PubMed

Adv Sci (Weinh). 2025 Feb 27:e2416453. doi: 10.1002/advs.202416453. Online ahead of print.ABSTRACTRisk stratification using multi-omics data deepens understanding of immunometabolism in successfully treated people with HIV (PWH) is inadequately explained. A personalized medicine approach integrating blood cell transcriptomics, plasma proteomics, and metabolomics is employed to identify the mechanisms of immunometabolic complications in prolonged treated PWH from the COCOMO cohort. Among the PWHs, 44% of PWH are at risk of experiencing immunometabolic complications identified using the network-based patient stratification method. Utilizing advanced machine learning techniques and a Bayesian classifier, five plasma protein biomarkers; Tubulin Folding Cofactor B (TBCB), Gamma-Glutamylcyclotransferase (GGCT), Taxilin Alpha (TXLNA), Pyridoxal Phosphate Binding Protein (PLPBP) and Large Tumor Suppressor Kinase 1 (LATS1) are identified as highly differentially abundant between healthy control (HC)-like and immunometabolically at-risk PWHs (all FDR<10-10). The personalized metabolic models predict metabolic perturbations, revealing disruptions in central carbon metabolic fluxes and host tryptophan metabolism in at-risk phenotype. Functional assays in primary cells and cortical forebrain organoids (FBOs) further validate this. Metabolic perturbations lead to persistent monocyte activation, thereby impairing their functions ex vivo. Furthermore, the chronic inflammatory plasma microenvironment contributes to synaptic dysregulation in FBOs. The endogenous plasma inflammatory microenvironment is responsible for chronic inflammation in treated immunometabolically complicated at-risk PWH who have a higher risk of cardiovascular and neuropsychiatric disorders.PMID:40013867 | DOI:10.1002/advs.202416453

mSystems. 2025 Feb 27:e0018625. doi: 10.1128/msystems.00186-25. Online ahead of print.ABSTRACTDuring infection, Histoplasma capsulatum yeasts interact with a variety of phagocytic cells, where macrophages represent an important niche for long-term intracellular fungal survival and replication. In the phagosomes of macrophages, a hostile environment where most microorganisms are killed, Histoplasma not only survives but overcomes several biological challenges and proliferates intracellularly. To better understand the characteristics of intracellular Histoplasma and the phagosomal environment, a metabolomic platform was used to analyze Histoplasma yeasts cultured on different carbon sources and yeasts extracted from macrophages, identifying metabolites associated with pathogenesis. Metabolomic results of in vitro-grown yeasts were further characterized with available transcriptomic data, informing underlying gene expression patterns in response to contrasting milieus. These approaches revealed that Histoplasma yeasts, unlike many other yeasts, do not ferment sugars to ethanol, and, when cultivated on glycolytic versus gluconeogenic carbon sources, produce distinct metabolomes with altered intracellular amino acid, lipid, and sugar contents. Furthermore, analysis of Histoplasma-inoculated media illustrated that Histoplasma secretes mannitol and anthranilates. Lastly, a comparison of the metabolomes derived from in vitro cultivation versus intracellular growth highlighted leucine and cysteine/cystine as amino acids, which may serve as sources of carbon, nitrogen, and sulfur to yeasts within macrophages. These results detail metabolites linked to Histoplasma metabolism during macrophage infection, identifying potential candidates to target for novel histoplasmosis therapeutics.IMPORTANCEIntracellular pathogens reside within host cells, surviving against innate immune responses while exploiting host resources to proliferate. Understanding the mechanisms that underlie their survival and proliferation is critical for developing novel treatments and therapeutics for the diseases these pathogens cause. While Histoplasma is a unique example of a true intra-phagosomal pathogen, insights into its pathogenesis may still inform the study of other intracellular pathogens.PMID:40013825 | DOI:10.1128/msystems.00186-25

