PubMed

Front Microbiol. 2025 Feb 27;16:1517082. doi: 10.3389/fmicb.2025.1517082. eCollection 2025.ABSTRACTBACKGROUND: Mongolian Medicine Qiqirigan-8 (MMQ-8) is a traditional Mongolian medicine formula used to treat fatty liver disease. However, the material basis and in vivo metabolic process of the therapeutic effect of MMQ-8 on non-alcoholic fatty liver disease (NAFLD) remain unclear.METHODS: The chemical composition of MMQ-8 was determined using Ultra-high-performance liquid chromatography-quadrupole Exactive Mass spectrometry analysis (UHPLC-QE-MS). C57BL/6J mice were fed a choline-deficient diet for 12 weeks to induce a NAFLD model. Hematoxylin and Eosin (H&E)-staining, combined with serum biochemical indexes, was used to observe liver appearance and characterize the pathological changes and functions of the liver. HE staining and Alcian Blue-Phosphoric Acid Schiff (AB-PAS) staining of the colon, along with ZO-1 immunofluorescence expression in the colon were used to reveal the effect of MMQ-8 on the disruption of the intestinal epithelial mucosal barrier in the NAFLD. The expression of intestinal tight junction genes was analyzed by qRT-PCR to observe the protective effect of MMQ-8 against intestinal epithelial mucosal barrier disruption. Fecal metagenomics and serum non-targeted metabolomics were used to reveal the effects of MMQ-8 on the gut microbiota and metabolism in mice with NAFLD. Finally, we emphasize the interaction between gut microbiota and metabolites through Spearman correlation coefficient analysis.RESULTS: Mongolian Medicine Qiqirigan-8 contains 17 active ingredients, which can reduce hepatic steatosis and lobular inflammation in mice with NAFLD, and have protective effects against liver injury. MMQ-8 reduced the infiltration of inflammatory cells in the colon epithelium of model mice while restoring the number of goblet cells. MMQ-8 significantly enhanced ZO-1 protein expression in the colon, as well as the mRNA expression of both ZO-1 and Occludin. Fecal metagenomics results showed that MMQ-8 reduced the Bacillota/Bacteroidota ratio in NAFLD mice. Increased the abundance of beneficial bacteria such as Porphyromonadaceae, Prevotella, and Bacteroidota. and suppressed the abundance of dysfunctional bacteria, such as Bacillota, Acetatifactor, and Erysipelotrichaceae. Furthermore, metabolomics studies revealed that MMQ-8 intervention significantly regulated the expression of metabolites related to glutathione metabolism, butyric acid metabolism, sphingolipid metabolism, and glycerophospholipid metabolism in NAFLD mice compared to the model group. These metabolic pathways play key roles in NAFLD. According to Spearman's correlation coefficient analysis, up-regulation of Porphyromonadaceae, Prevotella, and Bacteroidota after MMQ-8 intervention was negatively correlated with LPC levels in glycerophospholipid metabolic pathways, while positively correlated with PC levels. In contrast, the relationship between Bacillota and Acetatifactor, which were down-regulated after MMQ-8 intervention, was the opposite. In addition, the up-regulation of Porphyromonadaceae, Prevotella, and Bacteroidota after MMQ-8 intervention was positively correlated with fumaric acid, 2-oxoglutaric acid, adenosine, and L-glutathione levels, while those down-regulated after MMQ-8 intervention were positively correlated with the levels of Bacillota, Acetatifactor were negatively correlated with all the above metabolites. Thus, glutathione metabolism, butyric acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism and gut microbial ecosystem are tightly intertwined in this process.CONCLUSION: In summary, these findings indicate that MMQ-8 has a synergistic anti-NAFLD effect through its multi-component, multi-target, gut microbiota-modulating and multi metabolic pathway characteristics. The host's regulation of specific gut microbiota and involvement in multiple metabolic pathways may be one of the important mechanisms by which MMQ-8 exerts its therapeutic effects on NAFLD. It is worth noting that metabolic pathways such as glutathione metabolism, butyric acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, and the gut microbiota ecosystem are closely intertwined in this process.PMID:40083784 | PMC:PMC11905161 | DOI:10.3389/fmicb.2025.1517082

Int J Biol Sci. 2025 Feb 26;21(5):2313-2329. doi: 10.7150/ijbs.105667. eCollection 2025.ABSTRACTAcute kidney injury (AKI) is a worldwide clinical burden associated with high morbidity and mortality. Remote ischemic preconditioning (rIPC), a brief nonlethal ischemia and reperfusion (IR) in remote tissues or limbs, has been used in an attempt to protect against AKI, but its underlying signaling pathways has not been elucidated. In the present study, rIPC protected kidney function and pathological injury and mitigated NADPH oxidase 4 (NOX4) upregulation in different AKI models (cisplatin, LPS and IRI). Furthermore, rIPC significantly attenuated mitochondrial dysfunction and ameliorated tubular epithelial ferroptosis during AKI. Mechanistically, in wild-type AKI mice and TCMK-1 cells, rIPC effectively decreased kidney ROS production, preserved mitochondrial dynamics and mitophagy, and ameliorated tubular epithelial ferroptosis. Notably, these protective effects of rIPC were further enhanced by NOX4 knockout or silencing and mitigated by NOX4 overexpression. Our study showed that rIPC may attenuate mitochondrial dysfunction and ferroptosis in tubular epithelial cells in AKI by inhibiting NOX4-ROS signaling. NOX4 might be used as a biomarker for monitoring the biological effects of rIPC to optimize the rIPC protocol and facilitate future translational studies.PMID:40083709 | PMC:PMC11900797 | DOI:10.7150/ijbs.105667

