Objective:The incidence and mortality of colorectal carcinoma(CRC)continue to rise globally,highlighting the need to identify modifiable risk factors for early detection and prevention.Previous studies have demonstrat...Objective:The incidence and mortality of colorectal carcinoma(CRC)continue to rise globally,highlighting the need to identify modifiable risk factors for early detection and prevention.Previous studies have demonstrated significant associations between CRC risk and various serum metabolites as well as inflammatory cytokines;however,due to limitations in study design and potential confounding factors,the causal relationships remain unclear.This study aims to investigate the causal relationships between inflammatory cytokines,serum metabolites,and CRC risk,providing a theoretical basis for the development of novel early diagnostic biomarkers and therapeutic targets.Methods:A two-sample Mendelian randomization(MR)design was applied using summary statistics from genome-wide association studies(GWAS).Instrumental variables(IVs)were derived from:1)metabolomics GWAS data of 1400 serum metabolites(n=8299);2)cytokine GWAS data of 91 inflammatory factors(n=14824);and 3)CRC risk data from the FinnGen consortium(6847 cases and 314193 controls).The primary analysis was conducted using the inverse-variance weighted(IVW)method,with sensitivity analyses performed using MR Egger regression and the weighted median method.Effect estimates including odds ratios(OR),95%confidence intervals(CI),and false discovery rates(FDR)were calculated.Results:MR analysis indicated that higher levels of axin-1(AXIN1)(OR=0.84195%CI 0.714 to 0.991)and Fms-related tyrosine kinase 3 ligand(Flt3L)(OR=0.916,95%CI 0.844 to 0.994)were associated with a reduced risk of CRC.In contrast,higher levels of Delta/Notchlike epidermal growth factor-related receptor(DNER)(OR=1.119,95%CI 1.009 to 1.241)and vascular endothelial growth factor A(VEGF-A)(OR=1.078,95%CI 1.011 to 1.150)were associated with an increased risk of CRC(all P<0.05).Metabolomics association analysis further identified 144 serum metabolites significantly correlated with these four key inflammatory cytokines(FDR<0.05),suggesting that they may regulate CRC risk through inflammatory pathways.Conclusion:Specific inflammatory cytokines and serum metabolites have causal relationships with the risk of CRC.These findings provide insights for further exploration of potential risk factors and the development of effective prevention strategies for CRC.展开更多
new heterocyclic dipeptide with a highly functionalized 1,2-oxazadecaline core,named trichodermamide H(1),and three known analogues,along with three known polyketides,were isolated from the fermentation extract of the...new heterocyclic dipeptide with a highly functionalized 1,2-oxazadecaline core,named trichodermamide H(1),and three known analogues,along with three known polyketides,were isolated from the fermentation extract of the mangrovederived fungus Penicillium janthinellum XLN32122.The structure of 1 was elucidated on the basis of extensive 1D and 2D NMR spectra data analysis,HR-ESI-MS,electronic circular dichroism(ECD)calculations.Trichodermamide B(3)exhibited better inhibitory effect on nitric oxide(NO)production in lipopolysaccharide(LPS)induced RAW 264.7 cells with an IC_(50)value of(13.13±0.005)μmol/L than that of the positive control dexamethasone[IC_(50)=(136.84±1.33)μmol/L].Compound 3 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus(MRSA)with an IC_(50)value of 12.5μg/mL,while the positive control vancomycin showed an IC_(50)value of 1.563μg/mL.展开更多
Background:The gut microbiome has emerged as a critical modulator of cancer immunotherapy response.However,the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer(P...Background:The gut microbiome has emerged as a critical modulator of cancer immunotherapy response.However,the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer(PC)remain not fully explored.The study aimed to explore how gut metabolites regulate death-ligand 1(PD-L1)blockade via exosomes and boost immune checkpoint inhibitors(ICIs)in PC.Methods:We recruited 70 PC patients to set up into five subgroups.The integrated multi-omics analysis was performed.In parallel,we validated the function of gut microbiome-associated metabolites on PD-L1 production and immunotherapy treatment efficacy in PC cell lines and transgenic adenocarcinoma of the mouse prostate(TRAMP)models.Results:We identified two metabolites,16(R)-Hydroxyeicosatetraenoic acid(16(R)-HETE)and 6-Keto-Prostaglandin E1(6-Keto-PGE1),that positively correlated with the plasma exosomal PD-L1 levels.The in vitro experiments found that both 16(R)-HETE and 6-Keto-PGE1 can enhance PD-L1 expression at the mRNA,protein,and exosome levels in both human and mouse PC cell lines,which were also validated in vivo based on subcutaneous mouse models.Both metabolites significantly promoted the anti-PD-L1 efficacy against PC in situ on a TRAMP mouse model.Conclusions:Targeting the“gut-tumor metabolic axis”is a promising strategy to improve the efficacy of immune checkpoint inhibitors in tumors.展开更多
Objective Evidence suggests that depleted gut microbialα-diversity is associated with hypertension;however,whether metabolic markers affect this relationship remains unknown.We aimed to determine the potential metabo...Objective Evidence suggests that depleted gut microbialα-diversity is associated with hypertension;however,whether metabolic markers affect this relationship remains unknown.We aimed to determine the potential metabolites mediating the associations ofα-diversity with blood pressure(BP)and BP variability(BPV).Methods Metagenomics and plasma targeted metabolomics were conducted on 523 Chinese participants from the MetaSalt study.The 24-hour,daytime,and nighttime BP and BPV were calculated based on ambulatory BP measurements.Linear mixed models were used to characterize the relationships betweenα-diversity(Shannon and Chao1 index)and BP indices.Mediation analyses were performed to assess the contribution of metabolites to the observed associations.The influence of key metabolites on hypertension was further evaluated in a prospective cohort of 2,169 participants.Results Gut microbial richness(Chao1)was negatively associated with 24-hour systolic BP,daytime systolic BP,daytime diastolic BP,24-hour systolic BPV,and nighttime systolic BPV(P<0.05).Moreover,26 metabolites were strongly associated with richness(Bonferroni P<0.05).Among them,four key metabolites(imidazole propionate,2-hydroxy-3-methylbutyric acid,homovanillic acid,and hydrocinnamic acid)mediated the associations between richness and BP indices(proportions of mediating effects:14.1%–67.4%).These key metabolites were also associated with hypertension in the prospective cohort.For example,each 1-standard deviation unit increase in hydrocinnamic acid significantly reduced the risk of prevalent(OR[95%CI]=0.90[0.82,0.99];P=0.03)and incident hypertension(HR[95%CI]=0.83[0.71,0.96];P=0.01).Conclusion Our results suggest that gut microbial richness correlates with lower BP and BPV,and that certain metabolites mediate these associations.These findings provide novel insights into the pathogenesis and prevention of hypertension.展开更多
