PubMed

Ann Rheum Dis. 2025 Feb 12:S0003-4967(25)00057-3. doi: 10.1016/j.ard.2025.01.012. Online ahead of print.ABSTRACTOBJECTIVES: Primary knee osteoarthritis (KOA) is a heterogeneous disease with clinical and molecular contributors. Biofluids contain microRNAs and metabolites that can be measured by omic technologies. Multimodal deep learning is adept at uncovering complex relationships within multidomain data. We developed a novel multimodal deep learning framework for clustering of multiomic data from 3 subject-matched biofluids to identify distinct KOA endotypes and classify 1-year post-total knee arthroplasty (TKA) pain/function responses.METHODS: In 414 patients with KOA, subject-matched plasma, synovial fluid, and urine were analysed using microRNA sequencing or metabolomics. Integrating 4 high-dimensional datasets comprising metabolites from plasma and microRNAs from plasma, synovial fluid, or urine, a multimodal deep learning variational autoencoder architecture with K-means clustering was employed. Features influencing cluster assignment were identified and pathway analyses conducted. An integrative machine learning framework combining 4 molecular domains and a clinical domain was then used to classify Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain/function responses after TKA within each cluster.RESULTS: Multimodal deep learning-based clustering of subjects across 4 domains yielded 3 distinct patient clusters. Feature signatures comprising microRNAs and metabolites across biofluids included 30, 16, and 24 features associated with clusters 1 to 3, respectively. Pathway analyses revealed distinct pathways associated with each cluster. Integration of 4 multiomic domains along with clinical data improved response classification performance, surpassing individual domain classifications alone.CONCLUSIONS: We developed a multimodal deep learning-based clustering model capable of integrating complex multifluid, multiomic data to assist in uncovering biologically distinct patient endotypes and enhance outcome classifications to TKA surgery, which may aid in future precision medicine approaches.PMID:39948003 | DOI:10.1016/j.ard.2025.01.012

Am J Physiol Endocrinol Metab. 2025 Feb 13. doi: 10.1152/ajpendo.00396.2024. Online ahead of print.ABSTRACTGestational Diabetes Mellitus (GDM) represents a major public health concern due to adverse maternal post-partum and long-term outcome. Current strategies to manage GDM fail to reduce the maternal risk to develop later impaired glucose tolerance (IGT) and type 2 diabetes (T2D). In a rodent model of diet-induced GDM without obesity, we explored the perinatal metabolic adaptations in dams followed by either persistent or resolved post-partum IGT. Female Sprague-Dawley rats were fed a High-Fat High-Sucrose (HFHS) or a Chow (CTL) diet, one week before mating and throughout gestation (G). Following parturition, HFHS dams were randomized to two subgroups: one switched to Chow diet and the other one maintained on HFHS diet throughout lactation (L). Oral glucose tolerance tests (OGTT) were performed and plasma metabolome-lipidome were characterized at G12 and L12. We found that: (1) in GDM pregnant-dams, IGT was associated with incomplete fatty acid oxidation (FAO), enhanced gluconeogenesis, altered insulin signaling and oxidative stress; (2) improved glucose tolerance post-partum seemed to restore complete FAO along with elevation of nervonic acid-containing sphingomyelins, assumed to impart β-cell protection; and (3) persistence of IGT after delivery was associated with metabolites known to predict the early onset of insulin and leptin resistance, with maintained liver dysfunction. Our findings shed light on the impact of post-partum IGT evolution on maternal metabolic outcome after an episode of GDM. They suggest innovative strategies, implemented shortly after delivery and targeted on these biomarkers, should be explored to curb or delay the transition from GDM to T2D in these mothers.PMID:39947887 | DOI:10.1152/ajpendo.00396.2024

