PubMed

Plant J. 2025 Jan;121(2):e17220. doi: 10.1111/tpj.17220.ABSTRACTThe traditional Chinese medicinal plant Prunella vulgaris contains numerous triterpene saponin metabolites, notably ursolic and oleanolic acid saponins, which have significant pharmacological values. Despite their importance, the genes responsible for synthesizing these triterpene saponins in P. vulgaris remain unidentified. This study used a comprehensive screening methodology, combining phylogenetic analysis, gene expression assessment, metabolome-transcriptome correlation and co-expression analysis, to identify candidate genes involved in triterpene saponins biosynthesis. Nine candidate genes - two OSCs, three CYP716s and four UGT73s - were precisely identified from large gene families comprising hundreds of members. These genes were subjected to heterologous expression and functional characterization, with enzymatic activity assays confirming their roles in the biosynthetic pathway, aligning with bioinformatics predictions. Analysis revealed that these genes originated from a whole-genome duplication (WGD) event in P. vulgaris, highlighting the potential importance of WGD for plant metabolism. This study addresses the knowledge gap in the biosynthesis of triterpene saponins in P. vulgaris, establishing a theoretical foundation for industrial production via synthetic biology. Additionally, we present an efficient methodological protocol that integrates evolutionary principles and bioinformatics techniques in metabolite biosynthesis research. This approach holds significant value for studies focused on unraveling various biosynthetic pathways.PMID:39868644 | DOI:10.1111/tpj.17220

Physiol Plant. 2025 Jan-Feb;177(1):e70081. doi: 10.1111/ppl.70081.ABSTRACTRegulating potato tuber dormancy is crucial for crop productivity and food security. We conducted the first comprehensive physiological, transcriptomic, and metabolomic investigations of two varieties of long and short dormant potato tubers in order to clarify the mechanisms of dormancy release. In the current study, three different dormant stages of UGT (ungerminated tubers), MGT (minimally germinated tubers), and GT (germinated tubers) were obtained by treatment with the germination promoter gibberellin A3 and the germination inhibitor chlorpropham. The results revealed that the contents of reducing reducing sugar, sucrase, glutamine synthetase, and nitrate reductase were increased in the dormancy release stages, whereas the contents of sucrose and starch were decreased, leading to a change in the phenotype of the potato tuber bud eyes. According to transcriptomic and metabolomic investigations, four metabolomic pathways were impacted by the dormancy release process. Zeatin biosynthesis was identified in both potato varieties in the dormant release stage (trans-zeatin riboside, isopentenyl adenosine, 5'-methylthioadenosine, IPT, CYP735A, CKX, and UGT73C); glutathione metabolism was identified in short-dormant potato varieties ((5-L-Glutamyl)-L-amino acid, oxidized glutathione, GPX, IDH1, GGT1_5, and GST); and the pentose phosphate pathway (D-Xylulose 5-phosphate, ribose 1-phosphate, PGD, and RPIA) and the phenylpropanoid biosynthesis (caffeic acid, sinapine, CYP98A, and CSE) were identified in long-dormant potato varieties. In conclusion, the four pathways mentioned above involve DEGs and DEMs that are crucial to the control of tuber dormancy release. This work offers a theoretical foundation and useful recommendations for potato tuber quality improvement and molecular breeding.PMID:39868643 | DOI:10.1111/ppl.70081

Food Funct. 2025 Jan 27. doi: 10.1039/d4fo06068g. Online ahead of print.ABSTRACTOysters are well-known for their health benefits such as immuno-modulatory functions. The intestinal microbiome serves as a key mediator between diet and immune regulation. This study aimed to investigate whether oyster consumption could alleviate cyclophosphamide (Cy)-induced immunosuppression by promoting intestinal homeostasis. In mice treated with Cy, a significant decrease in immune cells and cytokines was observed. In contrast, mice supplemented with oyster powder demonstrated elevated numbers of immune cells in the spleen and small intestine, as well as enhanced serum production of IL-1β, IL-2, TNF-α, and IFN-γ. Furthermore, oyster consumption improved the composition of the gut microbiota by promoting beneficial bacteria and inhibiting harmful ones. Metabolomics analysis revealed that oyster powder treatment significantly enhanced the arginine biosynthesis pathway, and further analysis found that the consumption of oysters led to increased arginine levels. Correlation analysis showed a significant positive correlation between L-arginine and immune-related markers. Collectively, these findings suggest that oyster consumption may enhance immunity by modulating the gut microbiota and boosting arginine biosynthesis pathways. Dietary oyster consumption could be an effective strategy to support immune health.PMID:39868593 | DOI:10.1039/d4fo06068g

J Exp Bot. 2025 Jan 27:eraf029. doi: 10.1093/jxb/eraf029. Online ahead of print.ABSTRACTArabidopsis has served as a model plant for studying the genetic networks that guide gynoecium development. However, less is known about other species such as tomato, a model for fleshy fruit development and ripening. Here, we study in tomato the transcription factor SPATULA (SPT), a bHLH-family member that in Arabidopsis is known to be important for gynoecium development. We analysed the expression of SlSPT during flower and fruit development, and its interaction with proteins previously reported as interactors of AtSPT in the gynoecium. We also generated and characterised loss-of-function tomato lines using CRISPR-Cas9. The results show that SlSPT forms homodimers and partially conserves the interactions reported in Arabidopsis with some HECATE proteins, and has a role in floral organ development, particularly in stamen fusion, style and stigma development, and trichome formation on the carpels. Furthermore, lack of SlSPT causes altered exocarp pigmentation. A metabolomic analysis of the exocarp showed perturbations in several pathways in the slspt mutant, with the flavonoid biosynthesis being the most affected, which could potentially impact the nutritional value of the fruit. In summary, the results show conserved functions during gynoecium development and novel roles that enrich the knowledge of the SPT gene in fleshy fruits.PMID:39868567 | DOI:10.1093/jxb/eraf029

