PubMed

Front Plant Sci. 2025 Mar 31;16:1517434. doi: 10.3389/fpls.2025.1517434. eCollection 2025.ABSTRACTThe role of brassinolides (BRs) in regulating the synthesis of plant secondary metabolites has been recognized. However, the effect of brassinolides on the synthesis of saikosaponin in Bupleurum chinense DC. (B. chinense) is still unresolved, To address this knowledge gap, experiments were conducted in which different concentrations (0 mg/L as CK, 0.1 mg/L, 0.2 mg/L, and 0.4 mg/L) of BRs solution were sprayed on B. chinense taproot in the present study. We measured the growth indicators of each group of B. chinense, used quantitative real-time PCR (qRT-PCR) to determine the expression level of genes related to the biosynthesis of saikosaponin, used terpenoid-targeted metabolomics to determine the accumulation of saikosaponin, and verified the metabolomics results by HPLC. Following a 12-day treatment with the 0.2 mg/L BRs solution, the fresh and dry root weights, the taproot length, and the taproot diameter of B. chinense escalated by 60.35%, 60.11%, 25.17%, and 28.07% respectively, in comparison with the CK group. The expression of genes related to the biosynthesis of saikosaponin (HMGR, DXR, IPPI, FPS, SE, P450-2, and P450-3) significantly increased. Moreover, a terpenoid-targeted metabolomic investigation identified 27 distinct saikosaponins, inclusive of saikosaponin A and D, with a notable accumulation observed in 17 saikosaponins. The HPLC findings indicated that the contents of saikosaponin A and D elevated by 72.64% and 80.75% respectively when treated with 0.2 mg/L BRs solution. Conversely, the treatment of 0.4 mg/L BRs solution did not exhibit any significant alteration in the concentrations of saikosaponin A and D when compared to the CK group. In conclusion, the 0.2 mg/L BRs solution demonstrates a more pronounced regulatory impact on the synthesis of saikosaponin A and D. Our investigation revealed that the accumulation of these crucial medicinal bioactive compounds, saikosaponin A and D, can be enhanced through the application of a 0.2 mg/L BRs solution in the ecological cultivation of B. chinense.PMID:40230607 | PMC:PMC11994733 | DOI:10.3389/fpls.2025.1517434

Front Plant Sci. 2025 Mar 31;16:1552429. doi: 10.3389/fpls.2025.1552429. eCollection 2025.ABSTRACTINTRODUCTION: With the rapid decline in wild Bupleurum scorzonerifolium (BSW) resources, large-scale planting of cultivated B. scorzonerifolium (BSC) has begun. However, the effects of growth years on the quality of BSC, as well as the quality difference between BSC and BSW remain unclear.METHODS: This study utilized trait characteristics, microstructure, cell wall components, sugar components, main pharmacological substances, metabolomics, and transcriptomics as key indicators and techniques, to comprehensively characterize and investigate the molecular mechanisms underlying the quality differences between BSC of different growth ages (1-3 years) and between BSC and BSW.RESULTS AND DISCUSSION: As the growth years increased, the root weight of BSC continuously increased, accompanied by root head expansion. Root length and middle and lower section diameters showed significant increases from 1 to 2 years, stabilizing from 2 to 3 years. The ratio of phloem width to xylem radius, along with the contents of total saponins and saikosaponins a, b2, c, and d, exhibited a trend of initial decrease, followed by an increase. Additionally, the number and size of oil cavities and ducts, as well as the volatile oil content, continuously increased. Metabolomic and transcriptomic analyses identified saponins and terpenoids as the primary differential components between different BSC growth years, with genes Bchns02G071080 and Bchns05G031860 (saponins) and Bchns01G03800 (terpenoids) identified as potential key regulatory genes. Furthermore, compared to the long-established, high-quality BSW, 3-year-old BSC (BSC3) showed the closest resemblance in morphological traits, microstructure, and chemical component content, particularly for key pharmacological substances, such as volatile oil, total saponins, and saikosaponins a, b2, c, and d. Considering both quality and economic benefits, BSC3 is recommended as a substitute for BSW. To the best of our knowledge, this is the first study to report the effects of growth years on the quality of BSC, offering valuable insights for guiding the artificial cultivation and quality assurance of B. scorzonerifolium.PMID:40230605 | PMC:PMC11994674 | DOI:10.3389/fpls.2025.1552429