Harmful Algae. 2025 Feb;142:102793. doi: 10.1016/j.hal.2024.102793. Epub 2024 Dec 25.ABSTRACTCopepods may contribute to harmful algal bloom formation by selectively rejecting harmful cells. Additionally, copepods and the chemical cues they exude, copepodamides, have been shown to induce increased toxin production in paralytic and amnesic toxin producing microalgae. However, it is unknown if diarrhetic shellfish toxin (DST) producers such as Dinophysis respond to copepods or copepodamides in a similar fashion. Here we expose laboratory cultures of Dinophysis sacculus and D. acuminata to direct grazing by Acartia sp. copepods or copepodamides and measure their toxins after three days. Total Dinophysis-produced toxins (DPTs), okadaic acid, pectenotoxin-2, and C9-diol ester of okadaic acid, increased by 8 - 45 % in D. sacculus but was significantly different from controls only in the highest (10 nM) copepodamide treatment whereas toxin content was not affected in D. acuminata. Growth rate was low across all groups and explained up to 91 % of the variation in toxin content. DPTs were redistributed from internal compartments to the extracellular medium in the highest copepodamide treatments (5 - 10 nM), which were two to three times higher than controls and indicates an active release or passive leakage of toxins. Untargeted analysis of endometabolomes indicated significant changes in metabolite profiles for both species in response to the highest copepodamide treatments, independent of known toxins. However, it is not clear whether these are stress responses or caused by more complex mechanisms. The relatively small grazer-induced effect in Dinophysis observed here, compared to several species of Alexandrium and Pseudo-nitzschia reported previously, suggests that DPT production in Dinophysis is likely not induced by copepods, except perhaps in patches with high copepod densities. Thus, DPTs may, represent either a constitutive chemical defence for Dinophysis, or serve an altogether different purpose.PMID:39947851 | DOI:10.1016/j.hal.2024.102793

J Microbiol Biotechnol. 2025 Feb 13;35:e2410040. doi: 10.4014/jmb.2410.10040.ABSTRACTNecrotizing enterocolitis (NEC) is a life-threatening inflammatory bowel disease linked to gut microbiome dysbiosis. This study evaluates the efficacy of Limosilactobacillus reuteri strain DS0384, which secretes N-carbamyl glutamic acid (NCG), in modulating lipid peroxidation and inflammatory pathways in NEC. After pretreatment with DS0384, NEC mouse model was induced by gavage with bacteria-containing formula. NCG levels in the ileum were measured via CE-TOFMS metabolomic analysis. Additionally, rat small intestinal epithelial IEC-6 cells were exposed to lipopolysaccharide (LPS), treated with DS0384 DNA (D-DNA), and/or transfected to overexpress fatty acid synthase (FASN) and Toll-like receptor 4 (TLR4). Lipid peroxidation, peroxidation and inflammatory factors and NF-κB pathways were analysed. Immunofluorescence was used to measure the expression levels of ZO-1 and TLR4 in the ileum. DS0384 treatment significantly reduced more histological abnormalities, apoptosis, and TLR4 expression in NEC mice, while restoring NCG levels, downregulating FASN and inhibiting lipid peroxidation and inflammation. Pre-treatment with D-DNA maintained cell vitality, reduced apoptosis, and suppressed TLR4/NF-κB-mediated inflammasome activation. Overexpression of FASN or TLR4 reversed these effects. DS0384 is a promising therapeutic against NEC, enhancing gut barrier integrity and modulating inflammatory and oxidative responses, suggesting potential clinical benefits in preventing NEC progression.PMID:39947675 | DOI:10.4014/jmb.2410.10040

J Proteome Res. 2025 Feb 13. doi: 10.1021/acs.jproteome.4c00814. Online ahead of print.ABSTRACTSickle cell disease and β-Thalassemia are two of the most prevalent hemoglobinopathies worldwide. Both occur due to genetic mutations within the HBB gene and are characterized by red blood cell dysfunction, anemia, and end-organ injury. The spleen and liver are the primary organs where erythrophagocytosis, engulfing the red blood cells, occurs in these diseases. Understanding metabolism and protein composition within these tissues can therefore inform the extent of hemolysis and disease progression. We utilized a multiomics approach to highlight metabolomic and proteomic differences in the spleen and liver. The Berkley sickle cell disease (Berk-SS), heterozygous B1/B2 globin gene deletion (HbbTh3/+) a known β-Thalassemia model, and wildtype (WT, C57/Bl6) murine models were evaluated in this report. This analysis showed Berk-SS and HbbTh3/+ shared distinct antioxidant and immunosuppressive splenic phenotypes compared to WT mice with divergence in purine metabolism, gluconeogenesis, and glycolysis. In contrast, Berk-SS mice have a distinct liver pro-inflammatory phenotype not shared by HbbTh3/+ or WT mice. Together, these data emphasize that metabolic and proteomic reprogramming of the spleen and livers in Berk-SS and HbbTh3/+mice may be relevant to the individual disease processes.PMID:39947632 | DOI:10.1021/acs.jproteome.4c00814

