PubMed

J Environ Sci (China). 2025 Sep;155:466-474. doi: 10.1016/j.jes.2024.08.008. Epub 2024 Aug 13.ABSTRACTCadmium (Cd) is a common environmental heavy metal pollutant known for its toxic effects on various plants and animals. Cd contamination also poses a threat to Pardosa pseudoannulata, a predator in rice paddies. Results indicate that Cd pollution significantly reduced the levels of Metallothionein, phenoloxidase, and Ca2+. Furthermore, through metabolomics and 16S rDNA sequencing, alterations in the gut microbiota and immune-related metabolites of P. pseudoannulata were identified. The abundance of harmful bacteria such as Staphylococcus increased significantly, while levels of l-Tyrosine, glutathione disulfide, l-Dopa, among others, decreased markedly. Pearson correlation analysis revealed significant associations between various gut microbes and immune-related metabolites, suggesting that Cd may alter the immune system of P. pseudoannulata by modulating its gut microbiota.PMID:40246481 | DOI:10.1016/j.jes.2024.08.008

J Environ Sci (China). 2025 Sep;155:423-430. doi: 10.1016/j.jes.2024.07.006. Epub 2024 Jul 14.ABSTRACTThe problem of soil polycyclic aromatic hydrocarbon (PAH) pollution in coking plant sites has been widely studied in recent years, but there is a lack of research on the correlation between soil microorganisms, soil metabolomics, and soil properties. Thus, in this study, the long-term impact of coke combustion on soil microbial community structure, enzyme activities, and metabolic pathways within a former coking plant site was investigated. Soil samples were collected from both the coking production area (CA group) and office area (OLA group), approximately 0 to 20 cm in depth. Compared with OLA group, elevated levels of 16 PAHs in the list of US EPA were detected by gas chromatography-mass spectrometry in the CA group. Several dominant microorganisms, such as Altererythrobacter, Lysobacter, and Sulfurifustis, were identified by 16 s ribosomal DNA sequencing in the CA group. The fatty acid biosynthesis pathway exhibited specific inhibition, while the phenylalanine metabolic pathway was promoted in response to PAH stress. Long-term PAH exposure led to the inhibition of soil urease activity. The co-occurrence network of microorganisms revealed intricate patterns of co-metabolism and co-adaptation within complex bacterial communities, facilitating their adaptation to and decomposition of soil-borne PAHs. This research could provide valuable insights into the community characteristics and metabolic mechanisms of microorganisms inhabiting PAH-polluted soil within coking plant sites. The findings enhance our understanding of the indigenous soil microbiome and its intricate network dynamics under the persistent stress of PAHs, contributing to a more comprehensive knowledge of soil ecosystems in such environments.PMID:40246477 | DOI:10.1016/j.jes.2024.07.006

Rheum Dis Clin North Am. 2025 May;51(2):213-231. doi: 10.1016/j.rdc.2025.01.002. Epub 2025 Mar 6.ABSTRACTDysbiosis is a feature of patients with systemic sclerosis (SSc). While a causal relationship between the gastrointestinal (GI) microbiota and SSc pathogenesis has not been established, alterations in the GI microbiota are appreciated early in the SSc disease course. Moreover, recent research has illuminated specific microbial signatures that define SSc phenotypes. This review summarizes new research on the GI microbiome in SSc with a focus on technical advancements and the emerging study of the GI metabolome. This review also addresses diverse modalities for manipulating the GI microbiome with the hope of developing preventative treatment strategies to avert progression of SSc.PMID:40246439 | DOI:10.1016/j.rdc.2025.01.002

