PubMed

J Agric Food Chem. 2025 Apr 24. doi: 10.1021/acs.jafc.5c02458. Online ahead of print.ABSTRACTUlcerative colitis (UC) is a chronic inflammatory bowel disease with a rising incidence globally, whereas existing treatments exhibit significant limitations. Coix seed polysaccharide (CSP), a component of traditional Chinese medicine known for its immunomodulatory and antioxidant properties, has not been thoroughly investigated for its role in UC. In this study, CSP was prepared via water extraction and ethanol precipitation, and its protective effects and mechanisms were evaluated using a dextran sulfate sodium salt (DSS)-induced UC mouse model. The results demonstrated that CSP significantly ameliorated DSS-induced UC symptoms, including weight loss, an elevated Disease Activity Index, colon shortening, increased levels of inflammatory cytokines, and intestinal barrier damage. Moreover, CSP reshaped the DSS-induced gut microbiota dysbiosis by increasing gut microbial diversity and regulating the abundance of specific genera, such as increasing Anaerotruncus. Metabolomic analysis revealed that CSP significantly modulated the levels of 116 metabolites, particularly enhancing the beneficial metabolite 3-hydroxybutyrate. Importantly, the preventive effect of CSP on UC was dependent on the gut microbiota and could be transferred via fecal microbiota transplantation. This study demonstrates that CSP, a microecology-regulating polysaccharide, effectively modulates gut microbiota and alleviates symptoms of UC. These findings support the potential of CSP as a dietary supplement for UC prevention and underscore its value in the development of medicinal foods and functional food applications.PMID:40274530 | DOI:10.1021/acs.jafc.5c02458

Chin J Nat Med. 2025 Apr;23(4):480-491. doi: 10.1016/S1875-5364(25)60855-7.ABSTRACTAndrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4+ IL-17A+ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.PMID:40274350 | DOI:10.1016/S1875-5364(25)60855-7

J Med Chem. 2025 Apr 24. doi: 10.1021/acs.jmedchem.4c02549. Online ahead of print.ABSTRACTTo assess how much structural diversity remains unexploited in simple drug scaffolds, we investigated ring systems functionalized with amine handles. Starting from the ring systems database GDB-4c, we enumerated 1139 possible amines and diamines with up to two five-, six-, or seven-membered rings. From the 680 cases not listed in PubChem, we synthesized several unprecedented cis- and trans-fused azepanes and tested possible targets predicted using the polypharmacology browser PPB2. From this screening campaign, an N-benzylated azepane emerged as a potent inhibitor of monoamine transporters with some selectivity toward norepinephrine (NET, SLC6A2) and dopamine transporter (DAT, SLC6A3) inhibition (IC50 < 100 nM) in combination with σ-1R inhibition (IC50 ≈ 110 nM). The in vitro profile, favorable pharmacokinetic properties, and preliminary behavioral and metabolomic effects in mice suggest a potential of N-benzylated bicyclic azepanes to target neuropsychiatric disorders. These experiments highlight the potential of simple but still unexplored scaffolds for drug discovery.PMID:40274264 | DOI:10.1021/acs.jmedchem.4c02549

Int J Biol Macromol. 2025 Apr 22:143437. doi: 10.1016/j.ijbiomac.2025.143437. Online ahead of print.ABSTRACTMoringa oleifera Lamarck seeds (MOS) have been traditionally used in folk medicine and documented for their potential to alleviate type 2 diabetes symptoms, but the potential mechanisms are still unknown. The purpose of this article is to investigate the effects of MSAP (alkali-extracted polysaccharide from MOS) on diabetic rats by assessing its impact on the gut microbiome, diabetes-related biochemical markers, and fecal metabolomics. The results demonstrated that the fasting blood glucose, glucose tolerance, insulin tolerance, insulin level and lipopolysaccharides (LPS) level in the rats treated with MSAP were all improved. Specifically, MSAP was found to modulate the composition and diversity of the gut microbiota, increasing the ratio of Firmicutes/Bacteroidetes, which enhanced the quantity of probiotic Lactobacillus and butyrate-producing bacteria, such as Roseburia, thereby reinforcing the intestinal epithelial barrier. Furthermore, fecal metabolomics indicates that MSAP actively regulates pathways closely associated with diabetes, including sphingolipid metabolism, amino acid synthesis and catabolism, retrograde endogenous cannabinoid signaling, and the modulation of TRP channels by inflammatory mediators. By integrating microbiome and metabolomics data, this study elucidated the mechanisms through which MSAP alleviates diabetes. In conclusion, the findings suggest that polysaccharides from MOS hold potential as a medicinal and edible homologous food for diabetes management.PMID:40274155 | DOI:10.1016/j.ijbiomac.2025.143437