J Dairy Sci. 2025 Feb 11:S0022-0302(25)00069-4. doi: 10.3168/jds.2024-25648. Online ahead of print.ABSTRACTUnderstanding the nutritional protein requirements of yak calves is the basis of precise feed formulation. Regulating feed protein can reduce environmental impacts, which is particularly crucial for the rearing and management of yak calves. In this study, we used a combination of comparative slaughter, feeding, and digestibility trials to determine the net protein requirements of suckling yak calves. Thirty-five yak male calves with similar weights at 60 d of age were divided into 5 groups: early slaughter (ES), mid-term slaughter (MS), late slaughter (AL), 70% feeding (R70), and 40% feeding (R40). The ES, MS, and AL groups were used for comparative slaughter trials, while the AL, R70, and R40 groups were used for ad libitum feeding experiments. The results indicated that at different feeding levels, low feeding levels were not conducive to calf growth. For yak calves with body weights of approximately 40-90 kg, the nitrogen digestibility ranged from 49.36% to 59.32%, and the nitrogen retention rate ranged from 36.59% to 48.97%. The net protein requirement for yak calf maintenance is 2.90 g/kgW0.75·d-1. The equation for the net protein requirement for yak calf growth is NPg(kg) = 0.0543 × EBW0.0833(kg). Muscle metabolomics results indicated that the protein content in the muscle tissue did not increase with feeding level or body weight. With an increase in the feeding level, the nutritional protein level provided by the diet increases, which regulates changes in steroid hormone biosynthesis, ovarian steroidogenesis, cortisol synthesis and secretion, and carbon metabolism, promoting an increase in hormone-like metabolites in the muscle tissue. These data we obtained provide guidance for the efficient rearing of yak calves and provide basic data for further research on the nutritional requirements.PMID:39947599 | DOI:10.3168/jds.2024-25648

Metabolism. 2025 Feb 11:156157. doi: 10.1016/j.metabol.2025.156157. Online ahead of print.ABSTRACTOBJECTIVE: Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the different metabolic effects of a series of thiazolidinediones, including rosiglitazone, pioglitazone, and the second-generation compound MSDC-0602 K, on human mesenchymal stem cells (MSCs).METHODS: We developed 13C subcellular metabolomic tracer analysis measuring separate mitochondrial and cytosolic metabolite pools, lipidomic network-based isotopologue models, and bioorthogonal click chemistry, to demonstrate that MSDC-0602 K differentially affected bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs). In BM-MSCs, MSDC-0602 K promoted osteoblastic differentiation and suppressed adipogenesis. This effect was clearly distinct from that of the earlier drugs and that on AT-MSCs.RESULTS: Fluxomic data reveal unexpected differences between this drug's effect on MSCs and provide mechanistic insight into the pharmacologic inhibition of mitochondrial pyruvate carrier 1 (MPC). Our study demonstrates that MSDC-0602 K retains the capacity to inhibit MPC, akin to rosiglitazone but unlike pioglitazone, enabling the utilization of alternative metabolic pathways. Notably, MSDC-0602 K exhibits a limited lipogenic potential compared to both rosiglitazone and pioglitazone, each of which employs a distinct lipogenic strategy.CONCLUSIONS: These findings indicate that the new-generation drugs do not compromise bone structure, offering a safer alternative for treating insulin resistance. Moreover, these results highlight the ability of cell compartment-specific metabolite labeling by click reactions and tracer metabolomics analysis of complex lipids to discover molecular mechanisms within the intersection of carbohydrate and lipid metabolism.PMID:39947516 | DOI:10.1016/j.metabol.2025.156157

