PubMed

bioRxiv [Preprint]. 2025 Jan 17:2025.01.16.633236. doi: 10.1101/2025.01.16.633236.ABSTRACTInvasive Lobular Carcinoma (ILC), a distinct subtype of breast cancer is hallmarked by E-Cadherin loss, slow proliferation, and strong hormone receptor positivity. ILC faces significant challenges in clinical management due to advanced stage at diagnosis, late recurrence, and development of resistance to endocrine therapy - a cornerstone of ILC treatment. To elucidate the mechanisms underlying endocrine resistance in ILC, ILC cell lines (MDA-MB-134-VI, SUM44PE) were generated to be resistant to tamoxifen, a selective estrogen receptor modulator. The tamoxifen-resistant (TAMR) cells exhibit a 2-fold increase tamoxifen IC 50 relative to parental cells. Metabolomics and RNA-sequencing revealed deregulation of alanine, aspartate, and glutamate metabolism, purine metabolism, and arginine and proline metabolism in TAMR cells. Among the fifteen commonly dysregulated genes in these pathways, low ASS1 expression was identified in the TAMR cells and was significantly correlated with poor outcome in ILC patients, specifically in the context of endocrine therapy. Our study reveals methylation mediated silencing of ASS1 in TAMR cells as a likely mechanism of downregulation. Demethylation restored ASS1 expression and correspondingly reduced tamoxifen IC 50 toward parental levels. Nucleic acid biosynthesis is augmented in TAMR cells, evidenced by increase in nucleotide intermediates. Both TAMR cell lines demonstrated increased expression of several nucleic acid biosynthesis enzymes, including PAICS, PRPS1, ADSS2, CAD, and DHODH . Furthermore, CAD, the key multifunctional protein of de novo pyrimidine biosynthesis pathway is differentially activated in TAMR cells. Treating TAMR cell with Decitabine, a demethylating agent, or Farudodstat, a pyrimidine biosynthesis inhibitor, markedly augmented efficacy of tamoxifen. Collectively, our study unveils ASS1 downregulation as a novel mechanism underlying acquired tamoxifen resistance in ILC and establishes a metabolic link between ASS1 and nucleic acid biosynthesis. Restoring ASS1 expression or inhibiting pyrimidine biosynthesis restored tamoxifen sensitivity. ASS1 could be a potential biomarker and therapeutic target in tamoxifen resistant ILC patients, warranting further investigation.PMID:39868332 | PMC:PMC11761122 | DOI:10.1101/2025.01.16.633236

bioRxiv [Preprint]. 2025 Jan 16:2025.01.10.632413. doi: 10.1101/2025.01.10.632413.ABSTRACTBACKGROUND: For patients with head and neck squamous cell carcinoma (HNSCC), failure of definitive radiation combined with cisplatin nearly universally results in death. Although hyperactivation of the Nrf2 pathway can drive radiation and cisplatin resistance along with suppressed anti-tumor immunity, treatment-refractory HNSCC tumors may retain sensitivity to targeted agents secondary to synergistic lethality with other oncogenic drivers (e.g., NOTCH1 mutations).PURPOSE: We evaluated the efficacy of PI3K inhibitors (PI3Ki) in bypassing Nrf2-mediated cisplatin resistance in HNSCC.METHODS: We measured transcriptomic, metabolomic and signaling changes driven by PI3Kis in cisplatin-resistant HNSCCs in vitro and tested efficacy in vivo in subcutaneous, orthotopic and metastatic xenograft models using immunodeficient and humanized murine models of HNSCC coupled with spatial transcriptomics.RESULTS: The PI3K pathway is activated in Nrf2-driven cisplatin-resistant HNSCC and is suitable for blockade as demonstrated in an in vivo shRNA screen. The PI3Ki gedatolisib inhibits cisplatin-resistant HNSCC proliferation, induces G2M arrest and potentiates cisplatin effectiveness through activation of autophagy, senescence and disruption of fatty acid metabolism. Gedatolisib suppresses HNSCC tumor growth in orthotopic and metastatic settings and demonstrates profound anti-tumor activity in humanized murine models of HNSCC, coupled with a reduction in hypoxia-rich regions and reduced infiltration by regulatory T lymphocytes.CONCLUSION: Our findings emphasize the critical role of the PI3K-AKT-mTOR pathway in cisplatin-resistant HNSCC and highlight the therapeutic potential of PI3K inhibitors. Gedatolisib induced metabolic regulation and substantial re-sensitization of resistant cells to cisplatin, positioning it as a promising candidate for combination therapies aimed at overcoming primary chemo-radiation failure in HNSCC.STATEMENT OF TRANSLATIONAL RELEVANCE: Cisplatin resistance, whether intrinsic or acquired, translates to treatment failure and nearly universal death in head and neck squamous cell carcinoma (HNSCC). However, the development of effective systemic regimens for cisplatin-resistant HNSCC has not yet been successful. Here, we present, for the first time, a mechanistic, biomarker-informed strategy for effective targeting of the PI3Kinase pathway in cisplatin-resistant HNSCC with substantial anti-tumor activity in both orthotopic and metastatic models, which may be capable of bypassing or reversing cisplatin resistance in this disease.PMID:39868226 | PMC:PMC11761649 | DOI:10.1101/2025.01.10.632413

