PubMed

Emerg Microbes Infect. 2025 Feb 18:2469662. doi: 10.1080/22221751.2025.2469662. Online ahead of print.ABSTRACTAfrican swine fever (ASF) is a highly contagious and severe infectious disease caused by African swine fever virus (ASFV). The disease significantly threatens the sustainable development of the global pig industry. Unfortunately, there are currently no safe and efficacious vaccines and antiviral agents available except in Vietnam. Antioxidative stress is a critical factor in antiviral strategies. In this study, we show that ASFV infection elevates the level of reactive oxygen species (ROS) and suppresses the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in vitro and in vivo. Moreover, overexpressing Nrf2 can significantly inhibit ASFV replication. Through high-throughput screening of natural small molecules against ASFV, we identify resveratrol (RES), an Nrf2 activator, as a compound capable of inducing the cellular antiviral responses and effectively inhibiting ASFV replication in primary porcine alveolar macrophages (PAMs). Notably, untargeted metabolomics profiling reveals that glutathione is the primary differential metabolite related to the antiviral activities of RES against ASFV. Mechanistically, RES exerts its antiviral effects by inducing the production of reduced glutathione (GSH) via the activation of the Nrf2 signaling pathway and simultaneously reducing the elevated levels of ROS caused by ASFV infection. In conclusion, RES exhibits broad efficacy as a potentially effective compound for inhibiting ASFV infection and alleviating the oxidative stress induced by ASFV infection via the Nrf2 signaling pathway.PMID:39964001 | DOI:10.1080/22221751.2025.2469662

J Child Psychol Psychiatry. 2025 Feb 18. doi: 10.1111/jcpp.14125. Online ahead of print.ABSTRACTBACKGROUND: The impact of maternal sleep disturbances during pregnancy on long-term neurodevelopment and the role of metabolites in this process are not well understood. In a prospective cohort study, we aimed to investigate the associations between maternal sleep disturbances during each trimester and child intelligence quotient (IQ) at the age of 4 years and to identify metabolites that might mediate these relationships.METHODS: This study included 1,870 mother-child pairs from the Shanghai Birth Cohort (SBC). Maternal sleep quality was assessed using the Pittsburgh sleep quality index (PSQI) questionnaire in the first and second trimesters, and a simplified version of the PSQI was used in the third trimester. Child IQ was evaluated at age 4 using the Wechsler Primary and Preschool Scale of Intelligence-Fourth Edition (WPPSI-IV). We conducted untargeted analyses of maternal serum metabolomics in the first trimester in 1,461 subjects. We employed multiple linear regression models to examine the associations between maternal sleep disturbances during each trimester and child IQ. Additionally, we utilized longitudinal latent class analysis (LLCA) to identify patterns of sleep quality changes throughout the three trimesters and employed multiple linear regression models to investigate how these sleep patterns across the entire pregnancy were associated with child IQ. We applied a 'meet-in-the-middle' approach to identify potential metabolites linking maternal sleep disturbances during early pregnancy with child IQ.RESULTS: Longer sleep latency was associated with lower child Full-Scale IQ (FSIQ) and verbal comprehension index (VCI) for the first trimester, while lower child fluid reasoning index (FRI) for the second trimester. Longer sleep latency throughout the pregnancy was associated with decreased FSIQ (β = -4.68; 95% CI: -8.32, -1.03), VCI (β = -6.38; 95% CI: -10.39, -2.37), and FRI (β = -4.29; 95% CI: -7.96, -0.63). We found that inositol, indoleacrylic acid, and 4-hydroxyquinoline emerged as potential biomarkers that play an intermediary role in the association between maternal sleep disturbances and child IQ.CONCLUSIONS: Sleep disturbance during pregnancy may be a risk factor for compromised IQ in preschool-aged offspring. Alterations in inositol and tryptophan metabolism might be the mediator for the link between maternal sleep disturbances and child IQ.PMID:39963848 | DOI:10.1111/jcpp.14125