J Biol Chem. 2025 Feb 11:108293. doi: 10.1016/j.jbc.2025.108293. Online ahead of print.ABSTRACTMammals adaptively regulate energy metabolism in response to environmental changes such as starvation and cold circumstances. Thioredoxin-interacting protein (Txnip), known as a redox regulator, serves as a nutrient sensor regulating energy homeostasis. Txnip is essential for mice to adapt to starvation, but its role in adapting to cold circumstances remains unclear. Here, we identified Txnip as a pivotal factor for maintaining non-shivering thermogenesis in mice. Txnip protein levels in brown adipose tissue (BAT) were upregulated by the acute cold exposure. Txnip-deficient (Txnip-/-) mice acclimated to thermoneutrality (30°C) exhibited significant BAT enlargement and triglyceride accumulation with downregulation of BAT signature and metabolic gene expression. Upon acute cold exposure (5°C), Txnip-/- mice showed a rapid decline in BAT surface temperatures with the failure of increasing metabolic respiration, developing lethal hypothermia. The BAT dysfunction and cold susceptibility in Txnip-/- mice were corrected by acclimation to 16°C, protecting the mice from life-threatening hypothermia. Transcriptomic and metabolomic analysis using dissected BAT revealed that despite preserving glycolysis, the BAT of Txnip-/- mice failed to activate the catabolism of branched-chain amino acids and fatty acids in response to acute cold stress. These findings illustrate that Txnip is required for maintaining basal BAT function and ensuring cold-induced thermogenesis.PMID:39947474 | DOI:10.1016/j.jbc.2025.108293

J Ethnopharmacol. 2025 Feb 11:119485. doi: 10.1016/j.jep.2025.119485. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Triptolide (TP) is an abietane-type diterpenoid isolated from the traditional Chinese herb Tripterygium wilfordii Hook. F, which is used to relieve rheumatism, alleviate joint pain and swelling, and promote blood circulation for more than 600 years in China. The most common preparations containing TP from Tripterygium wilfordii Hook F, which are Tripterygium tablets and Tripterygium glycoside tablets, are widely used in clinical for treating rheumatoid arthritis and other autoimmune diseases at present. However, the clinical application is hindered by severe systemic toxicity induced by TP, especially hepatotoxicity. It is crucial to discover potent and specific detoxification strategy for TP.AIM OF STUDY: According to our previous study, TP-induced hepatotoxicity is primarily related to macrophages. This study aimed to investigate the alleviation effects of macrophage depletion on the TP-induced liver injury in mice and to explore the related mechanisms by integration of metabolomics and proteomics.MATERIALS AND METHODS: Mice were treated with clodronate liposomes to deplete macrophage before administration of triptolide. The alleviation effects were evaluated by biochemical analysis of serum and histopathology observation of the hepatic tissues. Metabolomics and proteomics were carried out to explore the mechanism of macrophage depletion on triptolide-induced liver injury. The levels of mRNA and protein of TLR4- MyD88-NF-κB axis were further detected.RESULTS: The altered levels of biochemistry indicators, including aminotransferase (ALT) and aspartate aminotransferase (AST), albumin (ALB), and γ-glutamyltranspeptidase (GGT) were significantly recovered, and histopathological liver injury also showed restoring tendency in mice with macrophage depletion compared to mice with TP-treatment. The inflammation indicator interleukin-6 (IL-6) and interleukin-1β (IL-1β) were recovered significantly after depletion of macrophage. Results of metabolomics and proteomics demonstrated that macrophage depletion exerted protective effects on triptolide-induced liver injury by regulating 85 metabolites and 202 proteins. Joint analysis of multi-omics data suggested macrophage depletion could regulate lipid metabolism and maintain inflammatory homeostasis. The increased expression of NF-κB, TLR4, and MyD88 were decreased after depletion of macrophage.CONCLUSION: TP-induced hepatotoxicity is mainly associated with dysfunction of macrophages and imbalance of inflammatory homeostasis. The findings of this study may help facilitate the development of novel therapeutic strategies.PMID:39947369 | DOI:10.1016/j.jep.2025.119485