bioRxiv [Preprint]. 2025 Jan 14:2025.01.11.632570. doi: 10.1101/2025.01.11.632570.ABSTRACTSingle-omics approaches often provide a limited view of complex biological systems, whereas multiomics integration offers a more comprehensive understanding by combining diverse data views. However, integrating heterogeneous data types and interpreting the intricate relationships between biological features-both within and across different data views-remains a bottleneck. To address these challenges, we introduce COSIME (Cooperative Multi-view Integration and Scalable Interpretable Model Explainer). COSIME uses backpropagation of Learnable Optimal Transport (LOT) to deep neural networks, enabling the learning of latent features from multiple views to predict disease phenotypes. In addition, COSIME incorporates Monte Carlo sampling to efficiently estimate Shapley values and Shapley-Taylor indices, enabling the assessment of both feature importance and their pairwise interactions-synergistically or antagonistically-in predicting disease phenotypes. We applied COSIME to both simulated data and real-world datasets, including single-cell transcriptomics, single-cell spatial transcriptomics, epigenomics, and metabolomics, specifically for Alzheimer's disease-related phenotypes. Our results demonstrate that COSIME significantly improves prediction performance while offering enhanced interpretability of feature relationships. For example, we identified that synergistic interactions between microglia and astrocyte genes associated with AD are more likely to be active at the edges of the middle temporal gyrus as indicated by spatial locations. Finally, COSIME is open-source and available for general use.PMID:39868220 | PMC:PMC11761389 | DOI:10.1101/2025.01.11.632570

bioRxiv [Preprint]. 2025 Jan 14:2025.01.12.632645. doi: 10.1101/2025.01.12.632645.ABSTRACTBACKGROUND: Metabolic processes form the basis of the development, functioning and maintenance of the brain. Despite accumulating evidence of the vital role of metabolism in brain health, no study to date has comprehensively investigated the link between circulating markers of metabolic activity and in vivo brain morphology in the general population.METHODS: We performed uni- and multivariate regression on metabolomics and MRI data from 24,940 UK Biobank participants, to estimate the individual and combined associations of 249 circulating metabolic markers with 91 measures of global and regional cortical thickness, surface area and subcortical volume. We investigated similarity of the identified spatial patterns with brain maps of neurotransmitters, and used Mendelian randomization to uncover causal relationships between metabolites and the brain.RESULTS: Intracranial volume and total surface area were highly significantly associated with circulating lipoproteins and glycoprotein acetyls, with correlations up to .15. There were strong regional associations of individual markers with mixed effect directions, with distinct patterns involving frontal and temporal cortical thickness, brainstem and ventricular volume. Mendelian randomization provided evidence of bidirectional causal effects, with the majority of markers affecting frontal and temporal regions.DISCUSSION: The results indicate strong bidirectional causal relationships between circulating metabolic markers and distinct patterns of global and regional brain morphology. The generated atlas of associations provides a better understanding of the role of metabolic pathways in structural brain development and maintenance, in both health and disease.PMID:39868214 | PMC:PMC11761619 | DOI:10.1101/2025.01.12.632645