AIM:To explore the causal relationship between several possible behavioral factors and high myopia(HM)using multivariable Mendelian randomization(MVMR)approach and to find the mediators among them with mediation analy...AIM:To explore the causal relationship between several possible behavioral factors and high myopia(HM)using multivariable Mendelian randomization(MVMR)approach and to find the mediators among them with mediation analysis.METHODS:The causal effects of several behavioral factors,including screen time,education time,time spent outdoors,and physical activity,on the risk of HM using univariable Mendelian randomization(MR)and MVMR analyses were first assessed.Genome-wide association study summary statistics of serum metabolites were also used in mediation analysis to determine the extent to which serum metabolites mediate the effects of behavioral factors on HM.RESULTS:MR analyses indicated that both increased time spent outdoors and a higher frequency of moderate physical activity significantly reduced the risk of HM.Further MVMR analysis confirmed that moderate physical activity independently contributed to a lower risk of HM.Additionally,MR analyses identified 13 serum metabolites significantly associated with HM,of which 12 were lipids and one was an amino acid derivative.Mediation analysis revealed that six lipid metabolites mediated the protective effects of moderate physical activity on HM,with the highest mediation proportion observed for 1-(1-enyl-palmitoyl)-GPC(p-16:0;30.83%).CONCLUSION:This study suggests that in addition to outdoor time,moderate physical activity habits may have an independent protective effect against HM and pointed to lipid metabolites as priority targets for the prevention due to low physical activity.These results emphasize the importance of physical activity and metabolic health in HM and underscore the need for further study of these complex associations.展开更多
Genome-wide association study(GWAS)data are used to explore the associations between blood metabolites and 5 respiratory diseases:asthma,tuberculosis(TB),chronic obstructive pulmonary disease(COPD),cor pulmonale,and b...Genome-wide association study(GWAS)data are used to explore the associations between blood metabolites and 5 respiratory diseases:asthma,tuberculosis(TB),chronic obstructive pulmonary disease(COPD),cor pulmonale,and bronchitis.The main method of analysis used is the inverse-variance weighted(IVW)approach,complemented by several sensitivity analyses,including MR-Egger regression,the weighted median,the weighted mode,Cochran’s Q test,and the pleiotropy test.Additional directional tests,Meta-analysis and metabolic pathway analyses are conducted for deeper insights.3 metabolites showing significant causal relationships are identified.Catechol glucuronide levels as a protective factor have a positive causal relationship with asthma;the creatine to carnitine ratio has a negative causal relationship with COPD as a risk factor;and the adenosine 5’-diphosphate(ADP)to N-acetylglucosamine to N-acetylgalactosamine ratio as a protective factor has a positive causal relationship with bronchitis.Additionally,13 metabolites demonstrate strong causal relationships.Furthermore,we delineate 14 metabolic pathways related to the outcomes,including 6 associated with asthma,2 with TB,1 with COPD,4 with cor pulmonale,and 1 with bronchitis.A causal relationship between blood metabolites and 5 respiratory diseases has been established.The identified metabolites and pathways offer new insights into the underlying mechanisms of these diseases,necessitating further experimental validation.展开更多
Five novel sulfur-containing benzyl metabolites, designated as gastrabenzylsulfoxides A and B(1 and 2), gastrabenzylsulfinate A(3) and gastrabenzylsulfides A and B(4 and 5), along with four known compounds(6-9), were ...Five novel sulfur-containing benzyl metabolites, designated as gastrabenzylsulfoxides A and B(1 and 2), gastrabenzylsulfinate A(3) and gastrabenzylsulfides A and B(4 and 5), along with four known compounds(6-9), were isolated from the aqueous extracts of Gastrodia elata.Compounds 1 and 4 are 4-hydroxy-3-(4′-hydroxybenzyl)benzyl-substituted sulfoxide and sulfide, respectively, which are unprecedented in natural products. Compound 3 represents a rare sulfinate. Several isolates and their sulfone and disulfide analogs(10-13) were synthesized to evaluate their anti-inflammatory activity. Notably, the synthesized sulfone 10 demonstrated significant alleviation of symptoms in multiple in vivo inflammatory models.展开更多
Chemical exposure during prenatal development has significant implications for both maternal and child health.Compared to blood,saliva is a non-invasive and less resource-intensive,alternative.Given the temporal varia...Chemical exposure during prenatal development has significant implications for both maternal and child health.Compared to blood,saliva is a non-invasive and less resource-intensive,alternative.Given the temporal variability of xenobiotic metabolites(XM),repeated sampling is essential.Therefore,saliva offers a valuable tool for the longitudinal assessment of prenatal exposomes.Despite its potential,no studies have explored saliva for XM measurement.This study pioneered using saliva to assess XM detectability and investigate the associations between prenatal XM and endogenous metabolomes in pregnant women.Saliva samples were analysed using mass spectrometry from 80 pregnant women at 24–34 weeks gestation.Metabolomes and exposomes were annotated using the Human Metabolome and U.S.Environmental Protection Agency databases.Metabolome-XM associations were clustered using Glay community clustering.Linear regression models,adjusted for age,estimated associations between catecholamines and XMs.XM levels were validated in a cohort of women(n=14)with and without preeclampsia.Our study identified 582 metabolomes and 125 XM in saliva,demonstrating its potential as a matrix for exposure measurement.After false discovery rate correction,18109 significant metabolome-XM associations were identified.Community clustering revealed 37 connected clusters,with the largest cluster(238 nodes)enriched in tyrosine and catecholamine metabolism.Food-contactchemicals and food-additives were significantly associated with higher catecholamine and their metabolite levels.Subgroup analyses revealed higher concentrations of these chemicals in women with preeclampsia compared to healthy controls.This study demonstrates that saliva contains valuable molecular data for measuring exposomes.Food-related chemicals were associated with higher catecholamine levels,which may be relevant to the prevalence of hypertensive crises in pregnancy.展开更多
Background Metabolic dysregulation has been implicated in major depressive disorder(MDD).Aims We aimed to explore the potential role of plasma metabolites in MDD.Methods We conducted Mendelian randomisation(MR)analysi...Background Metabolic dysregulation has been implicated in major depressive disorder(MDD).Aims We aimed to explore the potential role of plasma metabolites in MDD.Methods We conducted Mendelian randomisation(MR)analysis to evaluate the causal effects of 871 circulating metabolites on MDD,using the Genome-Wide Association Studies datasets of MDD(N=1035760)and metabolites(N=8299).Bayesian colocalisation and druggability analyses were employed to identify genetic variants contributing to both MDD and levels of metabolites in plasma and to pinpoint metabolites with therapeutic potential,respectively.Results MR analysis identified 11 metabolites associated with MDD(false discovery rate<0.05).Eight metabolites,including arachidonate(20:4n6)(odds ratio(OR):0.97),1-arachidonoyl-GPC(20:4n6)(OR:0.98),1-(1-enylpalmitoyl)-2-palmitoleoyl-GPC(P-16:0/16:1)(OR:0.97),succinoyltaurine(OR:0.98),3-methoxycatechol sulphate(1)(OR:0.98)and 11β-hydroxyandrosterone glucuronide(OR:0.97),showed protective effects against MDD.Three metabolites were associated with increased risk,namely,butyrylglycine(OR:1.03),3-carboxy-4-methyl-5-propyl-2-furanpropanoate(OR:1.02)and 1-(1-enyl-stearoyl)-2-oleoyl-GPE(P-18:0/18:1)(OR:1.02).Colocalisation analysis supported shared genetic signals between five lipid metabolites and MDD,particularly at loci harbouring FADS and ATP9A.Notably,a majority of metabolites associated with MDD are being explored as therapeutic targets for various psychiatric disorders.Conclusions Genetically predicted levels of certain circulating metabolites make a causal contribution to MDD.Further investigation of their roles may provide novel pathophysiological insights and give clues for targeted therapies.展开更多
