PubMed

J Dent Res. 2025 Feb 4:220345241305590. doi: 10.1177/00220345241305590. Online ahead of print.ABSTRACTPyroptosis, a gasdermin-mediated immunogenic cell death, has been shown to elicit adaptive antitumor immune responses, thereby augmenting the response to cancer immunotherapy when pyroptosis is therapeutically activated. However, despite increased gasdermin E (GSDME) expression, significant pyroptosis remains elusive in certain tumor types, and the underlying regulatory mechanisms are poorly understood. In this study, we observed high signal regulatory protein α1 (SIRPA) expression in head and neck squamous cell carcinoma (HNSCC) cells, a target in cancer immunotherapy. Intriguingly, SIRPA inhibition markedly augmented pyroptosis activity in tumor tissues and modulated tumor growth in a HNSCC mouse model. Subsequent investigations revealed that SIRPA knockout upregulated GSDME expression and potentiated cisplatin-induced pyroptosis in cancer cells. Integrative transcriptomics and metabolomics analysis suggested that the SIRPA knockout profoundly altered protein ubiquitination and augmented argininosuccinic acid levels in cancer cells. Specifically, we demonstrated that ubiquitin-specific peptidase 18 (USP18), a deubiquitinating enzyme, targets GSDME for deubiquitination and that USP18 knockdown suppressed cisplatin-induced pyroptosis. Notably, we found that succinylation of GSDME, which is mediated by succinyl-CoA, promotes GSDME cleavage without affecting caspase-3 activation. Further experiments indicated that SIRPA expression in tumor cells can decrease the antitumor efficacy of chemotherapy and immunotherapy in HNSCC mouse models. In summary, our findings reveal a novel mechanism of pyroptosis evasion in HNSCC, whereby tumor-intrinsic SIRPA enhances GSDME ubiquitylation and inhibits its succinylation. These insights suggest that inhibiting SIRPA expression may improve the efficacy of immunotherapy for HNSCC by inducing pyroptosis.PMID:39904995 | DOI:10.1177/00220345241305590

Nat Commun. 2025 Feb 4;16(1):1317. doi: 10.1038/s41467-024-55635-7.ABSTRACTRetinal thickness is a marker of retinal health and more broadly, is seen as a promising biomarker for many systemic diseases. Retinal thickness measurements are procured from optical coherence tomography (OCT) as part of routine clinical eyecare. We processed the UK Biobank OCT images using a convolutional neural network to produce fine-scale retinal thickness measurements across > 29,000 points in the macula, the part of the retina responsible for human central vision. The macula is disproportionately affected by high disease burden retinal disorders such as age-related macular degeneration and diabetic retinopathy, which both involve metabolic dysregulation. Analysis of common genomic variants, metabolomic, blood and immune biomarkers, disease PheCodes and genetic scores across a fine-scale macular thickness grid, reveals multiple novel genetic loci including four on the X chromosome; retinal thinning associated with many systemic disorders including multiple sclerosis; and multiple associations to correlated metabolites that cluster spatially in the retina. We highlight parafoveal thickness to be particularly susceptible to systemic insults. These results demonstrate the gains in discovery power and resolution achievable with AI-leveraged analysis. Results are accessible using a bespoke web interface that gives full control to pursue findings.PMID:39904976 | DOI:10.1038/s41467-024-55635-7