bioRxiv [Preprint]. 2025 Jan 18:2025.01.17.633452. doi: 10.1101/2025.01.17.633452.ABSTRACTPreviously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP/PS1 and wild-type mice. APP/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the "sphingolipid rheostat", reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals.PMID:39868189 | PMC:PMC11761635 | DOI:10.1101/2025.01.17.633452

bioRxiv [Preprint]. 2025 Jan 17:2025.01.15.633247. doi: 10.1101/2025.01.15.633247.ABSTRACTGlycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer's disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of non-enzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain. In this two-pronged study, we evaluate the therapeutic efficacy of an orally bioavailable prodrug of our lead glyoxalase substrate, pro-ψ-GSH, for the first time in a transgenic Alzheimer's disease mouse model. This prodrug delivers pharmacodynamically relevant brain concentrations of ψ-GSH upon oral delivery. Chronic oral dosing of pro-ψ-GSH effectively reverses the cognitive decline observed in the APP/PS1 mouse model. The prodrug successfully mirrors the robust effects of the parent drug i.e., reducing amyloid pathology, glycation stress, neuroinflammation, and the resultant neurodegeneration in these mice. We also report the first metabolomics study of such a treatment, which yields key biomarkers linked to the reversal of AD-related metabolic dysregulation. Collectively, this study establishes pro-ψ-GSH as a viable, disease-modifying therapy for AD and paves the way for further preclinical advancement of such therapeutics. Metabolomic signatures identified could prove beneficial in the development of treatment-specific clinically translatable biomarkers.PMID:39868172 | PMC:PMC11761491 | DOI:10.1101/2025.01.15.633247

iScience. 2024 Dec 20;28(1):111656. doi: 10.1016/j.isci.2024.111656. eCollection 2025 Jan 17.ABSTRACTAging is accompanied by a decline in neovascularization potential and increased susceptibility to ischemic injury. Here, we confirm the age-related impaired neovascularization following ischemic leg injury and impaired angiogenesis. The age-related deficits in angiogenesis arose primarily from diminished EC proliferation capacity, but not migration or VEGF sensitivity. Aged EC harvested from the mouse skeletal muscle displayed a pro-angiogenic gene expression phenotype, along with considerable changes in metabolic genes. Metabolomics analysis and 13C glucose tracing revealed impaired ATP production and blockade in glycolysis and TCA cycle in late passage HUVECs, which occurred at nicotinamide adenine dinucleotide (NAD⁺)-dependent steps, along with NAD+ depletion. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD⁺, enhances late-passage EC proliferation and sprouting angiogenesis from aged mice aortas. Taken together, our study illustrates the importance of NAD+-dependent metabolism in the maintenance of EC proliferation capacity with age, and the therapeutic potential of NAD precursors.PMID:39868046 | PMC:PMC11763620 | DOI:10.1016/j.isci.2024.111656

Front Immunol. 2025 Jan 10;15:1543009. doi: 10.3389/fimmu.2024.1543009. eCollection 2024.ABSTRACTTuberculous meningitis (TBM), a severe form of non-purulent meningitis caused by Mycobacterium tuberculosis (Mtb), is the most critical extrapulmonary tuberculosis (TB) manifestation, with a 30-40% mortality rate despite available treatment. The absence of distinctive clinical symptoms and effective diagnostic tools complicates early detection. Recent advancements in nucleic acid detection, genomics, metabolomics, and proteomics have led to novel diagnostic approaches, improving sensitivity and specificity. This review focuses on nucleic acid-based methods, including Xpert Ultra, metagenomic next-generation sequencing (mNGS), and single-cell sequencing of whole brain Tissue, alongside the diagnostic potential of metabolomic and proteomic biomarkers. By evaluating the technical features, diagnostic accuracy, and clinical applicability, this review aims to inform the optimization of TBM diagnostic strategies and explores the integration and clinical translation of multi-omics technologies.PMID:39867878 | PMC:PMC11757110 | DOI:10.3389/fimmu.2024.1543009