To investigate the in vitro digestion and fermentation properties of soybean oligosaccharides(SBOS)extracted from defatted soybean meal,the changes in monosaccharide composition and molecular mass were analyzed.Subseq...To investigate the in vitro digestion and fermentation properties of soybean oligosaccharides(SBOS)extracted from defatted soybean meal,the changes in monosaccharide composition and molecular mass were analyzed.Subsequently,the effect of SBOS on microbial community structure and metabolites was studied by 16S rRNA gene sequencing and untargeted metabolomics based on liquid chromatography-mass spectrometry.Results showed that SBOS was not easily enzymolyzed during simulated digestion and could reach the large intestine through the digestive system.The significant decrease in the molecular mass of SBOS after in vitro fermentation indicated its utilization by the gut microbiota,which increased the contents of short-chain fatty acids and lactic acid,thereby reducing the pH of the fermentation broth.Moreover,the core community was found to consist of Blautia,Lactobacillaceae,and Pediococcus.SBOS up-regulated beneficial differential metabolites such as myo-inositol,lactose,and glucose,which were closely related to galactose,amino sugar,and nucleotide sugar metabolism.This study will provide a reference for exploring the relationship between the gut microbiota and the metabolites of SBOS,and provide a basis for the development and application of SBOS as an ingredient for functional products.展开更多
Background:The composition of the intestinal flora and the resulting metabolites af-fect patients'sleep after surgery.Methods:We intended to elucidate the mechanisms by which disordered intestinal flora modulate t...Background:The composition of the intestinal flora and the resulting metabolites af-fect patients'sleep after surgery.Methods:We intended to elucidate the mechanisms by which disordered intestinal flora modulate the pathophysiology of postoperative sleep disturbances in hosts.In this study,we explored the impacts of anesthesia,surgery,and postoperative sleep duration on the fecal microbiota and metabolites of individuals classified postpro-cedurally as poor sleepers(PS)and good sleepers(GS),as diagnosed by the bispec-tral index.We also performed fecal microbiota transplantation in pseudo-germ-free(PGF)rats and applied Western blotting,immunohistochemistry,and gut permeability analyses to identify the potential mechanism of its effect.Results:Research finding shows the PS group had significantly higher postopera-tive stool levels of the metabolites tryptophan and kynurenine than the GS group.PGF rats that received gut microbiota from PSs exhibited less rapid eye movement(REM)sleep than those that received GS microbiota(GS-PGF:11.4%±1.6%,PS-PGF:4.8%±2.0%,p<0.001).Measurement of 5-hydroxytryptophan(5-HTP)levels in the stool,serum,and prefrontal cortex(PFC)indicated that altered 5-HTP levels,includ-ing reduced levels in the PFC,caused sleep loss in PGF rats transplanted with PS gut flora.Through the brain-gut axis,the inactivity of tryptophan hydroxylase 1(TPH1)and TPH2 in the colon and PFC,respectively,caused a loss of REM sleep in PGF rats and decreased the 5-HTP level in the PFC.Conclusions:These findings indicate that postoperative gut dysbiosis and defective 5-HTP metabolism may cause postoperative sleep disturbances.Clinicians and sleep researchers may gain new insights from this study.展开更多
Ethiprole is widely used as a second-generation phenyl pyrazole insecticide.Previous studies indicated that ethiprole exhibited thyroid toxicity while two main metabolites(ethiprole sulfone(M1)and ethiprole sulfide(M2...Ethiprole is widely used as a second-generation phenyl pyrazole insecticide.Previous studies indicated that ethiprole exhibited thyroid toxicity while two main metabolites(ethiprole sulfone(M1)and ethiprole sulfide(M2))of ethiprole showed higher acute toxicity than ethiprole.Therefore,assessing the thyroid toxicity of its metabolites is crucial for safety assessment.In this study,the thyroid toxicity and underlying mechanisms of ethiprole and its metabolites were explored using in silico,in vitro,and in vivo assays,with the aim of conducting a comparative study on thyroid toxicity.Molecular docking analysis showed that ethiprole,M1 and M2 could bind with thyroid receptor isoforms and exhibited higher binding affinity compared to 3,3,5-triiodothyronine(T3).GH3 cell proliferation assays revealed that ethiprole,M1 and M2 all served as thyroid hormone antagonists to hinder the T3-induced cell proliferation.Using the zebrafish model,we further investigated that exposure to ethiprole,M1,and M2 disrupted thyroid hormone levels and the transcriptional expressions of hypothalamus-pituitary-thyroid(HPT)axis-related genes.Ethiprole induced thyroid disrupting effects by binding with the thyroid receptor beta,M1 mainly through binding with the corticotropin releasing factor receptor-1,and M2 exposure firstly inhibited the thyroid peroxidase enzyme activity.M2 showed the highest developmental toxicity and thyroid disrupting effects,which significantly reducing hatching rates,increasing deformity rates,exhibiting the lowest lethal concentration 50 value and showing the most serious transcription inhibitory effects on the HPT axis.This study suggested the risk assessment of metabolites should be considered in assessing potential environmental risk of ethiprole.展开更多
This study investigates the relationships between exposures to ambient air pollution—specifically particulate matter 2.5 (PM_(2.5)) and its metabolites—and the risk of depression.Nonlinear and linear regression,Baye...This study investigates the relationships between exposures to ambient air pollution—specifically particulate matter 2.5 (PM_(2.5)) and its metabolites—and the risk of depression.Nonlinear and linear regression,Bayesian kernel machine regression,and toxicogenomic analysis were key approaches.PM_(2.5)exposure was positively associated with the risk of developing depression,whereas phenylglyoxylic acid exposure was negatively associated with depression risk.We found a significant overall relationship between ambient air pollution and depression,particularly at the 55th and 60th percentiles.Although statistical significance was not reached at the 65th percentile,there was a noticeable upward trend,indicating a potential association.Interestingly,no significant connection was found between a combination of metabolites from ambient air pollution and depression.PM_(2.5)and phenylglyoxylic acid emerged as the most influential compounds in the models,respectively.PM_(2.5)exposure altered the expression of 42 specific targets associated with depression,especially POMC,SCL6A4,IL6,and SOD2.The study identified specific pathways related to insulin secretion,energy metabolism,blood circulation,tube diameter,and maintenance of blood vessel diameter,as well as key molecular mechanisms involving hsa-miR-124-3p,hsa-miR-155-5p,hsa-miR-16-5p,and SP1.These mechanisms were found to underlie the etiology of depression associated with PM_(2.5)exposure.In conclusions,PM_(2.5)and phenylglyoxylic acid were found to be associated with depression.Further work is needed to gain insight into the molecular mechanisms by which these chemicals affect depression,especially pathways related to insulin secretion and blood circulation.展开更多
A new alkaloid,diacedolinate(1),along with fourteen known compounds(2-15)was isolated from the sponge associated fungus Penicillium crustosum SCSIO 41442.The structures of these compounds were determined by spectrum a...A new alkaloid,diacedolinate(1),along with fourteen known compounds(2-15)was isolated from the sponge associated fungus Penicillium crustosum SCSIO 41442.The structures of these compounds were determined by spectrum analysis and ECD.All compounds were evaluated for their antioxidant and antimicrobial activities.The results showed that compound 1 exhibited weak antioxidant activity with an IC_(50)value of(71.00±0.14)μg·mL^(−1),while compound 2,in contrast,displayed broad antioxidant activity with an IC_(50)value of(1.25±0.10)μg·mL^(−1),compared with the positive control,vitamin C.In addition,compounds 9,10,11,and 15 demonstrated broad-spectrum antimicrobial activity against a variety of pathogens,including MRSA,Colletotrichum asianum HNM 408,Colletotrichum acutatum HNM RC178,and Alternaria alternate,with MIC values ranging from 2.5 to 160μg·mL^(−1).The bioactivities of these compounds are reported here for the first time.展开更多