Geroscience. 2025 Feb 4. doi: 10.1007/s11357-025-01544-6. Online ahead of print.ABSTRACTWe assessed the association of serum metabolites with the occurrence of major adverse cardiovascular events (MACE) in middle-aged and elderly individuals, explored the value of metabolomics in predicting MACE, and compared the distinctions in MACE risk-related metabolic biomarkers between middle-aged and elderly groups. Among the participants of the UK Biobank who underwent baseline assessment through nuclear magnetic resonance (NMR)-based metabolomic profiling of 168 serum metabolites and had complete covariates and clinical lipid parameters, we included those without a previous diagnosis of ischemic heart disease, cerebrovascular disease, heart failure, or cardiac arrest and not on lipid-lowering medications. Relevant covariates included sociodemographic characteristics, lifestyle factors, clinical information, and fasting time. Cox regression gave adjusted hazard ratios for metabolites, including the concentrations of various lipoprotein particles, compositional profiles of different lipoproteins, ketone bodies, amino acids, fatty acids, and additional low-molecular-weight metabolic biomarkers. The least absolute shrinkage and selection operator (LASSO) regression was applied to these metabolites to screen characteristic metabolic variables. Selected feature metabolic biomarkers were added to the established model for predicting MACE risk; risk differentiation (C-statistic) and reclassification (continuous net reclassification improvement [NRI], integrated differentiation index [IDI]) were evaluated. This study included 54,561 UK Biobank participants (34,797 middle-aged adults and 19,764 elderly adults) and was followed for a median of more than 12 years. Of these, there are 1799 middle-aged individuals and 2527 elderly individuals incident of MACE (ischemic heart disease, stroke, and cardiovascular deaths). After adjusting for relevant covariates, Cox regression yielded metabolic biomarkers associated with the occurrence of MACE in the population (false discovery rate controlled P < 0.05). In the elderly, the metabolites associated with increased MACE risk were notably diminished compared to the middle-aged; and the elderly group underscored the protective function of medium and small HDL and their constituents, docosahexaenoic acid, and glycine. The more comprehensive model, which additionally includes the feature metabolic biomarkers, demonstrated enhanced discriminatory power and predictive accuracy for MACE occurrence among middle-aged individuals, evidenced by improved C-statistics (from 0.711 [95% CI 0.699-0.722] to 0.723 [0.711-0.734]), a continuous NRI of 0.247 [0.207-0.315], and an absolute IDI of 0.005 [0.004-0.008]. Its evaluation value is superior to that in the elderly. Our study explored the association of circulating metabolites with MACE risk in middle-aged and elderly adults and made comparisons. Metabolomic insights have revealed biomarkers associated with new-onset MACE in different age populations, highlighting the value of protective metabolites in the elderly. This provides instrumental information to possibly implement precision medicine for preventing MACE.PMID:39904969 | DOI:10.1007/s11357-025-01544-6

Mol Neurobiol. 2025 Feb 4. doi: 10.1007/s12035-025-04719-6. Online ahead of print.ABSTRACTTemporal lobe epilepsy (TLE) arises mostly because of an initial injury. Certain stimuli can make a normal brain prone to repeated, spontaneous seizures via a process called epileptogenesis. This study examined the plasma metabolomics profile in rats with the induced TLE to identify feasible biomarkers that can distinguish progression of epileptogenesis in three different time points and reveal the underlying mechanisms of epileptogenesis. Status epilepticus (SE) was induced by repetitive intraperitoneal injections of low-dose lithium chloride-pilocarpine hydrocholoride. Blood samples were collected 48 h, 1 week, and 6 weeks after SE, respectively. Plasma metabolites were analyzed by nuclear magnetic resonance (NMR) spectrometry. Statistical analysis was performed using MetaboAnalyst 6.0. An orthogonal partial least squares discriminant analysis (OPLS-DA) model was employed to represent variations between the TLE model groups and respective controls. Volcano plot analysis was used to identify key features, applying a fold-change criterion of 1.5 and a t-test threshold of 0.05. 48 h after SE, dimethyl sulfone (DMSO2) and creatinine levels were decreased, whereas glycine and creatine levels were increased. The only metabolite that changed 1 week after SE was pyruvic acid, which was increased compared to its control level. Lactic acid, pyruvic acid, and succinic acid levels were increased 6 weeks after SE. The identified metabolites were especially related to the tricarboxylic acid cycle and glycine, serine, and threonine metabolism. The results illustrate that distinct plasma metabolites can function as phase-specific biomarkers in TLE and reveal new insights into the mechanisms underlying SE.PMID:39904962 | DOI:10.1007/s12035-025-04719-6