Drug Des Devel Ther. 2025 Jan 22;19:439-455. doi: 10.2147/DDDT.S479682. eCollection 2025.ABSTRACTPURPOSE: Mitoxantrone (MTX) is largely restricted in clinical usage due to its significant cardiotoxicity. Multiple studies have shown that an imbalance in the gut-heart axis plays an important role in the development of cardiovascular disease (CVD). We aim to explore the possible correlations between gut microbiota (GM) compositions and cardiometabolic (CM) disorder in MTX-triggered cardiotoxicity mice.METHODS: MTX cumulative dose of 6 mg/kg was administered to healthy Kunming male mice to trigger cardiotoxicity, with 1 mg/kg twice weekly for a duration of 3 weeks. Plasma CK-MB and LDH levels were determined, and the heart tissue histopathology was assessed, followed by utilizing an integrated liquid chromatography-mass spectrometry (LC-MS)-based heart metabolomics study alongside the 16S ribosomal RNA (rRNA) sequencing method to assess MTX impact on GM and CM profiles in mice, establishing associations between GM and CM profiles through the Pearson correlation coefficient calculation.RESULTS: MTX caused CK-MB and LDH level elevations and cardiotoxicity in our mouse model. MTX primarily affected the processes of protein digestion and absorption, mineral absorption, membrane transport, production of aminoacyl-transfer RNA (tRNA), metabolism of nucleotides, lipids, and amino acids, as well as autophagy. Additionally, MTX increased Romboutsia, Enterococcus, and Turicibacter abundances and lowered norank_f__Muribaculaceae, Alistipes, Odoribacter, norank_f__Lachnospiraceae, norank_f__Ruminococcaceae, norank_f__Oscillospiraceae, unclassified_f__Ruminococcaceae, NK4A214_group, Colidextribacter, norank_f__norank_o__Clostridia_vadinBB60_group, Rikenella, and Anaerotruncus abundances. The correlation analyses showcased variations in the abundance of diverse flora, such as Romboutsia, Enterococcus, Turicibacter, and norank_f__Muribaculaceae, which were related to MTX-induced cardiac injury.CONCLUSION: Our study supports the claim that MTX provokes cardiotoxicity by modifying CM and GM profiles. Our results offer new possibilities for controlling MTX-triggered cardiotoxicity.PMID:39867867 | PMC:PMC11766154 | DOI:10.2147/DDDT.S479682

Drug Des Devel Ther. 2025 Jan 21;19:389-404. doi: 10.2147/DDDT.S482510. eCollection 2025.ABSTRACTBACKGROUND: Corilagin is widely distributed in various medicinal plants. In recent years, numerous pharmacological activities of Corilagin have been reported, including anti-inflammatory, antiviral, hepatoprotective, anti-tumor, and anti-fibrosis effects. However, there is still a need for systematic metabolomics analysis to further elucidate its mechanisms of action. The aim of this study was to explore the pharmacological mechanism of Corilagin.METHODS: This study utilized gas chromatography-mass spectrometry (GC-MS) to analyze central target tissues, comprehensively exploring the pharmacological mechanism of Corilagin in mouse models. We identified the differential metabolites by multivariate analyses, which include principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Using MetaboAnalyst 5.0 and the KEGG database was used to depict the 12 key metabolic pathways.RESULTS: Compared with the control group, the Corilagin induced 20, 9, 11, 7, 16, 19, 14, 15, and 16 differential metabolites in the intestine, lung, kidney, stomach, heart, liver, hippocampus, cerebral cortex, and serum, respectively. And 12 key pathways involving glucose metabolism, lipid metabolism, and amino acid metabolism were identified following Corilagin treatment.CONCLUSION: This research provides insight into the action mechanism of Corilagin's anti-oxidative, anti-inflammatory, anti-atherosclerotic, hepatoprotective, anti-tumor, and neuroprotective properties.PMID:39867865 | PMC:PMC11762444 | DOI:10.2147/DDDT.S482510