Environ Toxicol Chem. 2025 Apr 17:vgaf068. doi: 10.1093/etojnl/vgaf068. Online ahead of print.ABSTRACTDissolution methods such as co-solvents are used to solubilize insoluble compounds in exposure experiments. Several exposure studies have followed the guidelines from the Organization for Economic Co-operation and Development where co-solvents are applied at 0.01% v/v of the total exposure volume. Although no observable apical endpoint abnormalities were reported following these guidelines, little is known about the molecular-level impacts of co-solvents used in exposure studies. A targeted metabolomics approach using liquid chromatography coupled with triple quadrupole mass spectrometry was used to assess Daphnia magna responses to four commonly used co-solvents, including acetone (ACT), acetonitrile (ACN), methanol (MeOH), and dimethyl sulfoxide (DMSO), at three different levels (0.01%, 0.05%, and 0.1% v/v) over 48 hr. Based on the observed metabolic disruptions, exposure to MeOH and DMSO induced higher metabolic perturbations in amino acid levels and associated biochemical pathways in comparison to ACT and ACN exposures. However, as with mixtures, when co-solvents are combined with the pollutants under investigation, there is a possibility for additive, synergistic, or antagonistic interactions. Hence, to examine the possible impairments in co-solvent and pollutant mixtures, ACT and ACN applied at 0.01% v/v were chosen to be tested with phenanthridine (PN). Daphnia magna exposure to PN dissolved in ACT had less disruptions; in contrast to PN prepared in ACN, which triggered a higher degree of antagonism in the D. magna metabolic profile. Consequently, exposing D. magna to ACT applied at 0.01% v/v resulted in the lowest metabolic perturbation in both parts of this study, suggesting that it is the least disruptive co-solvent for molecular-level exposure studies involving D. magna.PMID:40246286 | DOI:10.1093/etojnl/vgaf068

Free Radic Biol Med. 2025 Apr 15:S0891-5849(25)00230-8. doi: 10.1016/j.freeradbiomed.2025.04.020. Online ahead of print.ABSTRACTIschemic stroke concurrent with gut microbiome dysbiosis induces intestinal damage, which exacerbates cerebral infarction. Probiotic or prebiotic interventions that reverse gut microbiome dysbiosis can promote recovery after ischemic stroke. Akkermansia muciniphila (AKK) safeguards intestinal health and is a promising probiotic; however, its role in ischemic stroke remains unclear. In this study, we found that live AKK, but not pasteurized AKK, mitigated ischemic-stroke-induced neurological injury, reduced cerebral infarction, and enhanced both blood-brain and intestinal barrier integrity. Moreover, the AKK supernatant reduced intestinal and cerebral injury, demonstrating efficacy comparable to that of live AKK. Metabolomic analysis revealed that the AKK supernatant was significantly enriched in indole lactic acid (ILA), a tryptophan metabolite. ILA levels were elevated in the serum and brains of pseudo-germ-free stroke rats administered AKK. Exogenous gavage with ILA mitigated ischemic-stroke-induced brain and intestinal damage. Mechanistically, ILA activated the aryl hydrocarbon receptor (AhR) and the nuclear transcription factor Nrf2, leading to the upregulation of SLC7A11 and GPX4 protein expression. This attenuated lipid peroxidation and intracellular iron accumulation triggered by ischemic stroke. Notably, intervention with the AhR inhibitor CH223191 abrogated the protective effects of ILA in ischemic stroke rats. These findings suggest that the therapeutic efficacy of AKK in ischemic stroke is at least partially attributable to ILA-mediated ferroptosis inhibition via AhR activation. AKK was selectively enriched by Puerariae lobatae Radix-resistant starch (PRS), promoting ILA generation more effectively than inulin and β-glucan. AKK and PRS synergistically alleviated ischemic-stroke-induced impairments, outperforming monomicrobial or prebiotic treatment alone. These findings reveal the unique mechanisms of AKK in ischemic stroke and provide a viable strategy for the clinical treatment of ischemic stroke through a novel synbiotic combination.PMID:40246252 | DOI:10.1016/j.freeradbiomed.2025.04.020

