flux balance analysis (dFBA) offers insight into the dynamics of metabolic pathways. However, explaining secondary metabolism remains a challenge. A multiphase and multi-objective dFBA scheme (MPMO model) has been proposed for this purpose. However, its formulation is discontinuous, changing from phase to phase; its accuracy in predicting intracellular fluxes is hampered by the lack of a mechanistic link between phases; and its simulation requires considerable computational effort. To address these limitations, we combine a novel model with a genome-scale model to predict the distribution of intracellular fluxes throughout batch fermentation. This integrated multiphase continuous model (IMC) has a unique formulation over time, and it incorporates empirical regulatory descriptions to automatically identify phase transitions and incorporates the hypotheses that yeasts might vary their cellular objective over time to adapt to the changing environment. We validated the predictive capacity of the IMC model by comparing its predictions with intracellular metabolomics data for Saccharomyces uvarum during batch fermentation. The model aligns well with the data, confirming its predictive capabilities. Notably, the IMC model accurately predicts trehalose accumulation, which was enforced in the MPMO model. We further demonstrate the generalizability of the IMC model, explaining the dynamics of primary and secondary metabolism of three Saccharomyces species. The model provides biological insights consistent with the literature and metabolomics data, establishing it as a valuable tool for exploring the dynamics of novel fermentation processes.IMPORTANCEThis work presents an integrated multiphase continuous dynamic genome-scale model (IMC model) for batch fermentation, a crucial process widely used in industry to produce biofuels, enzymes, pharmaceuticals, and food products or ingredients. The IMC model integrates a continuous kinetic model with a genome-scale model to address the critical limitations of existing dynamic flux balance analysis schemes, such as the difficulty of explaining secondary metabolism, the lack of mechanistic links between growth phases, or the high computational demands. The model also introduces the hypothesis that cells adapt the FBA objective over time. The IMC improves the accuracy of intracellular flux predictions and simplifies the implementation process with a unique dFBA formulation over time. Its ability to predict both primary and secondary metabolism dynamics in different Saccharomyces species underscores its versatility and robustness. Furthermore, its alignment with empirical metabolomics data validates its predictive power, offering valuable insights into metabolic processes during batch fermentation. These advances pave the way for optimizing fermentation processes, potentially leading to more efficient production of target compounds and novel biotechnological applications.PMID:39840996 | DOI:10.1128/msystems.01615-24

J Virol. 2025 Jan 22:e0182724. doi: 10.1128/jvi.01827-24. Online ahead of print.ABSTRACTLumpy skin disease virus (LSDV) infection poses a significant threat to global cattle farming. Currently, effective therapeutic agents are lacking. TMP269, a small molecule inhibitor of class IIa histone deacetylase inhibitor, plays a vital role in cancer therapy. In this study, we demonstrated that TMP269 treatment inhibits the early-stage replication of LSDV in a dose-dependent manner. RNA sequencing data revealed that metabolism-related signaling pathways were significantly enriched after LSDV infection. Furthermore, untargeted metabolomics analysis revealed that lysophosphatidic acid (LPA), a key metabolite of the glycerophospholipid pathway, was upregulated following LSDV infection and downregulated after TMP269 treatment. In addition, exogenous LPA promotes LSDV replication by activating the mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) signaling pathway and suppressing the host's innate immune response. Furthermore, treatment with the LPA receptor inhibitor Ki16425 suppressed LSDV replication and promoted the host's innate immune response. These findings suggest that LSDV infection can induce LPA expression and aid viral activation of the MEK/ERK signaling pathway and escape of the host's innate immune response, whereas TMP269 treatment can inhibit LPA production and limit its promotion of LSDV replication. These data identified the antiviral mechanism of TMP269 and a novel mechanism by which LSDV inhibits host innate immune responses, providing insights into the development of new preventive or therapeutic strategies targeting altered metabolic pathways.IMPORTANCELumpy skin disease virus (LSDV) poses a significant threat to global cattle farming. Owing to insufficient research on LSDV infection, pathogenesis, and immune escape mechanisms, prevention and control methods against LSDV infection are lacking. Here, we found that TMP269, a class IIa histone deacetylase inhibitor, significantly inhibited LSDV replication. We further demonstrated that TMP269 altered LSDV infection-induced host glycerophospholipid metabolism. In addition, TMP269 decreased the accumulation of lysophosphatidic acid (LPA), a key metabolite in glycerophospholipid metabolism, induced by LSDV infection, and exogenous LPA-promoted LSDV replication by activating the mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) signaling pathway and suppressing the host innate immune response. Our findings identified the antiviral mechanism of TMP269 and a novel mechanism by which LSDV manipulates host signaling pathways to promote its replication, offering insights into the development of novel antiviral agents against LSDV infection.PMID:39840984 | DOI:10.1128/jvi.01827-24