Bioinform Adv. 2025 Jan 21;5(1):vbae209. doi: 10.1093/bioadv/vbae209. eCollection 2025.ABSTRACTMOTIVATION: Missing values are prevalent in high-throughput measurements due to various experimental or analytical reasons. Imputation, the process of replacing missing values in a dataset with estimated values, plays an important role in multivariate and machine learning analyses. The three missingness patterns, including missing completely at random, missing at random, and missing not at random, describe unique dependencies between the missing and observed data. The optimal imputation method for each dataset depends on the type of data, the cause of the missingness, and the nature of relationships between the missing and observed data. The challenge is to identify the optimal imputation solution for a given dataset.RESULTS: ImpLiMet: is a user-friendly web-platform that enables users to impute missing data using eight different methods. For a given dataset, ImpLiMet suggests the optimal imputation solution through a grid search-based investigation of the error rate for imputation across three missingness data simulations. The effect of imputation can be visually assessed by histogram, kurtosis, and skewness, as well as principal component analysis comparing the impact of the chosen imputation method on the distribution and overall behavior of the data.AVAILABILITY AND IMPLEMENTATION: ImpLiMet is freely available at https://complimet.ca/shiny/implimet/ and https://github.com/complimet/ImpLiMet.PMID:39867531 | PMC:PMC11761345 | DOI:10.1093/bioadv/vbae209

Front Mol Neurosci. 2025 Jan 10;17:1482999. doi: 10.3389/fnmol.2024.1482999. eCollection 2024.ABSTRACTINTRODUCTION: To further advance our understanding of Muscular Dystrophies (MDs) and Spinocerebellar Ataxias (SCAs), it is necessary to identify the biological patterns associated with disease pathology. Although progress has been made in the fields of genetics and transcriptomics, there is a need for proteomics and metabolomics studies. The present study aimed to be the first to document serum metabolic signatures of MDs (DMD, BMD, and LGMD 2A) SCAs (SCA 1-3), from a South Asian perspective.METHODS: A total of 28 patients (SCA 1-10, SCA 2-2, SCA 3-2, DMD-10, BMD-2, LGMD-2) and eight controls (aged 8-65 years) were included. Metabolomic analysis was performed by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS), with support from the Houston Omics Collaborative.RESULTS AND DISCUSSION: Amino acid metabolism was the primary altered super pathway in DMD followed by carbohydrate metabolism and lipid metabolism. In contrast, BMD and LGMD 2A exhibited a more prominent alteration in lipid metabolism followed by amino acid metabolism. In SCAs, primarily lipid, amino acid, peptide, nucleotide, and xenobiotics pathways are affected. Our findings offer new insights into the variance of metabolite levels in MD and SCA, with substantial implications for pathology, drug development, therapeutic targets and clinical management. Intriguingly, this study identified two novel metabolites associated with SCA. This pilot cross-sectional study warrants further research involving larger groups of participants, to validate our findings.PMID:39866907 | PMC:PMC11759312 | DOI:10.3389/fnmol.2024.1482999

Front Plant Sci. 2025 Jan 10;15:1446210. doi: 10.3389/fpls.2024.1446210. eCollection 2024.ABSTRACTFrequent and extreme drought exerts profound effects on vegetation growth and production worldwide. It is imperative to identify key genes that regulate plant drought resistance and to investigate their underlying mechanisms of action. Long-chain fatty acids and their derivatives have been demonstrated to participate in various stages of plant growth and stress resistance; however, the effects of medium-chain fatty acids on related functions have not been thoroughly studied. Here, we integrate lipidomic, transcriptomic, and genetic analyses to elucidate the roles of the medium-chain acyl-acyl carrier protein thioesterase of Umellularia californica FatB (UcFatB) in drought tolerance and plant growth. Arabidopsis and tomato transgenic lines overexpressing UcFatB showed that the medium chain fatty acids mainly affect the male reproductive process of plant development. Transcriptomic and non-targeted lipid metabolomic combination analysis revealed significant changes in lauric acid-related metabolic pathways, as evidenced by increased phosphatidylcholine accumulation and upregulated stress-response gene expression. Consistent with the thicker waxy cutin layer and increased membrane integrity, UcFatB-overexpression enhanced drought tolerance in both Arabidopsis and tomato. Furthermore, methyl laurate and phosphatidylcholine application improved tomato drought resistance and fruit yield. These findings provide new insights into the potential genetic resources and cost-effective chemicals for enhancing drought resistance in crops.PMID:39866321 | PMC:PMC11757637 | DOI:10.3389/fpls.2024.1446210