J Ethnopharmacol. 2025 Apr 22:119862. doi: 10.1016/j.jep.2025.119862. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Trigonella foenum-graecum L. (HLB), a widely recognized traditional Chinese medicine, has been historically used for the treatment of diabetes mellitus and its complications. However, the efficacy and mechanism of HLB in the treatment of type 2 diabetes mellitus (T2DM) combined with metabolic-associated fatty liver disease (MAFLD) remain poorly understood AIM OF THE STUDY: To investigate the therapeutic effects of HLB on T2DM combined with MAFLD in mice and elucidate its underlying mechanisms MATERIALS AND METHODS: The indices of glucose and lipid metabolism, along with oxidative stress markers, were measured using commercially available assay kits. Histopathological analyses of liver and colon tissues were conducted. Additionally, the mRNA expression levels of genes related to fatty acid metabolism, inflammatory factors, and intestinal tight junction proteins were quantified using reverse transcription polymerase chain reaction (RT-PCR). Microbiome, metabolomic, and transcriptomic analyses were employed to evaluate gut microbiota composition, metabolic profiles, and liver differential genes, respectively.RESULTS: After a 4-week treatment period, HLB effectively ameliorated abnormalities of glucose-lipid metabolism, hepatic oxidative stress, and inflammatory responses. Furthermore, HLB modulated hepatic function and intestinal damage. Through comprehensive multi-omics analysis, the observed improvements were attributed to the remodeling of the gut microbiota and its metabolic alterations, including an increased abundance of beneficial bacteria, regulation of bile acid metabolism CONCLUSIONS: These findings not only provide a theoretical foundation for the broader application of HLB in traditional Chinese medicine but also offer novel insights into the potential pharmacological mechanisms underlying HLB's efficacy in T2DM and MAFLD treatment.PMID:40274034 | DOI:10.1016/j.jep.2025.119862

Food Chem. 2025 Apr 16;484:144319. doi: 10.1016/j.foodchem.2025.144319. Online ahead of print.ABSTRACTAging plays a crucial role in enhancing the flavor of Huangjiu. This study aims to elucidate the changes in taste attributes of aged Huangjiu and explore the correlation between non-volatile compounds. It showed that aging made the sourness, bitterness, and astringency more pronounced. The content of organic acids and amino acids exhibited specific patterns with aging years. The total taste activity value of organic acids showed an increasing trend, peaking at 54.40 in Huangjiu aged 15 years, which served as a key indicator of sourness intensity. A total of 22 potential contributors to umami and 18 to bitterness were screened based on weighted gene coexpression network analysis. The total content of potential umami contributors was significantly higher in fresh Huangjiu and aging stage I, but declined in later periods, while bitterness contributors increased gradually throughout the aging process. This study provided theoretical support for the taste characteristics of aged Huangjiu.PMID:40273878 | DOI:10.1016/j.foodchem.2025.144319