Plant Sci. 2025 Apr 15:112516. doi: 10.1016/j.plantsci.2025.112516. Online ahead of print.ABSTRACTThe enzyme phosphoenolpyruvate carboxylase (PEPC) plays an important role in the photosynthetic metabolism of higher plants. Although the photosynthetic pathway involving PEPC has been clarified, further investigation is required to elucidate the effects of different light intensity treatments on plant photosynthetic and metabolism of PEPC. In this study, wild-type (WT) Arabidopsis was used as a control to investigate the effect of SaPEPC1 overexpression on the photosynthesis and metabolism of Arabidopsis. The results showed that intense light promoted and weak light inhibited the growth of Arabidopsis. Under different light intensity treatments, overexpression of SaPEPC1 led to increases in the photosynthetic rate (Pn) and photosynthetic enzyme activity (PEPC, Rubisco, PPDK, NADP-ME), a decrease in the intercellular CO2 concentration (Ci), and increases in sucrose accumulation, leaf length, leaf width, and shoot fresh weight. Transcriptomic data analysis revealed that the starch, sucrose, and glutathione metabolic pathways were significantly enriched in transgenic Arabidopsis under intense light. This was accompanied by the up-regulation of multiple differentially expressed genes related to starch and sucrose metabolism, including AtBAM5, AtSUS6, and AtTPS5; the expression of most genes related to glutathione metabolism was down-regulated. A targeted metabolomic data analysis of transgenic Arabidopsis yielded 56 metabolites, the majority of which were found to participate in the tricarboxylic acid (TCA) cycle, followed by glycolysis. The content of L-aspartate, fumaric acid, malic acid, oxaloacetate, citric acid, and succinic acid was higher in transgenic lines than in WT under intense light. In conclusion, the overexpression of SaPEPC1 in Arabidopsis resulted in an increase in the photosynthetic rate and promoted the TCA cycle, and these changes were more pronounced under intense light treatment.PMID:40246244 | DOI:10.1016/j.plantsci.2025.112516

J Stomatol Oral Maxillofac Surg. 2025 Apr 15:102372. doi: 10.1016/j.jormas.2025.102372. Online ahead of print.ABSTRACTOBJECTIVE: Oral Cavity Cancer (OCC) pathogenesis is complex, extending beyond traditional risk factors. While observational studies link oral microbiome dysbiosis, metabolic disturbances, and inflammation to OCC, inherent confounding limits causal inference regarding the putative 'microbiome-metabolite-inflammation' axis in OCC. Establishing causality is crucial.METHODS: We employed a two-sample Mendelian randomization (MR) framework using large-scale GWAS data to address this gap. We systematically evaluated causal effects of 43 oral microbial taxa, 1400 diverse circulating metabolites, and 91 inflammatory proteins on OCC risk. We performed univariable MR (UVMR) for direct effects, multivariable MR (MVMR) adjusting for interactions, and mediation MR dissecting causal pathways.RESULTS: UVMR identified protective effects for Clostridiales (OR = 0.89) and Rothia sp. ASV0016 (OR = 0.91), and increased risk for Bacteroidales (OR = 1.09). Furthermore, 60 metabolites (e.g., glycohyocholate increasing risk; 16α-hydroxy DHEAS-3-sulfate decreasing risk) and two proteins (Cystatin D increasing risk, OR = 1.26; MCP-1 decreasing risk, OR = 0.69) showed causal links to OCC. Crucially, mediation analyses indicated protective microbial effects were partially mediated via specific metabolites, including 5α-androstan-3α,17β-diol disulfate (Clostridiales) and carboxyethyl-GABA (Rothia sp.).CONCLUSIONS: This study provides robust genetic evidence supporting causal roles for specific oral microbes and metabolites in OCC etiology. It offers mechanistic insights into the 'oral microbiome-host metabolism' axis, providing a basis for novel microbiome/metabolite-based biomarkers for early detection and risk assessment, and identifying potential preventative or therapeutic targets.PMID:40246198 | DOI:10.1016/j.jormas.2025.102372