Circ Res. 2025 Feb 18. doi: 10.1161/CIRCRESAHA.124.325642. Online ahead of print.ABSTRACTBACKGROUND: Chronic kidney disease (CKD) has emerged as a significant risk factor that accelerates atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the modulators underlying this exacerbated pathobiology are ill-defined. Recent work has demonstrated that uremic toxins are associated with limb amputation in PAD and have pathological effects in both the limb muscle and vasculature. Herein, we use multiomics to identify novel modulators of disease pathobiology in patients with PAD and CKD.METHODS: A cross-sectional study enrolled 4 groups of participants: controls without PAD or CKD (n=28), patients with PAD only (n=46), patients with CKD only (n=31), and patients with both PAD and CKD (n=18). Both targeted (uremic toxins) and nontargeted metabolomics in plasma were performed using mass spectrometry. Calf muscle biopsies were used to measure histopathology, perform bulk and single-nucleus RNA sequencing, and assess mitochondrial function. Differential gene and metabolite analyses, as well as pathway and gene set enrichment analyses, were performed.RESULTS: Patients with both PAD and CKD exhibited significantly lower calf muscle strength and smaller muscle fiber areas compared with controls and those with only PAD. Compared with controls, mitochondrial function was impaired in patients with CKD, with or without PAD, but not in PAD patients without CKD. Plasma metabolomics revealed substantial alterations in the metabolome of patients with CKD, with significant correlations observed between uremic toxins (eg, kynurenine and indoxyl sulfate) and both muscle strength and mitochondrial function. RNA sequencing analyses identified downregulation of mitochondrial genes and pathways associated with protein translation in patients with both PAD and CKD. Single-nucleus RNA sequencing further highlighted a mitochondrial deficiency in muscle fibers along with unique remodeling of fibro-adipogenic progenitor cells in patients with both PAD and CKD, with an increase in adipogenic cell populations.CONCLUSIONS: CKD significantly exacerbates ischemic muscle pathology in PAD, as evidenced by diminished muscle strength, reduced mitochondrial function, and altered transcriptome profiles. The correlation between uremic toxins and muscle dysfunction suggests that targeting these metabolites may offer therapeutic potential for improving muscle health in PAD patients with CKD.PMID:39963788 | DOI:10.1161/CIRCRESAHA.124.325642

Front Plant Sci. 2025 Feb 3;16:1527477. doi: 10.3389/fpls.2025.1527477. eCollection 2025.ABSTRACTNeopicrorhiza scrophulariiflora (Pennell) D.Y.Hong (N. scrophulariiflora) is an important wild medicinal plant that belongs to the Plantaginaceae family. Its main active ingredients, picroside I (P-I) and picroside II (P-II), possess anti-inflammatory, anticancer, and antibacterial properties. Due to overharvesting, N. scrophulariiflora resources are facing the risk of depletion, urgently requiring resource protection and rational utilization. However, the biosynthetic pathways and related genes of active compounds in N. scrophulariiflora have not been fully investigated. In this study, widely targeted metabolomics and RNA-seq technology were employed to perform a joint analysis of the metabolome and transcriptome in different tissues of N. scrophulariiflora, including the roots, stems, and leaves. A total of 196 flavonoids and 63 terpenoids were identified. Among the 158,254 annotated genes, 74 were annotated as related to iridoid synthesis. Using bioinformatics methods such as clustering analysis, phylogenetic tree construction, and weighted gene co-expression network analysis (WGCNA), 43 candidate genes were identified that may be involved in the biosynthesis of picroside-I and picroside-II, of which 26 genes were significantly correlated with the synthesis of picrosides and their intermediates. Transcriptome analysis revealed the expression patterns of differentially expressed genes, and metabolomic analysis revealed the distribution characteristics of metabolites in different tissues of N. scrophulariiflora. Through qRT-PCR validation, we found that three NsF3H/NsF3D genes, four NsUGD/NsUPD genes, one Ns2HFD gene, and three NsSQM genes may participate in the iridoid biosynthesis pathway. These findings provide important genetic and metabolomic information for an in-depth understanding of the biosynthetic mechanisms of iridoids and lay the foundation for the protection and sustainable utilization of N. scrophulariiflora.PMID:39963531 | PMC:PMC11830703 | DOI:10.3389/fpls.2025.1527477