Ecotoxicol Environ Saf. 2025 Apr 23;297:118169. doi: 10.1016/j.ecoenv.2025.118169. Online ahead of print.ABSTRACTHigh concentrations of energetic compounds in soil pose a serious threat to the ecology and human health. In this study, a combination of plant-microbe remediation was used to remediate soil contaminated with high TNT concentrations. This study aimed to reveal the remediation efficiency, metabolic potential, and microbial community structure in high-concentration TNT-contaminated soils following combined remediation. Five plants and microorganisms were combined to remediate soil contaminated with high concentrations of TNT (1434 mg/kg). The TNT residues in the soil were only 69-125 mg/kg after 60 days. The combined plant-microbe remediation enhanced the soil nitrogen cycle, carbon cycle, and phosphorus metabolism. Untargeted metabolome gas chromatography-mass spectrometry analysis showed that the combined remediation restored fatty acid metabolism, amino acid metabolism, and sugar metabolism pathways in TNT-contaminated soil. Subsequent 16S rRNA diversity analysis showed that the combined microbial agents occupied soil ecological niches. Interaction network analysis showed that phytomicrobial remediation improved the rate of recovery of TNT-contaminated soil by reshaping the microbial structure and metabolic cycles.PMID:40273611 | DOI:10.1016/j.ecoenv.2025.118169

Phytomedicine. 2025 Apr 13;142:156746. doi: 10.1016/j.phymed.2025.156746. Online ahead of print.ABSTRACTBACKGROUND: Artemisia annua. L, as a valuable Chinese medicine, has been applied for millennia in China. Its major active ingredient, artemisinin, has demonstrated diverse pharmacological properties, including anti-inflammatory, antioxidant, and anti-diabetic effects. Recent studies suggest that artesunate (ART), an artemisinin derivative, exhibits promising therapeutic effects on diabetic complications. Nevertheless, the role and underlying mechanisms of ART in the treatment of diabetic xerostomia (DX) remain unclear.AIM: This study aimed to elucidate the effects of ART on DX in a type 2 diabetes mellitus (T2DM) rat model, primarily from the perspective of oral microbiota and salivary gland (SG) metabolism, and to further explore potential mechanisms involved.METHODS: Various assessments including blood levels, insulin resistance (IR), saliva flow rate, as well as histological analyses through hematoxylin and eosin and Masson staining were performed to verify the reliability of DX model and protective effects of ART on the DX. Untargeted metabolomics and 16S rDNA sequencing were employed to respectively evaluate effects of ART on metabolite changes in SG and oral microbiota in the DX rats. Network pharmacology was employed to predict key pathways and targets with critical roles in ART's therapeutic effect on DX. Additionally, molecular docking and molecular dynamics (MD) simulations were utilized to evaluate interactions between ART and the identified key pathway targets. Surface plasmon resonance (SPR) experiment was performed to verify our computational predictions. Finally, molecular biology experiments were conducted to further validate the identified key pathway targets.RESULTS: ART treatment ameliorated the hyperglycemia, IR and hyposalivation, and ameliorated pathological changes and oxidative stress of SGs in the DX rats. Besides, 16S rDNA sequencing suggested that ART alleviated the perturbation of oral microbiota (such as Veillonella, Lactobacillus, Clostridium sensu stricto 1, Escherichia-Shigella, and Dubosiella). Untargeted metabolomics revealed that steroid hormone biosynthesis, taurine and hypotaurine metabolism of SGs in the DX rats were partially corrected by ART treatment. Correlation analysis demonstrated an obvious association between the oral microbiota species and SG metabolites. Network pharmacology analysis identified NF-κB pathway as a critical pathway of ART in treating DX. Meanwhile, molecular docking and MD simulation suggested stable binding of ART to NF-κB/NLRP3 pathway targets, particularly NLRP3. Furthermore, SPR confirmed a stable binding of ART to NLRP3, a key target in the NF-κB/NLRP3 pathway. Oxidative stress indicators involved in NF-κB pathway, including MDA and SOD levels, were significantly reduced after ART intervention. Western blotting and qRT-PCR experiments further revealed that ART inhibited increase of NF-κB/NLRP3 pathway related targets expression, including NF-κB, NLRP3, Caspase1, IL-1β, IL-18, TNF-α, and IL-6 in the SGs of DX rats.CONCLUSION: ART exerted beneficial therapeutic effects on DX by modulating oral microbiota dysbiosis and restoring SG's metabolic profiles, and inhibiting activation of NF-κB/NLRP3 pathway, suggesting its potential novel application in DX treatment.PMID:40273561 | DOI:10.1016/j.phymed.2025.156746