Front Pharmacol. 2025 Feb 27;16:1498280. doi: 10.3389/fphar.2025.1498280. eCollection 2025.ABSTRACTThe fruits of Lycium ruthenicum Murr. (Solanaceae) are employed in ethnomedicine and used as a functional food. Their antioxidant, anti-aging, and hypolipidemic activities have been investigated in modern research. This study indicated that the ethanolic extract of the fruits of L. ruthenicum Murr. (LRM) improved oxidative and heat stress tolerance, reduced the accumulation of lipofuscin, and retarded the aging process in Caenorhabditis elegans (Rhabditidae). Furthermore, the pharyngeal pumping rate and body length decreased under LRM treatment. Moreover, metabolomic analysis and the DPClusO algorithm revealed that LRM regulated a series of lifespan-related pathways centered on glycine, serine, and threonine metabolism. These results suggest that LRM prolongs the lifespan of Caenorhabditis elegans via dietary restriction. Moreover, feruloyl putrescine, a kind of polyamine, was found in differential metabolites, which may be the metabolite of caffeoyl-spermidine in LRM. These findings from this exploratory study offer a new insight into the roles of L. ruthenicum in anti-aging activity as a functional food.PMID:40083385 | PMC:PMC11903438 | DOI:10.3389/fphar.2025.1498280

J Periodontal Res. 2025 Mar 14. doi: 10.1111/jre.13379. Online ahead of print.ABSTRACTAIMS: To explore the potential of metabolomic profiles of oral rinse samples to distinguish between patients with severe periodontitis (stage III/IV) and non-periodontitis controls. This is coupled to an analysis of differences in metabolomic profiles between individuals without periodontitis, patients with localized periodontitis, and patients with generalized periodontitis.METHODS: Periodontitis patients and controls were recruited, all aged ≥ 40 years. Study participants were asked to rinse vigorously for 30 s with 10 mL phosphate buffered saline. Metabolites were identified using a semi-targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) platform.RESULTS: In total, 38 periodontitis patients (18 localized, 20 generalized stage III/IV periodontitis patients) and 16 controls were included. Metabolomic profiles of oral rinse samples were able to distinguish patients with severe periodontitis (stage III/IV) from non-periodontitis controls. Among various variables for the severity of periodontitis, we found that the number of sites with deep pockets (PPD) ≥ 6 mm explained best the differences in metabolomic profiles between controls and patients with severe periodontitis. Subjects with a high number of sites with PPD ≥ 6 mm were characterized by a higher level of phosphorylated nucleotides, amino acids, peptides, and dicarboxylic acids. Metabolomic profiles were also significantly different between controls vs. generalized periodontitis and between localized periodontitis vs. generalized periodontitis (p < 0.05).CONCLUSION: Our study demonstrates that simply collected oral rinse samples are suitable for LC-MS/MS based metabolomic analysis. We show that a metabolomic profile with a substantial number of metabolites can distinguish severe periodontitis patients from non-periodontitis controls. These observations can be a basis for further studies into screening to identify subjects with the risk of having severe periodontitis.PMID:40083241 | DOI:10.1111/jre.13379

Physiol Plant. 2025 Mar-Apr;177(2):e70157. doi: 10.1111/ppl.70157.ABSTRACTWaterlogging is a major abiotic stress restricting crop yield globally, and aerenchyma formation is one of the most important adaptive strategies in waterlogging-tolerant plants. However, the conservation of this process remains poorly understood, and additional pathways are yet to be identified. Here, physiological, anatomical, transcriptomic, and metabolomic analyses were conducted on wheat seedlings under normal and waterlogging conditions. Waterlogging caused growth inhibition and physiological damage, as well as induced aerenchyma formation in roots. A total of 10,346 differentially expressed genes and 3,419 differential metabolites were identified in roots. In addition to the AP2/ERF (APETALA2/ETHYLENE RESPONSIVE FACTOR) gene family, integrating analyses also revealed the role of LOB/AS2 (LATERAL ORGAN BOUNDARIES/ASYMMETRIC LEAVES2) in aerenchyma formation under waterlogging. It was revealed that the classical pathway of aerenchyma formation mediated by ethylene response, as well as synergy of calcium ion and reactive oxygen species, was deeply conserved in both monocots and eudicots during 160 million years of evolution through gene co-expression networks of cross-species. The newly introduced concept 'Regulatome' supported the classical pathway of aerenchyma formation, with a proposed model of the jasmonic acid signalling pathway involved in waterlogging, suggesting its usefulness in gene identification and function exploration. These findings provide a novel insight into the regulatory mechanisms of aerenchyma formation and breeding approaches for developing wheat cultivars with high waterlogging tolerance.PMID:40083176 | DOI:10.1111/ppl.70157