Front Plant Sci. 2025 Jan 10;15:1523582. doi: 10.3389/fpls.2024.1523582. eCollection 2024.ABSTRACTINTRODUCTION: Melatonin significantly enhances the tolerance of plants to biotic and abiotic stress, and plays an important role in plant resistance to salt stress. However, its role and molecular mechanisms in eggplant salt stress resistance have been rarely reported. In previous studies, we experimentally demonstrated that melatonin can enhance the salt stress resistance of eggplants.METHODS: In this study, we treated salt-stressed eggplant plants with melatonin and a control treatment with water, then conducted physiological and biochemical tests, transcriptomic and metabolomic sequencing, and RT-qPCR validation at different stages after treatment.RESULTS: The results showed that exogenous melatonin can alleviate the adverse effects of salt stress on plants by increasing the activity of antioxidant enzymes, reducing the content of reactive oxygen species in plants, and increasing the content of organic osmoprotectants. Transcriptomic and metabolomic data, as well as combined analysis, indicate that melatonin can activate the metabolic pathways of plant resistance to adverse stress. Compared to the control treatment with water, melatonin can activate the genes of the α-linolenic acid metabolism pathway and promote the accumulation of metabolites in this pathway, with significant effects observed 48 hours after treatment, and significantly activates the expression of genes such as SmePLA2, SmeLOXs and SmeOPR et al. and the accumulation of metabolites such as α-Linolenic acid, (9R,13R)-12-oxophytodienoic acid, 9(S)-HpOTrE and (+)-7-iso-Jasmonic acid. RT-qPCR validated the activating effect of melatonin on the candidate genes of the a-linolenic acid metabolism pathway.DISCUSSION: This study analyzed the molecular mechanism of melatonin in alleviating eggplant salt stress, providing a theoretical foundation for the application of melatonin in enhancing eggplant salt stress resistance in production.PMID:39866315 | PMC:PMC11759302 | DOI:10.3389/fpls.2024.1523582

Front Plant Sci. 2025 Jan 10;15:1471729. doi: 10.3389/fpls.2024.1471729. eCollection 2024.ABSTRACTINTRODUCTION: This study aims to investigate the impact of geographical origin on the metabolite composition and bioactivity of Thesium chinense Turcz. (TCT), a member of the Apiaceae family renowned for its wide range of pharmacological properties, including antioxidant, antimicrobial, and anti-inflammatory effects. In this study, we investigated the whole plants of TCT from different regions in China, aiming to explore the geographical variation of TCT.METHODS: A non-targeted metabolomics approach was employed using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were utilized to identify and differentiate the metabolite profiles. We investigated the bioactivity, antioxidant activity, total flavonoid content (TFC), and the content of characteristic compounds from TCT sourced from different regions. This aims to further explore the metabolic differences and quality characteristics of TCT from various origins.RESULTS: PCA and PLS-DA analyses indicated that samples from different origins could be clearly distinguished. The analysis revealed 54 differential metabolites, predominantly flavonoids and alkaloids. KEGG pathway analysis indicated significant variations in the biosynthesis pathways of flavonoids and flavanols among the samples. TCT from Anhui province exhibited the highest TFC and strongest antioxidant and anti-inflammatory activities, while samples from Jilin province showed the lowest.DISCUSSION: A strong correlation was observed between metabolite content and geographical origins, suggesting that the bioactivity of TCT is significantly influenced by its provenance. Additionally, the antioxidant and anti-inflammatory activities of TCT were validated, showing a strong predictive relationship with TFC. This research highlights the potential of metabolomics in discerning the subtleties of plant metabolomes, contributing to the advancement of traditional Chinese medicine and its integration into modern healthcare practices.PMID:39866314 | PMC:PMC11760594 | DOI:10.3389/fpls.2024.1471729

Front Plant Sci. 2025 Jan 10;15:1549017. doi: 10.3389/fpls.2024.1549017. eCollection 2024.NO ABSTRACTPMID:39866312 | PMC:PMC11757233 | DOI:10.3389/fpls.2024.1549017