New Phytol. 2025 Feb 27. doi: 10.1111/nph.20434. Online ahead of print.ABSTRACTThe increased positive impact of plant diversity on ecosystem functioning is often attributed to the accumulation of mutualists and dilution of antagonists in diverse plant communities. While increased plant diversity alters traits related to resource acquisition, it remains unclear whether it reduces defence allocation, whether this reduction differs between roots and leaves, or varies among species. To answer these questions, we assessed the effect of plant species richness, plant species identity and their interaction on the expression of 23 physical and chemical leaf and fine root defence traits of 16 plant species in a 19-yr-old biodiversity experiment. Only leaf mass per area, leaf and root dry matter content and root nitrogen, traits associated with both, resource acquisition and defence, responded consistently to species richness. However, species richness promoted a decoupling of these defences in leaves and fine roots, possibly in response to resource limitations in diverse communities. Species-specific responses were rare and related to chemical defence and mutualist collaboration, likely responding to species-specific antagonists' dilution and mutualists' accumulation. Overall, our study suggests that resource limitation in diverse communities might mediate the relationship between plant defence traits and antagonist dilution.PMID:40013369 | DOI:10.1111/nph.20434

Front Endocrinol (Lausanne). 2025 Feb 12;16:1522756. doi: 10.3389/fendo.2025.1522756. eCollection 2025.ABSTRACTBACKGROUND: Cardiovascular Disease (CVD) is the leading cause of global mortality, with its incidence rate rising year by year due to the prevalence of metabolic diseases. Existing primary and secondary prevention strategies for cardiovascular disease have limitations in identifying some high-risk groups, and 1.5-level prevention aims to achieve more precise intervention by early identification of subclinical target organ damage. This study introduces oral (tongue coating) microbiota as metabolic markers for the first time, in combination with multiple metabolic factors, to explore their potential in assessing subclinical target organ damage and optimizing cardiovascular risk stratification, in order to provide a new path for the early identification and intervention of CVD.METHODS: This study is a prospective cohort study aimed at assessing the association between tongue coating microbiota characteristics and multiple metabolic factors with subclinical target organ damage, and identifying high-risk groups suitable for cardiovascular 1.5-level prevention. The study will be conducted in Suzhou City, Jiangsu Province, China, planning to include 5000-6000 eligible subjects, with inclusion criteria of age ≥18 years, excluding individuals with a history of CVD and other serious diseases. Baseline assessment includes demographic information, lifestyle (including dietary patterns), medical history, physical examination, and collection of tongue coating microbiota samples. Subjects will be followed up every 2 years, with the primary outcome being the first occurrence of coronary heart disease and stroke, and the secondary outcome being subclinical target organ damage.DISCUSSION: This study focuses on cardiovascular 1.5-level prevention strategy, combining metabolic factors with tongue coating microbiota characteristics, aiming to optimize the risk assessment system for subclinical target organ damage. This approach can not only fill the gap in traditional risk assessment but also provide new ideas for the early identification and intervention of CVD. In the future, the feasibility and effectiveness of this strategy will be verified through multicenter studies, and it is expected to be promoted to a wider medical system, significantly improving the health management level of high-risk groups for CVD.TRIAL REGISTRATION NUMBER: http://itmctr.ccebtcm.org.cn, identifier ITMCTR2024000616.PMID:40013311 | PMC:PMC11860102 | DOI:10.3389/fendo.2025.1522756

J Inflamm Res. 2025 Feb 22;18:2629-2646. doi: 10.2147/JIR.S495784. eCollection 2025.ABSTRACTBACKGROUND: Acute myocardial infarction (AMI) is a critical cardiovascular event characterized by sudden coronary blood flow interruption, leading to myocardial ischemia and necrosis. Despite advances in acute therapeutic measures, understanding the metabolic damage related to AMI, particularly through specific protein expressions, remains limited. This study utilized Olink cardiovascular metabolomics technology to explore cardiovascular metabolism-related protein biomarkers associated with AMI, aiming to address the clinical need for early diagnosis and targeted therapy.METHODS: This study utilized Olink cardiovascular metabolomics technology to analyze 92 cardiovascular metabolism-related proteins in coronary blood samples from 20 AMI patients and 10 healthy controls. Differentially expressed proteins were identified using statistical t-tests, followed by functional enrichment analysis (GO and KEGG) and protein-protein interaction network construction. Five core proteins were validated in plasma samples from an additional 125 AMI patients and 120 healthy controls via enzyme-linked immunosorbent assay. To evaluate diagnostic performance, receiver operating characteristic curves were generated using GEO-related datasets, and Mendelian randomization analysis was employed to investigate the causal relationship between core proteins and AMI risk.RESULTS: The study identified 32 proteins with significantly altered expression levels between AMI patients and healthy controls. Among these, five core proteins-PCOLCE, FCN2, REG1A, DEFA1, and CRTAC1-were significantly associated with key biological processes such as metabolism, collagen formation, and the PI3K/AKT signaling pathway. These proteins showed strong correlations with clinical indicators, including BMI, LVEF, NT-proBNP, CK-MB, and cTnT. FCN2 and DEFA1 were further validated as having a causal relationship with AMI risk, indicating their potential as diagnostic biomarkers.CONCLUSION: The identified core proteins PCOLCE, FCN2, REG1A, DEFA1, and CRTAC1 are potential biomarkers for the early diagnosis and risk assessment of AMI. These findings suggest that these proteins could serve as targets for future therapeutic interventions aimed at mitigating cardiovascular metabolic damage in AMI.PMID:40013238 | PMC:PMC11863793 | DOI:10.2147/JIR.S495784