Biotechnol Bioeng. 2025 Mar 13. doi: 10.1002/bit.28971. Online ahead of print.ABSTRACTCancer-associated fibroblasts are increasingly recognized to have a high impact on prostate tumor growth and drug resistance. Here, we bioengineered organotypic prostate cancer 3D in vitro models to better understand tumor-stroma interplay, the metabolomic profile underlying such interactions, and their impact on standard-of-care therapeutics performance. The assembly of robust and uniform spheroids was evaluated and compared in monotypic PC-3 and heterotypic microtumors comprised of either a healthy or malignant stroma and prostate cancer cells. Our findings demonstrate that the precise inclusion of prostate cancer stromal elements is crucial to generating robust PC-3 prostate cancer spheroids with reproducible morphology and size. The inclusion of cancer-associated fibroblasts promoted the establishment of more compact microtumors exhibiting characteristic expression of major proteins. Exometabolomic profile analysis also highlighted the impact of stromal cells on tumor models metabolism. The optimized heterotypic spheroids were additionally exploited for screening standard-of-care therapeutics, exhibiting a higher resistance when compared to their monotypic counterparts. Our findings demonstrate that including stromal elements in PC-3 prostate cancer models is crucial for their use as increasingly organotypic testing platforms, being relevant for screening candidate anti-cancer therapeutics and for the discovery of potential combinations with emerging anti-stroma therapies.PMID:40083131 | DOI:10.1002/bit.28971

Diabetes Obes Metab. 2025 Mar 13. doi: 10.1111/dom.16309. Online ahead of print.ABSTRACTAIM: This study investigated the role of RAP1B in hepatic lipid metabolism and its implications in obesity and associated metabolic disorders, focusing on the molecular mechanisms through which RAP1B influences lipid accumulation, inflammation and oxidative stress in liver tissues and hepatocyte cell lines.MATERIALS AND METHODS: Liver-specific RAP1B-knockout (LKO) and overexpression (OE) mice were generated and fed a high-fat diet for 18 weeks to evaluate systemic and hepatic metabolic changes. Comprehensive metabolic phenotyping included measurements of body weight, body fat content, activity levels, energy expenditure (EE), respiratory exchange ratio (RER), glucose tolerance test and insulin tolerance test. RAP1B-knockdown AML12 hepatocytes were used for in vitro studies. Comprehensive transcriptome and metabolome analyses identified differentially expressed genes and key metabolic shifts. Biochemical and histological analyses were performed to assess lipid accumulation, oxidative stress and inflammatory markers.RESULTS: We found that LKO mice exhibited significant reductions in body weight, fat pad size and liver mass, along with decreased hepatic lipid accumulation due to enhanced lipid breakdown. These mice demonstrated improved glucose tolerance and insulin sensitivity without changes in food intake. Liver histology showed reduced F4/80-positive macrophage infiltration, indicating decreased inflammatory cell recruitment. Additionally, markers of oxidative stress were significantly lower, and molecular analysis revealed downregulation of the MAPK(p38) and NF-κB signaling pathways, further supporting an anti-inflammatory hepatic environment. In contrast, OE mice showed increased liver weight, aggravated hepatic lipid accumulation driven by enhanced lipogenesis, worsened insulin resistance and elevated inflammation.CONCLUSIONS: This study highlights RAP1B's pivotal role in hepatic metabolism and positions it as a potential therapeutic target for obesity and related metabolic disorders.PMID:40083059 | DOI:10.1111/dom.16309

Anim Microbiome. 2025 Mar 13;7(1):26. doi: 10.1186/s42523-025-00393-0.ABSTRACTBACKGROUND: Nutrients are one of the key determinants of gut microbiota variation. However, the intricate associations between the amino acid (AA) profile and the dynamic fluctuations in the gut microbiota and resistome remain incompletely elucidated. Herein, we investigated the temporal dynamics of AA profile and gut microbiota in the colon of pigs over a 24-hour period, and further explored the dynamic interrelationships among AA profile, microbiota, and resistome using metagenomics and metabolomics approaches.RESULTS: JTK_circle analysis revealed that both the AA profile and the gut microbiota exhibited rhythmic fluctuations. With respect to the feed intake, all AAs except L-homoserine (PAdj = 0.553) demonstrated significant fluctuations. Over 50% of Lactobacillaceae, Ruminococcaceae, Clostridiaceae, and Eubacteriaceae species reached their peaks during T15 ∼ T21 when 50% of Lachnospiraceae species experienced a trough. The eLSA results showed that most AAs positively correlated with Prevotellaceae species but negatively correlated with Lactobacillaceae and Lachnospiraceae species. Moreover, most of the AAs negatively correlated with the mobile genetic elements Tn916 and istA group but positively correlated with plasmids. Further partial least squares structural equation model analysis indicated that AAs affected the antibiotic resistance gene dynamics through mobile genetic elements and the gut microbiota.CONCLUSIONS: Taken together, the AA profile and the gut microbiota exhibit robust fluctuations over a day. The AA profile can affect the gut microbiota and resistome in a direct or indirect manner. These findings may provide new insights into a potential strategy for manipulating the gut microbiota and resistome.PMID:40083031 | DOI:10.1186/s42523-025-00393-0