Int J Nanomedicine. 2025 Feb 12;20:1921-1948. doi: 10.2147/IJN.S499161. eCollection 2025.ABSTRACTPURPOSE: Trichinella spiralis has evolved complex immunomodulatory mechanisms mediated by excretory-secretory products (ESL1) that enable its survival in the host. Consequently, ESL1 antigens display excellent potential for treating autoimmune diseases such as multiple sclerosis (MS). However, whether timely controlled delivery of ESL1 antigens in vivo, as in natural infections, could enhance its therapeutic potential for MS is still unknown.METHODS: To test this, we encapsulated ESL1 antigens into biodegradable poly (lactide-co-glycolic) acid (PLGA) nanofibers by emulsion electrospinning as a delivery system and assessed their release dynamics in vitro, and in an animal MS model, experimental autoimmune encephalomyelitis (EAE), induced 7 days after PLGA/ESL1 subcutaneous implantation. PLGA/ESL1 effects on EAE symptoms were monitored along with multiple immune cell subsets in target organs at the peak and recovery of EAE. Gut barrier function and microbiota composition were analyzed using qPCR, 16S rRNA sequencing, and metabolomic analyses.RESULTS: ESL1 antigens, released from PLGA and drained via myeloid antigen-presenting cells through lymph nodes, protected the animals from developing EAE symptoms. These effects correlated with reduced activation of myeloid cells, increased IL-10 expression, and reduced accumulation of proinflammatory natural killer (NK) cells, T helper (Th)1 and Th17 cells in the spleen and central nervous system (CNS). Additionally, CD4+CD25hiFoxP3+ regulatory T cells and IL-10-producing B cells were expanded in PLGA/ESL1-treated animals, compared to control animals. The migration of ESL1 to the guts correlated with locally reduced inflammation and gut barrier damage. Additionally, PLGA/ESL1-treated animals displayed an unaltered microbiota characterized only by a more pronounced protective mevalonate pathway and expanded short-chain fatty acid-producing bacteria, which are known to suppress inflammation.CONCLUSION: The delivery of T. spiralis ESL1 antigens via biodegradable electrospun PLGA nanofiber implants efficiently protected the animals from developing EAE by inducing a beneficial immune response in the spleen, gut, and CNS. This platform provides excellent grounds for further development of novel MS therapies.PMID:39963417 | PMC:PMC11830953 | DOI:10.2147/IJN.S499161

Front Cell Infect Microbiol. 2025 Feb 3;15:1546991. doi: 10.3389/fcimb.2025.1546991. eCollection 2025.ABSTRACTIndole, a crucial bacterial signaling molecule, plays a fundamental role in regulating various physiological processes within bacteria, including growth, acid tolerance, biofilm development, motility, and other cellular functions. Its regulatory influence extends beyond indole-producing bacteria, significantly impacting the physiological activities in non-indole-producing species. In this study, we demonstrate that indole enhances the pathogenicity and viability of Klebsiella pneumoniae using the Galleria mellonella infection model and serum killing assay. Concurrently, indole has varying effects on biofilm formation in K. pneumoniae, with some strains showing enhanced biofilm formation ability. To elucidate the underlying molecular mechanisms, transcriptome analysis revealed that indole exposure in K. pneumoniae led to the upregulation of genes associated with pili formation and iron acquisition systems, while simultaneously inducing oxidative stress responses. Additionally, our analysis uncovered extensive metabolic remodeling. Specifically, we observed significant upregulation of genes involved in simple carbohydrate utilization pathways, including those responsible for galactose, mannose, and maltose metabolism, as well as enhanced expression of genes associated with pyrimidine biosynthesis. These findings collectively indicate that indole enhances the intestinal colonization and pathogenicity of K. pneumoniae primarily by modulation of fimbriae expression and metabolic pathway regulation.PMID:39963410 | PMC:PMC11830697 | DOI:10.3389/fcimb.2025.1546991