Front Microbiol. 2025 Feb 12;16:1522075. doi: 10.3389/fmicb.2025.1522075. eCollection 2025.ABSTRACTBACKGROUND: Despite the extensive research conducted on heat responses of Lentinula edodes heterokaryotic cells, the responses of the two sexually compatible monokaryons to heat stress (HS) remain largely unknown.METHODS: To bridge this gap, we examined the nucleus-specific (SP3 and SP30) heat resistant mechanisms using an integrated physiological, metabolomic and transcriptomic approach.RESULTS: The results showed that HS elicited the boost of ROS and hampered mycelium growth for both monokaryons. Metabolome and transcriptome analysis demonstrated that the two sexually compatible monokaryons responded differently to HS. For SP3, the differentially expressed genes (DEGs) were significantly enriched in Mitogen-Activated Protein Kinase (MAPK) signaling, cell cycle and sugar metabolism, whereas those DEGs for SP30 were enriched in glyoxylate and dicarboxylate metabolism, and protein processing. The differentially accumulated metabolites (DAMs) of both strains were enriched in the glycerophospholipid metabolism, alpha-linolenic acid metabolism, biosynthesis of cofactors, etc, but were regulated differently in each strain. The enriched KEGG pathways for SP3 tend to be downregulated, whereas those in SP30 exhibited a contrary trend. The genes in MAPK signaling pathway were associated with the glycerophospholipid metabolism in SP3, but not in SP30. Omics-integration analysis revealed distinguishing regulatory networks and identified completely different hub genes for the two strains.DISCUSSION: Our findings revealed, for the first time, the different heat-resistance mechanisms of the two compatible nuclei and provided candidate metabolites, responsive genes and regulatory pathways for further experimental validation.PMID:40012783 | PMC:PMC11861359 | DOI:10.3389/fmicb.2025.1522075

Front Microbiol. 2025 Feb 10;16:1511885. doi: 10.3389/fmicb.2025.1511885. eCollection 2025.ABSTRACTINTRODUCTION: The gut microbiota and bile acids (BAs) have emerged as factors involved in the development of non-alcoholic fatty liver disease (NAFLD). Xiaohua Funing decoction (XFD) is a traditional Chinese medicine formula used for the treatment of NAFLD. Previous studies have indicated that XFD protects liver function, but the underlying mechanism remains unclear.METHODS: In this study, a Wistar rat model of NAFLD (Mod) was established via a high-fat diet. The effects of obeticholic acid (OCA) and XFD on Mod rats were subsequently evaluated. Wistar rats in the control (Con) group were fed a standard diet. There were eight rats in each group, and the treatment lasted for 12 weeks. Furthermore, metagenomic sequencing and BA metabolomic analyses were performed.RESULTS: Compared to the Con group, the Mod group presented significant differences in body and liver weights; serum total cholesterol (TC) and triglyceride (TG) levels; and liver TG, TC, and bile salt hydrolase levels (p < 0.05 or p < 0.01). Importantly, OCA and XFD administration normalized these indicators (p < 0.05 or p < 0.01). Pathology of the liver and white fat steatosis was observed in the Mod group, but steatosis was significantly alleviated in the OCA and XFD groups (p < 0.05 or p < 0.01). The abundances of Bacteroidales_bacterium, Prevotella_sp., bacterium_0.1xD8-71, and unclassified_g_Turicibacter in the Mod group were significantly different from those in the Con group (p < 0.05 or p < 0.01), whereas the abundance of Bacteroidales_bacterium was greater in the XFD group. A total of 17, 24, and 24 differentially abundant BAs were detected in the feces, liver, and serum samples from the Mod and Con groups, respectively (p < 0.05 or p < 0.01). In the feces, liver, and serum, XFD normalized the levels of 16, 23, and 14 BAs, respectively, including glycochenodeoxycholic acid, deoxycholic acid, murideoxycholic acid, lithocholic acid, 23-nordeoxycholic acid, and 3β-ursodeoxycholic acid. In addition, glycochenodeoxycholic acid was identified as a potential biomarker of NAFLD.DISCUSSION: In summary, our experiments revealed that XFD regulates the gut microbiota and BAs, providing beneficial effects on liver lipid accumulation in NAFLD.PMID:40012777 | PMC:PMC11863611 | DOI:10.3389/fmicb.2025.1511885