J Lipid Res. 2025 Apr 15:100808. doi: 10.1016/j.jlr.2025.100808. Online ahead of print.ABSTRACTPlasmalogens are a distinct subclass of glycerophospholipids that exhibit unique structural features, notably possessing a vinyl ether linkage at the sn1 position of the glycerol backbone. These specialised lipids play crucial roles in various biological functions. Although the biosynthetic pathway of plasmalogens has been well-characterised, their catabolism remains less studied. In this study, we investigated the impact of global and tissue-specific loss-of-function of a plasmalogen catabolising enzyme, lysoplasmalogenase (TMEM86B), on circulatory and tissue lipidomes. We generated both global and hepatocyte-specific Tmem86b knockout mice using cre-loxP technology. Mice with homozygous global inactivation of Tmem86b (Tmem86b KO mice) were viable and did not display any marked phenotypic abnormalities. Tmem86b KO mice demonstrated significantly elevated levels of the plasmalogens, alkenylphosphatidylethanolamine (PE(P)) and alkenylphosphatidylcholine (PC(P)), as well as lysoplasmalogens, in the plasma, liver, and natural killer cells compared to their wild-type counterparts. The endogenous alkenyl chain composition of plasmalogens remained unaltered in Tmem86b KO mice. Consistent with the global knockout findings, hepatocyte-specific Tmem86b knockout mice also exhibited increased plasmalogen levels in the plasma and liver compared to their floxed control counterparts. Overall, our findings shed light on the role of Tmem86b in plasmalogen catabolism, demonstrating how its ablation leads to an increase in select tissues and cells. This study enhances our understanding of the regulatory mechanisms governing plasmalogen metabolism and highlights the potential of targeting Tmem86b to therapeutically raise plasmalogen levels.PMID:40245986 | DOI:10.1016/j.jlr.2025.100808

J Lipid Res. 2025 Apr 15:100803. doi: 10.1016/j.jlr.2025.100803. Online ahead of print.ABSTRACTIn obesity, adipose tissue (AT) expansion is accompanied by chronic inflammation. Altered lipid composition in the visceral or gonadal white AT (GWAT) directly drive AT macrophage (ATM) accumulation and activation to a proinflammatory phenotype. Sex steroid hormones modulate visceral vs subcutaneous lipid accumulation that correlates with metabolic syndrome, especially in men and post-menopausal women who are more prone to abdominal obesity. Prior studies demonstrated sex differences in GWAT lipid species in HFD-fed mice, but the role of sex hormones is still unclear. We hypothesized that sex hormone alterations with gonadectomy (GX) would further impact lipid composition in the obese GWAT. Untargeted lipidomics of obese GWAT identified sex differences in phospholipids, sphingolipids, sterols, fatty acyls, saccharo-lipids and prenol-lipids. Males had significantly more precursor fatty acids (palmitic, oleic, linoleic and arachidonic acid) than females and GX mice. Targeted lipidomics for fatty acids and oxylipins in the HFD-fed male and female GWAT stromal vascular fraction (SVF) identified higher omega-6 to omega-3 free fatty acid profile in males and differences in polyunsaturated fatty acids (PUFAs)-derived prostaglandins, thromboxanes and leukotrienes. Both obese male and female GWAT SVF showed increased levels of arachidonic acid (AA) derived oxylipins compared to their lean counterparts. Bulk RNA sequencing of sorted GWAT ATMs highlighted sex and diet differences in PUFA and oxylipin metabolism genes. These findings of sexual dimorphism in both stored lipid species and PUFA derived mediators with diet and GX emphasize sex-differences in lipid metabolism pathways that drive inflammation responses and metabolic disease risk in obesity.PMID:40245983 | DOI:10.1016/j.jlr.2025.100803