J Multidiscip Healthc. 2025 Feb 12;18:813-825. doi: 10.2147/JMDH.S504325. eCollection 2025.ABSTRACTBACKGROUND: Schizophrenia (SZ) is a chronic, severe mental disorder that presents significant challenges to diagnosis and effective treatment. Emerging evidence suggests that gut microbiota may play a role in the disease's pathogenesis. However, fewer studies have directly investigated the potential links between oral microbiota and SZ.PURPOSE: This study aimed to explore the relationship between salivary microbiota dysbiosis and SZ, examining microbial and metabolic alterations that may contribute to SZ pathophysiology.METHODS: Salivary samples from 30 hospitalized patients diagnosed with SZ and 10 healthy controls were collected. The microbial and metabolic profiles were analyzed using 16S rRNA gene sequencing and metabolomic profiling. Clinical parameters, including oral health status, were also evaluated to minimize variability in sampling.RESULTS: Patients with SZ exhibited significantly poorer oral health compared to healthy controls, with more missing teeth and worse periodontal status. Microbiota sequencing revealed notable alterations in the overall structure and composition of the salivary microbiome in SZ patients, characterized by increased abundance of specific genera such as Neisseria and Porphyromonas. Metabolomic analysis indicated significant differences between the SZ and control groups, with upregulation of key metabolic pathways, including "β-alanine metabolism" and "vitamin digestion and absorption". Correlations between microbial dysbiosis and elevated levels of certain metabolites, such as L-methionine sulfoxide (L-MetO) and tyramine, were observed, suggesting links to oxidative stress.CONCLUSION: The study highlights the presence of significant dysbiosis and metabolic dysfunction in the salivary microbiota of SZ patients, suggesting that alterations in the oral microbiome may contribute to SZ pathogenesis. These results provide new insights into potential diagnostic biomarkers and therapeutic targets for SZ. Further studies with larger sample sizes are required to validate these findings.PMID:39963326 | PMC:PMC11831016 | DOI:10.2147/JMDH.S504325

J Agric Food Chem. 2025 Feb 17. doi: 10.1021/acs.jafc.4c10795. Online ahead of print.ABSTRACTImazethapyr, a widely used herbicide, exhibits a long persistence in soils and can cause injury to rotational crops. Here, we discovered that imazethapyr inhibits primary root elongation in Arabidopsis by inhibiting cell division and expansion rather than damaging the organization of root meristem. Integration of transcriptomic and metabolomic analysis revealed that imazethapyr downregulated multiple genes related to cell wall loosening and modification, leading to increased cell wall thickness and inhibited cellular expansion in Arabidopsis roots. Furthermore, imazethapyr upregulated auxin biosynthesis and transport, resulting in enhanced auxin accumulation at root tips. Elevated auxin concentrations triggered apoplast alkalization and the inactivation of wall-loosening enzymes, further suppressing root growth. This research provides new insights into the molecular mechanism underlying imazethapyr phytotoxicity and offers potential strategies for developing crops that are better adapted to soils contaminated with imidazolinone herbicides.PMID:39962894 | DOI:10.1021/acs.jafc.4c10795

Cell Commun Signal. 2025 Feb 17;23(1):92. doi: 10.1186/s12964-025-02088-0.ABSTRACTBACKGROUND: Glycosylation is an important posttranslational modification of proteins and in most cases indispensable for proper protein function. Like most soluble proteins, IgA, the second most prevalent antibody in human serum, contains several N- and O-glycosylation sites. While for IgG the impact of Fc glycosylation on effector functions and inflammatory potential has been studied intensively, only little is known for IgA. In addition, only glimpses exist regarding the regulation of IgA glycosylation. We have previously shown that IgA1 and IgA2 differ functionally and also show differences in their glycosylation pattern. The more pro-inflammatory IgA2 which is linked to autoimmune diseases displays decreased sialylation, galactosylation, fucosylation and bisection as compared to IgA1. In the present study, we aimed to investigate these differences in glycosylation in detail and to explore the mechanisms underlying them.METHODS: IgA1 and IgA2 was isolated from serum of 12 healthy donors. Site specific glycosylation was analyzed by mass spectrometry. In addition, human bone marrow plasma cells were investigated using single cell mRNA sequencing, flow cytometry and ELISpot.RESULTS: We found that certain glycoforms greatly differ in their abundance between IgA1 and IgA2 while others are equally abundant. Overall, the IgA2 glycans displayed a more immature phenotype with a higher prevalence of oligomannose and fewer fully processed glycans. Of note, these differences can't be explained by differences in the glycosylation enzyme machinery as mRNA sequencing and flow cytometry analysis showed equal enzyme expression in IgA1 and IgA2 producing plasma cells. ELISpot analysis suggested a slightly increased antibody production rate in IgA2 producing plasma cells which might contribute to its lower glycan processing rates. But this difference was only minor, suggesting that further factors such as steric accessibility determine glycan processing. This is supported by the fact that glycans at different positions on the same IgA chain differ dramatically in fucosylation, sialylation and bisection.CONCLUSION: In summary, our detailed overview of IgA1 and IgA2 glycosylation shows a class, subclass, and site-specific glycosylation fingerprint, most likely due to structural differences of the protein backbones.PMID:39962487 | DOI:10.1186/s12964-025-02088-0