Front Microbiol. 2025 Feb 12;16:1441143. doi: 10.3389/fmicb.2025.1441143. eCollection 2025.ABSTRACTINTRODUCTION: The objective of this study was to evaluate the effects of the dietary lysine (Lys)/ methionine (Met) ratio in a low-protein diet on short-chain fatty acid (SCFA) profiles, villus morphology, antioxidant capacity, and immune status of the jejunum in Tibetan sheep.METHODS: A total of 90 weaned Tibetan sheep, each 2 months old with an initial weight of 15.37 ± 0.92 kg, were randomly divided into three treatment groups. These groups were supplemented with different Lys/Met ratios of 3 [low protein-high methionine (LP-H)], 2 [low protein-medium methionine (LP-M)], and 1 [low protein-low methionine (LP-L)] in the basal diet (10% crude protein). The feeding trial lasted 100 days, including a 10-day acclimation period and a 90-day experimental period.RESULTS: The hematoxylin-eosin (H&E) sections showed that the LP-L group had a significantly increased villus height compared to the LP-M and LP-H groups (p < 0.05). In addition, the LP-L group showed higher levels of Superoxide dismutase (SOD) activity and Total Antioxidant Capacity (T-AOC) concentrations (p < 0.05). A lower concentration of Interleukin-1 beta (IL-1β) was observed in the LP-H group (p < 0.05). The activities of α-amylase, chymotrypsin, and lipase were higher in the LP-L group compared to the LP-H group (p < 0.05). Bacterial sequencing showed that both Chao1 and ACE richness were significantly increased in the LP-L group (p < 0.05), suggesting that the species richness in the jejunum is connected to the ratio of dietary Lys/Met. Furthermore, lowering the dietary Lys/ Met ratio significantly increased the abundance of Romboutsia, the Ruminococcus gauvreauii group, the Lachnospiraceae NK3A20 group, Ruminococcus 2, and the Christensenellaceae R-7 group (p < 0.05) while decreasing the abundance of Methanobrevibacter (p < 0.05). Several differential metabolites, including beta-alanine, pantothenate, pantothenic acid, phosphoenolpyruvate, cysteine, adenosine 5'-diphosphate, isodeoxycholic acid, glutamate conjugated cholic acid, and 3-dehydrocholic acid, were significantly increased in the LP-L group (p < 0.05). The functional analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations indicated that these metabolites were mainly involved in pantothenate and CoA biosynthesis, ferroptosis, and the tricarboxylic acid cycle. Several genes related to barrier function, such as Occludin and Muc- 2, were upregulated in the LP-L group (p < 0.05), while IL-6 and TNF-α were downregulated (p < 0.05).DISCUSSION: Collectively, our results suggest that the dietary Met/ Lys ratio could affect the jejunal SCFA concentration by modulating the microbial community and regulating metabolism, thereby contributing to jejunal barrier function. Our findings provide a theoretical basis for the application of Lys/Met diet supplementation in the nutritional management of Tibetan sheep, particularly when reducing the dietary crude protein (CP) level.PMID:40012772 | PMC:PMC11861081 | DOI:10.3389/fmicb.2025.1441143