Pest Manag Sci. 2025 Jan 27. doi: 10.1002/ps.8637. Online ahead of print.ABSTRACTBACKGROUND: Long-term use of chemical weed control has led to some weedy species evolving herbicide resistance traits with fitness advantage. Our previous studies revealed glyphosate resistance in an Eleusine indica population due to copy number variation of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) comes with fitness advantage under non-competitive conditions. Here, transcriptomics and targeted metabolomics were used to investigate physiological basis associated with the fitness advantage.RESULTS: Relative copy number of EPSPS gene and plant dry weight of the glyphosate-resistant (R) population was 88.3- and 1.2- times, respectively, higher than that in the wild type (WT) plants that were isolated from within the R population. Seven genes were screened to be relevant to fitness growth trait by RNA-seq. The level of aromatic amino acids Tryptophan (Trp), Phenylalanine (Phe) and Tyrosine (Tyr), products in the shikimate pathway catalyzed by EPSPS, was 1.2-times higher in R compared to the WT plants. The metabolites associated with Trp metabolism indole-3-acetic acid (IAA), 3-indolepropionic acid (IPA), indole-3-acetamide (IAM) in the R plants were 2.0-, 1.8- and 1.4- times higher than that in the WT plants, respectively.CONCLUSION: All the results indicate that fitness advantage in the studied R E. indica population may be caused by higher IAA production due to over-expression of the EPSPS gene and pleiotropically by elevated carbon metabolism. The findings in this research can provide reference information for control strategies to the glyphosate-resistant E. indica. © 2025 Society of Chemical Industry.PMID:39868503 | DOI:10.1002/ps.8637

Plant J. 2025 Jan;121(2):e17227. doi: 10.1111/tpj.17227.ABSTRACTMicroalgae possess diverse lipid classes as components of structural membranes and have adopted various lipid remodeling strategies involving phospholipids to cope with a phosphorus (P)-limited environment. Here, we report a unique adaptative strategy to P deficient conditions in two cold-adapted microalgae, Raphidonema monicae and Raphidonema nivale, involving the lipid class diacylglyceryl glucuronide (DGGA) and the betaine lipid diacylglyceryl-N,N,N-trimethylhomoserine. Lipidomic analyses showed that these two lipid classes were present only in trace amounts in nutrient replete conditions, whereas they significantly increased under P-starvation concomitant with a reduction in phospholipids, suggesting a physiological significance of these lipid classes to combat P-starvation. Additionally, we found two putative sulfoquinovosyldiacylglycerol (SQDG) synthases, known to be involved in DGGA synthesis in higher plants, in the draft genome of R. monicae, and compared it with SQDG synthases found in other organisms such as higher plants, Streptophyta, and Chlorophyta. DGGA has not been previously recognized in Chlorophyta, and our findings suggest that the lipid class may be present in other closely related green algae too. Thus, this study expands our knowledge on diverse lipid remodeling responses of Chlorophycean algae to adapt to low P environments.PMID:39868466 | DOI:10.1111/tpj.17227

J Food Sci Technol. 2025 Feb;62(2):377-388. doi: 10.1007/s13197-024-06036-7. Epub 2024 Jul 25.ABSTRACTPile fermentation plays a crucial role in the formation of the unique flavor of Liupao tea, which can effectively reduce the bitterness of the tea and promote the formation of red tea soup. In this study, the non-volatiles changes of Liupao tea during pile fermentation processing were fully analyzed by UPLC-QTOF-MS/MS. A total of 271 metabolites with significant differences were identified in Liupao tea during pile fermentation(P < 0.01, VIP > 1), and their trends were grouped into 10 subclasses by K-means analysis. Three differential metabolites Choline Alfoscerate, N1-Methyl-4-pyridone-5-carboxamide, and 2-Aminovalienone were shared among the three different pile fermentation periods. The results provided valuable information for understanding the dynamic changes of non-volatile substances during the pile fermentation process of Liupao tea.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-024-06036-7.PMID:39868396 | PMC:PMC11757836 | DOI:10.1007/s13197-024-06036-7

J Orthop Translat. 2025 Jan 7;50:56-70. doi: 10.1016/j.jot.2024.10.003. eCollection 2025 Jan.ABSTRACTOsteoarthritis (OA) is a progressive degenerative disease affected by many factors, and there is currently no effective treatment. In recent years, the latest progress in metabolomics in OA research has revealed several metabolic pathways and new specific metabolites involved in OA. Metabolites play significant roles in the identification and management of OA. This review looks back on the development history of metabolomics and the progress of this technology in OA as well as its potential clinical applications. It summarizes the applications of metabolites in the field of OA and future research directions. This understanding will advance the identification of metabolic treatment goals for OA.THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The development of metabolomics offers possibilities for the treatment of OA. This article reviews the relationship between metabolites associated with chondrocytes and OA. Selectively altering these three metabolic pathways and their associated metabolites may hold great potential as new focal points for OA treatment.PMID:39868350 | PMC:PMC11762942 | DOI:10.1016/j.jot.2024.10.003

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