BMC Microbiol. 2025 Feb 17;25(1):77. doi: 10.1186/s12866-025-03789-9.ABSTRACTBACKGROUND: Streptophenazines, a class of phenazine compounds with a variety of alkyl side chains and activity against methicillin-resistant Staphylococcus aureus (MRSA), are mainly derived from soil or marine microbial secondary metabolites. However, the discovered phenazine compounds still do not meet the needs of the development of anti-MRSA lead compounds. Here, we examined secondary metabolites of Streptomyces albovinaceus WA10-1-8 isolated from Periplaneta americana, for streptophenazines with anti-MRSA activity.RESULTS: In this study, a guidance method combining high-performance liquid chromatography-ultraviolet (HPLC-UV) with molecular networking analysis was used to isolate and identify a series of streptophenazines (A-T) from S. albovinaceus WA10-1-8. Among them, a new streptophenazine containing a dihydroxyalkyl chain structure named streptophenazine T was isolated and identified for the first time. The results of bioactivity assays showed that streptophenazine T had anti-MRSA activity with a minimum inhibitory concentration (MIC) of 150.23 µM, while the MICs of streptophenazine A, B, G, and F were 37.74-146.12 µM.CONCLUSIONS: This study was the first to report multiple streptophenazine compounds with anti-MRSA activity expressed by Streptomyces isolated from insect niches. These results provided a valuable reference for future exploration of new streptophenazine compounds with activity against drug-resistant bacteria.PMID:39962376 | DOI:10.1186/s12866-025-03789-9

Sci Rep. 2025 Feb 17;15(1):5807. doi: 10.1038/s41598-025-90140-x.ABSTRACTThe plasma lipidome and immune cells are instrumental in shaping the health profile of an organism, and their influence on diseases is profound. However, the intricate interactions between cholangiocarcinoma (CCA) and these physiological components have yet to be comprehensively explored. Employing Mendelian randomization (MR), our study delved into the causal links among immune cells, the lipidome, and CCA. The research design meticulously considered both the direct associations and the mediating roles of immune cells within the complex interplay between the lipidome and CCA. Our analysis uncovered significant correlations between the levels of Sphingomyelin (d34:1), Phosphatidylcholine (0-16:0, 22:5) and Sterol ester (27:1/16:0) and CCA. Moreover, we have pinpointed various immune cells that play a mediating role in the impact of the lipidome on CCA. For example, Sphingomyelin (d34:1) can impact CCA through the IgD on IgD+ CD38- unswitched memory (unsw mem) B cell (B cell panel), IgD on unsw mem (B cell panel) and Naive CD4+ %CD4+ (maturation stages of T cell). The proportion of mediating effects further sheds light on the intricate interplay among the lipidome, immune cells, and their cumulative influence on CCA. Our study illuminates the intricate relationship among the lipidome, immune cells, and CCA. These findings suggest that the lipidome could serve as a promising and potentially effective therapeutic target in the treatment of CCA.PMID:39962308 | DOI:10.1038/s41598-025-90140-x