Pharm Res. 2025 Feb 4. doi: 10.1007/s11095-025-03820-8. Online ahead of print.ABSTRACTPURPOSE: Indole-3-carbinol (I3C) is shown to possess multiple pharmacological activities such as anti-inflammatory, antimicrobial, antioxidant, antiviral, and anti-cancer activities. It is widely accepted as modulator of multiple signaling pathways particularly those related to cell cycle, cell growth and division, angiogenesis, apoptosis and immunity. We explored the metabolic reprogramming based on treatment with I3C in mice prostate tissue.METHODS: In this study we utilized Pten knockout (KO)-induced prostate tumorigenesis mouse model to examine mechanism of action of I3C via metabolic rewiring. Phosphatase and tensin homolog deleted on chromosome 10 (Pten), a tumor suppressor gene is frequently found to be mutated or deleted in prostate cancer. Untargeted metabolomics was performed using liquid-chromatography mass-spectrometry (LC-MS) based platform to investigate Pten-dependent and Pten-independent metabolic targets of I3C.RESULTS: The most impacted pathways by I3C included pyrimidine metabolism, arginine and proline metabolism, porphyrin metabolism, citrate cycle and lipoic acid metabolism.CONCLUSION: These pathways taken together help in understanding the overall health beneficial effects of I3C.PMID:39904853 | DOI:10.1007/s11095-025-03820-8

J Neurol. 2025 Feb 4;272(3):183. doi: 10.1007/s00415-025-12909-4.ABSTRACTSpinal muscular atrophy (SMA) is a rare neuromuscular disease caused by biallelic mutations in the SMN1 gene, leading to progressive muscle weakness due to degeneration of the anterior horn cells. Since 2017, SMA patients can be treated with the anti-sense oligonucleotide Nusinersen, which promotes alternative splicing of the SMN2 gene, by regular intrathecal injections. In this prospective study, we applied metabolomic, lipidomic, and proteomic analysis to examine sequential CSF samples from 13 SMA patients and controls. This multi-omic approach identified over 800 proteins and 400 small molecules including lipids. Multivariate analysis of multi-omic data successfully discriminated between the CSF derived from SMA patients and control subjects. Lipidomic analysis revealed increased levels of cholesteryl esters and lyso-phospholipids, along with reduced levels of cholesterol and phospholipids in the CSF of SMA patients as compared to healthy controls. These data, combined with results from functional assays, led us to conclude that SMA patients exhibit altered levels and function of high-density-lipoprotein (HDL)-like particles in the CSF. Notably, Nusinersen therapy was observed to reverse disease-specific profile changes toward a physiological state, potentially explicable by restoring HDL function.PMID:39904776 | DOI:10.1007/s00415-025-12909-4

Gut. 2025 Feb 4:gutjnl-2024-333479. doi: 10.1136/gutjnl-2024-333479. Online ahead of print.ABSTRACTBACKGROUND: Chronic restraint stress (CRS) is a tumour-promoting factor. However, the underlying mechanism is unknown.OBJECTIVE: We aimed to investigate whether CRS promotes head and neck squamous cell carcinoma (HNSCC) by altering the oral microbiota and related metabolites and whether kynurenine (Kyn) promotes HNSCC by modulating CD8+ T cells.DESIGN: 4-nitroquinoline-1-oxide (4NQO)-treated mice were exposed to CRS. Germ-free mice treated with 4NQO received oral microbiota transplants from either CRS or control mouse donors. 16S rRNA gene sequencing and liquid chromatography-mass spectrometry were performed on mouse saliva, faecal and plasma samples to investigate alterations in their microbiota and metabolites. The effects of Kyn on HNSCC were studied using the 4NQO-induced HNSCC mouse model.RESULTS: Mice subjected to CRS demonstrated a higher incidence of HNSCC and oral microbial dysbiosis than CRS-free control mice. Pseudomonas and Veillonella species were enriched while certain oral bacteria, including Corynebacterium and Staphylococcus species, were depleted with CRS exposure. Furthermore, CRS-altered oral microbiota promoted HNSCC formation, caused oral and gut barrier dysfunction, and induced a host metabolome shift with increased plasma Kyn in germ-free mice exposed to 4NQO treatment. Under stress conditions, we also found that Kyn activated aryl hydrocarbon receptor (AhR) nuclear translocation and deubiquitination in tumour-reactive CD8+ T cells, thereby promoting HNSCC tumourigenesis.CONCLUSION: CRS-induced oral microbiota dysbiosis plays a protumourigenic role in HNSCC and can influence host metabolism. Mechanistically, under stress conditions, Kyn promotes CD8+ T cell exhaustion and HNSCC tumourigenesis through stabilising AhR by its deubiquitination.PMID:39904603 | DOI:10.1136/gutjnl-2024-333479