Curr Pharm Des. 2025 Jan 24. doi: 10.2174/0113816128337697250106001808. Online ahead of print.ABSTRACTINTRODUCTION: Fungal endophytes have mutualistic associations with the plant's host, communicating through genetic and metabolic processes. As a result, they gain the ability to generate therapeutically effective metabolites and their derivatives.METHODS: The current study aims to assess antioxidant potential along with the identification of robust metabolites within the crude extract of a potent endophytic fungus Xylaria ellisii isolated from leaf tissues of the Acorus calamus Linn plant.Four endophytic fungi were obtained from leaf tissues of Acorus calamus Linn., and identified morphologically and molecularly as distinct species. Each ethyl acetate extract of the isolated fungi exhibited a unique chemical profile in the HPTLC fingerprint at various wavelengths. The ethyl acetate (EA) extract from the fungal strain ACL-4 (Xylaria ellisii) demonstrated the strongest antioxidant activity among the four fungal endophytes examined, with an EC50 value of 292.64 ± 3.558 μg/mL. Remarkably, fungal endophyte ACL-4 extract exhibited superior antimicrobial activity at the less concentrations compared to ACL-ME extract of leaf crude.RESULTS: The extract of ACL-ME-treated HEK 293T cells exhibited significant toxicity, with an IC50 value of 1481.74 ± 23.772 μg/mL, compared to fungal strain ACL-4-treated HEK 293T cells, which had an IC50 value greater than 2000 μg/mL. Consequently, the crude extract of ACL-4 and ACL-ME along with the standard drug methotrexate exhibited cytotoxic activity against cancer cell line MDA-MB-231 with IC50 concentrations of 146.65 ± 0.394 μg/mL, 528.46 ± 10.912 μg/mL, and 134.11 ± 3.446 μg/mL, respectively. A total of 2,255 compounds were detected through LC-HRMS-based metabolomics in the crude metabolites of Xylaria ellisii, with certain compounds identified in multiple instances. Among this repertoire, 62 robust bioactive compounds were identified through meticulous screening, guided by existing literature. Comparative HPTLC fingerprint analysis, along with antioxidant efficacy assays of ethyl acetate extracts of Xylaria ellisii derived from Acorus calamus leaves and Cassia fistula twigs revealed the host-specific production of bioactive chemicals.CONCLUSION: The top-scoring Keap1 inhibitors derived from Xylaria ellisii, including Pregabalin (-6.083 Kcal/mol), Ferulic acid (-5.434 Kcal/mol), (R)-Piperidine-2-carboxylic acid (-5.31 Kcal/mol), Genipin (-5.197 Kcal/mol), and Brivaracetam (-5.17 Kcal/mol), respectively were considered as Keap 1 inhibitors, potentially mitigate oxidative stress.PMID:39865823 | DOI:10.2174/0113816128337697250106001808

Biotechnol Bioeng. 2025 Jan 26. doi: 10.1002/bit.28935. Online ahead of print.ABSTRACTMicrobes experience dynamic conditions in natural habitats as well as in engineered environments, such as large-scale bioreactors, which exhibit increased mixing times and inhomogeneities. While single perturbations have been studied for several organisms and substrates, the impact of recurring short-term perturbations remains largely unknown. In this study, we investigated the response of Saccharomyces cerevisiae to repetitive gradients of four different sugars: glucose, fructose, sucrose, and maltose. Due to different transport mechanisms and metabolic routes, nonglucose sugars lead to varied intracellular responses. To characterize the impact of the carbon sources and the dynamic substrate gradients, we applied both steady-state and dynamic cultivation conditions, comparing the physiology, intracellular metabolome, and proteome. For maltose, the repeated concentration gradients led to a significant decrease in biomass yield. Under glucose, fructose, and sucrose conditions, S. cerevisiae maintained the biomass yield observed under steady-state conditions. Although the physiology was very similar across the different sugars, the intracellular metabolome and proteome were clearly differentiated. Notably, the concentration of upper glycolytic enzymes decreased for glucose and maltose (up to -60% and -40%, respectively), while an increase was observed for sucrose and fructose when exposed to gradients. Nevertheless, for all sugar gradient conditions, a stable energy charge was maintained, ranging between 0.78 and 0.89. This response to maltose is particularly distinct compared to previous single-substrate pulse experiments or limitation to excess shifts, which led to maltose-accelerated death in earlier studies. At the same time, enzymes of lower glycolysis were elevated. Interestingly, common stress-related proteins (GO term: cellular response to oxidative stress) decreased during dynamic conditions.PMID:39865609 | DOI:10.1002/bit.28935