iScience. 2025 Mar 13;28(4):112221. doi: 10.1016/j.isci.2025.112221. eCollection 2025 Apr 18.ABSTRACTHere, we aim to improve our understanding of various colorectal cancer (CRC) risk factors (obesity, unhealthy diet, and gut microbiota/metabolome alteration), analyzing 120 patients with colon polyps, divided in normal-weight (NW) or overweight/obese (OB). Dietary habits data (validated EPIC questionnaires) revealed a higher consumption of processed meat among OB vs. NW patients. Both mucosa-associated microbiota (MAM) on polyps and lumen-associated microbiota (LAM) analyses uncovered distinct bacterial signatures in the two groups. Importantly, we found an enrichment of the pathogenic species Finegoldia magna in MAM of OB patients, regardless of their polyp stage. We observed distinct mucosal-associated metabolome signatures, with OB patients showing increased pyroglutamic acid and reduced niacin levels, and performed microbiota-metabolome integrated analysis. These findings support a model where different risk factors may contribute to tumorigenesis in OB vs. NW patients, highlighting the potential impact of processed meat consumption and F. magna on CRC development among OB patients.PMID:40230532 | PMC:PMC11995084 | DOI:10.1016/j.isci.2025.112221

Biomed Chromatogr. 2025 May;39(5):e70086. doi: 10.1002/bmc.70086.ABSTRACTXuanbi Decoction (XBD) is a classical traditional Chinese medicine (TCM) effective in treating different types of arthritis. This study aimed to integrate metabolomics with network pharmacology to identify active metabolic components of XBD, elucidate its therapeutic targets, and reveal the key signaling pathways involved in the treatment of gout. The study systematically analyzed the material basis and potential mechanisms underlying XBD efficacy in gouty arthritis (GA). First, 352 blood metabolites from XBD were screened by extracting the drug-containing serum and utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS). Twenty-two key ones were identified through correlation analysis. Two-hundred fifty-five metabolite-related targets and 764 GA-related targets were retrieved from multiple databases. Further analysis of the intersection of targets identified 60 key overlapping targets. PPI network analysis elucidated the interrelationships among the 60 targets. GO and KEGG pathway enrichment analyses were conducted on these crossover targets, identifying 25 GO terms and 20 KEGG pathways. Network diagrams were constructed, featuring "22 metabolites-60 targets-25 GO terms" and "22 metabolites-60 targets-20 KEGG pathways." Additionally, a comprehensive network map was constructed, featuring "9 XBD drugs-22 active metabolic components-60 core targets-25 signaling pathways," elucidating the multidimensional intervention mechanism of XBD on GA, offering insights into its clinical application in GA treatment.PMID:40230334 | DOI:10.1002/bmc.70086

Food Funct. 2025 Apr 15. doi: 10.1039/d5fo00475f. Online ahead of print.ABSTRACTHeart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by hypertension, metabolic disorders, and impaired diastolic function, with limited therapeutic options. Recent studies have highlighted the role of ferroptosis in the pathogenesis of HFpEF, and the inhibition of ferroptosis occurrence can significantly improve cardiac function. Limonin, a bioactive ingredient derived from citrus fruits, has been confirmed to exert potential anti-inflammatory and antioxidant effects in some cardiovascular diseases. This study aims to investigate the therapeutic effects of limonin on HFpEF and the underlying mechanisms of inhibiting ferroptosis. HFpEF mice were established by a combination of Nω-nitro-L-arginine methyl ester and a high-fat diet for 6 weeks. Subsequently, the HFpEF mice were treated with empagliflozin or limonin via oral gavage for an additional 6 weeks. Limonin curbed body weight gain and improved metabolic disorders and hypertension. Limonin also ameliorated concentric cardiac hypertrophy and diastolic dysfunction. Transcriptomics and metabolomics analyses revealed that limonin regulated ferroptosis-related pathways and lipid peroxidation. In vivo, limonin improved mitochondrial morphology, reduced cardiac Fe2+ levels and ferroptosis markers such as ROS, 4-HNE and MDA, and increased GSH levels, thereby enhancing antioxidant capacity. Mechanistically, limonin regulated the P53/SLC7A11/GPX4 signaling pathway, promoted the nuclear translocation of Nrf2 (its upstream signaling molecule), and subsequently activated its downstream antioxidant elements, ultimately inhibiting ferroptosis. Furthermore, limonin decreased the expressions of ACSL4, COX2, and ALOXs, which reduced the accumulation of lipid peroxides. These results demonstrate that limonin ameliorates HFpEF by targeting ferroptosis via modulation of the Nrf2/SLC7A11/GPX4 axis, providing a novel strategy for HFpEF treatment.PMID:40230319 | DOI:10.1039/d5fo00475f