Objective:Gut microbiota(GM)and blood metabolites are associated with the development of urticaria,yet their specific causal relationships in East Asian populations remain unclear.This study aims to elucidate the caus...Objective:Gut microbiota(GM)and blood metabolites are associated with the development of urticaria,yet their specific causal relationships in East Asian populations remain unclear.This study aims to elucidate the causal and mediating relationships among GM,blood metabolites,and urticaria in East Asians using Mendelian randomization(MR)analysis.Methods:Summary-level statistics for 500 GM taxa,112 blood metabolites,and urticaria were obtained from publicly available Genome-Wide Association Studies(GWAS)datasets.Bidirectional MR analyses were performed to examine causal associations among the GM,blood metabolites,and urticaria.The inverse variance weighted(IVW)method served as the primary analytical approach,supplemented by MR-Egger,weighted median,simple mode,and weighted mode methods.Sensitivity analyses included heterogeneity tests,horizontal pleiotropy assessments,and leave-one-out analyses.Mediation analysis was conducted to evaluate the potential mediating effects of blood metabolites on the causal pathways between GM and urticaria.Results:MR analyses identified 12 GM taxa exhibiting significant causal effects on urticaria susceptibility.Nine taxa,such as MF0017_galactose_degradation(OR=1.461,95%CI 1.098 to 1.944,P=0.009),were associated with increased urticaria risk.Three taxa,such as MF0001_arabinoxylan_degradation(OR=0.846,95%CI 0.737 to 0.973,P=0.019),showed protective effects with increased abundance.Additionally,6 blood metabolites demonstrated causal associations with urticaria.Notably,the risk of developing urticaria increases with rising fasting plasma glucose(FPG)levels(OR=1.971,95%CI 1.089 to 3.567,P=0.025).Mediation analysis further demonstrated that FPG partially mediated the protective effect of MF0001_arabinoxylan_degradation on urticaria,accounting for 11.30%of the total effect.Conclusion:This study has delineated specific GM taxa and blood metabolites that hold causal relevance to urticaria in East Asian populations.Notably,arabinogalactan degradation potentially mitigates urticaria risk via reducing FPG concentrations,offering genetic evidence to support therapeutic strategies targeting GM modulation and glucose regulation.展开更多
Nuclear magnetic resonance(NMR)spectroscopy is an excellent tool for simultaneous identification and quantification of metabolites(metabolomics).NMR quantification of human lipoprotein subfractions and their component...Nuclear magnetic resonance(NMR)spectroscopy is an excellent tool for simultaneous identification and quantification of metabolites(metabolomics).NMR quantification of human lipoprotein subfractions and their components has proven to be a powerful approach to reveal pathophysiological insights in numerous diseases[1,2].This method has now been standardized with excellent inter-laboratory reproducibility within 10 days for simultaneous quantification of 105 lipoprotein components and 24 low-molecular weight(LMW)metabolites[3];close clustering was also shown for 12 quality-control(QC)samples measured in 3 months although without statistical details[2].However,these reports[[1],[2],[3]]did not cover many vital parameters for lipoprotein components(e.g.,cholesterol-esters and total-lipids),fatty acids,and N-acetyl-glycoproteins(NAGs).展开更多
The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops,which modulates an approximately...The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops,which modulates an approximately 24-h cycle of endocrine and metabolic rhythms within cells and tissues.While circadian clocks regulate metabolic processes and related physiology,emerging evidence indicates that metabolism and circadian rhythm are intimately intertwined.In this review,we highlight the concept of metabolites,including lipids and other polar metabolites generated from intestinal microbial metabolism and nutrient intake,as time cues that drive changes in circadian rhythms,which in turn influence metabolism and aging.Furthermore,we discuss the roles of functional metabolites as circadian cues,paving a new direction on potential intervention targets of circadian disruption,pathological aging,as well as metabolic diseases that are clinically important.展开更多
The extreme environment of the polar regions has driven the evolution of unique metabolic mechanisms in microorganisms,resulting in structurally diverse and highly active secondary metabolites.These metabolites are no...The extreme environment of the polar regions has driven the evolution of unique metabolic mechanisms in microorganisms,resulting in structurally diverse and highly active secondary metabolites.These metabolites are not only crucial for microbial adaptation to extreme conditions,but also exhibit significant potential for applications in medicine,agriculture(e.g.,biocontrol),and industry.This review provides a comprehensive overview of 111 secondary metabolites derived from polar microorganisms reported between 2013 and 2025,with a focus on advances in their classification,biological activities,and biosynthetic gene cluster mining techniques.Additionally,it highlights key strategies for advancing future investigations,providing a valuable reference for continued exploration in this promising field.Notably,polar microbial secondary metabolites also hold promising applications in agriculture,particularly in biocontrol,soil health enhancement,and stress-resistant crop development.展开更多
The review by Bangolo et al highlights the role of the gut microbiome in cancerassociated anemia(CAA).However,the impact of microbiome-derived metabolites is underexplored.In this letter,we focus on short-chain fatty ...The review by Bangolo et al highlights the role of the gut microbiome in cancerassociated anemia(CAA).However,the impact of microbiome-derived metabolites is underexplored.In this letter,we focus on short-chain fatty acids,tryptophan metabolites,and polyamines as key mediators linking dysbiosis to impaired erythropoiesis and iron homeostasis.We also propose a research framework that integrates multi-omics analysis and gnotobiotic models.Finally,we discuss the clinical potential of metabolite-based diagnostics and microbiome-targeted therapies in managing CAA.展开更多
Inflammatory bowel disease(IBD)is a chronic gastrointestinal disease with a high incidence.Treatment for IBD includes medications and diet,and common anti-inflammatory medications have limitations like drug resistance...Inflammatory bowel disease(IBD)is a chronic gastrointestinal disease with a high incidence.Treatment for IBD includes medications and diet,and common anti-inflammatory medications have limitations like drug resistance and serious adverse effects.Accumulating evidence has demonstrated that dietary flavonoids exhibit an alleviative effect on IBD by influencing gut microbiota.The microbiota-derived metabolites also regulate IBD and maintain intestinal homeostasis.In this review,we investigate the therapeutic effect of gut microbiota and metabolites on IBD by intestinal immune and intestinal barrier function.We demonstrate the underlying mechanism of dietary flavonoids as an anti-inflammatory molecule alleviating IBD by regulating gut microbiota,short chain fatty acid(SCFA),bile acid(BA),tryptophan(Trp)metabolism and lipopolysaccharides(LPS)-toll-like receptor 4(TLR4)signaling pathway.Based on structural differences of flavonoids,we summarize the recent research progress on the role of different dietary flavonoids in alleviating IBD by gut microbiota and metabolites in animal and clinical trials.This review indicates that dietary flavonoids targeting gut microbiota and metabolites provide a promising strategy for the treatment of inflammation and novel insights into the management of IBD.展开更多