Physiol Plant. 2025 Jan-Feb;177(1):e70114. doi: 10.1111/ppl.70114.ABSTRACTSoil salinization and alkalization are the foremost abiotic stresses adversely affecting plant growth and yield worldwide. Salvadora persica is an important facultative halophyte that has been reported for its high salinity tolerance ability. The present study undertakes the growth, photosynthetic efficiency, chlorophyll fluorescence, antioxidative defense, ionomic adjustments, and metabolomic responses of S. persica to understand its resilience mechanisms under saline-alkali stress. Our findings reveal that S. persica undergoes substantial physiological, ionomic, and metabolic modulations for endurance under saline-alkali stress. Under saline-alkali stress, metabolomic analysis identified 75 differentially accumulated metabolites (DAMS), including amino acids, sugars, sugar alcohols, organic acids, polyphenols, and phytohormones. Notable upregulated metabolites included quercetin (+4-fold), naringenin (+2.6-fold), glycerol (+2.4-fold), and proline (+1.7-fold), whereas D-mannitol (-3.8-fold), D-talose (-2.9-fold), and GA3 (-2.8-fold) were significantly downregulated. Pathway enrichment analysis revealed alterations in key metabolic pathways, such as amino acid metabolism, starch and sucrose metabolism, tricarboxylic acid cycle (TCA cycle), glycolysis/gluconeogenesis, and photosynthetic carbon fixation. A 2-fold reduction in glucose indicated an enhanced glycolytic flux to support energy needs under stress. The study highlights S. persica's adaptive strategy of slower nitrogen metabolism, increased glycolysis, and downregulated TCA cycle, giving an indication towards a slower growth rate under saline-alkali stress to reallocate energy for osmolyte biosynthesis. The amino acids, sugars, and sugar alcohols emerged as major contributors to osmotic adjustment. A robust antioxidant defense system exists in S. persica to mitigate ROS under saline-alkali stress. These findings provide insights into the mechanisms of saline-alkali tolerance in the halophyte S. persica, offering valuable direction for developing saline-alkali-tolerant crops.PMID:39962363 | DOI:10.1111/ppl.70114

Commun Biol. 2025 Feb 17;8(1):251. doi: 10.1038/s42003-025-07674-z.ABSTRACTThe correlation between persistent human cytomegalovirus (HCMV) infection and poor prognosis in colorectal cancer (CRC) patients has garnered increasing attention. UL82 is a tegument protein of HCMV, and our previous research indicated that the presence of UL82 is significantly associated with reduced overall survival in CRC patients. However, the mechanism by which UL82 affects the prognosis of CRC patients remains unclear. In this study, we investigated the role of UL82 in CRC progression through both in vitro and in vivo experiments, and revealed its downstream regulatory pathways by integrating transcriptomics, metabolomics, and proteomics. Our findings first revealed that UL82 significantly promoted CRC cell proliferation by increasing the proportion of cells in the S phase of the cell cycle. Additionally, UL82 enhanced the expression of the oncogene AGR2, while knockdown of AGR2 abolished the proliferative effect of UL82. Interestingly, UL82 interacted with the transcription factor DDX5, which transcriptionally inhibited AGR2 expression. Furthermore, this UL82-AGR2 axis promoted nucleotide metabolism in CRC cells by enhancing the levels of nucleotide synthesis enzymes DTYMK, RRM2, and TYMS. In conclusion, our study suggests that the UL82/DDX5 complex may promote nucleotide metabolism and cell cycle progression of CRC by upregulating AGR2 and UL82 may serve as a potential prognostic biomarker for CRC patients.PMID:39962326 | DOI:10.1038/s42003-025-07674-z

Sci Rep. 2025 Feb 17;15(1):5731. doi: 10.1038/s41598-025-90212-y.ABSTRACTA study was conducted to evaluate the three-dimensional clinostat simulated microgravity effect on mouse models, focusing on the central nervous system. Eighteen mice were divided into three groups: control, survival box, and clinostat + survival box. Behavioral tests, femur micro-CT, brain transcriptomics, serum metabolomics, and fecal microbiomics were performed. Results showed decreased activity, altered gait, enhanced fear memory, bone loss, immune/endocrine changes in brain transcriptome, and altered metabolic pathways in serum and gut microbiota in clinostat-treated mice. The model closely mimics spaceflight-induced transcriptome changes, suggesting its value in studying microgravity-related neurological alterations and highlighting the need for attention to emotional changes in space.PMID:39962314 | DOI:10.1038/s41598-025-90212-y