J Agric Food Chem. 2025 Apr 15. doi: 10.1021/acs.jafc.5c00079. Online ahead of print.ABSTRACTNonalcoholic fatty liver disease (NAFLD) is a growing global health threat. Human milk oligosaccharides (HMOs) exhibit prebiotic properties that may alleviate NAFLD progression. Herein, our study demonstrates that 3-fucosyllactose (3-FL), a distinctive and crucial HMO, significantly attenuates body weight gain, enhances hepatic lipid metabolism, and reduces inflammation in a high-fat diet (HFD)-induced NAFLD mouse model. These findings suggest its potential as a dietary supplement for preventing and alleviating NAFLD progression. Subsequently, fecal metagenomic and nontargeted metabolomics analyses revealed that 3-FL treatment significantly alleviated HFD-induced gut microbiota dysbiosis, with a specific enhancement of the pantothenate (vitamin B5) metabolic pathways. Our targeted metabolite analysis further revealed a significant increase in both hepatic and fecal pantothenate concentrations, which contributed to the enhancement of the coenzyme A (CoA)-mediated lipid metabolism pathway. Furthermore, the subsequent population cohort analyses revealed a significant correlation between serum pantothenate levels and the progression of NAFLD, thereby reinforcing its candidacy as a noninvasive diagnostic biomarker. These findings show that 3-FL acts as an effective prebiotic to alleviate NAFLD symptoms, in part by enhancing the gut microbiota-mediated pantothenate/CoA metabolic pathway.PMID:40230307 | DOI:10.1021/acs.jafc.5c00079

Insect Sci. 2025 Apr 14. doi: 10.1111/1744-7917.70054. Online ahead of print.ABSTRACTMigratory insects are capable of long-distance flight and strong fecundity, but often have finite amounts of resources available for these energy-demanding traits. Although the trade-off between flight and reproduction has been reported in migratory insects, the optimal timing of flight to reproduction transition remains largely unknown. Here, using the gregarious phase of migratory locust Locusta migratoria, we report that 4-d-old adult females possessed the strongest flight capacity in the first gonadotrophic cycle. Tethered flight assays demonstrated that the timing point between ending of previtellogenesis and beginning of vitellogenesis, when vitellogenin (Vg) was not yet massively synthesized, was optimal for locust flight. Transcriptome and metabolome analyses showed that glycogen and triglyceride were primarily synthesized in the fat body of adult females during previtellogenic stage. Sustained flight of adult females significantly reduced Vg expression levels accompanied by blocked oocyte growth, prolonged preoviposition period and declined egg number. In addition, long-term flight led to significantly reduced expression of juvenile hormone (JH) synthesis genes JHAMT, HMGR, and allatotropin, but not JH metabolism genes JHE and JHEH. Application of JH mimic to JH-deprived 4-d-old adult females at a lower dose was conducive to flight. In contrast, JH administration at higher doses stimulated vitellogenesis and egg production but suppressed flight capacity. Our results suggest that JH along with energy metabolism regulate the optimal timing of flight to reproduction switch in adult females of migratory locust. The findings shed new light on the regulation of trade-off between flight and reproduction, as well as the sustainable control of migratory locusts.PMID:40229961 | DOI:10.1111/1744-7917.70054