Aquat Toxicol. 2025 Apr 12;283:107367. doi: 10.1016/j.aquatox.2025.107367. Online ahead of print.ABSTRACTThiamethoxam, a widely applied neonicotinoid pesticide, poses a non-negligible risk to aquatic organisms and has garnered considerable attention. The biological impacts of thiamethoxam on chironomid larvae and protective strategies for tolerance remain to be investigated. In this study, we addressed the functional role of gut microbiota and determined the potential effects of thiamethoxam on physiological status, microbial commensals, and gut metabolome profile. A disturbed physiological status was induced by semi-lethal and sub-lethal thiamethoxam, with a higher concentration resulting in a more rapid and stronger response, as reflected by a conspicuous alteration of detoxifying and oxidative markers. Our results also demonstrated that an intact gut microflora was necessary for chironomid larvae to survive better under thiamethoxam-challenged condition. A low dosage of thiamethoxam could remarkably decrease the relative abundance of beneficial bacterial strains (e.g. Cetobacterium and Tyzzerella) while significantly increase the prevalence of opportunistic pathogens, including the genera Serratia, Shewanella, Aeromonas and Pseudomonas. Additionally, an evident variability of bacterial correlations was observed, and the thiamethoxam exposure impaired the genus-genus interaction and destabilized the whole community structure. The metabolome profile revealed that the toxic factor induced a significant downregulation of metabolites involved in glycolysis, amino acid metabolism and fatty acid metabolism pathways. Notably, the integration of metabolomics and gut microbiota data highlighted that representative substrates related to energy metabolism were negatively correlated with the elevated opportunities pathogens when chironomid larvae were challenged with thiamethoxam. These results suggested that a balanced microbial community was pivotal for maintaining energy expenditure and intake system, thus conferring benefits for chironomid larvae to defend against the invading thiamethoxam and preserve their physical well-being. This work provides theoretical guidance for the practical use of thiamethoxam in aquatic ecosystem and offers insights into the potential mechanisms utilized by chironomid larvae to detoxify pesticides.PMID:40245703 | DOI:10.1016/j.aquatox.2025.107367

J Pharm Biomed Anal. 2025 Apr 11;262:116896. doi: 10.1016/j.jpba.2025.116896. Online ahead of print.ABSTRACTThe gut microbiota plays a relevant role in human health by metabolizing dietary components into bioactive molecules, including short-chain fatty acids and trimethylamine. Understanding how dietary interventions modulate microbial metabolism is key to developing strategies for reducing harmful metabolites such as TMA, a precursor of the pro-atherogenic trimethylamine-N-oxide. In this study, we integrated a dynamic in vitro gastrointestinal model (simgi®) with nanopore sequencing technology and metabolomics to investigate the impact of red thyme extract on microbial trimethylamine metabolism from L-carnitine. Metabarcoding, metagenomic, and metatranscriptomic analyses were performed alongside targeted metabolite quantification. Our results showed that microbial trimethylamine production primarily occurred in the transverse and descending colon compartments, coinciding with increased transcriptional activity of taxa harboring gbu cluster, associated with trimethylamine production. The administration of red thyme extract transiently reduced L-carnitine utilization but had a limited effect on overall trimethylamine levels. In parallel, short-chain fatty acids analysis revealed a shift in microbial fermentation patterns, with Acidaminococcus emerging as a dominant butyrate producer. Carbohydrate-active enzyme profiling identified Bacteroides and Parabacteroides genera as key mucin utilizers under the simulation conditions. These findings highlight the metabolic plasticity of the gut microbiota in response to the presence of L-carnitine and reduced complex carbohydrates availability, and provide new insights into microbial functional responses to dietary interventions targeting trimethylamine metabolism. Additionally, this study represents the first integration of nanopore-based metagenomics and genome-centric metatranscriptomics with targeted metabolomics in a dynamic in vitro gastrointestinal model. This multi-omics approach enabled a detailed reconstruction of the microbial metabolic network involved in L-carnitine utilization and trimethylamine formation, offering a powerful tool for mechanistic studies of gut microbiota-diet interactions.PMID:40245686 | DOI:10.1016/j.jpba.2025.116896