Eur J Pharmacol. 2025 Feb 2:177345. doi: 10.1016/j.ejphar.2025.177345. Online ahead of print.ABSTRACT3,4-Methylenedioxymethamphetamine (MDMA), commonly known as a recreational drug, may also offer therapeutic benefits for mental health. Population-based studies suggest that MDMA users have a lower risk of demyelinating diseases, such as depression. Given the role of the gut microbiota in mediating MDMA's effects, we hypothesized that MDMA might confer mental health benefits via the gut-brain axis. Cuprizone (CPZ) induces demyelination by chelating copper, which leads to oligodendrocyte death and subsequent myelin loss. This study investigated the impact of MDMA on brain demyelination in CPZ-treated mice, focusing on the gut-brain axis. Repeated intermittent MDMA administration (10 mg/kg, three times weekly for 6 weeks) significantly reduced demyelination in the corpus callosum (CC) of CPZ-treated mice. Gut microbiota and non-targeted metabolomics analyses revealed notable differences in specific gut bacteria and plasma (β-D-allose and L-sorbose) or fecal metabolite (carnitine) levels between MDMA-treated and vehicle-treated CPZ-exposed mice. Negative correlations were found between the levels of metabolites (β-D-allose, L-sorbose, and carnitine) and the relative abundance of Romboutsia and Romboutsia timonensis. These findings suggest that intermittent MDMA administration may alleviate demyelination in the CC of CPZ-treated mice via the gut-brain axis. Further research is needed to elucidate the roles of gut microbiota and metabolites in MDMA's effects on brain demyelination and to investigate other demyelination models.PMID:39904416 | DOI:10.1016/j.ejphar.2025.177345

Transl Oncol. 2025 Feb 3;53:102303. doi: 10.1016/j.tranon.2025.102303. Online ahead of print.ABSTRACTBACKGROUND: Understanding the mechanisms underlying the metastasis of breast cancer cells to the lungs is challenging, and appropriate simulation of the tumor microenvironment with mimetic cancer-stroma crosstalk is essential. β4 integrin is known to contribute to triggering a variety of different signaling cues involved in the malignant phenotype of cancer but its role in organ-specific metastasis needs further study. In this work, a multi-compartment microfluidic tumor model was developed to evaluate cancer cell invasion.MATERIALS AND METHODS: To model the primary tumor microenvironment, breast cancer cells (MCF7) and cancer-associated fibroblasts (CAFs) were co-cultured within the tumor compartment of the microfluidic chip while normal lung fibroblasts (NLFs) were seeded in a different compartment, as the secondary tumor site, separated from the tumor compartment via a Matrigel™ layer resembling the extracellular matrix.RESULTS: The cytotoxic effect of β4 integrin blockade on cancer cells gradually increased after 48 and 72 h of co-culture. Invasion of breast cancer cells in both single and coculture models was characterized in response to β4 integrin blockade. The invasion rate and gap closure of MCF7/CAF_NLF was significantly higher than MCF7_NLF (P < 0.0001). β4 integrin inhibition reduced the rate of gap closure and invasion of both (P < 0.0001).CONCLUSIONS: Biomimetic microfluidic-based tumor models hold promise for studying cancer metastasis mechanisms. Precise manipulation, simulation, and analysis of the cancer microenvironment are made possible by microfluidics.PMID:39904278 | DOI:10.1016/j.tranon.2025.102303