J Transl Med. 2025 Apr 14;23(1):440. doi: 10.1186/s12967-025-06113-1.ABSTRACTBACKGROUND: Autoimmune diseases such as Systemic Lupus Erythematosus (SLE), Sjögren's Syndrome (SS), and Hashimoto's Thyroiditis (HT) frequently exhibit neuropsychiatric manifestations, including cognitive impairment, depression, anxiety, and so on, yet the exact pathogenesis underlying this association remain incompletely understood. Dysfunction of brain resting-state functional networks and cerebrospinal fluid (CSF) metabolite disturbances have been widely reported in psychiatric disorders. However, the application of resting-state functional magnetic resonance imaging (rsfMRI) and CSF metabolomics in the diagnosis and monitoring of autoimmune psychosis is still limited.METHODS: A two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationships between three autoimmune diseases (SLE, SS, and HT, n = 14,267 to 402,090 individuals) and 191 rsfMRI phenotypes (n = 47,276 individuals), as well as 338 CSF metabolites. The genome-wide association study (GWAS) of three autoimmune diseases was used as the exposure, whereas rsfMRI phenotypes and 338 CSF metabolites were treated as the outcome. Inverse variance weighted (IVW) with P value < 0.05 was regarded as the primary approach for calculating causal estimates. Additionally, the false discovery rate (FDR)-adjusted P value (PFDR) < 0.05 was utilized to account for multiple testing. MR Egger method, weighted median method, simple mode method and weighted mode method were used for sensitive analysis.RESULTS: Our analyses identified 5 causal relationships between SLE and the 191 rsfMRI phenotypes, 48 between SS and the 191 rsfMRI phenotypes, and 4 between HT and the 191 rsfMRI phenotypes. Additionally, we found 8 causal relationships between HT and CSF metabolites. Furthermore, all three diseases were significantly associated with the temporal lobe and triple networks (default mode network (DMN), salience network (SN), and central executive network (CEN)), which are the core brain regions and functional networks for cognition. Following FDR correction, 6 causal relationships between SS and the 191 rsfMRI phenotypes were further validated.CONCLUSIONS: Our study pinpoints important brain functional networks and CSF metabolites potentially implicated in the pathogenesis of psychiatric disorders associated with autoimmune diseases and highlights critical brain regions for the development of novel therapeutics.PMID:40229769 | DOI:10.1186/s12967-025-06113-1

BMC Plant Biol. 2025 Apr 15;25(1):469. doi: 10.1186/s12870-025-06440-x.ABSTRACTBACKGROUND: Fagopyrum tataricum (Tartary buckwheat) is known for its high phenolic content, particularly rutin. High concentrations of these compounds secreted in the tissue culture medium can lead to its darkening and the eventual death of explants in in vitro cultures. This study aims to enhance the morphogenesis of F. tataricum callus cultures by utilising phenylalanine ammonia-lyase (PAL) inhibitors and polyvinylpyrrolidone (PVP) to mitigate oxidative browning and improve tissue viability.RESULTS: We analysed the response of protoplasts isolated from morphogenic callus to media supplemented with varying concentrations of PAL inhibitors (AIP, AOPP, OBHA) and PVP. The flow cytometry results revealed that 10 µM AIP and 1% PVP yielded exclusively diploid plants, whereas higher concentrations (100 µM AIP and 3% PVP) failed to regenerate plants. Moreover, AOPP and OBHA addition resulted in the regeneration of tetraploid plants. Further analysis of proembryogenic cell complexes (PECCs) isolated from Tartary buckwheat morphogenic calli responses to AIP and PVP indicated that 100 µM AIP was most effective for plant regeneration. Metabolomic analysis showed that AIP treatments reduced phenolic compounds, notably rutin, and increased the GSH/GSSG ratio, indicating reduced oxidative stress. Gene expression analysis highlighted elevated expression of somatic embryogenesis-related genes (LEC2, BBM) and WUSCHEL in AIP-treated callus.CONCLUSIONS: This study demonstrates that AIP enhances the regeneration potential of F. tataricum callus cultures, offering valuable insights for optimising tissue culture techniques for industrial crops. Additionally, we have detailed the metabolomic changes in calli treated with PVP and AIP, highlighting their impact on metabolism.PMID:40229725 | DOI:10.1186/s12870-025-06440-x