Stem Cell Res Ther. 2025 Mar 13;16(1):138. doi: 10.1186/s13287-025-04255-z.ABSTRACTBACKGROUND: Aging entails a progressive decline in physiological functions, elevating the risk of age-related diseases like heart failure or aortic stenosis. Stem cell therapies, especially those that use paracrine signaling, can potentially mitigate the adverse effects of aging.OBJECTIVES: The objective is to explore the potential of small extracellular vesicles (sEVs) derived from young adipose-derived stem cells (ADSC-sEVs) in reversing structural, molecular, and functional changes associated with aging in the heart.METHODS: Aged C57BL/6J mice were treated intravenously with ADSC-sEVs from young mice or PBS as controls. Young mice were included to identify specific age-associated changes. The impact of sEV treatment on cardiac function was assessed using transthoracic echocardiography and physical endurance tests. Histological and molecular analyses were conducted on heart tissue to evaluate structural changes and markers of senescence, inflammation, and oxidative stress. A comprehensive metabolomic analysis was also performed on heart tissues to identify changes in metabolic profiles associated with aging and treatment status.RESULTS: The administration of ADSC-sEVs significantly improves several aging-associated cardiac parameters, including oxidative stress, inflammation, and cellular senescence reductions. We also report on the age-related reversal of myocardial structure and function changes, highlighted by decreased fibrosis and improved vascularization. Notably, echocardiographic assessments reveal that sEV treatments ameliorate diastolic dysfunction and left ventricle structural alterations typically associated with aging. Furthermore, the treatment shifts the heart metabolome towards a more youthful profile.CONCLUSIONS: These results denote the potential of ADSC-sEVs as a novel, noninvasive therapeutic strategy for mitigating cardiac aging-associated functional decline.PMID:40082997 | DOI:10.1186/s13287-025-04255-z

BMC Med. 2025 Mar 13;23(1):159. doi: 10.1186/s12916-025-03988-1.ABSTRACTBACKGROUND: To understand potential racial differences in disease susceptibility and develop targeted prevention strategies, it is essential to establish biological differences between racial groups in healthy individuals. However, knowledge about how race impacts metabolites is limited. We therefore performed a cross-sectional study using comprehensive metabolomics analysis to investigate racial differences in metabolites among 506 non-Hispanic White (NHW) women and 163 non-Hispanic Black (NHB) women.METHODS: We performed untargeted plasma metabolomic profiling using Metabolon's platform (Durham, NC®) and identified 1074 metabolites in 9 super-pathways. We used multivariable linear regression models, adjusted for confounders, to identify associations between race and metabolites. We applied a Bonferroni correction (p-value < 10-5) to account for multiple testing.RESULTS: We identified 26 metabolites that differed significantly between NHW and NHB women. Seven, 10, 17, and 23 metabolites showed absolute percentage differences ≥ 50, ≥ 40%, ≥ 30%, and ≥ 20%, respectively. Xenobiotics (n = 5) and amino acids (n = 2) exhibited the largest absolute percentage differences (≥ 50%) between NHB and NHW women. In the xenobiotics super-pathway, NHB women had higher thymol sulfate, 2-naphthol sulfate, and 2-hydroxyfluorene sulfate, derived from the exposure to polycyclic aromatic hydrocarbons, while NHW women had higher xanthine metabolites. In the amino acid super-pathway, lysine and tryptophan metabolites were lower in NHB women.CONCLUSIONS: We report differences in several metabolites between NHW and NHB women. These findings require validation in a different study and could provide insight into investigating how racial differences in metabolites may impact disease burden across diverse populations.PMID:40082900 | DOI:10.1186/s12916-025-03988-1