Environ Int. 2025 Apr 12;199:109457. doi: 10.1016/j.envint.2025.109457. Online ahead of print.ABSTRACTThe intestinal microbiome is essential for gastrointestinal and overall health, yet its response to air pollution in children remains underexplored. In a study involving 412 young children from the ENVIRONAGE cohort, stool samples were analysed via Illumina Miseq sequencing to assess microbiome alpha diversity (observed richness, species evenness, and Shannon diversity) and composition. Exposure to previous year particulate air pollution (black carbon, PM2.5, coarse PM, and PM10) was modeled using high-resolution spatial-temporal interpolation models. Multiple linear regression models were adjusted for a priori selected covariables and stratified by sex. Furthermore, we performed a differential relative abundance analysis at family and genus level, while accounting for the same covariables. Statistically significant effect modification by sex was apparent for several intestinal alpha diversity indices and air pollutants. In boys, we observed negative associations between particulate air pollution exposure and intestinal microbiome richness (estimates ranging from -5.55 to -9.06 per interquartile range (IQR) increase in particulate air pollution exposure) and Shannon diversity (estimates ranging from -0.058 to -0.095 per IQR increase). Differently, in girls non-significant positive associations were observed with species evenness (estimates ranging from 0.019 to 0.020 per IQR increase) and Shannon diversity (estimate 0.065 per IQR increase in black carbon). After multiple testing correction, we reported several bacterial families and genera (Streptococcaceae, Clostridiales Incertae Sedis XIII, Coriobacteriaceae, Streptococcus, and Paraprevotella) to be oppositely associated with particulate air pollution exposure in boys and girls. Our findings show a sex-dependent association between particulate air pollution exposure and intestinal microbiome composition, highlighting boys as potentially more vulnerable to diversity loss associated with childhood exposure to particulate pollution.PMID:40273556 | DOI:10.1016/j.envint.2025.109457

Syst Appl Microbiol. 2025 Apr 12;48(3):126606. doi: 10.1016/j.syapm.2025.126606. Online ahead of print.ABSTRACTThe tree of life comprises many deep-branching lineages with no or only very few cultured representatives. One such lineage is the phylum Elusimicrobiota, which contains only two described species and whose biology has been only poorly explored. We isolated three new species from this phylum from the intestinal tracts of cockroaches. Like their closest relative, Elusimicrobium minutum, the only member of the family Elusimicrobiaceae described to date, they are small, pleomorphic gram-negative rods characterized by a distinct cell cycle, and like all ultramicrobacteria, they pass through a 0.22-μm filter membrane. Physiological characterization of all isolates revealed that they are obligately anaerobic fermenters that lack catalase and cytochrome c oxidase activities but can remove oxygen from their environment in a non-respiratory manner. Their substrate range is limited to a few hexoses, such as d-glucose, d-galactose, and N-acetyl-d-glucosamine, which are fermented to lactate, acetate, ethanol, and hydrogen as major products. Comparative genome analysis, which included more than 100 MAGs of uncultured lineages of Elusimicrobiaceae, revealed the underlying metabolic pathways and outlined a new phylogenomic framework of the family. Based on phylogenomic, physiological, and morphological evidence, we describe the new isolates as Parelusimicrobium proximum gen. nov., sp. nov., Elusimicrobium posterum sp. nov., and Elusimicrobium simillimum sp. nov. under the rules of ICNP. Based on high-quality genomes of all uncultured representatives, we propose a comprehensive taxonomy of all lineages in the family under the rules of SeqCode, including the new genera Avelusimicrobium, Proelusimicrobium, and the candidate genus "Pseudelusimicrobium".PMID:40273542 | DOI:10.1016/j.syapm.2025.126606