Liver Int. 2025 Feb;45(2):e70006. doi: 10.1111/liv.70006.ABSTRACTBACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of hepatocellular carcinoma (HCC). In this study, we combine metabolomic and gene expression analysis to compare HCC tissues with non-tumoural tissues (NTT).METHODS: A non-targeted metabolomic strategy LC-MS was applied to 52 pairs of human MASLD-HCC and NTT separated into 2 groups according to fibrosis severity F0F1-F2 versus F3F4. The expression of genes related to de Novo lipogenesis (DNL) and fatty acid oxidation (FAO) has been analysed by quantitative RT-PCR and/or interrogation of RNA-seq datasets in 259 pairs of tissues (MASLD-HCC vs. VIRUS-HCC).RESULTS: Metabolomic analysis revealed that acylcarnitines were the main discriminating metabolites according to fibrosis severity when we compared MASLD-HCC-F0F1-F2 versus NTT and MASLD-HCC-F3F4 versus NTT. Based on these metabolomic data, the analysis of a panel of 15 selected genes related to DNL and FAO indicated that there is no difference between the 2 groups of MASLD-HCC. In contrast the same comparative gene analysis according to the aetiology of HCC: MASLD-HCC versus VIRUS-HCC showed that both aetiologies shared the same upregulation of genes involved in DNL. However, five genes involved in FAO (HADHA, CRAT, CPT1, CPT2 and PPARA) are upregulated exclusively in MASLD-HCC. This result indicates that FAO and DNL pathways are simultaneously activated in MASLD-HCC in contrast to VIRUS-HCC.CONCLUSIONS: These results suggest that, the involvement of adaptive metabolic pathways is different depending on the aetiology of HCC. Moreover, the dogma that simultaneous activation of FAO and DNL is incompatible in cancer would not apply to MASLD-HCC.PMID:39840890 | DOI:10.1111/liv.70006

Pediatr Allergy Immunol. 2025 Jan;36(1):e70029. doi: 10.1111/pai.70029.NO ABSTRACTPMID:39840827 | DOI:10.1111/pai.70029

Adv Sci (Weinh). 2025 Jan 22:e2412817. doi: 10.1002/advs.202412817. Online ahead of print.ABSTRACTOsteoarthritis (OA) is a globally prevalent degenerative joint disease. Recent studies highlight the role of ferroptosis in OA progression. Targeting ferroptosis regulation presents a promising therapeutic strategy for OA; however, current research primarily focuses on single targets associated with ferroptosis. In this study, a reactive oxygen species (ROS)-responsive nanoparticle is developed by linking deferasirox (DEF) and pterostilbene (PTE) with thioketal and incorporating cerium ions (Ce), creating Ce@D&P nanoparticles (NPs), which offer multitarget regulation of ferroptosis. The characteristics of Ce@D&P NPs are evaluated and their therapeutic effects on IL-1β-stimulated chondrocytes are verified. Results show that Ce@D&P NPs reduce ROS levels, mitigate inflammation, chelate iron to inhibit ferroptosis, and balance extracellular matrix (ECM) metabolism in chondrocytes. Mechanistically, transcriptomics and metabolomics analyses suggest that Ce@D&P NPs exerted their effects by regulating oxidative stress and lipid metabolism in chondrocytes. To better treat destabilization of the medial meniscus (DMM)-induced OA in mice, Ce@D&P NPs via intra-articular injection are delivered. The results show that Ce@D&P NPs alleviate cartilage matrix damage and slow OA progression. Overall, the findings indicate that Ce@D&P NPs represent a promising multitarget drug delivery system, and Ce@D&P NPs may be an effective strategy for OA treatment.PMID:39840543 | DOI:10.1002/advs.202412817

Adv Sci (Weinh). 2025 Jan 22:e2412551. doi: 10.1002/advs.202412551. Online ahead of print.ABSTRACTPatients with ulcerative colitis (UC) have a higher risk of developing colorectal cancer (CRC), however, the metabolic shifts during the UC-to-CRC transition remain elusive. In this study, an AOM-DSS-induced three-stage colitis-associated colorectal cancer (CAC) model is constructed and targeted metabolomics analysis and pathway enrichment are performed, uncovering the metabolic changes in this transition. Spatial metabolic trajectories in the "normal-to-normal adjacent tissue (NAT)-to-tumor" transition, and temporal metabolic trajectories in the "colitis-to-dysplasia-to-carcinoma" transition are identified through K-means clustering of 74 spatially and 77 temporally differential metabolites, respectively. The findings reveal two distinct metabolic profile categories during the inflammation-to-cancer progression: those with consistent changes, either increasing (e.g., kynurenic acid, xanthurenic acid) or decreasing (e.g., long-chain fatty acids, LCFAs), and those enriched at specific disease stages (e.g., serotonin). Further analysis of metabolites with consistent temporal trends identifies eicosapentaenoic acid (EPA) as a key metabolite, potentially exerting anti-inflammatory and anti-cancer effects by inhibiting insulin-like growth factor binding protein 5 (IGFBP5). This study reveals novel metabolic mechanisms underlying the transition from UC to CAC and suggests potential targets to delay the progression.PMID:39840505 | DOI:10.1002/advs.202412551