Ecotoxicol Environ Saf. 2025 Feb 3;291:117791. doi: 10.1016/j.ecoenv.2025.117791. Online ahead of print.ABSTRACTCurrent research on the relationship between environmental endocrine disrupting chemicals (EDCs) and breast cancer remains insufficient, with limited evidence and inconsistent conclusions. Mendelian randomization (MR) is a robust method for establishing causality, as it reduces biases from confounding factors and reverse causation. This study uses MR to investigate the effects of three types of EDCs, including bisphenols, parabens, and phthalates, on the risk of overall breast cancer and its subtypes-Luminal A, Luminal B, triple negative, human epidermal growth factor receptor 2-enriched, and estrogen receptor-positive/negative. The study also examines the 1400 blood metabolome as potential mediators and explores EDCs-associated DNA methylation changes as potential factors, with a focus on European populations. Our results shows that n-butyl paraben (n-BuP) is positively associated with Luminal A, mono-methyl phthalate is negatively associated with Luminal B, and mono-iso-butyl phthalate (MiBP) is positively associated with triple negative breast cancer (TNBC). Mediation analysis reveals that blood metabolites, such as caffeic acid sulfate and the caffeine-to-paraxanthine ratio, mediate the effect of n-BuP on Luminal A, while methylsuccinate mediate the effect of MiBP on TNBC. Epigenetic analysis shows associations between EDCs exposure-related DNA methylation changes at specific CpG sites (cg26325335, cg08537847, cg27454300) and different breast cancer risks. These findings not only suggest potential biomarkers for early detection and intervention but also underscore the imperative for further research to rigorously validate these associations.PMID:39904262 | DOI:10.1016/j.ecoenv.2025.117791

Redox Biol. 2025 Jan 30;80:103509. doi: 10.1016/j.redox.2025.103509. Online ahead of print.ABSTRACTThe activation of inflammatory macrophages plays a pivotal role in the development of liver fibrosis (LF). Ferroptosis contributes to the clearance of inflammatory macrophages and the release of profibrotic factors. Glycyrrhetic Acid 3-O-Mono-β-d-glucuronide (GAMG) is a natural compound, the potential role of which on LF remains uncertain. In this study, GAMG treatment significantly reduced hepatocyte steatosis, fibroplasia, inflammatory cell infiltration, and collagen fiber deposition in LF mice. In addition, GAMG remarkably decreased the content of collagen protein and improved liver function indicators. Single-cell RNA sequencing revealed that GAMG significantly affected the changes of macrophage subsets in LF, and Funrich analysis identified IRF1 as a key transcription factor regulating the macrophage genome. IRF1 was significantly increased while ferroptosis related SLC7A11 was significantly down-regulated in GAMG treated inflammatory macrophages. Mass spectrometry metabolomics analysis showed that GAMG significantly affected metabolites associated with LF. In vivo and in vitro experiments further verified that GAMG induced ferroptosis of inflammatory macrophages through the IRF1/SLC7A11 axis, and ultimately alleviated LF. Therefore, GAMG induces ferroptosis of inflammatory macrophages by activating the IRF1/SLC7A11 axis, which provides a new strategy for the treatment of LF.PMID:39904190 | DOI:10.1016/j.redox.2025.103509

J Pharm Biomed Anal. 2025 Jan 31;257:116715. doi: 10.1016/j.jpba.2025.116715. Online ahead of print.ABSTRACTComplex amine metabolic disorders are implicated in ischemic stroke and can further exacerbate brain damage. Therefore, ameliorating their metabolic disorder would be an effective way to improve recovery from brain damage after ischemia/reperfusion (I/R) injury. In this work, the protective effects of Edaravone (Eda), Ginaton injection (Gin), and their combination (Eda+Gin) against cerebral I/R injury in a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model were preliminarily investigated from the perspective of spatial metabolomics. Compared to single-drug treatment, the optimized combination treatment with Eda and Gin significantly decreased infarct volumes, improved neurological function, and inhibited neuronal damage and glial cell activation in MCAO/R rats. Also, combination treatment could prolong the blood circulation time of quercetin, ginkgolide C, and eight flavonoid glycosides compared to Gin treatment alone. More importantly, the spatial metabolic alterations of amine metabolites in MCAO/R rats before and after drug treatment were comprehensively interrogated using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) coupled with laser-assisted chemical transfer (LACT)-based on tissue chemical derivatization, such as amino acids, dipeptides, tripeptides, neurotransmitters, and the other amine metabolites. MALDI MSI results showed that the drastic metabolic disorders occurred in the cerebral cortex (CTX) and striatum (STR) and combination treatment exerted a better regulatory effect on the perturbed spatial amine metabolism. Therefore, combination treatment with Eda and Gin could significantly reduce ischemic brain damage and correct spatial metabolic disorders of amine metabolites, providing a potential treatment strategy for cerebral I/R injury.PMID:39904130 | DOI:10.1016/j.jpba.2025.116715