Mult Scler Relat Disord. 2025 Apr 11;98:106440. doi: 10.1016/j.msard.2025.106440. Online ahead of print.ABSTRACTBACKGROUND: Multiple sclerosis (MS) is an autoimmune disease in which inflammation plays a pivotal role in its pathogenesis. The inflammatory response is regulated by a complex network of cells and mediators, including circulating proteins such as cytokines and inflammatory mediators. Metabolomics is a powerful analytical approach that may provide diagnostic and therapeutic targets for MS. However, the causal effects of circulating inflammatory proteins and cerebrospinal fluid metabolites (CSFMs) on MS, as well as whether CSFMs act as mediators, remain unclear.OBJECTIVE: In this study, we obtained data on circulating inflammatory proteins, CSFMs, and MS from the largest genome-wide association study (GWAS) dataset of the International Multiple Sclerosis Genetics Consortium (IMSGC).METHODS: We utilized the Mendelian randomization (MR) mediation analysis method to investigate the causal relationships among circulating inflammatory proteins, CSFMs and MS. Inverse variance weighting (IVW) served as the primary statistical method. Additionally, we explored whether CSFMs act as mediators in the pathway from circulating inflammatory proteins to MS.RESULTS: Our findings reveal that there are five inflammatory proteins associated with MS. MR analysis reveals a positive correlation between the genetic prediction of three inflammatory proteins and the occurrence of MS. Our study reveals a link between 10 CSFMs and MS. Further MR analysis reveals a positive correlation between the genetic prediction of 6 CSFMs and the development of MS. Notably, CSFMs do not exhibit a reverse effect on MS. Our study establishes a significant causal effect of circulating inflammatory proteins and CSFMs on the progression of MS. Furthermore, CSFMs do not serve as an intermediary factor in the pathway connecting inflammatory proteins with MS. Circulating inflammatory proteins and CSFMs are causally associated with MS, and CSFMs do not appear to be intermediate factors in the pathway from inflammatory proteins to MS.PMID:40245661 | DOI:10.1016/j.msard.2025.106440

Food Chem. 2025 Apr 11;483:144316. doi: 10.1016/j.foodchem.2025.144316. Online ahead of print.ABSTRACTIn order to better understand the stability and safety of chicken meat during its storage, to comprehend the changing law of chicken meat, and to screen markers that could characterize the deterioration of chicken meat. In this study, traditional methods for the determination of physicochemical indicators, gas chromatography-ion mobility spectrometry (GC-IMS), electronic nose, and electronic tongue were used to elucidate the quality profiles of chilled chickens during the shelf-life of 0, 1, 2, 4, 6, 8, and 10 d at 4 °C, and non-targeted and targeted metabolomics were utilized for the screening and validation of deterioration markers of chicken meat. The results indicated that the texture of the chilled chicken changed first, followed by volatile flavors. Important aldehydes degrade and ketones and alcohols increase in chicken during storage. Purine metabolism was identified as the primary pathway influencing the deterioration of meat quality, with IMP and AICAR emerging as potential markers for meat quality deterioration. This study systematically analyzed the change rule of chicken meat during its shelf-life, screened markers that could characterize the deterioration of chicken meat, and these results provided a scientific basis for the quality control and shelf-life prediction of chicken meat. Additionally, it laid a foundation for the development of more effective preservation technology, deterioration early warning systems, and fast and convenient detection methods.PMID:40245630 | DOI:10.1016/j.foodchem.2025.144316

Food Chem. 2025 Apr 8;483:144264. doi: 10.1016/j.foodchem.2025.144264. Online ahead of print.ABSTRACTTheabrownin is a key contributor to the flavor and health benefits of dark tea, but its structural characterization and anti-inflammatory properties remain underexplored. This study systematically investigated the physicochemical characteristics and anti-inflammatory mechanisms of Tibetan dark tea theabrownin (TTB). Our findings demonstrate that TTB is a hydroxyl- and carboxyl-rich polyphenolic aromatic polymer, composed of polyphenols, lipids, polysaccharides, and proteins. TTB modulated the NF-κB/Nrf2 signaling pathway, reducing inflammatory cytokines and oxidative stress, which in turn led to a decreased M1/M2 macrophage ratio and alleviated systemic inflammation. Fecal metabolomics analysis indicated that TTB exerts anti-inflammatory effects potentially by regulating key microbial metabolites, such as allantoic acid, and critical metabolic pathways like purine metabolism, as well as the metabolism of lysine, cysteine, phenylalanine, and pyruvate, etc. These findings provide insights into TTB's physicochemical properties and its mechanisms in alleviating systematic inflammation, providing a theoretical basis for the health-promoting effects of Tibetan dark tea.PMID:40245629 | DOI:10.1016/j.foodchem.2025.144264