J Transl Med. 2025 Mar 13;23(1):319. doi: 10.1186/s12967-025-06339-z.ABSTRACTBACKGROUND: Prior studies have elucidated that alterations in gut microbiota are associated with a spectrum of tumors and metabolic disorders. However, the diagnostic value of gut microbiota in epithelial ovarian cancer remains insufficiently investigated.METHODS: A total of 34 patients with a diagnosis of epithelial ovarian cancer (EOC), 15 patients with benign ovarian tumors (TB), and 30 healthy volunteers (NOR) were enrolled in this study. Fecal samples were collected, followed by sequencing of the V3-V4 region of the 16S rRNA gene. The clinical data and pathological characteristics were comprehensively recorded for further analysis, PICRUSt2 was utilized to conduct an analysis of microbial functional predictions, WGCNA networks were constructed by integrating microbiome and clinical data. LEfSe analysis was employed to identify microbial diagnostic markers, LASSO and SVM analyses were used to screen microbial diagnostic markers in conjunction with the Cally index, to establish a Microbial-Cally diagnostic model. Bootstrap resampling was utilized for the internal validation of the model, whereas the Hosmer-Lemeshow test and decision curve analysis (DCA) were employed to evaluate the diagnostic performance of the model. Plasma samples were subjected to untargeted metabolomics profiling, followed by differential analysis to identify key metabolites that are significantly altered in epithelial ovarian cancer. At the same time, Spearman correlation analysis was used to study the association between key microbiota and differential metabolites. The supernatants from Escherichia coli and Bifidobacterium cultures were co-cultured with SKOV3 cells. Cell proliferation, migration, and invasion were evaluated using Cell Counting Kit-8 (CCK-8) assay, Transwell migration and invasion assays. Apoptosis was assessed by flow cytometry analysis of fluorescence signals from Annexin V and propidium iodide (PI) staining.RESULTS: Compared to Nor and TB populations, individuals diagnosed with EOC demonstrated a significantly diminished gut microbiota diversity when contrasted with both normal controls and those presenting benign conditions. Specifically, the relative abundance of Bilophila, Bifidobacterium, and other probiotics was significantly reduced in patients diagnosed with epithelial ovarian cancer (EOC), while Escherichia and Shigella demonstrated a marked enrichment within this cohort. Differential microorganisms were identified through the application of machine learning techniques to delineate the characteristic microbial profiles associated with the EOC patients. A significant correlation was identified between the Cally index and microorganisms. In conclusion, we utilized microbial biomarkers alongside the Cally to establish a diagnostic model for epithelial ovarian cancer, receiver operating characteristic (ROC) curve Area Under Curve (AUC) of 0.976 (95%CI 0.943-1.00), The AUC obtained from the Bootstrap internal validation was 0.974. The Hosmer-Lemeshow test revealed a robust concordance between the observed probabilities and the predicted probabilities generated by the model. The decision curve analysis revealed that the model provided a significant net clinical benefit. A total of 233 differential metabolites were identified between the EOC group and the NT (NOR and TB) groups. Among these, eight specific metabolites (HMDB0243492, C09265, HMDB0242046, HMDB0240606, C04171, HMDB0060557, HMDB0252797, and C21412) were exclusively derived from the microbiome. Notably, metabolite HMDB0240606 exhibited a significant positive correlation with Escherichia coli and Shigella, while it showed a significant negative correlation with Ruminococcus. In vitro studies demonstrated that Bifidobacterium possessed anti-tumor activity, whereas Escherichia coli exhibited pro-tumor activity.CONCLUSION: This study provides the inaugural comprehensive analysis of gut microbiota composition and its differential profiles among patients with epithelial ovarian cancer, those with benign ovarian tumors, and healthy controls in Hunan province, China.PMID:40082895 | DOI:10.1186/s12967-025-06339-z

BMC Plant Biol. 2025 Mar 13;25(1):325. doi: 10.1186/s12870-025-06340-0.ABSTRACTBACKGROUND: This study investigated the effects of inoculating Lactobacillus parafarraginis alone or in combination with citric acid on the silage quality, microbial community structure, and metabolic characteristics of hybrid Pennisetum. The experiment included three treatments: (1) addition of 10 ml distilled water (CON); (2) addition of 1 × 106 cfu/g L. parafarraginis (LP); (3) addition of 1 × 106 cfu/g L. parafarraginis and 1% citric acid (LCA). The fermentation was maintained at 25 ℃ for 60 days.RESULTS: The addition of L. parafarraginis increased the dry matter, water-soluble carbohydrates, and crude protein content of the silage and decreased the fiber contents. Moreover, lactic acid content was notably higher, and pH values were lower in the L. parafarraginis group, with higher lactic acid bacteria (LAB) compared with the CON. The microbial community analysis indicated that adding L. parafarraginis promoted the proliferation of beneficial LAB and inhibited spoilage bacteria, such as Clostridium. In the LCA, amino acid metabolism was improved, particularly with an increase in L-tyrosine concentration, along with significant enrichment of pathways related to tryptophan metabolism.CONCLUSIONS: The addition of L. parafarraginis improved the fermentation quality of the silage, reduced undesirable microorganisms, and increased the content of organic acids, indicating its potential to enhance the flavor of the silage. Compared with individual treatments, the combination of L. parafarraginis and citric acid improved amino acid metabolism and enriched pathways related to tryptophan metabolism, further enhancing the quality of the silage. These findings highlight the potential of L. parafarraginis, especially in combination with citric acid, as an effective additive for producing high-quality, nutritious hybrid Pennisetum silage.PMID:40082791 | DOI:10.1186/s12870-025-06340-0

Cell Death Differ. 2025 Mar 13. doi: 10.1038/s41418-025-01474-y. Online ahead of print.ABSTRACTThe plasma concentrations of acyl CoA binding protein (ACBP) encoded by the gene diazepam binding inhibitor (DBI) are increased in patients with severe osteoarthritis (OA). Here, we show that knee OA induces a surge in plasma ACBP/DBI in mice subjected to surgical destabilization of one hind limb. Knockout of the Dbi gene or intraperitoneal (i.p.) injection of a monoclonal antibody (mAb) neutralizing ACBP/DBI attenuates OA progression in this model, supporting a pathogenic role for ACBP/DBI in OA. Furthermore, anti-ACBP/DBI mAb was also effective against OA after its intraarticular (i.a.) injection, as monitored by sonography, revealing the capacity of ACBP/DBI to locally reduce knee inflammation over time. In addition, i.a. anti-ACBP/DBI mAb improved functional outcomes, as indicated by the reduced weight imbalance caused by OA. At the anatomopathological level, i.a. anti-ACBP/DBI mAb mitigated histological signs of joint destruction and synovial inflammation. Of note, i.a. anti-ACBP/DBI mAb blunted the OA-induced surge of plasma ACBP/DBI, as well as that of other inflammatory factors including interleukin-1α, interleukin-33, and tumor necrosis factor. These findings are potentially translatable to OA patients because joints from OA patients express both ACBP/DBI and its receptor GABAARγ2. Moreover, a novel mAb against ACBP/DBI recognizing an epitope conserved between human and mouse ACBP/DBI demonstrated similar efficacy in mitigating OA as an anti-mouse ACBP/DBI-only mAb. In conclusion, ACBP/DBI might constitute a promising therapeutic target for the treatment of OA.PMID:40082721 | DOI:10.1038/s41418-025-01474-y