Front Neurosci. 2025 Feb 12;19:1538115. doi: 10.3389/fnins.2025.1538115. eCollection 2025.ABSTRACTBACKGROUND: Increasing evidence have shown that gestational diabetes mellitus (GDM) is associated with the risk of autism in offspring. However, the underlying mechanisms have not yet been fully elucidated.METHODS: A mouse model of gestational diabetes mellitus (GDM) was established to investigate its impact on offspring. Behavioral analyses were conducted to assess social novelty and stereotypic behaviors. Neuronal excitability in the prefrontal cortex (PFC) was evaluated using c-Fos staining after social behavior stimulation. Single-cell transcriptomics and metabolomics were employed to analyze changes in the GABAergic system.RESULTS: Behavioral analyses revealed that GDM led to impaired social novelty and increased stereotypic behaviors in male offspring. c-Fos staining showed hyperexcitability in the PFC of male offspring from the GDM group following social behavior stimulation. Single-cell transcriptomics and metabolomics identified alterations in the GABAergic system, including a decrease in GABAergic neurons and reduced GABA levels. This reduction in GABA was associated with decreased GAD2 expression due to DNA hypermethylation in the GAD2 promoter region.CONCLUSION: These data suggest that GDM induces autistic-like behaviors, including reduced social novelty and increased stereotypic behaviors, in offspring by affecting the GABAergic system. These findings provide new insights into how GDM may influence neurodevelopment in offspring.PMID:40012680 | PMC:PMC11861160 | DOI:10.3389/fnins.2025.1538115

Proteomics. 2025 Feb 27:e202400150. doi: 10.1002/pmic.202400150. Online ahead of print.ABSTRACTThe development of the gut microbiome in infancy is a vulnerable process that may be perturbed by antibiotics or supported by probiotics. Although effects of these "biotics" have been well-studied through DNA sequencing, it remains unclear how the resulting compositional changes affect the microbiome metabolic functions. Additionally, limits in method standardization require careful quality assessment of studies reporting fecal metabolome. We conducted a systematic search in Embase and MEDLINE for studies describing fecal metabolites from term and near-term infants, together with anti-, pre-, or probiotic intervention. The search identified 680 articles, of which 60 were assessed for eligibility and 21 were included. We first developed operational checklists for transparent and reproducible reporting and evaluated the quality of metabolomic methodologies. This analysis supported our aim to summarize changes in the fecal metabolome induced by biotic interventions. Despite a varying quality of metabolomic methodology, we identified similarities in the fecal metabolome profiles in response to specific biotic interventions. Among the most frequently observed metabolites, which were consistently reported to be altered after biotic interventions, were bile acids, aromatic amino acids, and short-chain fatty acids. We conclude with a discussion on appropriate experimental design, controls, and metabolomics reporting to guide future research permitting meta-analyses.PMID:40012440 | DOI:10.1002/pmic.202400150

Curr Pharm Des. 2025 Feb 25. doi: 10.2174/0113816128358507250102111154. Online ahead of print.ABSTRACTBACKGROUND: Stomach Heat Syndrome (SHS) arises from the excessive consumption of spicy and greasy foods, resulting in the infiltration of pathogens and increased gastric activity, ultimately culminating in gastric injury. Coptis chinensis Franch (CC), a frequently employed remedy in Traditional Chinese Medicine (TCM) for dampness elimination, fire purging, and detoxification, has been extensively utilized.OBJECTIVE: This study aimed to explore the functional role and in-depth molecular mechanism of CC in treating SHS.METHODS: The CC Alcohol Extract (CCAE) was obtained and analyzed using HPLC. A rat model of SHS hemorrhagic lesions was established using a combination of 8% chili powder and 60% ethanol. After oral administration of CCAE, gastric histology, Myeloperoxidase (MPO), Malondialdehyde (MDA), and Superoxide Dismutase (SOD) levels were evaluated. Further, the gene expressions of Interleukin-6 (IL-6), Interleukin-1β (IL-1β), and Tumor Necrosis Factor-α (TNF-α) were assessed, respectively, using H&E staining, colorimetry, qRT-PCR, and immunohistochemistry analyses. The network pharmacology in multiple databases, transcriptome sequencing, and non-targeted metabolomic analyses were used to identify signal pathways and molecular targets. Subsequent cellular and molecular experiments were also conducted to validate the mechanisms.RESULTS: The findings demonstrated that the CCAE administration effectively mitigated SHS symptoms in rats and reduced inflammatory cytokines levels and oxidative stress. Berberine (Bbr) was identified as the primary active component responsible for the anti-SHS effects of CC. Additionally, the multi-omics analysis revealed that Bbr primarily regulates amino acid metabolism, unsaturated fatty acid metabolism, the TNF signaling pathway, and the JAK-STAT signaling pathway. Furthermore, Bbr was found to inhibit the phosphorylation of JAK2, STAT3, and p65.CONCLUSION: CC alleviated SHS-related gastric disease by suppressing inflammatory responses and enhancing gastric mucosal function through the JAK2-STAT3-NF-κB signaling pathway and amino acid metabolism, with Bbr serving as the key component.PMID:40012286 | DOI:10.2174/0113816128358507250102111154