Food Chem. 2025 Apr 10;483:144217. doi: 10.1016/j.foodchem.2025.144217. Online ahead of print.ABSTRACTMetabolomics was first applied to explore the formation pathway and regulatory factors for advanced glycation end products (AGEs) in preserved egg yolk (PEY) during pickling. Most reactions that contributed to formation of AGEs, including oxidation and/or degradation of matrix/precursors and Maillard reaction, occurred primarily in PEY in early stage, and lipid oxidation occurred prior to protein oxidation. Additionally, the formation of Nε-carboxymethyl-lysine (CML) in PEY was mainly attributed to glyoxal derived from D-glucuronic acid in early stage based on the correlation between metabolites and AGEs. Reactive oxygen radicals from oxidized lipids also promoted the enrichment of CML and Nε-carboxymethyl-lysine (CEL). Moreover, during later stage, the accumulation of CEL was enhanced through methylglyoxal from Schiff bases, and acidic compounds could inhibit AGEs via hindering Maillard reaction. This manuscript pioneered the application of metabolomics to reveal the formation pathway of AGEs, and will provide new perspective on AGEs formation in foods.PMID:40245624 | DOI:10.1016/j.foodchem.2025.144217

Science. 2025 Apr 18;388(6744):297-303. doi: 10.1126/science.adp2433. Epub 2025 Apr 17.ABSTRACTThe extracellular space (apoplast) in plants is a key battleground during microbial infections. To avoid recognition, the bacterial model phytopathogen Pseudomonas syringae pv. tomato DC3000 produces glycosyrin. Glycosyrin inhibits the plant-secreted β-galactosidase BGAL1, which would otherwise initiate the release of immunogenic peptides from bacterial flagellin. Here, we report the structure, biosynthesis, and multifunctional roles of glycosyrin. High-resolution cryo-electron microscopy and chemical synthesis revealed that glycosyrin is an iminosugar with a five-membered pyrrolidine ring and a hydrated aldehyde that mimics monosaccharides. Glycosyrin biosynthesis was controlled by virulence regulators, and its production is common in bacteria and prevents flagellin recognition and alters the extracellular glycoproteome and metabolome of infected plants. These findings highlight a potentially wider role for glycobiology manipulation by plant pathogens across the plant kingdom.PMID:40245141 | DOI:10.1126/science.adp2433

Cancer Res. 2025 Apr 17. doi: 10.1158/0008-5472.CAN-24-3209. Online ahead of print.ABSTRACTThe gut microbiome significantly influences the effectiveness of immune checkpoint blockade (ICB) therapy. However, its clinical application is hindered by the absence of cost-effective production methods. In this study, we demonstrated that oral mannose supplementation inhibits ovarian tumor growth in immunocompetent mice through the enrichment of Faecalibaculum rodentium (F. rodentium). Administration of F. rodentium not only suppressed tumor progression but also enhanced anti-tumor immune responses. Mannose supplementation fostered an immune stimulatory tumor microenvironment, characterized by the expansion and differentiation of progenitor exhausted CD8+ T cells (Tpex). Metabolomics analysis identified propionate and butyrate as critical metabolites driving the mannose-mediated tumor-suppressive effects, which was validated in vivo. Mechanistically, propionate and butyrate enhanced histone acetylation to promote Tpex cell expansion. Moreover, a mannose-related gene signature was associated with favorable response to ICB therapy across multiple cancer types. Supplementation with mannose also improved the efficacy of anti-PD-1 therapy and PARP inhibitor (PARPi) treatment. These findings highlight the role of F. rodentium-derived metabolites propionate and butyrate as key stimulators of Tpex cell expansion, thereby activating anti-tumor immune responses. This underscores the therapeutic potential of mannose supplementation in enhancing cancer immunotherapy outcomes in high-grade serous ovarian cancer.PMID:40245117 | DOI:10.1158/0008-5472.CAN-24-3209