基金supported by the Natural Science Foundation of Hunan Province (2022JJ30987)the Key Research and Development Project of Hunan Province (2024JK2107),China。
文摘Objective:The incidence and mortality of colorectal carcinoma(CRC)continue to rise globally,highlighting the need to identify modifiable risk factors for early detection and prevention.Previous studies have demonstrated significant associations between CRC risk and various serum metabolites as well as inflammatory cytokines;however,due to limitations in study design and potential confounding factors,the causal relationships remain unclear.This study aims to investigate the causal relationships between inflammatory cytokines,serum metabolites,and CRC risk,providing a theoretical basis for the development of novel early diagnostic biomarkers and therapeutic targets.Methods:A two-sample Mendelian randomization(MR)design was applied using summary statistics from genome-wide association studies(GWAS).Instrumental variables(IVs)were derived from:1)metabolomics GWAS data of 1400 serum metabolites(n=8299);2)cytokine GWAS data of 91 inflammatory factors(n=14824);and 3)CRC risk data from the FinnGen consortium(6847 cases and 314193 controls).The primary analysis was conducted using the inverse-variance weighted(IVW)method,with sensitivity analyses performed using MR Egger regression and the weighted median method.Effect estimates including odds ratios(OR),95%confidence intervals(CI),and false discovery rates(FDR)were calculated.Results:MR analysis indicated that higher levels of axin-1(AXIN1)(OR=0.84195%CI 0.714 to 0.991)and Fms-related tyrosine kinase 3 ligand(Flt3L)(OR=0.916,95%CI 0.844 to 0.994)were associated with a reduced risk of CRC.In contrast,higher levels of Delta/Notchlike epidermal growth factor-related receptor(DNER)(OR=1.119,95%CI 1.009 to 1.241)and vascular endothelial growth factor A(VEGF-A)(OR=1.078,95%CI 1.011 to 1.150)were associated with an increased risk of CRC(all P<0.05).Metabolomics association analysis further identified 144 serum metabolites significantly correlated with these four key inflammatory cytokines(FDR<0.05),suggesting that they may regulate CRC risk through inflammatory pathways.Conclusion:Specific inflammatory cytokines and serum metabolites have causal relationships with the risk of CRC.These findings provide insights for further exploration of potential risk factors and the development of effective prevention strategies for CRC.
基金Project supported by the National Natural Science Foundation of China(No.32160108)the Science and Technology Special Fund of Hainan Province(No.ZDYF2024SHFZ116)+2 种基金the Specific Research Fund of the Innovation Center for Academicians of Hainan Province(No.YSPTZX202309)the Scientific Research Project of Hainan Higher Education Institutions(No.Hnky2022ZD-6)the Hainan Normal University National College Student Innovation Training Program(No.202411658006)。
文摘new heterocyclic dipeptide with a highly functionalized 1,2-oxazadecaline core,named trichodermamide H(1),and three known analogues,along with three known polyketides,were isolated from the fermentation extract of the mangrovederived fungus Penicillium janthinellum XLN32122.The structure of 1 was elucidated on the basis of extensive 1D and 2D NMR spectra data analysis,HR-ESI-MS,electronic circular dichroism(ECD)calculations.Trichodermamide B(3)exhibited better inhibitory effect on nitric oxide(NO)production in lipopolysaccharide(LPS)induced RAW 264.7 cells with an IC_(50)value of(13.13±0.005)μmol/L than that of the positive control dexamethasone[IC_(50)=(136.84±1.33)μmol/L].Compound 3 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus(MRSA)with an IC_(50)value of 12.5μg/mL,while the positive control vancomycin showed an IC_(50)value of 1.563μg/mL.
基金supported by Tianjian advanced biomedical laboratory key research and development projectHenan Province Natural Science Foundation(Grant Number 242300421283)Major Science and Technology Project of Henan Province(221100310200)。
文摘Background:The gut microbiome has emerged as a critical modulator of cancer immunotherapy response.However,the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer(PC)remain not fully explored.The study aimed to explore how gut metabolites regulate death-ligand 1(PD-L1)blockade via exosomes and boost immune checkpoint inhibitors(ICIs)in PC.Methods:We recruited 70 PC patients to set up into five subgroups.The integrated multi-omics analysis was performed.In parallel,we validated the function of gut microbiome-associated metabolites on PD-L1 production and immunotherapy treatment efficacy in PC cell lines and transgenic adenocarcinoma of the mouse prostate(TRAMP)models.Results:We identified two metabolites,16(R)-Hydroxyeicosatetraenoic acid(16(R)-HETE)and 6-Keto-Prostaglandin E1(6-Keto-PGE1),that positively correlated with the plasma exosomal PD-L1 levels.The in vitro experiments found that both 16(R)-HETE and 6-Keto-PGE1 can enhance PD-L1 expression at the mRNA,protein,and exosome levels in both human and mouse PC cell lines,which were also validated in vivo based on subcutaneous mouse models.Both metabolites significantly promoted the anti-PD-L1 efficacy against PC in situ on a TRAMP mouse model.Conclusions:Targeting the“gut-tumor metabolic axis”is a promising strategy to improve the efficacy of immune checkpoint inhibitors in tumors.
基金supported by the National Science and Technology Major Program for Noncommunicable Chronic Diseases(2023ZD0503500)the National Natural Science Foundation of China(82030102,12126602,91857118)+1 种基金the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-010,2019-I2M-2-003)the National High Level Hospital Clinical Research Funding(2022-GSP-GG-1,2022-GSP-GG-2)。
文摘Objective Evidence suggests that depleted gut microbialα-diversity is associated with hypertension;however,whether metabolic markers affect this relationship remains unknown.We aimed to determine the potential metabolites mediating the associations ofα-diversity with blood pressure(BP)and BP variability(BPV).Methods Metagenomics and plasma targeted metabolomics were conducted on 523 Chinese participants from the MetaSalt study.The 24-hour,daytime,and nighttime BP and BPV were calculated based on ambulatory BP measurements.Linear mixed models were used to characterize the relationships betweenα-diversity(Shannon and Chao1 index)and BP indices.Mediation analyses were performed to assess the contribution of metabolites to the observed associations.The influence of key metabolites on hypertension was further evaluated in a prospective cohort of 2,169 participants.Results Gut microbial richness(Chao1)was negatively associated with 24-hour systolic BP,daytime systolic BP,daytime diastolic BP,24-hour systolic BPV,and nighttime systolic BPV(P<0.05).Moreover,26 metabolites were strongly associated with richness(Bonferroni P<0.05).Among them,four key metabolites(imidazole propionate,2-hydroxy-3-methylbutyric acid,homovanillic acid,and hydrocinnamic acid)mediated the associations between richness and BP indices(proportions of mediating effects:14.1%–67.4%).These key metabolites were also associated with hypertension in the prospective cohort.For example,each 1-standard deviation unit increase in hydrocinnamic acid significantly reduced the risk of prevalent(OR[95%CI]=0.90[0.82,0.99];P=0.03)and incident hypertension(HR[95%CI]=0.83[0.71,0.96];P=0.01).Conclusion Our results suggest that gut microbial richness correlates with lower BP and BPV,and that certain metabolites mediate these associations.These findings provide novel insights into the pathogenesis and prevention of hypertension.