Food Chem. 2025 Jan 24;474:142933. doi: 10.1016/j.foodchem.2025.142933. Online ahead of print.ABSTRACTPurple teas are gaining popularity due to their significant health benefits. This study analyzed flavonoid metabolites in the second leaves of three purple tea varieties with stable purple shoots-'Hongfei' (HF), 'Danfei' (DF), and 'Ziya 24' (ZY24)-using UPLC-MS/MS, with 'Yinghong 9' (YH9), a green tea, as the control. The most abundant anthocyanins were cyanidin-3-O-glucoside, cyanidin-O-syringic acid, and pelargonidin-3-O-glucoside in HF, while ZY24 and DF accumulated additional delphinidin and petunidin derivatives. DF also contained malvidin-3-O-galactoside. Furthermore, 22 significantly enriched non-anthocyanin flavonoids were identified as potential co-pigments contributing to the vibrant leaf coloration. These findings reveal key anthocyanin and flavonoid profiles responsible for the distinct purple hues in the tender shoots of different purple tea varieties.PMID:39904087 | DOI:10.1016/j.foodchem.2025.142933

Chem Biodivers. 2025 Feb 4:e202402187. doi: 10.1002/cbdv.202402187. Online ahead of print.ABSTRACTAcalypha indica is a weed used in traditional cancer treatments. In this study, we present the first attempt to use a metabolomic approach to identify cytotoxic compounds from A. indica extract with potential anticancer properties. The leaves of A. indica were extracted using ethanol, ethyl acetate, chloroform, and n-hexane. The cytotoxic activity against MCF-7 cells was evaluated, revealing 50% inhibition concentration (IC50) values ranging from 51.88 ± 7.80 to 226.86 ± 13.27 µg/mL. Metabolite profiling using liquid chromatography-high-resolution mass spectroscopy identified 27 metabolites and principal component analysis successfully differentiated the extracts, indicating variability in the compounds extracted using each solvent. To identify the cytotoxic compounds, orthogonal partial least-squares discriminant analysis was used to correlate metabolite profiles with IC50 values from the cytotoxic assay. From the results obtained, we successfully predicted six compounds contributing to the anticancer activity of A. indica, namely hernanol, 13(S)-HpOTrE, (±)9-HpODE, (+)-catechin, traumatic acid, and one compound as assumed to be theobromine. In silico analysis predicted that (+)-catechin and hernanol bind to the alpha-estrogen receptor with an affinity similar to that of doxorubicin.PMID:39903842 | DOI:10.1002/cbdv.202402187

Anal Chem. 2025 Feb 4. doi: 10.1021/acs.analchem.4c01565. Online ahead of print.ABSTRACTAlthough untargeted mass spectrometry-based metabolomics is crucial for understanding life's molecular underpinnings, its effectiveness is hampered by low annotation rates of the generated tandem mass spectra. To address this issue, we introduce a novel data-driven approach, Biotransformation-based Annotation Method (BAM), that leverages molecular structural similarities inherent in biochemical reactions. BAM operates by applying biotransformation rules to known "anchor" molecules, which exhibit high spectral similarity to unknown spectra, thereby hypothesizing and ranking potential structures for the corresponding "suspect" molecule. BAM's effectiveness is demonstrated by its success in annotating query spectra in a global molecular network comprising hundreds of millions of spectra. BAM was able to assign correct molecular structures to 24.2% of examined anchor-suspect cases, thereby demonstrating remarkable advancement in metabolite annotation.PMID:39903752 | DOI:10.1021/acs.analchem.4c01565