Sci Rep. 2025 Mar 13;15(1):8643. doi: 10.1038/s41598-025-93722-x.ABSTRACTBlueberry (Vaccinium myrtillus L.) is a rich source of secondary metabolites known for their potent antioxidant, anti-inflammatory, and cytoprotective properties. These compounds are essential in neutralizing reactive oxygen species (ROS), which are implicated in oxidative stress-related diseases. In this study, we induced oxidative stress in IEC-6 small intestine cells using hydrogen peroxide (H2O2), creating a cellular model to investigate the biochemical response. The obtained results showed that a blueberry extract (BLUBE) significantly exhibited strong antioxidant capacity, as evidenced by DPPH, FRAP and ABTS in vitro tests. Additionally, BLUBE effectively inhibited the release of reactive species in cells and enhanced cytoprotective response, as indicated by improved wound healing and clonogenic potential reduction of stress fibers rearrangement and apoptosis. Metabolomic analysis, specifically High-Resolution Mass Spectrometry (HR-MS), was employed to elucidate the metabolic alterations associated with the protective activity of BLUBE against oxidative stress in IEC-6 cells. Chemometric approaches were applied to preprocess the data, explore variability, and identify systematic biases, ensuring the removal of batch effects and other experimental artifacts. A Partial Least Squares Discriminant Analysis classification model confirmed clear group stratifications with high accuracy (98.75 ± 2.31%), sensitivity, and specificity, aiding in the identification of significant metabolites for pathway enrichment analysis. Key metabolic pathways, including sphingolipid metabolism, taurine and hypotaurine metabolism, glycerophospholipid metabolism, and cysteine and methionine metabolism, were significantly modulated, supporting the biochemical basis of BLUBE's protective effects. In fact, BLUBE was able to partially reverse the downregulation of these pathways, effectively reducing oxidative stress and promoting cell survival. This study highlights the power of HR-MS-based metabolomics in uncovering the mechanisms of nutraceuticals and emphasizes the potential of BLUBE as a protective agent for oxidative stress-related diseases. It also underscores the growing significance of metabolomics in the food and pharmaceutical industries.PMID:40082563 | DOI:10.1038/s41598-025-93722-x

Metabolomics. 2025 Mar 13;21(2):40. doi: 10.1007/s11306-025-02228-0.ABSTRACTBACKGROUND: Advancements in the research of intracellular metabolome have the potential to affect our understanding of biological processes. The applications and findings of intracellular metabolome analysis are useful in understanding cellular pathways, microbial interactions, and the detection of secreted metabolites and their functions.AIM OF REVIEW: This work focuses on the analysis of intracellular metabolomes in microorganisms. The techniques used for analyzing the intracellular metabolomes including metabolomics approaches such as mass spectrometry, nuclear magnetic resonance, liquid chromatography, and gas chromatography are discussed.KEY SCIENTIFIC CONCEPTS OF REVIEW: Challenges such as sample preparation, data analysis, metabolite extraction, sample storage and collection, and processing techniques were investigated, as they can highlight emerging technologies and advancements in metabolome analysis, future applications in drug discovery, personalized medicine, systems biology, and the limitations and challenges in studying the metabolome of microorganisms.PMID:40082321 | DOI:10.1007/s11306-025-02228-0

Environ Sci Technol. 2025 Mar 13. doi: 10.1021/acs.est.5c02623. Online ahead of print.ABSTRACTThis study hypothesized that perfluorooctanesulfonate (PFOS) exposure disrupts maternal-fetal metabolism, affecting fetal liver hematopoietic stem cell (FL-HSC) development. Pregnant mice received PFOS (0.3 and 3 μg/g bw) and were sacrificed on gestation day 14.5. Metabolomic analysis of maternal plasma revealed disruptions in steroid hormone, purine, carbohydrate, and amino acid metabolism, which aligned with the enriched pathways in amniotic fluid (AF). FL analysis indicated increased purine metabolism and disrupted glucose and amino acid metabolism. FL exhibited higher levels of polyunsaturated fatty acids, glycolytic and TCA metabolites, and pro-inflammatory cytokine IL-23, crucial for hematopoiesis regulation. Transcriptomic analysis of FL-HSCs revealed disturbances in the PPAR signaling pathway, pyruvate metabolism, oxidative phosphorylation, and amino acid metabolism, correlating with FL metabolic changes. Metabolomic analysis indicated significant rises in glycerophospholipid and vitamin B6 metabolism related to HSC expansion and differentiation. Flow cytometric analysis confirmed increased HSC populations and progenitor activation for megakaryocyte, erythrocyte, and lymphocyte lineages. The CFU assay showed a significant increase in BFU-E and CFU-G, but a decrease in CFU-GM in FL-HSCs from the H-PFOS group, indicating altered differentiation potential. These findings provide for the first time insights into the effects of PFOS on maternal-fetal metabolism and fetal hematopoiesis, highlighting implications for pollution-affected immune functions.PMID:40082253 | DOI:10.1021/acs.est.5c02623