EBioMedicine. 2025 Apr 23;115:105706. doi: 10.1016/j.ebiom.2025.105706. Online ahead of print.ABSTRACTBACKGROUND: Ovarian cancer (OC) ranks as the most lethal gynaecological malignancy worldwide, with early diagnosis being crucial yet challenging. Current diagnostic methods like transvaginal ultrasound and blood biomarkers show limited sensitivity/specificity. This study aimed to identify and validate serum metabolic biomarkers for OC diagnosis using the largest cohort reported to date.METHODS: We constructed a large-scale OC-associated cohort of 1432 subjects, including 662 OC, 563 benign ovarian disease, and 207 healthy control subjects, across retrospective (n = 1073) and set-aside validation (n = 359) cohorts. Serum metabolic fingerprints (SMFs) were recorded using nanoparticle-enhanced laser desorption/ionization mass spectrometry (NELDI-MS). A diagnostic panel was developed through machine learning of SMFs in the discovery cohort and validated in independent verification and set-aside validation cohorts. The identified metabolic biomarkers were further validated using liquid chromatography MS and their biological functions were assessed in OC cell lines.FINDINGS: We identified a metabolic biomarker panel including glucose, histidine, pyrrole-2-carboxylic acid, and dihydrothymine. This panel achieved consistent areas under the curve (AUCs) of 0.87-0.89 for distinguishing between malignant and benign ovarian masses across all cohorts, and improved to AUCs of 0.95-0.99 when combined with risk of ovarian malignancy algorithm (ROMA). In vitro validation provided initial biological context for the metabolic alterations observed in our diagnostic panel.INTERPRETATION: Our study established a reliable serum metabolic biomarker panel for OC diagnosis with potential clinical translations. The NELDI-MS based approach offers advantages of fast analytical speed (∼30 s/sample) and low cost (∼2-3 dollars/sample), making it suitable for large-scale clinical applications.FUNDING: MOST (2021YFA0910100), NSFC (82421001, 823B2050, 824B2059, and 82173077), Medical-Engineering Joint Funds of Shanghai Jiao Tong University (YG2021GD02, YG2024ZD07, and YG2023ZD08), Shanghai Science and Technology Committee Project (23JC1403000), Shanghai Institutions of Higher Learning (2021-01-07-00-02-E00083), Shanghai Jiao Tong University Inner Mongolia Research Institute (2022XYJG0001-01-16), Sichuan Provincial Department of Science and Technology (2024YFHZ0176), Innovation Research Plan by the Shanghai Municipal Education Commission (ZXWF082101), Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20210700), Basic-Clinical Collaborative Innovation Project from Shanghai Immune Therapy Institute, Guangdong Basic and Applied Basic Research Foundation (2024A1515013255).PMID:40273469 | DOI:10.1016/j.ebiom.2025.105706