BMC Genomics. 2025 Apr 14;26(1):373. doi: 10.1186/s12864-025-11578-x.ABSTRACTBACKGROUND: The light environment significantly influences crop growth, development, quality, and yield, particularly in controlled-environment agriculture. Recent advances in artificial lighting technology have allowed growers to precisely control the light environment in terms of duration, spectrum, and intensity. Starch and protein are the most significant nutritional constituents of maize kernels. However, little is known about the effects of the light environment on starch and protein content in maize kernels. Therefore, we investigated the effects of natural light and supplemental exposure to blue (B), far-red (FR), and red (R) light on starch and protein content in kernels of the inbred maize line B73.RESULTS: Exposure to supplemental B, FR, or R light resulted in significant increases in starch content but decreases in protein content. Notably, protein content was lowest under B light. Substantial proportions of genes (5.03-75.23%) and metabolites (46.89-85.64%) were regulated by different wavelengths of light. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, as well as weighted gene co-expression network analysis (WGCNA), revealed that differentially expressed genes (DEGs) under B, FR, and R light were involved in pathways related to starch and protein synthesis. KEGG metabolomic analysis showed that differentially abundant metabolites (DAMs) were primarily associated with histidine, D-amino acid, cysteine, and methionine metabolism. Nine DEGs related to starch synthesis were identified as potential candidates for investigating the effects of light quality on starch synthesis, and 14 DEGs related to protein synthesis provided evidence for the influence of light quality on protein synthesis in maize.CONCLUSIONS: This study identified the regulatory network governing starch and protein content in B73 maize kernels under different light conditions, contributing to a deeper understanding of how light quality affects the nutritional components of maize kernels.PMID:40229716 | DOI:10.1186/s12864-025-11578-x

Biol Proced Online. 2025 Apr 14;27(1):14. doi: 10.1186/s12575-025-00276-3.ABSTRACTBACKGROUND: The global incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) is increasing annually, which has become a major public-health concern. MAFLD is typically associated with obesity, hyperlipemia, or metabolic syndrome. Dietary induction is one of the most common methods for preparing animal models of MAFLD. However, there are phenotypic differences between methionine-choline-deficient diet (MCDD) and high fat diet (HFD) models.METHODS: To explore the differences in hepatic fatty acid metabolism between MCDD and HFD induced MAFLD, we analyzed serum and liver tissue from the two MAFLD models.RESULTS: We found that liver fat accumulation and liver function damage were common pathological features in both MAFLD models. Furthermore, in the MCDD model, the expression of hepatic fatty acid transport proteins increased, while the expression of hepatic fatty acid efflux proteins and mRNA decreased, along with a decrease in blood lipid levels. In the HFD model, the expression of hepatic fatty acid uptake proteins, efflux proteins and efflux mRNA increased, along with an increase in blood lipid levels.CONCLUSION: Impaired fatty acid oxidation and increased hepatic fatty acid uptake play key roles in the pathogenesis of the two MAFLD models. The inverse changes in de novo lipogenesis and fatty acid efflux may represent an important pathological mechanism that leads to the phenotypic differences between the MCDD and HFD models.PMID:40229695 | DOI:10.1186/s12575-025-00276-3

BMC Plant Biol. 2025 Apr 15;25(1):470. doi: 10.1186/s12870-025-06497-8.ABSTRACTBACKGROUND: Carrot is a root vegetable abundant in numerous nutritional values. Sugar is one of the most important carbohydrates in horticultural products that play important roles in plant growth and development and response to biotic and abiotic stresses. However, the dynamics of the metabolites including sugar during carrot root development still remain unclear. Here, the differential metabolites in carrot roots at different developmental stages were measured using an UPLC-ESI-MS/MS system. The accumulation profiles of metabolites, especially sugars, as well as the transcript patterns of Sugars Will Eventually be Exported Transporter (SWEET) genes were intensively examined.RESULTS: The results identified 727 metabolites over all the samples detected, of which, 539 metabolites were found to be differential accumulated. A total of 34 differentially accumulated sugar metabolites were identified over the period of root development. Furthermore, 17 DcSWEET genes were detected to be specifically expressed in the roots, indicating a potential for root enlargement and sugar accumulation in carrot root.CONCLUSIONS: The results from the current study would help carrot breeding focused on yield and quality improvement.PMID:40229666 | DOI:10.1186/s12870-025-06497-8