J Agric Food Chem. 2025 Mar 13. doi: 10.1021/acs.jafc.4c11506. Online ahead of print.ABSTRACTThe occurrence of pediatric diarrhea is frequently associated with inflammatory responses, compromised barrier function, and dysbiosis in the gut. These conditions are commonly triggered by stressors, similar to postweaning diarrhea observed in piglets. Garlic-derived exosome-like nanoparticles (GELNs) hold the potential for ameliorating stress-induced diarrhea, yet supporting evidence remains scarce. Following the successful isolation of GELNs, this study employed weaned piglets as a model to evaluate the regulatory effects of GELNs on intestinal barrier integrity, mucosal inflammation, and the gut microbiota and its metabolites. Weaned Bama miniature piglets were orally administered phosphate buffer saline (PBS) or GELNs, and 1 week later, samples were collected following slaughter. Histological and molecular biological techniques were performed to examine intestinal structure, tight junction protein expression, mucin secretion, T lymphocyte infiltration, and the levels of pro-inflammatory cytokines. The composition of the gut microbiota was analyzed using 16S rRNA sequencing, while its derived metabolites were profiled via untargeted metabolomics. Subsequently, correlation analyses were performed to evaluate the associations between the microbiota and its derived metabolites, as well as between the microbiota and the key indicators of intestinal barrier function and cytokine levels in response to GELNs. The isolated GELNs exhibit typical exosome characteristics in size and morphology, alongside a rich content of proteins and RNAs. The incidence of diarrhea in weaned piglets was reduced with supplementation of GELNs at a dosage of 50 mg/kg body weight, compared to the control group. In addition, piglets receiving GELNs displayed an increase in mucin content within the tissues of the jejunum, ileum, and colon, a decrease in CD8+ T lymphocyte counts in the colon, and suppression of pro-inflammatory cytokines (IL-8 and TNF-α) levels in the mucosal layers of both the jejunum and ileum. Furthermore, 16S rRNA sequencing unveiled that GELNs reshaped the colonic microbiota in weaned piglets by augmenting beneficial bacteria, notably Lactobacillus and Lactobacillus reuteri, correlating strongly with diminished TNF-α protein levels and heightened mucin expression. Metabolite analysis demonstrated a significant increase in indole-3-propionic acid, derived from the gut microbiota, in piglets supplemented with GELNs. This increase was positively correlated with the abundance of Lactobacillus and Lactobacillus reuteri and negatively linked with the protein levels of IL-8 and TNF-α in the gut. In summary, our study demonstrates that GELNs mitigate stress-related intestinal mucosal inflammation and enhance mucin production in the gut of weaned piglets, which is potentially achieved through the optimization of gut microbiota composition, specifically by increasing the abundance of Lactobacillus and Lactobacillus reuteri, as well as via the induction of the anti-inflammatory microbial metabolite indole-3-propionic acid. The findings presented here provide essential groundwork for the future development of GELNs as a therapeutic strategy aimed at enhancing gut homeostasis disruption caused by stress in both weaned piglets and children.PMID:40082245 | DOI:10.1021/acs.jafc.4c11506

J Zhejiang Univ Sci B. 2025 Jan 25;26(3):286-301. doi: 10.1631/jzus.B2300777.ABSTRACTUlcerative colitis (UC) is an inflammatory condition of the intestine, resulting from an increase in oxidative stress and pro-inflammatory mediators. In this study, the extract of endophytic bacterium Rhizobium aegyptiacum was prepared for the first time using liquid chromatography-mass spectrometry (LC-MS). In addition, also for the first time, the protective potential of R. aegyptiacum was revealed using an in vivo rat model of UC. The animals were grouped into four categories: normal control (group I), R. aegyptiacum (group II), acetic acid (AA)‍-induced UC (group III), and R. aegyptiacum-treated AA-induced UC (group IV). In group IV, R. aegyptiacum was administered at 0.2 mg/kg daily for one week before and two weeks after the induction of UC. After sacrificing the rats on the last day of the experiment, colon tissues were collected and subjected to histological, immunohistochemical, and biochemical investigations. There was a remarkable improvement in the histological findings of the colon tissues in group IV, as revealed by hematoxylin and eosin (H&E) staining, Masson's trichrome staining, and periodic acid-Schiff (PAS) staining. Normal mucosal surfaces covered with a straight, intact, and thin brush border were revealed. Goblet cells appeared magenta in color, and there was a significant decrease in the distribution of collagen fibers in the mucosa and submucosal connective tissues. All these findings were comparable to the respective characteristics of the control group. Regarding cyclooxygenase-2 (COX-2) immunostaining, a weak immune reaction was shown in most cells. Moreover, the colon tissues were examined using a scanning electron microscope, which confirmed the results of histological assessment. A regular polygonal unit pattern was seen with crypt orifices of different sizes and numerous goblet cells. Furthermore, the levels of catalase (CAT), myeloperoxidase (MPO), nitric oxide (NO), interleukin-6 (IL-6), and interlukin-1β (IL-1β) were determined in the colonic tissues of the different groups using colorimetric assay and enzyme-linked immunosorbent assay (ELISA). In comparison with group III, group IV exhibited a significant rise (P<0.05) in the CAT level but a substantial decline (P<0.05) in the NO, MPO, and inflammatory cytokine (IL-6 and IL-1β) levels. Based on reverse transcription-quantitative polymerase chain reaction (RT-qPCR), the tumor necrosis factor-‍α (TNF-‍α) gene expression was upregulated in group III, which was significantly downregulated (P<0.05) by treatment with R. aegyptiacum in group IV. On the contrary, the heme oxygenase-1 (HO-1) gene was substantially upregulated in group IV. Our findings imply that the oral consumption of R. aegyptiacum ameliorates AA-induced UC in rats by restoring and reestablishing the mucosal integrity, in addition to its anti-oxidant and anti-inflammatory effects. Accordingly, R. aegyptiacum is potentially effective and beneficial in human UC therapy, which needs to be further investigated in future work.PMID:40082206 | DOI:10.1631/jzus.B2300777