Neurology. 2025 May 27;104(10):e213592. doi: 10.1212/WNL.0000000000213592. Epub 2025 Apr 24.ABSTRACTBACKGROUND AND OBJECTIVES: Coffee intake is linked to a reduced risk of Parkinson disease (PD), but whether this effect is mediated by gut microbiota and metabolomic changes remains unclear. This study examines PD-associated metabolomic shifts, caffeine metabolism, and their connection to gut microbiome alterations in a multicenter study.METHODS: We conducted an untargeted serum metabolomic assay using liquid chromatography with high-resolution mass spectrometry on an exploratory cohort recruited from National Taiwan University Hospital (NTUH). A targeted metabolomic assay focusing on caffeine and its 12 downstream metabolites was conducted and validated in an independent cohort from University Malaya Medical Centre (UMMC). In the exploratory cohort, the association of each caffeine metabolite with gut microbiota changes was investigated by metagenomic shotgun sequencing. A clustering-based approach was used to correlate microbiome changes with plasma caffeine metabolite level and clinical severity. Body mass index, antiparkinsonism medication use, and dietary habits (including coffee and tea intake) were recorded.RESULTS: Sixty-three patients with PD and 54 controls from NTUH formed the exploratory cohort while 36 patients with PD and 20 controls from UMMC served as an validation cohort to replicate the plasma caffeine findings. A total of 5,158 metabolites were detected from untargeted metabolomic analysis, with 3,131 having high confidence for analysis. Compared with controls, the abundance of 56 metabolites was significantly higher and that of 7 metabolites was significantly lower (adjusted p < 0.05 and log2 fold change >1) in patients with PD. Caffeine metabolism was significantly lower in patients with PD (p = 0.0013), and serum levels of caffeine and its metabolites negatively correlated with motor severity (p < 0.01). Targeted metabolomic analysis confirmed reduced levels of caffeine and its metabolites, including theophylline, paraxanthine, 1,7-dimethyluric acid, and 5-acetylamino-6-amino-3-methyluracil, in patients with PD; these findings were replicated in the validation cohort (p < 0.05). A clustering approach found that 56 microbiome species enriched in patients with PD negatively correlated with caffeine and its metabolites paraxanthine and theophylline (both p < 0.05), notably Clostridium sp000435655, Acetatifactor sp900066565, Oliverpabstia intestinalis, and Ruminiclostridium siraeum.DISCUSSION: This study identifies PD-related changes in microbial-caffeine metabolism compared with controls. Our findings offer insights for future functional research on caffeine-microbiome interactions in PD.PMID:40273394 | DOI:10.1212/WNL.0000000000213592

Plant Physiol. 2025 Apr 24:kiaf159. doi: 10.1093/plphys/kiaf159. Online ahead of print.ABSTRACTPlant secondary metabolites undergo changes in response to UV-B irradiation. Although UV-B irradiation reduces flavor-associated volatile compounds in detached peach (Prunus persica L. Batsch) fruit, the underlying regulatory mechanisms remain unclear. By integrating proteomic, transcriptomic and metabolomic data from peach fruit following UV-B irradiation, we discovered that the detached fruit responds to UV-B by suppressing the biosynthesis of the flavor-related monoterpene linalool. We identified PpMADS2, a transcription factor that regulates linalool biosynthesis by activating terpene synthase 1 (PpTPS1) expression. PpMADS2 overexpression in peach and tomato fruits significantly increased linalool levels compared to the controls. Proteomic data and immunoblots revealed a decrease in PpMADS2 abundance following exposure to UV-B. Moreover, our results demonstrated that PpMADS2 interacts with the E3 ubiquitin ligase PpCOP1 both in vitro and in vivo. The UV-B induced 26S-proteasome-mediated degradation of PpMADS2 is largely PpCOP1-dependent. Taken together, our findings demonstrate that linalool biosynthesis in detached peach fruit exposed to UV-B radiation is governed by the PpCOP1-PpMADS2-PpTPS1 module. This study enhances our understanding of the interplay between light signaling and fruit flavor quality. Multi-omics approaches offer valuable resources for investigating the mechanisms underlying how light influences metabolism in fruit crops.PMID:40273302 | DOI:10.1093/plphys/kiaf159