J Crohns Colitis. 2025 Feb 4:jjaf020. doi: 10.1093/ecco-jcc/jjaf020. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Ulcerative colitis (UC) is a metabolism-related chronic intestinal inflammatory disease. Disease extent is a key parameter of UC. Using serum metabolic profiling to identify non-invasive biomarkers of disease extent may inform therapeutic decisions and risk stratification.METHODS: The orthogonal partial least squares-discriminant analysis (OPLS-DA) was performed to identify the metabolites. Least absolute shrinkage and selection operator (LASSO) regression, random forest-recursive feature elimination (RF-RFE), and support vector machine-recursive feature elimination (SVM-RFE) algorithms were used to screen metabolites. Five machine learning algorithms (XGboost, KNN, NB, RF, and SVM) were used to construct prediction model.RESULTS: A total of 220 differential metabolites between the patients with UC and healthy controls (HCs) were confirmed by the OPLS-DA model. Machine learning screened eight essential metabolites for distinguishing patients with UC from HCs. A total of 23, 6, and 6 differential metabolites were obtained through machine learning between group E1 and E2, E1 and E3, and E2 and E3. The RF model had a prediction accuracy of up to 100% in all three training sets. The serum levels of tridecanoic acid were significantly lower and pelargonic acid were significantly higher in patients with extensive colitis than in the other groups. The serum level of asparaginyl valine in patients with rectal UC was significantly lower than that in E2 and E3 groups.CONCLUSIONS: Our findings revealed the metabolic landscape of UC and identified biomarkers for different disease extents, confirming the value of metabolites in predicting the occurrence and progression of UC.PMID:39903649 | DOI:10.1093/ecco-jcc/jjaf020

Physiol Rep. 2025 Feb;13(3):e70206. doi: 10.14814/phy2.70206.ABSTRACTLittle is known about the exercise-induced adaptations of the metabolome in endurance and strength athletes in comparison with sedentary subjects. In order to analyze exercise-induced effects, quantitative, targeted metabolomics (Biocrates MxP® Quant 500) were performed in plasma samples before and after one bout of endurance or resistance exercise (RE) in 12 strength-trained weightlifters (ST), 10 endurance-trained runners (ET) and 12 sedentary controls (CG) at the end of each of three characteristic training phases. Performance and anthropometric data were significantly different between CG and athletes. A significant exercise-induced increase in lactate (Lac) was observed in all groups after all exercise tests. After endurance exercise (EE), there were significant increases in acetylcarnitine, arachidonic acid, and docosahexaenoic acid in CG and ET while aconitic acid, hippuric acid, glutamate, hexoses, xanthine were significantly increased in ET only. Only CG showed increases in several triglycerides following EE. RE, however, induced significant increases in Lac only. In summary, EE induces distinct increases in some metabolites of the fatty acid metabolism and the oxidative defense system in ET and CG. There are some indications for specific adaptations of the energy metabolism after long lasting endurance training with a distinct exercise-induced response of the metabolome in ET.PMID:39903553 | DOI:10.14814/phy2.70206

Metab Brain Dis. 2025 Feb 4;40(2):118. doi: 10.1007/s11011-025-01549-2.ABSTRACTThe genetic predisposition and environmental factors both trigger the complex neurological dyskinesia of essential tremor (ET). Gut dysbiosis may facilitate the occurrence and development of neurological diseases. Therefore, it is worth exploring the inner connections between gut microbiota and ET. First, the gut microbiota of 19 ET patients and 21 healthy controls (HCs) were analysed with metagenomics approach. Second, the potential linkages between gut microbiome and serum metabolome profiles were explored by integrative analysis. The gut microbiota disorders were present in ET patients. The LEfSe method showed a significant decrease in Bacteroides. The functional analysis revealed that there were differences in gut microbial apoptosis, retinol metabolism, and steroid hormone biosynthesis pathways. The levels of various lipids and lipid-like molecules alter in serum of ET patients, which correlated with altered gut microbial abundance, indicating the alterations in lipid metabolism involved in apoptosis pathway in ET. All of these data point to the gut dysbiosis in ET, and some changed gut microbial species were linked to abnormalities in blood lipid metabolism, which open up new avenues for investigation into the pathophysiology of ET.PMID:39903340 | DOI:10.1007/s11011-025-01549-2