Small. 2025 Apr 17:e2501944. doi: 10.1002/smll.202501944. Online ahead of print.ABSTRACTDepression is a significant global health concern with limited effective treatment strategies to date. Elevated homocysteine is identified as a critical factor contributing to the severity of depression by aggravating neuroinflammation. Herein, this study develops a diverse array of homocysteine-stimulated responsive covalent organic frameworks (COFs) as novel therapeutic agents. Using Schiff-base condensation reactions between cystamine/selenocystamine and various C2- and C3-symmetric aryl aldehydes, it successfully synthesized a library of 20 COFs. The sensitivity and specificity of the resultant COFs for homocysteine clearance are validated using serum samples from patients with depression and a mouse model. Non-targeted metabolomics and transcriptomics analyses revealed that these COFs not only exogenously and directly scavenge homocysteine but also synergistically enhance the transsulfuration pathway within the endogenous metabolic cycle for efficient clearance. Furthermore, these COFs mitigated neuroinflammation by inhibiting inflammatory responses, scavenging reactive oxygen species, and modulating neuronal and microglial activity. They also activated neuroactive ligand-receptor signaling pathways and preserved mitochondrial function, thereby maintaining oxidative phosphorylation. Collectively, these mechanisms resulted in significant improvements in anxiety and depressive behaviors in mice. This study pioneers the therapeutic application of homocysteine-responsive COFs for depression treatment, opening up tremendous opportunities for the biomedical applications of COFs.PMID:40245113 | DOI:10.1002/smll.202501944

PLoS Biol. 2025 Apr 17;23(4):e3003119. doi: 10.1371/journal.pbio.3003119. Online ahead of print.ABSTRACTStem cells have lower facultative heterochromatin as defined by trimethylation of histone H3 lysine 27 (H3K27me3) compared to differentiated cells. However, the mechanisms underlying these differential H3K27me3 levels remain elusive. Because H3K27me3 levels are diluted 2-fold in every round of replication and then restored through the rest of the cell cycle, we reasoned that the cell cycle length could be a key regulator of total H3K27me3 levels. Here, we propose that a short G1 phase restricts H3K27me3 levels in stem cells. To test this model, we determined changes to H3K27me3 levels in mouse embryonic stem cells (mESCs) globally and at specific loci upon G1 phase lengthening - accomplished by thymidine block or growth in the absence of serum (with the "2i medium"). H3K27me3 levels in mESCs increase with G1 arrest when grown in serum and in 2i medium. Additionally, we observed via CUT&RUN and ChIP-seq that regions that gain H3K27me3 in G1 arrest and 2i media overlap, supporting our model of G1 length as a critical regulator of the stem cell epigenome. Furthermore, we demonstrate the inverse effect - that G1 shortening in differentiated human HEK293 cells results in a loss of H3K27me3 levels. Finally, in human tumor cells with extreme H3K27me3 loss, lengthening of the G1 phase leads to H3K27me3 recovery despite the presence of the dominant negative, sub-stoichiometric H3.K27M mutation. Our results indicate that G1 length is an essential determinant of H3K27me3 landscapes across diverse cell types.PMID:40245079 | DOI:10.1371/journal.pbio.3003119

J Agric Food Chem. 2025 Apr 17. doi: 10.1021/acs.jafc.5c01911. Online ahead of print.ABSTRACTHuman milk oligosaccharides (HMOs) may shape intestinal homeostasis, although the optimal form of HMOs to restore the gut microbiota in antibiotic-induced dysbiosis remains unclear. Here, we found that HMOs with various structures modulate microbial communities differently after antibiotic exposure. Lacto-N-neotetraose (LNnT) better promotes the recovery of intestinal microbiota (chiefly Lactobacillus) and increases the level of Bifidobacterium compared to 3'-sialyllactose, 2'-fucosyllactose, and the mixture. Additionally, LNnT decreases the potential pathogenic bacteria Klebsiella level and the microbial dysbiosis index. Although supplementation with LNnT does not decrease the Clostridioides difficile burden or alleviate the decline in the fecal numbers of Lactobacillus and Bifidobacterium after C. difficile infection (CDI), LNnT attenuates intestinal epithelial damage, decreases inflammatory status, and alters metabolome profiles after CDI. Collectively, LNnT may function as a promising prebiotic to promote gut microbiota recovery in the context of antibiotic-induced dysbiosis.PMID:40244944 | DOI:10.1021/acs.jafc.5c01911