Ecotoxicol Environ Saf. 2025 Feb 12;291:117772. doi: 10.1016/j.ecoenv.2025.117772. Online ahead of print.ABSTRACTFreshwater plants are threatened by microplastics (MPs). While many studies have reported the effects of MPs on aquatic plants and animals, few have examined the effects of MPs on plant metabolism at different light intensities. We explore cellular, metabolic, and stress responses of Vallisneria natans at different light intensities (0, 20, 90, 160, 280 μmol·m-2·s-1), without and with (50 mg·L-1) MPs. The experiment showed that that the strong light promotes adsorption and accumulation of MPs on leaf and root tissues, affected growth rate, and changed metabolic pathways, inhibited photosynthetic processes, and enhanced oxidative stress responses in V. natans. Metabolomic analysis and experimental validation revealed that the combination of 280 μmol m-2·s-1 and MPs interfered most severely with plant carbon and nitrogen metabolism, lipid metabolism, and amino acid metabolism pathways compared with the combination of 90 μmol m-2·s-1 and MPs. This condition also significantly inhibited the activities of photosynthesis and energy transfer-related regulators and proteins, as well as stimulated oxidative stress-related pathways and exacerbated oxidative stress toxicity responses. The results of the research indicate that the highest light intensity tested can increase the accumulation of MPs, leading to V. natans cell damage, inhibition of photosynthetic metabolism, and the risk of oxidative toxic stress. Our results provide a basis for the analysis of the growth and metabolism processes and risk assessment of aquatic plants under the action of light and MPs.PMID:39947062 | DOI:10.1016/j.ecoenv.2025.117772

Eur J Med Chem. 2025 Feb 7;287:117379. doi: 10.1016/j.ejmech.2025.117379. Online ahead of print.ABSTRACTObesity is recognized as a metabolic disorder, and its treatment and management pose ongoing challenges worldwide. Hawthorn, a traditional Chinese herb used to alleviate digestive issues and reduce blood lipid levels, has unclear mechanisms of action regarding its active components in the treatment of obesity. This study investigated the anti-obesity effects of vitexin, a major flavonoid compound found in hawthorn, in high-fat diet (HFD)-induced C57BL/6 mice. The results demonstrated that vitexin significantly reduced body weight, liver weight, blood lipid levels, and inflammatory markers in obese mice, while also inhibiting hepatic lipid accumulation. Mechanistic studies revealed that vitexin likely suppresses adipogenesis by modulating the PI3K-AKT signaling pathway, as evidenced by reduced expression of PI3K, phosphorylated AKT, phosphorylated mTOR, and SREBP-1c in the livers of vitexin-treated obese mice. Additionally, vitexin inhibited NFκB expression by regulating IκBα phosphorylation, thereby alleviating obesity-induced liver injury. These findings suggest that vitexin may be the primary active component in hawthorn responsible for reducing blood lipid levels, highlighting its potential in the treatment of obesity and its associated metabolic disorders.PMID:39947052 | DOI:10.1016/j.ejmech.2025.117379

Food Chem. 2025 Feb 8;475:143307. doi: 10.1016/j.foodchem.2025.143307. Online ahead of print.ABSTRACTHouttuynia cordata (H. cordata) is a commonly consumed fresh food. However, it is prone to rapid decay after harvesting. The current storage methods possess their own drawbacks. Consequently, this study aimed to investigate a novel type of protectant Methyl jasmonate (MeJA), to explore its effect on the postharvest quality and metabolic changes of H. cordata. The results indicated that MeJA treatment reduced weight loss, decay, malondialdehyde content and oxidase activity while maintaining antioxidant properties. Utilizing untargeted metabolomics, eleven differential phenolic compounds and six volatile components were identified. Correlation analysis revealed that polyphenol oxidase (PPO) was the main enzyme responsible for the decay. Four phenolic compounds, including phloretin, were the substrates that caused the rot. Additionally, 1-Hepten-3-one could be used as a flavor component for evaluating the freshness of H. cordata. In conclusion, MeJA treatment presents a potential approach for maintaining the quality of H. cordata.PMID:39946923 | DOI:10.1016/j.foodchem.2025.143307