Transl Psychiatry. 2025 Feb 17;15(1):54. doi: 10.1038/s41398-025-03277-8.ABSTRACTThe microbiota-gut-brain axis plays a pivotal role in neuropsychiatric disorders, particularly in depression. Escitalopram (ESC) is a first-line antidepressant, however, its regulatory mechanisms on the microbiota-gut-brain axis in the treatment of depression remain unclear. The antidepressant effects of ESC were evaluated using the forced swim test in Wistar-Kyoto (WKY) rats, while damage in the gut and brain regions was assessed through H&E staining and immunohistochemistry. The therapeutic mechanisms in WKY rats with depression-like behavior were investigated through 16S rRNA sequencing of the gut microbiota, serum untargeted metabolomics, and hippocampal proteomics. Results indicated that ESC intervention improved depressive-like behaviors, as evidenced by increased swimming times in WKY rats, and also restored intestinal permeability and brain tissue integrity. Significant changes in the gut microbiota composition, particularly an increase in Bacteroides barnesiae, as well as increases in serum sphingolipid metabolites (Sphinganine 1-phosphate, Sphingosine, and Sphingosine-1-phosphate) and hippocampal proteins (Sptlc1, Enpp5, Enpp2), were strongly correlated. These robust correlations suggest that ESC may exert its antidepressant effects by modulating sphingolipid metabolism through the influence of gut microbiota. Accordingly, this research elucidates novel mechanisms underlying the antidepressant efficacy of ESC and highlights the pivotal importance of the microbiota-gut-brain axis in mediating these effects.PMID:39962083 | DOI:10.1038/s41398-025-03277-8

Sci Rep. 2025 Feb 17;15(1):5780. doi: 10.1038/s41598-024-81874-1.ABSTRACTOpuntia ficus-indica red fruit (OFI-RF) is a member of the Cactaceae family and native to South America. Phytochemical evaluation of the plant has revealed variable bioactive components; therefore, this study explored the medicinal value of butanol (BE) and ethylacetate extracts (EE) by evaluating their antidiabetic, antioxidant and antihypercholesterolemic properties. Selected solvents were used for phytochemical extraction according to established protocols, and then pharmacological effects of phenolic and betanin-rich extracts were evaluated. Results indicated that butanol was the most effective solvent for extracting polyphenolics followed by ethyl acetate, yielding: 148.91 ± 0.95 and 110.96 ± 0.61 μg/g, respectively. Identification analysis of OFI-RF using UPLC/HESI-MS/MS revealed a diverse range of 101 metabolites, including polyphenolics (phenolic acids, phenolic glycosides, flavanols, flavanonols, flavonoids and biflavonoids), alkaloids, pyridine, betalains, coumarins, vitamins, fatty acids and other therapeutic compounds. Biological studies (in vitro and in vivo) demonstrated that both EE and BE exhibited significant antidiabetic, antioxidant and antihypercholestremic activities. These findings were further supported via histopathological examination.PMID:39962060 | DOI:10.1038/s41598-024-81874-1

Nat Commun. 2025 Feb 17;16(1):1700. doi: 10.1038/s41467-025-56442-4.ABSTRACTThe promise of integrating Electronic Medical Records (EMR) and genetic data for precision medicine has largely fallen short due to its omission of environmental context over time. Post-genomic data can bridge this gap by capturing the real-time dynamic relationship between underlying genetics and the environment. This perspective highlights the pivotal role of integrating EMR and post-genomics for personalized health, reflecting on lessons from past efforts, and outlining a roadmap of challenges and opportunities that must be addressed to realize the potential of precision medicine.PMID:39962039 | DOI:10.1038/s41467-025-56442-4