Histochem Cell Biol. 2025 Apr 14;163(1):44. doi: 10.1007/s00418-025-02372-7.ABSTRACTPeroxisomes have gained increasing attention and are now considered vital players in normal physiological functions. To gain further insight into how peroxisomal defects influence cellular functions, we developed BV-2 microglial models featuring CRISPR/Cas9 gene-edited mutations in peroxisomal Acox1 or Abcd1 and Abcd2 genes. The Acox1-/- BV-2 cell line we generated lacks acyl-CoA oxidase 1, the key enzyme that initiates peroxisomal β-oxidation. In contrast, the double mutant Abcd1/d2-/- BV-2 cell line carries mutations in the genes encoding the membranous ABC transporters ABCD1 and ABCD2, which are responsible for transporting fatty acyl-thioesters inside peroxisome. Here, for the first time, we used analytical fractionation to compare these three genotypes. Through flow cytometry, we observed an increase in cell granularity in these mutant cells, which could be associated with alterations in peroxisome distribution and mitochondrial dynamics. Additionally, the analysis of organelle markers in microglial cells, employing differential centrifugation, exhibited an enrichment of peroxisomes particularly in both L and P fractions of these BV-2 cell line models. The use of an isopycnic Nycodenz density gradient showed that peroxisomes sedimented with a median density of 1.18 g/ml. Notably, our results revealed no significant differences in the distribution profiles of organelles when comparing microglial BV-2 Wt cells with deficient Acox1‒/‒ or Abcd1/d2-/‒ BV-2 cells, which lack peroxisomal fatty acid beta-oxidation. Our study is the first to report on the fractionation of brain-derived microglial cells, laying valuable groundwork for future proteomic and/or metabolomic analyses of peroxisome fractions.PMID:40229507 | DOI:10.1007/s00418-025-02372-7

Sci Rep. 2025 Apr 14;15(1):12782. doi: 10.1038/s41598-025-97641-9.ABSTRACTCholangiocarcinoma (CCA) has high recurrence rates that severely limit long-term survival. Effective tools for accurate recurrence monitoring and diagnosis remain lacking. Metabolic reprogramming, a key driver of CCA growth and recurrence, is underutilized in cancer screening and management. This study aimed to identify metabolite-based biomarkers to evaluate recurrence severity, enhance disease management, and elucidate the molecular mechanisms underlying CCA recurrence. A comprehensive, non-targeted serum metabolomics analysis using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was conducted. Support Vector Machine (SVM) modeling was employed to develop a predictive framework based on metabolite biomarkers. The analysis revealed significant alterations in metabolomics and lipidomics across CCA recurrence subtypes. Notably, changes in metabolites such as amino acids, lipid-derived carnitines, and glycerophospholipids were associated with cancer progression through enhanced energy production and lipid remodeling. The SVM-constructed metabolite-based predictive model demonstrated predictive accuracy comparable to current clinical diagnostic standards. These findings provide novel insights into the metabolic mechanisms underlying CCA recurrence, addressing critical clinical challenges. By advancing early diagnostic approaches, particularly for preoperative detection, this study offers a reliable method for predicting recurrence in CCA patients. This enables effective treatment planning and supports the development of personalized therapeutic strategies, ultimately improving patient outcomes.PMID:40229491 | DOI:10.1038/s41598-025-97641-9

EMBO Rep. 2025 Apr 14. doi: 10.1038/s44319-025-00447-z. Online ahead of print.ABSTRACTGroup A Streptococcus (GAS) causes various human diseases linked to virulome expression predominantly regulated by the two-component system (TCS), CovR/S. Here, we demonstrate that asparagine (Asn) presence in a minimal chemically defined medium increases virulence gene expression in a CovR-dependent fashion. It also decreases the transcription of asparagine synthetase (AsnA), the ABC transporter responsible for Asn uptake (GlnPQ), and that of the hemolysin toxins responsible for scavenging Asn from the host. Metabolomics data show that Asn availability increases intracellular ADP/ATP ratio, which enhances phosphatase activity in structurally related CovS sensors and is probably responsible for the Asn-mediated decrease in CovR phosphorylation. Mutants deficient in AsnA, GlnPQ, asparaginase, (AsnB) activities are attenuated in a mouse model of human GAS invasive soft tissue infection. The similarity between the mechanisms of Asn-mediated regulation of GAS virulence and tumor growth suggests that, as in cancer, components maintaining Asn homeostasis could be targeted for anti-GAS treatments.PMID:40229432 | DOI:10.1038/s44319-025-00447-z