基金Supported by the Central High Level Hospital Clinical Research Funding(No.BJ-2024-089).
文摘AIM:To explore the causal relationship between several possible behavioral factors and high myopia(HM)using multivariable Mendelian randomization(MVMR)approach and to find the mediators among them with mediation analysis.METHODS:The causal effects of several behavioral factors,including screen time,education time,time spent outdoors,and physical activity,on the risk of HM using univariable Mendelian randomization(MR)and MVMR analyses were first assessed.Genome-wide association study summary statistics of serum metabolites were also used in mediation analysis to determine the extent to which serum metabolites mediate the effects of behavioral factors on HM.RESULTS:MR analyses indicated that both increased time spent outdoors and a higher frequency of moderate physical activity significantly reduced the risk of HM.Further MVMR analysis confirmed that moderate physical activity independently contributed to a lower risk of HM.Additionally,MR analyses identified 13 serum metabolites significantly associated with HM,of which 12 were lipids and one was an amino acid derivative.Mediation analysis revealed that six lipid metabolites mediated the protective effects of moderate physical activity on HM,with the highest mediation proportion observed for 1-(1-enyl-palmitoyl)-GPC(p-16:0;30.83%).CONCLUSION:This study suggests that in addition to outdoor time,moderate physical activity habits may have an independent protective effect against HM and pointed to lipid metabolites as priority targets for the prevention due to low physical activity.These results emphasize the importance of physical activity and metabolic health in HM and underscore the need for further study of these complex associations.
基金The National Natural Science Foundation of China-Regional Science Foundation Project“Research on constructing cell communication networks based on single-cell and spatial transcriptomics data”(62362062)The Multimodal Major Chronic Disease Prevention and Control Science and Engineering Key Laboratory Project of MIIT“Identification of novel drug targets for lung cancer via Mendelian randomization analysis based on blood proteomics”(MCD-2023-1-15).
文摘Genome-wide association study(GWAS)data are used to explore the associations between blood metabolites and 5 respiratory diseases:asthma,tuberculosis(TB),chronic obstructive pulmonary disease(COPD),cor pulmonale,and bronchitis.The main method of analysis used is the inverse-variance weighted(IVW)approach,complemented by several sensitivity analyses,including MR-Egger regression,the weighted median,the weighted mode,Cochran’s Q test,and the pleiotropy test.Additional directional tests,Meta-analysis and metabolic pathway analyses are conducted for deeper insights.3 metabolites showing significant causal relationships are identified.Catechol glucuronide levels as a protective factor have a positive causal relationship with asthma;the creatine to carnitine ratio has a negative causal relationship with COPD as a risk factor;and the adenosine 5’-diphosphate(ADP)to N-acetylglucosamine to N-acetylgalactosamine ratio as a protective factor has a positive causal relationship with bronchitis.Additionally,13 metabolites demonstrate strong causal relationships.Furthermore,we delineate 14 metabolic pathways related to the outcomes,including 6 associated with asthma,2 with TB,1 with COPD,4 with cor pulmonale,and 1 with bronchitis.A causal relationship between blood metabolites and 5 respiratory diseases has been established.The identified metabolites and pathways offer new insights into the underlying mechanisms of these diseases,necessitating further experimental validation.
基金supported by the National Natural Science Foundation of China (No. 82293680)the National Science and CAMS Innovation Fund for Medical Science (No. 2021-I2M-1-028)the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2021-RC350-009)。
文摘Five novel sulfur-containing benzyl metabolites, designated as gastrabenzylsulfoxides A and B(1 and 2), gastrabenzylsulfinate A(3) and gastrabenzylsulfides A and B(4 and 5), along with four known compounds(6-9), were isolated from the aqueous extracts of Gastrodia elata.Compounds 1 and 4 are 4-hydroxy-3-(4′-hydroxybenzyl)benzyl-substituted sulfoxide and sulfide, respectively, which are unprecedented in natural products. Compound 3 represents a rare sulfinate. Several isolates and their sulfone and disulfide analogs(10-13) were synthesized to evaluate their anti-inflammatory activity. Notably, the synthesized sulfone 10 demonstrated significant alleviation of symptoms in multiple in vivo inflammatory models.
基金supported by grants from Singhealth Duke-NUS Academic Medicine Research grant(AM/SU035/2020)NMRC Clinician-Scientist Individual Research Grant New Investigator Grant(CNIG20nov-0003).
文摘Chemical exposure during prenatal development has significant implications for both maternal and child health.Compared to blood,saliva is a non-invasive and less resource-intensive,alternative.Given the temporal variability of xenobiotic metabolites(XM),repeated sampling is essential.Therefore,saliva offers a valuable tool for the longitudinal assessment of prenatal exposomes.Despite its potential,no studies have explored saliva for XM measurement.This study pioneered using saliva to assess XM detectability and investigate the associations between prenatal XM and endogenous metabolomes in pregnant women.Saliva samples were analysed using mass spectrometry from 80 pregnant women at 24–34 weeks gestation.Metabolomes and exposomes were annotated using the Human Metabolome and U.S.Environmental Protection Agency databases.Metabolome-XM associations were clustered using Glay community clustering.Linear regression models,adjusted for age,estimated associations between catecholamines and XMs.XM levels were validated in a cohort of women(n=14)with and without preeclampsia.Our study identified 582 metabolomes and 125 XM in saliva,demonstrating its potential as a matrix for exposure measurement.After false discovery rate correction,18109 significant metabolome-XM associations were identified.Community clustering revealed 37 connected clusters,with the largest cluster(238 nodes)enriched in tyrosine and catecholamine metabolism.Food-contactchemicals and food-additives were significantly associated with higher catecholamine and their metabolite levels.Subgroup analyses revealed higher concentrations of these chemicals in women with preeclampsia compared to healthy controls.This study demonstrates that saliva contains valuable molecular data for measuring exposomes.Food-related chemicals were associated with higher catecholamine levels,which may be relevant to the prevalence of hypertensive crises in pregnancy.
文摘Background Metabolic dysregulation has been implicated in major depressive disorder(MDD).Aims We aimed to explore the potential role of plasma metabolites in MDD.Methods We conducted Mendelian randomisation(MR)analysis to evaluate the causal effects of 871 circulating metabolites on MDD,using the Genome-Wide Association Studies datasets of MDD(N=1035760)and metabolites(N=8299).Bayesian colocalisation and druggability analyses were employed to identify genetic variants contributing to both MDD and levels of metabolites in plasma and to pinpoint metabolites with therapeutic potential,respectively.Results MR analysis identified 11 metabolites associated with MDD(false discovery rate<0.05).Eight metabolites,including arachidonate(20:4n6)(odds ratio(OR):0.97),1-arachidonoyl-GPC(20:4n6)(OR:0.98),1-(1-enylpalmitoyl)-2-palmitoleoyl-GPC(P-16:0/16:1)(OR:0.97),succinoyltaurine(OR:0.98),3-methoxycatechol sulphate(1)(OR:0.98)and 11β-hydroxyandrosterone glucuronide(OR:0.97),showed protective effects against MDD.Three metabolites were associated with increased risk,namely,butyrylglycine(OR:1.03),3-carboxy-4-methyl-5-propyl-2-furanpropanoate(OR:1.02)and 1-(1-enyl-stearoyl)-2-oleoyl-GPE(P-18:0/18:1)(OR:1.02).Colocalisation analysis supported shared genetic signals between five lipid metabolites and MDD,particularly at loci harbouring FADS and ATP9A.Notably,a majority of metabolites associated with MDD are being explored as therapeutic targets for various psychiatric disorders.Conclusions Genetically predicted levels of certain circulating metabolites make a causal contribution to MDD.Further investigation of their roles may provide novel pathophysiological insights and give clues for targeted therapies.