Urol Oncol. 2025 Mar 12:S1078-1439(25)00065-1. doi: 10.1016/j.urolonc.2025.02.016. Online ahead of print.ABSTRACTBACKGROUND: Pathological grade is a morphological parameter of clear cell-renal cell carcinoma (ccRCC) and an independent predictor of cancer-specific survival. The aim of this study was to identify grade-dependent metabolic signatures and corresponding gene and protein expression changes that connect variations in cancer metabolism with nuclear grade, especially in high-grade tumors.METHODS: Forty ccRCC samples were collected and stratified according to nuclear grade: 23 low-grade (LG = G1-G2) and 17 high-grade (HG = G3-G4) samples. In addition, 122 patients with sarcomatoid ccRCC (sRCC) were classified according to the abundance of sarcomatoid features as low sarcomatoid (LS; sarcomatoid component<20%; n = 67) or high sarcomatoid (HS; sarcomatoid component≥20%; n = 55). Untargeted metabolomic analysis was performed. To study the relative changes in gene and protein expression in HG vs. LG ccRCC, data from 4 different datasets were downloaded and stratified according to nuclear grade. Immunohistochemistry and immunofluorescence were used to evaluate protein expression. Cancer-specific survival (CSS) and progression-free survival (PFS) were calculated using Kaplan-Meier analysis. Multivariate analysis was performed using a Cox regression model.RESULTS: The Warburg effect, in association with changes in Krebs cycle intermediates and related metabolites, was more prominent in HG ccRCC than in LG ccRCC. Additional alterations included metabolic reprogramming in the urea cycle and modulation of glutathione metabolism with the accumulation of reduced glutathione and carnitine derivatives in HG tumors, while the concentrations of long- and medium-chain fatty acids were greater in LG ccRCC. CSS and PFS were significantly decreased in patients with HS tumors. According to the multivariate analysis, the abundance of the sarcomatoid component was an adverse prognostic factor.CONCLUSIONS: ccRCC is characterized by a particular grade-dependent metabolic reprogramming. Metabolic pathways and associated molecular alterations are grade-specific and could represent potential therapeutic targets, especially in HG tumors. sRCC subclassification based on the abundance of sarcomatoid components into HS vs. LS tumors have prognostic value.PMID:40082108 | DOI:10.1016/j.urolonc.2025.02.016

Pestic Biochem Physiol. 2025 Apr;209:106350. doi: 10.1016/j.pestbp.2025.106350. Epub 2025 Feb 28.ABSTRACTThe red imported fire ant (RIFA), Solenopsis invicta Buren, poses threats to biodiversity, public safety, agriculture, and the economy, especially as global trade expands its reach into China. To address this, researchers screened fungal isolates from soil in Dongguan City, Guangdong Province, aiming to develop a biopesticide against RIFA. Metarhizium anisopliae, known for its biocontrol potential, was identified as a candidate. This insect pathogenic fungus parasitizes Lepidoptera pest larvae and Hemiptera stinkbugs, causing green rigidity and repeated infestations. Microscopic, morphological, and molecular analyses were conducted on the fungal isolates, with ZHKUJGZ1, a strain of M. anisopliae, showing promise. Tests revealed that inoculating RIFA workers with 1 × 107 cfu/mL of ZHKUJGZ1 resulted in an 83.33 ± 1.57 % mortality rate, with an LC50 of 8.36 × 106 cfu/mL. Untargeted metabolomics suggested that ZHKUJGZ1 enhances insecticidal activity by disrupting the nervous system, signaling, digestive system, amino acid metabolism, and biosynthesis in RIFA. This study highlights the potential of using entomopathogenic fungi like M. anisopliae isolated from Dongguan as an effective strategy for controlling RIFA, offering a promising biocontrol option for agricultural pests.PMID:40082041 | DOI:10.1016/j.pestbp.2025.106350