PLoS One. 2025 Apr 24;20(4):e0322034. doi: 10.1371/journal.pone.0322034. eCollection 2025.ABSTRACTINTRODUCTION: Urolithiasis is one of the most common diseases worldwide, characterized by high morbidity and significant treatment-related costs, with a rising prevalence of up to 20%. The relapse rate within the first 10 years after initial treatment is estimated to be about 60%. Given the increasing prevalence, healthcare-related costs associated with urinary tract stones in the USA are expected to reach up to US $1.24 billion annually by 2030. Current prophylactic therapy for urolithiasis recurrence includes lifestyle modifications, citrate supplementation, and pharmaceuticals. However, a high number of cases remain unresponsive to available pharmacological therapies. Though initially developed for the treatment of Diabetes mellitus, SGLT-2 inhibitors have shown promise in decreasing cardiac and renal endpoints across multiple indications. Recent registry studies have indicated that patients receiving SGLT-2 inhibitors exhibit lower rates of urolithiasis incidence, suggesting a potential reduction in recurrence rates and associated mortality.OBJECTIVES: We hypothesize that SGLT-2 inhibitors (Dapagliflozin), owing to their multiple pleiotropic effects, may offer a viable treatment option for the prophylaxis of high-risk calcium oxalate kidney stones and reduce urinary calcium oxalate output.METHODS: This study will proceed in two phases: an exploratory phase and a randomized controlled phase. In the exploratory phase, 22 participants with indications for dapagliflozin treatment will be evaluated before and after treatment initiation to ascertain the concrete effect size regarding oxalate and calcium-sparing effects. This data will inform the calculation of the study sample size (ranging from 17 to 104 participants) to include high-risk calcium oxalate kidney stone formers in a randomized controlled crossover study design. Treatment phases-one with dapagliflozin and one with placebo-will alternate with wash-out phases involving placebo. The primary outcome is the reduction of oxalate excretion in 24-hour urine samples compared to baseline values after 8 weeks of therapy. Secondary objectives include analysing effects on kidney function, the frequency of urolithiasis, and treatment tolerance. Additionally, in-depth metabolomics analyses will explore pathophysiological pathways during treatment. Investigators, patients, and research staff will be blinded to the randomization list. This study was initially registered under EudraCT (Nr:2022-000994-13) and has been transitioned to CTIS (Nr: 2024-519371-25-00) to comply with EU Regulation 536/2014, ensuring streamlined management and transparency.DISCUSSION: Dapagliflozin's pleiotropic effects may provide a novel prophylactic treatment option for urolithiasis. This study aims to evaluate potential treatment effects in a prospective RCT and elucidate potential pathophysiological pathways through in-depth metabolomics analyses. SGLT-2 inhibitors have the potential to transform the landscape of urolithiasis treatment, reduce the healthcare burden on individuals and the system, and significantly improve patient quality of life.PMID:40273182 | DOI:10.1371/journal.pone.0322034

JAMA. 2025 Apr 24. doi: 10.1001/jama.2025.2373. Online ahead of print.NO ABSTRACTPMID:40272827 | DOI:10.1001/jama.2025.2373

Biochem Genet. 2025 Apr 24. doi: 10.1007/s10528-025-11111-5. Online ahead of print.ABSTRACTAmmi majus L. is a suitable source for linear, angular furanocoumarins, which have significant medicinal value. There is still a lack of extensive research on the genes involved in the biosynthesis of those valuable metabolites. For this purpose, transcriptome sequencing was performed on immature fruit and the resulting data was assembled as a de novo by Trinity software. Afterward, around seventy thousand transcripts were identified. Further analysis revealed the identification of thirty-eight genes involved in the biosynthetic pathways of MEP, MVA, linear and angular furanocoumarins, monoterpenoids, and sesquiterpenes. The content of psoralen, xanthotoxol, isopimpinellin, and pimpinellin was also measured in vegetative leaves, immature fruit, and fruiting leaves. Generally, the concentration of the metabolites was higher in immature fruit compared to other tissues. The expression of Amblyferon-8-dimethylallyl-transferase (U8DT), Amblyferon-6-dimethylallyl-transferase (U6DT), Psoralen synthase (PS), and Xanthotoxol-o-methyltransferase (XOM) were much higher in the immature fruit tissue than those in fruiting and vegetative leaves. The results showed that the expression of the U8DT gene in immature fruit increased 13.3-fold compared to vegetative leaves. The U6DT and PS genes in immature fruit tissue exhibited a 1.6-fold increase in expression compared to vegetative leaves, while the XOM gene showed a 1.5-fold increase in immature fruit compared to vegetative leaves. Integrated metabolome and transcriptome analysis indicated that these genes may serve crucial roles in furanocoumarins biosynthesis in A. majus. These findings can be a good prospect for further research in secondary metabolite production and metabolite engineering in this plant.PMID:40272701 | DOI:10.1007/s10528-025-11111-5