文摘To investigate the in vitro digestion and fermentation properties of soybean oligosaccharides(SBOS)extracted from defatted soybean meal,the changes in monosaccharide composition and molecular mass were analyzed.Subsequently,the effect of SBOS on microbial community structure and metabolites was studied by 16S rRNA gene sequencing and untargeted metabolomics based on liquid chromatography-mass spectrometry.Results showed that SBOS was not easily enzymolyzed during simulated digestion and could reach the large intestine through the digestive system.The significant decrease in the molecular mass of SBOS after in vitro fermentation indicated its utilization by the gut microbiota,which increased the contents of short-chain fatty acids and lactic acid,thereby reducing the pH of the fermentation broth.Moreover,the core community was found to consist of Blautia,Lactobacillaceae,and Pediococcus.SBOS up-regulated beneficial differential metabolites such as myo-inositol,lactose,and glucose,which were closely related to galactose,amino sugar,and nucleotide sugar metabolism.This study will provide a reference for exploring the relationship between the gut microbiota and the metabolites of SBOS,and provide a basis for the development and application of SBOS as an ingredient for functional products.
基金supported by a grant from the National Natural Science Foundation of China(82171187).
文摘Background:The composition of the intestinal flora and the resulting metabolites af-fect patients'sleep after surgery.Methods:We intended to elucidate the mechanisms by which disordered intestinal flora modulate the pathophysiology of postoperative sleep disturbances in hosts.In this study,we explored the impacts of anesthesia,surgery,and postoperative sleep duration on the fecal microbiota and metabolites of individuals classified postpro-cedurally as poor sleepers(PS)and good sleepers(GS),as diagnosed by the bispec-tral index.We also performed fecal microbiota transplantation in pseudo-germ-free(PGF)rats and applied Western blotting,immunohistochemistry,and gut permeability analyses to identify the potential mechanism of its effect.Results:Research finding shows the PS group had significantly higher postopera-tive stool levels of the metabolites tryptophan and kynurenine than the GS group.PGF rats that received gut microbiota from PSs exhibited less rapid eye movement(REM)sleep than those that received GS microbiota(GS-PGF:11.4%±1.6%,PS-PGF:4.8%±2.0%,p<0.001).Measurement of 5-hydroxytryptophan(5-HTP)levels in the stool,serum,and prefrontal cortex(PFC)indicated that altered 5-HTP levels,includ-ing reduced levels in the PFC,caused sleep loss in PGF rats transplanted with PS gut flora.Through the brain-gut axis,the inactivity of tryptophan hydroxylase 1(TPH1)and TPH2 in the colon and PFC,respectively,caused a loss of REM sleep in PGF rats and decreased the 5-HTP level in the PFC.Conclusions:These findings indicate that postoperative gut dysbiosis and defective 5-HTP metabolism may cause postoperative sleep disturbances.Clinicians and sleep researchers may gain new insights from this study.
基金supported by the National Natural Science Foundation of China(Nos.42207320 and 22076214).
文摘Ethiprole is widely used as a second-generation phenyl pyrazole insecticide.Previous studies indicated that ethiprole exhibited thyroid toxicity while two main metabolites(ethiprole sulfone(M1)and ethiprole sulfide(M2))of ethiprole showed higher acute toxicity than ethiprole.Therefore,assessing the thyroid toxicity of its metabolites is crucial for safety assessment.In this study,the thyroid toxicity and underlying mechanisms of ethiprole and its metabolites were explored using in silico,in vitro,and in vivo assays,with the aim of conducting a comparative study on thyroid toxicity.Molecular docking analysis showed that ethiprole,M1 and M2 could bind with thyroid receptor isoforms and exhibited higher binding affinity compared to 3,3,5-triiodothyronine(T3).GH3 cell proliferation assays revealed that ethiprole,M1 and M2 all served as thyroid hormone antagonists to hinder the T3-induced cell proliferation.Using the zebrafish model,we further investigated that exposure to ethiprole,M1,and M2 disrupted thyroid hormone levels and the transcriptional expressions of hypothalamus-pituitary-thyroid(HPT)axis-related genes.Ethiprole induced thyroid disrupting effects by binding with the thyroid receptor beta,M1 mainly through binding with the corticotropin releasing factor receptor-1,and M2 exposure firstly inhibited the thyroid peroxidase enzyme activity.M2 showed the highest developmental toxicity and thyroid disrupting effects,which significantly reducing hatching rates,increasing deformity rates,exhibiting the lowest lethal concentration 50 value and showing the most serious transcription inhibitory effects on the HPT axis.This study suggested the risk assessment of metabolites should be considered in assessing potential environmental risk of ethiprole.
文摘This study investigates the relationships between exposures to ambient air pollution—specifically particulate matter 2.5 (PM_(2.5)) and its metabolites—and the risk of depression.Nonlinear and linear regression,Bayesian kernel machine regression,and toxicogenomic analysis were key approaches.PM_(2.5)exposure was positively associated with the risk of developing depression,whereas phenylglyoxylic acid exposure was negatively associated with depression risk.We found a significant overall relationship between ambient air pollution and depression,particularly at the 55th and 60th percentiles.Although statistical significance was not reached at the 65th percentile,there was a noticeable upward trend,indicating a potential association.Interestingly,no significant connection was found between a combination of metabolites from ambient air pollution and depression.PM_(2.5)and phenylglyoxylic acid emerged as the most influential compounds in the models,respectively.PM_(2.5)exposure altered the expression of 42 specific targets associated with depression,especially POMC,SCL6A4,IL6,and SOD2.The study identified specific pathways related to insulin secretion,energy metabolism,blood circulation,tube diameter,and maintenance of blood vessel diameter,as well as key molecular mechanisms involving hsa-miR-124-3p,hsa-miR-155-5p,hsa-miR-16-5p,and SP1.These mechanisms were found to underlie the etiology of depression associated with PM_(2.5)exposure.In conclusions,PM_(2.5)and phenylglyoxylic acid were found to be associated with depression.Further work is needed to gain insight into the molecular mechanisms by which these chemicals affect depression,especially pathways related to insulin secretion and blood circulation.