Nat Commun. 2025 Apr 14;16(1):3465. doi: 10.1038/s41467-025-58459-1.ABSTRACTWhile it has been suggested that alterations in the composition of gut microbial metabolites may play a causative role in the pathophysiology of autism spectrum disorder (ASD), it is not known how gut microbial metabolites are associated with ASD-specific brain alterations. In this cross-sectional, case-control observational study, (i) fecal metabolomics, (ii) task-based functional magnetic resonance imaging (fMRI), and (iii) behavioral assessments were obtained from 43 ASD and 41 neurotypical (NT) children, aged 8-17. The fMRI tasks used socio-emotional and sensory paradigms that commonly reveal strong evoked brain differences in ASD participants. Our results show that fecal levels of specific tryptophan-related metabolites, including kynurenate, were significantly lower in ASD compared to NT, and were associated with: 1) alterations in insular and cingulate cortical activity previously implicated in ASD; and 2) ASD severity and symptoms (e.g., ADOS scores, disgust propensity, and sensory sensitivities). Moreover, activity in the mid-insula and mid-cingulate significantly mediated relationships between the microbial tryptophan metabolites (indolelactate and tryptophan betaine) and ASD severity and disgust sensitivity. Thus, we identify associations between gut microbial tryptophan metabolites, ASD symptoms, and brain activity in humans, particularly in brain regions associated with interoceptive processing.PMID:40229237 | DOI:10.1038/s41467-025-58459-1

BMJ Open. 2025 Apr 14;15(4):e102029. doi: 10.1136/bmjopen-2025-102029.ABSTRACTINTRODUCTION: Myocardial protection against ischaemia-reperfusion injury is a key determinant of heart function and outcome following cardiac surgery in children. However, myocardial injury still occurs routinely following aortic cross-clamping, as demonstrated by the ubiquitous rise in circulating troponin. del Nido cardioplegia was designed to protect the immature myocardium and is widely used in the USA but has not previously been available in the UK, where St. Thomas' blood cardioplegia is most common. The del Nido versus St. Thomas' blood cardioplegia in the young (DESTINY) trial will evaluate whether one solution is better than the other at improving myocardial protection by reducing myocardial injury, shortening ischaemic time and improving clinical outcomes.METHODS AND ANALYSIS: The DESTINY trial is a multicentre, patient-blinded and assessor-blinded, parallel-group, individually randomised controlled trial recruiting up to 220 children undergoing surgery for congenital heart disease. Participants will be randomised in a 1:1 ratio to either del Nido cardioplegia or St. Thomas' blood cardioplegia, with follow-up until 30 days following surgery. The primary outcome is area under the time-concentration curve for plasma high-sensitivity troponin I in the first 24 hours after aortic cross-clamp release. Secondary outcome measures include the incidence of low cardiac output syndrome and Vasoactive-Inotropic Score in the first 48 hours, total aortic cross-clamp time, duration of mechanical ventilation and lengths of stay in the paediatric intensive care unit and the hospital.ETHICS AND DISSEMINATION: The trial was approved by the West Midlands-Coventry and Warwickshire National Health Service Research Ethics Committee (21/WM/0149) on 30 June 2021. Findings will be disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Parents will be informed of the results through a newsletter in conjunction with a national charity.TRIAL REGISTRATION NUMBER: ISRCTN13638147; Pre-results.PMID:40228861 | DOI:10.1136/bmjopen-2025-102029