Adv Anat Embryol Cell Biol. 2025;240:297-329. doi: 10.1007/978-3-031-70126-9_7.ABSTRACTNew and emerging technologies allow for a deeper and more comprehensive understanding of sperm physiology that can be harnessed to improve bull fertility selection. This chapter focuses on (1) the use of conventional and emerging flow cytometry techniques to further enhance functional sperm assessments; (2) new developments in proteomic and metabolomic biomarkers of bull fertility and how they can better inform fertility evaluations; and (3) the use of sperm selection technologies to optimize the fertility outcomes of bulls in artificial insemination service. As our knowledge of sperm physiology continues to expand, technology will allow for a faster translational capacity and continuous development of techniques. The technologies and techniques presented are current tools that can be used to enhance the efficiency, precision and accuracy of bull fertility assessments and better inform herd management.PMID:40272592 | DOI:10.1007/978-3-031-70126-9_7

Elife. 2025 Apr 24;14:RP105576. doi: 10.7554/eLife.105576.ABSTRACTA glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites-lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)-linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64-0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.PMID:40272416 | DOI:10.7554/eLife.105576

J Bone Miner Res. 2025 Apr 24:zjaf059. doi: 10.1093/jbmr/zjaf059. Online ahead of print.ABSTRACTAmbient air pollution has been associated with bone damage. However, no studies have evaluated the metabolomic response to air pollutants and its potential influence on bone health in postmenopausal women. We analyzed data from WHI participants with plasma samples. Whole-body, total hip, femoral neck, and spine BMD were determined using dual-energy X-ray absorptiometry (DXA) at enrollment and follow-up visits (Years 1, 3, 6, and 9 visits; Y1, Y3, Y6, Y9, respectively). Geocoded, participant address-specific, daily particulate matter nitrogen oxide (NO), nitrogen dioxide (NO2), particulate matter ≤10 μm (PM10), and sulfur dioxide (SO2) concentrations were averaged over 1-, 3-, and 5-yr periods before plasma sampling for metabolomic assessments. (at baseline and Y1 visit). The averages were then integrated using masked WHI participant identifiers. Statistical analyses included multivariable-adjusted linear mixed models, pathways analyses, and mediation modeling. At all averaging periods, NO, NO2, and SO2, but not PM10, were associated with taurine, inosine, and C38:4 phosphatidylethanolamine (PE). We found a partial potential mediation of C38:4 PE in the association between 1-yr average NO and lumbar spine BMD (p-value: 0.032). This is the first study suggesting phospholipids may partially mediate air pollution-related bone damage in postmenopausal women.PMID:40272393 | DOI:10.1093/jbmr/zjaf059

J Agric Food Chem. 2025 Apr 24. doi: 10.1021/acs.jafc.5c00194. Online ahead of print.ABSTRACTSilica nanoparticles (SiO2 NPs) have potential for mitigating salt stress in crops; however, the effects of surface modifications in enhancing their effectiveness remain unclear. This study investigated the effects of pristine and functionalized SiO2 NPs (SiO2-NH2 and SiO2-COOH) on soybean growth, root metabolism, and microbiome dynamics under 200 mM NaCl stress. All SiO2 NPs treatments significantly reduced Na+/K+, with SiO2-COOH NPs showing the greatest efficacy, reducing by 46.6%. Enhanced salt tolerance correlated with altered root metabolism, including increased l-tyrosine, uridine, and indole-3-acetamide levels and enrichment of stress-response pathways. Furthermore, SiO2-COOH NPs enhanced microbial diversity, increasing the abundance of beneficial genera Variovorax and Pseudomonas in the endosphere, and Haliangium and Arthrobacter in the rhizosphere. Microbe-metabolite correlations suggest that altered root exudation under functionalized SiO2 NPs treatments selectively recruits beneficial bacteria, enhancing salt tolerance. These findings highlight the potential of functionalized SiO2 NPs, particularly SiO2-COOH, as nanoenabled biostimulants for sustainable agriculture.PMID:40272208 | DOI:10.1021/acs.jafc.5c00194