文摘A new alkaloid,diacedolinate(1),along with fourteen known compounds(2-15)was isolated from the sponge associated fungus Penicillium crustosum SCSIO 41442.The structures of these compounds were determined by spectrum analysis and ECD.All compounds were evaluated for their antioxidant and antimicrobial activities.The results showed that compound 1 exhibited weak antioxidant activity with an IC_(50)value of(71.00±0.14)μg·mL^(−1),while compound 2,in contrast,displayed broad antioxidant activity with an IC_(50)value of(1.25±0.10)μg·mL^(−1),compared with the positive control,vitamin C.In addition,compounds 9,10,11,and 15 demonstrated broad-spectrum antimicrobial activity against a variety of pathogens,including MRSA,Colletotrichum asianum HNM 408,Colletotrichum acutatum HNM RC178,and Alternaria alternate,with MIC values ranging from 2.5 to 160μg·mL^(−1).The bioactivities of these compounds are reported here for the first time.
基金supported by the Natural Science Foundation of Hunan Province,China(2024JJ7627).
文摘Objective:Gut microbiota(GM)and blood metabolites are associated with the development of urticaria,yet their specific causal relationships in East Asian populations remain unclear.This study aims to elucidate the causal and mediating relationships among GM,blood metabolites,and urticaria in East Asians using Mendelian randomization(MR)analysis.Methods:Summary-level statistics for 500 GM taxa,112 blood metabolites,and urticaria were obtained from publicly available Genome-Wide Association Studies(GWAS)datasets.Bidirectional MR analyses were performed to examine causal associations among the GM,blood metabolites,and urticaria.The inverse variance weighted(IVW)method served as the primary analytical approach,supplemented by MR-Egger,weighted median,simple mode,and weighted mode methods.Sensitivity analyses included heterogeneity tests,horizontal pleiotropy assessments,and leave-one-out analyses.Mediation analysis was conducted to evaluate the potential mediating effects of blood metabolites on the causal pathways between GM and urticaria.Results:MR analyses identified 12 GM taxa exhibiting significant causal effects on urticaria susceptibility.Nine taxa,such as MF0017_galactose_degradation(OR=1.461,95%CI 1.098 to 1.944,P=0.009),were associated with increased urticaria risk.Three taxa,such as MF0001_arabinoxylan_degradation(OR=0.846,95%CI 0.737 to 0.973,P=0.019),showed protective effects with increased abundance.Additionally,6 blood metabolites demonstrated causal associations with urticaria.Notably,the risk of developing urticaria increases with rising fasting plasma glucose(FPG)levels(OR=1.971,95%CI 1.089 to 3.567,P=0.025).Mediation analysis further demonstrated that FPG partially mediated the protective effect of MF0001_arabinoxylan_degradation on urticaria,accounting for 11.30%of the total effect.Conclusion:This study has delineated specific GM taxa and blood metabolites that hold causal relevance to urticaria in East Asian populations.Notably,arabinogalactan degradation potentially mitigates urticaria risk via reducing FPG concentrations,offering genetic evidence to support therapeutic strategies targeting GM modulation and glucose regulation.
基金financial supports from the National Key R&D Program of China(Grant Nos.:2022YFC3400700 and 2022YFA0806400)the Shanghai Municipal Science and Technology Major Project,China(Grant No.:2017SHZDZX01)the National Natural Science Foundation of China(Grant No.:31821002).
文摘Nuclear magnetic resonance(NMR)spectroscopy is an excellent tool for simultaneous identification and quantification of metabolites(metabolomics).NMR quantification of human lipoprotein subfractions and their components has proven to be a powerful approach to reveal pathophysiological insights in numerous diseases[1,2].This method has now been standardized with excellent inter-laboratory reproducibility within 10 days for simultaneous quantification of 105 lipoprotein components and 24 low-molecular weight(LMW)metabolites[3];close clustering was also shown for 12 quality-control(QC)samples measured in 3 months although without statistical details[2].However,these reports[[1],[2],[3]]did not cover many vital parameters for lipoprotein components(e.g.,cholesterol-esters and total-lipids),fatty acids,and N-acetyl-glycoproteins(NAGs).
基金supported by grants from the Chinese Academy of Sciences(XDB39050800)the Major Project of Guangzhou National Laboratory(GZNL2024A03013)the National Natural Science Foundation of China(92357308 and 32321004)。
文摘The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops,which modulates an approximately 24-h cycle of endocrine and metabolic rhythms within cells and tissues.While circadian clocks regulate metabolic processes and related physiology,emerging evidence indicates that metabolism and circadian rhythm are intimately intertwined.In this review,we highlight the concept of metabolites,including lipids and other polar metabolites generated from intestinal microbial metabolism and nutrient intake,as time cues that drive changes in circadian rhythms,which in turn influence metabolism and aging.Furthermore,we discuss the roles of functional metabolites as circadian cues,paving a new direction on potential intervention targets of circadian disruption,pathological aging,as well as metabolic diseases that are clinically important.
基金supported by National Natural Science Foundation of China(Grant nos.32130109,41761134050).
文摘The extreme environment of the polar regions has driven the evolution of unique metabolic mechanisms in microorganisms,resulting in structurally diverse and highly active secondary metabolites.These metabolites are not only crucial for microbial adaptation to extreme conditions,but also exhibit significant potential for applications in medicine,agriculture(e.g.,biocontrol),and industry.This review provides a comprehensive overview of 111 secondary metabolites derived from polar microorganisms reported between 2013 and 2025,with a focus on advances in their classification,biological activities,and biosynthetic gene cluster mining techniques.Additionally,it highlights key strategies for advancing future investigations,providing a valuable reference for continued exploration in this promising field.Notably,polar microbial secondary metabolites also hold promising applications in agriculture,particularly in biocontrol,soil health enhancement,and stress-resistant crop development.
文摘The review by Bangolo et al highlights the role of the gut microbiome in cancerassociated anemia(CAA).However,the impact of microbiome-derived metabolites is underexplored.In this letter,we focus on short-chain fatty acids,tryptophan metabolites,and polyamines as key mediators linking dysbiosis to impaired erythropoiesis and iron homeostasis.We also propose a research framework that integrates multi-omics analysis and gnotobiotic models.Finally,we discuss the clinical potential of metabolite-based diagnostics and microbiome-targeted therapies in managing CAA.
基金supported by grants from the National Natural Science Foundation of China(31560459)Jiangxi Provincial Natural Science Foundation(20224ACB205014)The Double Thousands Talents Plan of Jiangxi(jxsq2018102075,jxsq2018102076)。
文摘Inflammatory bowel disease(IBD)is a chronic gastrointestinal disease with a high incidence.Treatment for IBD includes medications and diet,and common anti-inflammatory medications have limitations like drug resistance and serious adverse effects.Accumulating evidence has demonstrated that dietary flavonoids exhibit an alleviative effect on IBD by influencing gut microbiota.The microbiota-derived metabolites also regulate IBD and maintain intestinal homeostasis.In this review,we investigate the therapeutic effect of gut microbiota and metabolites on IBD by intestinal immune and intestinal barrier function.We demonstrate the underlying mechanism of dietary flavonoids as an anti-inflammatory molecule alleviating IBD by regulating gut microbiota,short chain fatty acid(SCFA),bile acid(BA),tryptophan(Trp)metabolism and lipopolysaccharides(LPS)-toll-like receptor 4(TLR4)signaling pathway.Based on structural differences of flavonoids,we summarize the recent research progress on the role of different dietary flavonoids in alleviating IBD by gut microbiota and metabolites in animal and clinical trials.This review indicates that dietary flavonoids targeting gut microbiota and metabolites provide a promising strategy for the treatment of inflammation and novel insights into the management of IBD.