Sci Total Environ. 2025 Feb 12;967:178838. doi: 10.1016/j.scitotenv.2025.178838. Online ahead of print.ABSTRACTMicrocystin-LR (MC-LR) is typically produced along with the occurrence of cyanobacterial blooms, potentially exerting deleterious effects on intestinal microbiota and health in aquatic animals. To date, the underlying mechanism by which MC-LR affects intestinal health remains elusive. In this study, adult male zebrafish were exposed to MC-LR to assess its impact on the microbiome and metabolome. Histopathological and biochemical results indicated that MC-LR damaged intestinal villi and epithelial cells, induced intestinal barrier injury and inflammatory response. Metabolomics results revealed that MC-LR induced amino acid, carbohydrate, lipid, energy metabolisms dysbiosis, and specifically promoted glycine, serine and threonine metabolism. Metagenomics results demonstrated that MC-LR altered the composition of intestinal microbiota, and microbial function prediction suggested that MC-LR promoted the functions associated with amino acid, lipid, carbohydrate and energy metabolisms. Multiomics and Metorigin analyses jointly confirmed that glycine, serine and threonine metabolism was predominantly regulated by dominant Proteobacteria, Firmicutes, Fusobacteriota and Bacteroidota under MC-LR stress. This study offers a comprehensive perspective on the toxicity of microbiota and microbiota-derived metabolism in fish intestines induced by MC-LR and deepens our comprehension of the disruptive influence of MC-LR on intestinal homeostasis in organisms.PMID:39946873 | DOI:10.1016/j.scitotenv.2025.178838

Spectrochim Acta A Mol Biomol Spectrosc. 2025 Feb 6;333:125867. doi: 10.1016/j.saa.2025.125867. Online ahead of print.ABSTRACTEarly diagnosis at the metabolomic level is crucial for the treatment of liver cirrhosis and hepatocellular carcinoma (HCC). In this study, attempts were made to investigate the excited-state kinetics of intrinsic fluorophores, tryptophan and nicotinamide adenine dinucleotide (NADH) to understand the metabolic changes associated with the transformation of normal liver into cirrhosis and HCC. Significant variations were observed in the values of average fluorescence lifetimes for 350 nm (τavg_350) and 450 nm (τavg_450) emissions for cirrhosis and HCC with respect to normal samples. The classification results of hierarchical cluster analysis (HCA) and receiver operator characteristics (ROC) based on the values of τavg_350 discriminates normal from liver diseased group (cirrhosis and HCC) with 86.95 % sensitivity and 96.43 % specificity. In the case of τavg_450 values, 95.65 % sensitivity is obtained for both HCA and ROC analyses. However, specificity of 100 % and 92.86 % was obtained in ROC and HCA analysis, respectively. The changes in the values of τavg_350, τavg_450 and NADHfree/NADHbound in cirrhosis cases after surgery are shifting towards the respective values of normal group. Among the decay kinetics of two emissions, the emission at 450 nm provides better discrimination than 350 nm emission.PMID:39946856 | DOI:10.1016/j.saa.2025.125867

Mol Genet Metab. 2025 Feb 4;144(3):109050. doi: 10.1016/j.ymgme.2025.109050. Online ahead of print.ABSTRACTIn lipid metabolism, the fatty acid (FA) elongation system synthesises a wide array of FAs, crucial for various biological functions. The role of this system is to lengthen FA carbon chains to produce FAs with ≥C16, and notably, very long-chain FAs (VLCFAs, C24-C26) and ultra long-chain FAs (ULCFAs, C28 to ≥C36). Elongation occurs in the endoplasmic reticulum (ER) through the actions of a complex of four ER-embedded enzymes, which includes the ELOVL proteins. Together with desaturases that introduce double bonds, these processes significantly increase the variety of FAs. VLCFAs and ULCFAs are required for the biosynthesis of complex lipids, notably glycero(phospho)lipids, ether(phospho)lipids and sphingolipids. The FA elongation system is therefore fundamental for membrane biogenesis and lipid homeostasis, and also for signalling pathways associated with inflammation and cell proliferation. This review focuses on the elongase enzymes, encoded by the ELOVL genes, which catalyze the first and rate-limiting step of the FA elongation cycle. We summarize the physiological roles of the elongase system, with emphasis on the less-characterized ULCFAs, their biological functions, and the functional tools, biomarkers and lipidomic studies used to study them. Additionally, we discuss how ELOVL enzyme defects contribute to disorders at the intersection of metabolic and neurodegenerative conditions, driven by disrupted lipid metabolism and misfolded enzymes in the ER and Golgi.PMID:39946831 | DOI:10.1016/j.ymgme.2025.109050