IET Syst Biol. 2025 Jan-Dec;19(1):e70004. doi: 10.1049/syb2.70004.ABSTRACTAs an economically important tree species, mulberry (Morus spp.) has exhibited a remarkable tolerance for salinity, drought and heavy metals. However, the precise mechanism of metabolome-mediated drought adaptation is unclear. In this study, two new mulberry varieties-'drought-sensitive guisangyou62 (GSY62) and highly drought-tolerant guiyou2024 (GY2024)'-after three days (62F or 2024F) and six days (62B or 2024B) of drought-stress conditions were subjected to transcriptome and metabolome analyses. The enrichment analysis demonstrated that the differentially expressed genes (DEGs) were mainly enriched in carbohydrate metabolism, amino acid metabolism, energy metabolism and secondary metabolite biosynthesis under drought-stress conditions. Notably, compared with the CK group (without drought treatment), 60 and 70 DEGs in GY2024 and GSY62 were involved in sucrose and starch biosynthesis, respectively. The genes encoding sucrose phosphate synthase 2 and 4 were downregulated in GY2024, with a lower expression. The genes encoding key enzymes in starch biosynthesis were upregulated in GY2024 and the transcriptional abundance was significantly higher than in GSY62. These results indicated that drought stress reduced sucrose synthesis but accelerated starch synthesis in mulberry.PMID:40012244 | DOI:10.1049/syb2.70004

Biotechnol J. 2025 Feb;20(2):e202500004. doi: 10.1002/biot.202500004.ABSTRACTPleuromutilin, a tricyclic diterpene compound with significant inhibitory activity against gram-positive bacteria and mycoplasmas, serves as a precursor for various veterinary and human medicines. Previous efforts have primarily focused on strain screening and fermentation process optimization to enhance pleuromutilin production in native pleuromutilin-producing strains, with the absence of genetic engineering strategies. In this study, we performed whole-genome sequencing of the pleuromutilin-producing strain Clitopilus passeckerianus T6 to identify the biosynthetic genes related to pleuromutilin production. Transcriptomic and metabolomic data were collected during the fermentation of C. passeckerianus T6, and gene transcription and metabolite accumulation in the pleuromutilin biosynthetic pathway were analyzed to identify the rate-limiting steps in pleuromutilin biosynthesis. Overexpression of the key genes ple-ggpps and ple-cyc increased pleuromutilin production by 50%, achieving a titer of 6.9 g/L. This study is the first to employ metabolic engineering to enhance pleuromutilin production in a native strain, providing a strategy for efficient pleuromutilin production.PMID:40012214 | DOI:10.1002/biot.202500004

Cell Commun Signal. 2025 Feb 26;23(1):112. doi: 10.1186/s12964-025-02093-3.ABSTRACTApolipoprotein E (APOE) has garnered significant attention as one of the most influential genetic risk factors for Alzheimer's disease (AD). While the pathogenic role of APOE4 in sporadic AD has been extensively studied, research on the protective effects of the APOE2 genotype and its underlying mechanisms remains limited. Additionally, the existence of sex differences in the protective effects of ApoE2 continues to be a topic of debate. In this study, we utilized humanized ApoE2- and ApoE3- target replacement mice to examine the sex-specific effects of ApoE2 on cognition. Compared with female ApoE3 mice, we found significantly lower spatial cognitive ability and impaired hippocampal synaptic ultrastructure in aged female ApoE2 mice, accompanied by reduced insulin signaling of the hippocampus. Further analyses by target metabolomics and transcriptomic analyses revealed that female ApoE2 mice exhibit an age-related decline in hippocampal inositol levels, and that alterations in inositol levels lower insulin signaling. Importantly, inositol supplementation was found to alleviate peripheral glucose intolerance, enhance insulin signaling, and ultimately improve cognitive function. Interestingly, these differences were not observed between male ApoE2 and ApoE3 mice. The research findings not only provide new insights into the impact of ApoE2 on cognition but also offer a new strategy for cognitive improvement through inositol supplementation in older women.PMID:40011916 | DOI:10.1186/s12964-025-02093-3