J Food Sci. 2025 Feb;90(2):e70033. doi: 10.1111/1750-3841.70033.ABSTRACTThe lipid accumulation associated with diabetes causes continuous liver and kidney damage. Laminaria japonica polysaccharide (fucoidan) has been shown to regulate the disorder in lipid metabolism caused by diabetes. Herein, we established a diabetes mellitus (DM) rat model through a high-fat and high-sugar diet combined with streptozotocin. An automatic biochemical analyzer was used to detect serum lipid content, and hematoxylin and eosin, Masson, periodic acid-silver-methenamine, and Oil Red O staining were used to observe changes in the structure of the kidney and liver, including fibrosis and lipid accumulation. We confirmed that fucoidan could ameliorate renal injury, lipid metabolism, and oxidative stress in streptozotocin-induced diabetic rat models. Metabolomics analysis demonstrated that amino acid metabolism is an important process. We further demonstrated a novel role of fucoidan in regulating kidney and liver lipid metabolism through the aryl hydrocarbon receptor (AhR)-mediated CD36 signaling pathway. Similar results were found in DM rats treated with an AhR inhibitor, as well as in those treated with a combination of both an AhR inhibitor and fucoidan. Importantly, we observed a higher expression of AhR/CD36 in the kidneys and liver of rats with DM, and the level of AhR/CD36 correlated with lipid accumulation and kidney function, suggesting that AhR/CD36 signaling could be a promising therapeutic target for fucoidan in treating lipid metabolism in DM. PRACTICAL APPLICATION: As the main component of Laminaria japonica, fucoidan has excellent antioxidant properties and protective effects against liver and kidney damage in diabetes mellitus. It can play a protective role in the daily diet of diabetic patients. Alternatively, it could be developed as a potential therapeutic drug for the treatment of diabetes.PMID:39902919 | DOI:10.1111/1750-3841.70033

Microbiol Spectr. 2025 Feb 4:e0146824. doi: 10.1128/spectrum.01468-24. Online ahead of print.ABSTRACTCeliac disease (CD) is an autoimmune disease caused by a loss of gluten tolerance in genetically predisposed individuals. While 30%-40% of people possess the predisposing alleles, only 1%-2% are diagnosed with CD, suggesting that environmental factors are involved in disease pathogenesis. To determine an association between pediatric CD and the gut microbiome, we analyzed fecal samples from a prospective cohort study (ABIS). These samples were collected from children who later developed CD (CD progressors) and age-matched healthy children (at ages 1, 2.5, and 5) with similar HLA genotypes, breastfeeding durations, and gluten exposure times. We previously reported gut microbiome differences at ages 2.5 and 5 in this cohort; here, we present findings from samples collected at age 1 (n = 5). We identified 14 ASVs differing significantly between CD progressors and controls, including taxa linked to CD pathogenesis. CD progressors had increased Firmicutes and higher alpha diversity in IgA- bacteria. Using PICRUSt, we analyzed metabolic pathways enriched in CD progressors compared to controls at ages 1, 2.5, and 5 (n = 5-16), revealing enriched inflammatory and pathogenic pathways potentially contributing to CD-related immune dysregulation. While results are based on the primary EdgeR analysis, we also applied a non-parametric method of statistical analysis, reporting those results with supplementary figures. In conclusion, our findings suggest distinct metabolic pathways enriched in the gut microbiome of CD progressors years before diagnosis, which could inform targeted therapeutics for CD. As discussed in the limitations section, this small pilot study should be replicated with larger sample sizes for broader generalization.IMPORTANCE: We analyzed gut microbiome data from children who later developed celiac disease (CD progressors) compared to healthy children in the first 5 years of life. Using fecal samples corresponding to the three phases of gut microbiome development, we uncovered enriched functional microbial pathways in CD progressors at age 1. Some of these pathways, implicated in bacterial pathogenesis, microbiota modulation, and inflammation, have been correlated with CD. We also identified taxa in CD progressors at age 1 including Lachnospiraceae, Alistipes, and Bifidobacterium dentium that were previously associated with CD. These findings suggest a potential role for these taxa and enriched pathways in pediatric CD onset years before diagnosis, highlighting potential for early interventions. While the findings of this exploratory study should be validated with larger sample sizes, our study suggests microbial metabolic pathways related to CD onset, enhancing our understanding of CD pathogenesis and the role of gut microbiome-mediated early alterations.PMID:39902908 | DOI:10.1128/spectrum.01468-24