Mol Neurobiol. 2025 Feb 17. doi: 10.1007/s12035-025-04765-0. Online ahead of print.ABSTRACTRecent evidence supports the causal role of both plasma metabolites and gut microbiota (GM) in Parkinson's disease (PD). However, it remains unclear whether GM are responsible for causing PD through plasma metabolites. Here, we used Mendelian randomization (MR) to investigate the intrinsic causal relationships among GM, plasma metabolites, and PD. Summary statistics were derived from a GWAS of 1400 metabolites (N = 8299), GM (N = 18,340), and PD (Ncase = 33,674 and Ncontrol = 449,056). We used two-step/mediation MR (TSMR) to study the mediating effect of plasma metabolites on the association between GM and the risk of developing PD. We detected 54 genetic traits that were causally associated with PD development. According to the TSMR analysis, ceramide had a mediating effect on the relationship between the genus Clostridium sensu stricto 1 and the risk of developing PD (15.35% mediation; 95% CI = 1.29-32.75%). 7-Alpha-hydroxy-3-oxo-4-cholestenoate had a mediating effect on the relationship between the genus Eubacterium xylanophilum group and the risk of developing PD (11.04% mediation; 95% CI = 0.11-27.07%). In the present study, we used MR analysis to investigate the connections among GM, plasma metabolites, and PD. This comprehensive investigation offers insights into the pathogenic mechanisms of PD and the roles of the intestinal microbiota and metabolites in this disease.PMID:39962023 | DOI:10.1007/s12035-025-04765-0

Bioconjug Chem. 2025 Feb 17. doi: 10.1021/acs.bioconjchem.4c00541. Online ahead of print.ABSTRACTIn order to effectively replicate within a host cell, the Legionella pneumophila bacterium secretes effector enzymes into the cytoplasm in order to manipulate cellular host pathways including host ubiquitination. Some of these effectors, the so-called SidE-family, mediate noncanonical phosphoribosyl serine ubiquitination (PR-ubiquitination) of host substrate proteins, contributing to the recruitment of ER-remodeling proteins and the formation of a Legionella-containing vacuole, which is crucial in the early stages of bacterial infection. PR-ubiquitination is a dynamic process that is reversed by other Legionella effectors called deubiquitinases for PR-ubiquitination (Dups). We recently discovered a reactive allosteric cysteine in close proximity to the catalytic triad of DupA, which can be exploited as a target for covalent probe development. We here report on the synthesis of vinyl-sulfonate and fluoro-sulfonate warhead-containing phosphoribosyl ubiquitin probes, where the Arg42 position of ubiquitin is linked to the C1 of ribose via a native guanidinium group, and compare them to triazole-linked probes. In vitro tests on recombinant DupA and SdeAPDE revealed that these probes are able to capture the enzymes covalently. In a pull-down proteomics experiment, DupA and DupB enzymes are enriched from Legionella-infected cell lysates, highlighting the potential of native Arg-riboside linked probes to capture Legionella effector enzymes in a complex proteome.PMID:39961749 | DOI:10.1021/acs.bioconjchem.4c00541

ACS Chem Neurosci. 2025 Feb 17. doi: 10.1021/acschemneuro.4c00844. Online ahead of print.ABSTRACTKynurenine-3-monooxygenase (KMO), a key enzyme in the kynurenine pathway (KP) of tryptophan metabolism, converts kynurenine into the neurotoxic intermediate quinolinic acid (QA). QA, an N-methyl-d-aspartate (NMDA) receptor agonist, increases glutamate release and inhibits its reuptake, resulting in excitotoxic cell death in the hippocampus and striatum. Plasma metabolomics study exhibited KP metabolites as the most altered pathway in patients with chronic kidney disease (CKD). Recently, QA was linked to the kidney-brain axis as one of the major neurotoxins responsible for cognitive impairment in advanced CKD stages. Various preclinical models are being tested to explore different intermediates of KP that can be targeted to ameliorate the central nervous system (CNS) complications of CKD. In this study, an adenine-induced CKD model was developed in C57BL/6 mice, where UPF 648, a selective KMO inhibitor, was administered to observe the changes in KP metabolites in the hippocampus. Treatment with UPF 648 did not alter kidney function or morphology in CKD. KMO inhibition led to decreased plasma QA levels and reduced levels of pro-inflammatory cytokine interleukin-1-β (IL-1β). UPF 648 treatment in CKD ameliorated the characteristic symptoms of motor dysfunction, anxiety, depression, and hippocampus-dependent memory. Important markers for neuronal survival and plasticity through the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TRKB)-cAMP-responsive element binding protein 1 (CREB1) pathway were upregulated in the hippocampus after KMO inhibition. In conclusion, KMO inhibition can be an exciting target to attenuate the neuropsychiatric burden of advanced stages in CKD.PMID:39961731 | DOI:10.1021/acschemneuro.4c00844