Sci Rep. 2025 Feb 26;15(1):6887. doi: 10.1038/s41598-025-90407-3.ABSTRACTFecal biomarkers are becoming an important analytical tool since feces are in direct contact with the inflamed intestine and site for the gut microbiome. The objective of this study was the identification of differential fecal metabolites by means of 1H-NMR to evaluate the management of male dairy beef calves, and which could become potential biomarkers of gastrointestinal disorders. Holstein calves were subjected to a protocol aimed to simulate real conditions of the dairy beef market. Three groups were studied: Control (CTR: high colostrum, no transport, milk replacer), LCMR (low colostrum, transport, milk replacer) and LCRS (low colostrum, transport, rehydrating solution). Fecal lactoferrin was determined as marker of intestinal inflammation, and metabolomic profiling was performed in feces collected the day after arrival to the farm. 41 polar and 10 non-polar metabolites were identified, of which proline, formate and creatine increased in the LCRS group, whereas butyrate and uracil decreased. Less differences were found in non-polar metabolites. Multivariate analysis indicated that most differences are found between the LCRS group and the others. In conclusion, this study indicates that feed restriction has a more important effect at this age than colostrum uptake and transport. These results should help to identify robust fecal biomarkers to assess calf intestinal health and improve management protocols.PMID:40011507 | DOI:10.1038/s41598-025-90407-3

Sci Rep. 2025 Feb 26;15(1):6875. doi: 10.1038/s41598-025-90019-x.ABSTRACTFeline chronic kidney disease (CKD) is one of the most frequently encountered diseases in veterinary practice, and the leading cause of mortality in cats over five years of age. While diagnosing advanced CKD is straightforward, current routine tests fail to diagnose early CKD. Therefore, this study aimed to identify early metabolic biomarkers. First, cats were retrospectively divided into two populations to conduct a case-control study, comparing the urinary and serum metabolome of healthy (n = 61) and CKD IRIS stage 2 cats (CKD2, n = 63). Subsequently, longitudinal validation was conducted in an independent population comprising healthy cats that remained healthy (n = 26) and cats that developed CKD2 (n = 22) within one year. Univariate, multivariate, and machine learning-based (ML) approaches were compared. The serum-to-urine ratio of 3-hydroxykynurenine was identified as a single biomarker candidate, yielding a high AUC (0.844) and accuracy (0.804), while linear support vector machine-based modelling employing metabolites and clinical parameters enhanced AUC (0.929) and accuracy (0.862) six months before traditional diagnosis. Furthermore, analysis of variable importance indicated consistent key serum metabolites, namely creatinine, SDMA, 2-hydroxyethanesulfonate, and aconitic acid. By enabling accurate diagnosis at least six months earlier, the highlighted metabolites may pave the way for improved diagnostics, ultimately contributing to timely disease management.PMID:40011503 | DOI:10.1038/s41598-025-90019-x

NPJ Biofilms Microbiomes. 2025 Feb 27;11(1):37. doi: 10.1038/s41522-025-00669-y.ABSTRACTPathogenesis of periodontitis is marked by microbiota dysbiosis and disrupted host responses. Porphyromonas gingivalis is a keystone pathogen of periodontitis which expresses various crucial virulence factors. This study aimed to clarify the role and mechanisms of P. gingivalis tryptophan-indole metabolic pathway in the pathogenesis of periodontitis. This study showed that periodontitis patients exhibited elevated tryptophan metabolism and salivary pathogen abundance. Tryptophanase gene-deficiency altered proteome and metabolome of P. gingivalis, inhibited P. gingivalis virulent factors expression, biofilm growth, hemin utilization, cell adhesion/invasion and pro-inflammation ability. Tryptophan-indole pathway of P. gingivalis stimulated periodontitis biofilm formation and induced oral microbiota dysbiosis. In periodontitis mice, this pathway of P. gingivalis aggravated alveolar bone loss and gingival tissue destruction, causing oral and gut microbiota dysbiosis. This study indicates that the tryptophan-indole pathway serves as a significant regulator of P. gingivalis virulence and oral microbiota dysbiosis, which is also associated with gut dysbiosis.PMID:40011497 | DOI:10.1038/s41522-025-00669-y