J Exp Clin Cancer Res. 2025 Jan 27;44(1):26. doi: 10.1186/s13046-025-03295-w.ABSTRACTPURPOSE: Glucose starvation induces the accumulation of disulfides and F-actin collapse in cells with high expression of SLC7A11, a phenomenon termed disulfidptosis. This study aimed to confirm the existence of disulfidptosis in pancreatic ductal adenocarcinoma (PDAC) and elucidate the role of Cancer Susceptibility 8 (CASC8) in this process.METHODS: The existence of disulfidptosis in PDAC was assessed using flow cytometry and F-actin staining. CASC8 expression and its clinical correlations were analyzed using data from The Cancer Genome Atlas (TCGA) and further verified by chromogenic in situ hybridization assay in PDAC tissues. Cells with CASC8 knockdown and overexpression were subjected to cell viability, EdU, transwell assays, and used to establish subcutaneous and orthotopic tumor models. Disulfidptosis was detected by flow cytometry and immunofluorescence assays. RNA sequencing and metabolomics analysis were performed to determine the metabolic pathways which were significantly affected after CASC8 knockdown. We detected the glucose consumption and the NADP+/NADPH ratio to investigate alterations in metabolic profiles. RNA immunoprecipitation combined with fluorescence in situ hybridization assay was used to identify protein-RNA interactions. Protein stability, western blotting and quantitative real-time PCR assays were performed to reveal potential molecular mechanism.RESULTS: Disulfidptosis was observed in PDAC and could be significantly rescued by disulfidptosis inhibitors. CASC8 expression was higher in PDAC samples compared to normal pancreatic tissue. High CASC8 expression correlated with a poor prognosis for patients with PDAC and contributed to cancer progression in vitro and in vivo. Furthermore, CASC8 was associated with disulfidptosis resistance under glucose starvation conditions in PDAC. Mechanistically, CASC8 interacted with c-Myc to enhance the stability of c-Myc protein, leading to the activation of the pentose phosphate pathway, a reduction of the NADP+/NADPH ratio and ultimately inhibiting disulfidptosis under glucose starvation conditions.CONCLUSIONS: This study provides evidence for the existence of disulfidptosis in PDAC and reveals the upregulation of CASC8 in this malignancy. Furthermore, we demonstrate that CASC8 acts as a crucial regulator of the pentose phosphate pathway and disulfidptosis, thereby promoting PDAC progression.PMID:39865281 | DOI:10.1186/s13046-025-03295-w

Biochemistry (Mosc). 2024 Dec;89(12):2133-2142. doi: 10.1134/S0006297924120034.ABSTRACTHypoxia poses a serious challenge for all animals; however, certain animals exhibit a remarkable resilience in the case of prolonged and severe hypoxia. The Siberian wood frog Rana amurensis is a unique amphibian capable of surviving for up to several months at almost complete anoxia. We investigated changes in the metabolome of R. amurensis at the onset of hypoxia (day 1) and within 1 h of reoxygenation after a long-term hypoxia using 1H NMR. We compared our results to the data obtained for animals exposed to 17 days of hypoxia and controls. Despite the differences between the samples analyzed in three different experimental series, we were able to obtain some interesting insights. In most studied vertebrates, succinate accumulates under hypoxic conditions and undergoes rapid conversion upon reoxygenation. We found that reoxygenation caused a decrease in the succinate content in the brain, but not in the liver, where it remained unchanged, suggesting an existence of a mechanism that inhibits succinate conversion. Furthermore, we observed intriguing differences in the behavior of two substances with unknown functions: glycerol and 2,3-butanediol. Glycerol exhibited rapid accumulation during hypoxia and equally rapid processing during reoxygenation. In contrast, 2,3-butanediol required an extended period of time to accumulate, yet persisted after reoxygenation. Overall, our data demonstrate rapid accumulation of most substances during exposure to hypoxia followed by their slower processing upon reoxygenation.PMID:39865027 | DOI:10.1134/S0006297924120034