Pharmacol Res. 2025 Feb 12;213:107654. doi: 10.1016/j.phrs.2025.107654. Online ahead of print.ABSTRACTChronic stress constitutes a major precipitating factor for Major Depressive Disorder (MDD), and comprehending individual differences in stress responses is crucial for the development of effective intervention strategies for MDD. Recent studies indicate that an individual's vulnerability to chronic stress is closely associated with gut microbiota composition, but the underlying mechanisms remain unclear. This study aims to investigate whether the gut microbiota and its metabolites can serve as gut-brain signaling molecules and explores how the gut microbiota affects stress sensitivity. Here, we showed that gut microbiome-derived indole-3-carboxaldehyde (I3C) can act as a gut-brain signaling molecule that links tryptophan metabolism by gut microbes to stress vulnerability in the host. First, we identified a specific reduction in gut microbiome-derived I3C levels in the hippocampus and colon through untargeted and targeted metabolomic analyses. Then, the study of gut microbiota suggested that the relative abundance of lactobacillus was reduced significantly in stress-susceptible rats, whereas fecal microbiota transplantation regulates stress vulnerability. Furthermore, supplementation with I3C and the representative I3C-producing strain, Lactobacillus reuteri, was shown to alleviate depression-like behaviors induced by chronic stress. Further research confirms that I3C can inhibit neuroinflammation and promote hippocampal neurogenesis through the aryl hydrocarbon receptors (AhR) signal pathway, thereby mitigating the host's susceptibility to stress. In conclusion, our findings elucidate that the gut microbiome-derived-I3C can help buffer the host's stress through the AhR/SOCS2/NF-κB/NLRP3 pathway, providing a gut-brain signaling basis for emotional behavior.PMID:39946793 | DOI:10.1016/j.phrs.2025.107654

Int Immunopharmacol. 2025 Feb 12;150:114279. doi: 10.1016/j.intimp.2025.114279. Online ahead of print.ABSTRACTOBJECTIVES: To explore the effects and biological mechanism of apabetalone on periodontal inflammation by regulating glycolysis and metabolites.METHODS: A ligature-induced periodontitis model was established in mice and apabetalone was administered on the ligation silk for two weeks. Inflammation levels and alveolar bone absorption were explored using micro-computed tomography and histopathological analysis. To observe the role of apabetalone in macrophage polarization and the macrophage-mediated immune microenvironment, a Luminex assay, quantitative real-time polymerase chain reaction, a conditioned medium experiment, a Seahorse extracellular flux assay and quantitative metabolomics were used for molecular biological analysis.RESULTS: Apabetalone-treated mice exhibited ameliorated alveolar bone loss and inflammatory infiltration in the periodontium. Furthermore, apabetalone significantly inhibited the production of proinflammatory cytokines and suppressed the levels of M1-specific biomarkers both in vivo and in vitro. Apabetalone also promoted the osteogenic potential of mouse periodontal ligament cells in a macrophage-mediated microenvironment. Apabetalone restrained LPS-induced glucose uptake and lactic acid production. Apabetalone inhibited glycolysis by suppressing the transcription and protein expression of hexokinase 2, glucose transporter 1 and phosphofructokinase-2/fructose-2,6- bisphosphatase 3 (PFKFB3) in a dose-dependent manner. Quantitative analysis of certain carbohydrates involved in energy metabolism revealed that apabetalone reserved the disruption of the tricarboxylic acid (TCA) cycle and inhibited glycolysis and the pentose phosphate pathway. In addition, apabetalone increased the oxygen consumption rate.CONCLUSION: Collectively, these findings indicate that apabetalone improves the periodontal immune microenvironment by regulating metabolites in macrophages. Apabetalone exerts anti-inflammatory and osteo-protective effects by replenishing the broken TCA cycle and suppressing glycolysis. Apabetalone is a potential candidate for the treatment of periodontitis.PMID:39946768 | DOI:10.1016/j.intimp.2025.114279