Cell Death Dis. 2025 Feb 26;16(1):134. doi: 10.1038/s41419-025-07447-w.ABSTRACTAcyl CoA binding protein encoded by diazepam binding inhibitor (ACBP/DBI) is a tissue hormone that stimulates lipo-anabolic responses and inhibits autophagy, thus contributing to aging and age-related diseases. Protein expression profiling of ACBP/DBI was performed on mouse tissues to identify organs in which this major tissue hormone is expressed. Transcriptomic and proteomic data bases corroborated a high level of human-mouse interspecies conservation of ACBP/DBI expression in different organs. Single-cell RNA-seq data confirmed that ACBP/DBI was strongly expressed by parenchymatous cells from specific human and mouse organs (e.g., kidney, large intestine, liver, lung) as well as by myeloid or glial cells from other organs (e.g., adipose tissue, brain, eye) following a pattern that was conserved among the two species. We identified a panel of 44 mRNAs that are strongly co-expressed with ACBP/DBI mRNA in normal and malignant human and normal mouse tissues. Of note, 22 (50%) of these co-expressed mRNAs encode proteins localized at mitochondria, and mRNAs with metabolism-related functions are strongly overrepresented (66%). Systematic data mining was performed to identify transcription factors that regulate ACBP/DBI expression in human and mouse. Several transcription factors, including growth response 1 (EGR1), E2F Transcription Factor 1 (E2F1, which interacts with retinoblastoma, RB) and transformation-related protein 53 (TRP53, best known as p53), which are endowed with oncosuppressive effects, consistently repress ACBP/DBI expression as well as its co-expressed mRNAs across multiple datasets, suggesting a mechanistic basis for a coregulation network. Furthermore, we identified multiple transcription factors that transactivate ACBP/DBI gene expression together with its coregulation network. Altogether, this study indicates the existence of conserved mechanisms determining the expression of ACBP/DBI in specific cell types of the mammalian organism.PMID:40011442 | DOI:10.1038/s41419-025-07447-w

Nat Commun. 2025 Feb 26;16(1):1982. doi: 10.1038/s41467-025-57142-9.ABSTRACTDysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.PMID:40011434 | DOI:10.1038/s41467-025-57142-9

Clin Rheumatol. 2025 Feb 26. doi: 10.1007/s10067-025-07373-4. Online ahead of print.ABSTRACTOBJECTIVE: Rheumatoid arthritis (RA) is frequently treated with traditional Chinese medicine (TCM), where patients are classified into distinct syndromes, such as heat-dampness syndrome (HD) and kidney-liver deficiency syndrome (KLD). However, an objective and systematic approach to differentiate these TCM syndromes remains lacking. This study is aimed at analyzing serum metabolomics to identify differential metabolites and pathways associated with HD and GS syndromes in RA patients and at evaluating their potential as diagnostic biomarkers.METHODS: Serum samples from RA patients classified into HD and KLD groups were analyzed using metabolomics. Partial least squares discriminant analysis was employed to identify significant metabolites, while pathway analysis was conducted using the Kyoto Encyclopedia of Genes and Genomes database. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic potential of key metabolites.RESULTS: Fifteen differential metabolites and two perturbed pathways-sphingolipid and D-amino acid metabolism-were identified between the KLD and HD groups. Notably, several metabolites, including C17-sphinganine and leucyl-alanine, demonstrated high diagnostic efficacy, with area under the curve (AUC) values exceeding 0.90. Correlation analysis revealed significant associations between certain metabolites and clinical indices, further substantiating their role in syndrome differentiation.CONCLUSION: This study presents a comprehensive analysis of serum metabolites in RA patients under different TCM syndromes. The identified metabolites hold potential as biomarkers for distinguishing HD and KLD groups, paving the way for more objective and evidence-based diagnostic approaches in TCM. Key Points • Differential metabolites were identified in the serum of RA patients with heat-dampness syndrome and kidney-liver deficiency syndrome, with their metabolic pathways primarily involving sphingolipid metabolism and D-amino acid metabolism. • Serum metabolites demonstrate high efficacy in distinguishing RA patients with different TCM syndromes. • Significant correlations were observed between serum differential metabolites and clinical indicators in RA patients with varying TCM syndromes.PMID:40011356 | DOI:10.1007/s10067-025-07373-4