J Med Chem. 2025 Apr 14. doi: 10.1021/acs.jmedchem.5c00614. Online ahead of print.ABSTRACTTo discover new antimalarials, a screen of the Janssen Jumpstarter library against Plasmodium falciparum uncovered the N-acetamide indole hit class. The structure-activity relationship of this chemotype was defined and culminated in the optimized frontrunner analog WJM664, which exhibited potent asexual stage activity and high metabolic stability. Resistant selection and whole-genome sequencing revealed mutations in PfATP4, which was validated as the target by showing that analogs exhibited reduced potency against parasites with resistance-conferring mutations in PfATP4, a metabolomic signature similar to that of the PfATP4 inhibitor KAE609, and inhibition of Na+-dependent ATPase activity consistent with on-target inhibition of PfATP4. WJM664 inhibited gamete development and blocked parasite transmission to mosquitoes but exhibited low efficacy in aPlasmodium berghei mouse model, which was attributed to ATP4 species differentiation and its moderate systemic exposure. Optimization of these attributes is required for N-acetamide indoles to be pursued for development as a curative and transmission-blocking therapy.PMID:40228810 | DOI:10.1021/acs.jmedchem.5c00614

Pharmacol Res. 2025 Apr 12:107736. doi: 10.1016/j.phrs.2025.107736. Online ahead of print.ABSTRACTSex-related differences in asparagine metabolism are associated with cancer prognosis. However, the effect of exogenous asparagine on colorectal cancer (CRC) growth in men and women remain unclear. This study aims to understand the relationship between exogenous asparagine supplementation and 17β-estradiol levels and to elucidate mechanisms underlying sex-dependent signaling during CRC development. We administered asparagine intraperitoneally to tumor-bearing immunodeficient male and female Rag2/Il2RG (R2G2) mice. Asparagine supplementation caused a significant increase in tumor asparagine levels in both the tumor-bearing male and female R2G2 mice but increased serum estradiol levels and suppressed tumor growth in female R2G2 mice only. Additionally, we combined transcriptome, metabolome and immunochemical analyses and found that intraperitoneal asparagine treatment induced sex-dependent intra-tumoral metabolic changes to asparagine, aspartate, glutamine and glutamate levels in CRC cells. We observed that in females, exogenous asparagine exerts a negative feed-back effect on de novo asparagine synthesis and is associated with the activation of a sub-population of macrophages that may secrete 17β-estradiol via an aromatase or cytochrome P450 family 19 (CYP19)-dependent mechanism, resulting in improved tumor-specific survival. Conversely, in male mice, asparagine treatment augments tumor growth and is related to decreased numbers of macrophages, reduction in CYP19-mediated 17β-estradiol secretion leading to worsened tumor-specific survival. Overall, our results reveal a novel and sex-specific role for exogenous asparagine during cancer progression and underscores the importance of understanding mechanisms that control asparagine biosynthesis.PMID:40228761 | DOI:10.1016/j.phrs.2025.107736

Neurobiol Learn Mem. 2025 Apr 12:108053. doi: 10.1016/j.nlm.2025.108053. Online ahead of print.ABSTRACTPrevious reports have shown an association between a Western high-fat diet (HFD) and poor cognitive performance. So far, there are no reports of whether a mild HFD can affect rabbit learning and hippocampal metabolic profile. This study was designed to explore whether feeding a mild HFD (5 % lard and 5 % soy oil) for 20 weeks affected eyeblink discrimination and discrimination reversal learning and hippocampal metabolic profiles. After 20 weeks on the HFD or a normal control diet, all rabbits received one day of adaptation, 20 daily sessions of two-tone discrimination (1-kHz CS + followed by air puff and 8-kHz CS- not followed by air puff), a rest day, and then 40 daily sessions of discrimination reversal (8-kHz CS + and 1-kHz CS-). Compared to rabbits fed a regular chow diet, rabbits fed a mild HFD showed better discrimination evidenced by higher responding to CS+, lower responding to CS-, and a larger discrimination index (CS+ - CS-). Widely targeted metabolomics analysis identified 1805 metabolites in the hippocampus, and significant HFD-induced changes in 162 and 165 differential metabolites in males and females, respectively. These included glycerophospholipids and fatty acyls. KEGG enrichment analysis showed glycerophospholipid metabolism (ko00564) was significantly enriched in the HFD group notably lysophosphatidylethanolamine and lysophosphatidylcholine. In summary, our data show a long-term mild HFD facilitated discrimination learning in rabbits without inducing a metabolic syndrome, and altered the hippocampal metabolic profile, which may affect neuronal cell membrane lipids and behavioral performance.PMID:40228735 | DOI:10.1016/j.nlm.2025.108053