Proc Natl Acad Sci U S A. 2025 Feb 18;122(7):e2423169122. doi: 10.1073/pnas.2423169122. Epub 2025 Feb 13.ABSTRACTAcute lymphoblastic leukemia (ALL) poses challenges in adult patients, considering its heterogeneous nature and often suboptimal treatment outcomes. Here, we performed a study on 201 newly diagnosed adult ALL cases (age ≥ 15 y) to generate intracellular and dynamic serum metabolomic profiles. Our findings revealed a predominant increase in bile acid (BA) metabolites in serum, alongside metabolic rewiring that supported highly proliferative states and actively metabolic signaling, such as enriched nucleotide metabolism in leukemic blasts. By integrating intracellular metabolomics and transcriptomics, we constructed the Comprehensive Metabolic Information Dataset (CMID), which facilitated the development of a clustering system to supplement current risk stratification. Furthermore, we explored potential metabolic interventions targeting the serum BA profile and energy metabolism in blasts. The combined use of simvastatin with vincristine and dexamethasone regimen demonstrated a synergistic therapeutic effect in a murine ALL model, effectively lowering key BA levels in serum and suppressing the infiltration of leukemic blasts in the liver. In light of the enhanced intracellular redox metabolism, combining FK866 (a nicotinamide phosphoribosyltransferase inhibitor) and venetoclax significantly prolonged survival in a patient-derived xenograft ALL model. Our findings, along with the resulting resources (http://www.genetictargets.com/MALL), provide a framework for the metabolism-centered management of ALL.PMID:39946534 | DOI:10.1073/pnas.2423169122

PLoS One. 2025 Feb 13;20(2):e0318159. doi: 10.1371/journal.pone.0318159. eCollection 2025.ABSTRACTOBJECTIVE: To investigate the role of quercetin-added pancreatic prescription food in regulating metabolic homeostasis in dogs.METHODS: The experimental dogs were divided into a control diet group and a prescription diet group. The control group was fed regular food, while the prescription group was fed pancreatic prescription food (3.9 g of quercetin was added in per 1 kg of food) for 8 weeks. Canine physical examination, complete blood count, and serum biochemical tests were conducted at 0 w, 4 w, and 8 w. Non-targeted metabolomics tests were performed using plasma samples at 0 w and 8 w.RESULTS: Dogs that received a quercetin-added pancreatic diet supplemented with quercetin showed no changes in the body weight, fasting blood glucose, body condition score, the indexes of whole blood program of red blood cells, white blood cells and platelets, and most blood biochemical indexes, but increased lipase levels in plasma at 8 w. Quercetin significant improved in metabolic homeostasis, especially in fatty acid, amino acid, and bile acid metabolism. Untargeted metabolomics analysis revealed that quercetin activates ABC transport and arginine/proline pathways, suggesting potential benefits for pancreatitis in large animals, while maintaining comparable safety parameters.CONCLUSIONS: Quercetin-added prescription food enhances fatty acid and amino acid metabolism, demonstrating its potential to promote pancreatic function and sustain metabolic homeostasis.PMID:39946409 | DOI:10.1371/journal.pone.0318159

PLoS One. 2025 Feb 13;20(2):e0313683. doi: 10.1371/journal.pone.0313683. eCollection 2025.ABSTRACTExtracellular vesicles (EV) are membranous vesicles considered as significant players in cell-to-cell communication. Milk provides adequate nutrition, transfers immunity, and promotes neonatal development, and milk EV are suggested to play a crucial role in these processes. Milk samples were obtained on days 0, 7, and 14 after parturition from sows receiving either a standard diet (ω-6:ω-3 = 13:1) or a test diet enriched in ω-3 (ω-6:ω-3 = 4:1). EV were isolated using ultracentrifugation coupled with size exclusion chromatography, and characterized by nanoparticle tracking analysis, transmission electron microscopy, and assessment of EV markers via Western blotting. The lipidome was determined following a liquid chromatography-quadrupole time-of-flight mass spectrometry approach. Here, we show that different stages of lactation (colostrum vs mature milk) have a distinct extracellular vesicle lipidomic profile. The distinct lipid content can be further explored to understand and regulate milk EV functionalities and primordial for enabling their diagnostic and therapeutic potential.PMID:39946395 | DOI:10.1371/journal.pone.0313683