PubMed

J Dairy Sci. 2024 Dec 16:S0022-0302(24)01268-2. doi: 10.3168/jds.2024-25614. Online ahead of print.ABSTRACTColorectal cancer (CRC) arises from the accumulation of abnormal mutations in colorectal cells during prolonged inflammation. This study aimed to investigate the potential of probiotic fermented milk containing the probiotic strain, Bifidobacterium animalis ssp. lactis BX-245 (BX-245), in alleviating tumor burden in CRC mice induced by azoxymethane and dextran sodium sulfate. The study monitored changes in tumor size and number, gut microbiota, metabolomics, and inflammation levels before and after the intervention. Our findings indicate that intragastric administration of BX245-fermented milk effectively modulated the intratumor microbiota, as well as the gut microbiota and its metabolism. We also observed a decreased relative abundance of intratumor Akkermansia in the CRC mice, while the intratumor Parabacteroides exhibited a significant positive correlation with tumor number and weight. Moreover, administering BX245-fermented milk significantly reduced gut barrier permeability, alleviated gut barrier damage, and increased serum interleukin-2 and interferon-γ levels compared with the ordinary fermented milk group. Collectively, our data suggest that administering probiotic fermented milk containing specific functional strains like BX245 could result in a reduction in tumor burden in CRC mice. Conversely, ordinary fermented milk did not show the same tumor-inhibiting effects. The current results are preliminary, and further confirmation is necessary to establish the causal relationship among probiotic milk, changes in gut microbiota, and disease alleviation.PMID:39694256 | DOI:10.3168/jds.2024-25614

Am J Obstet Gynecol. 2024 Dec 16:S0002-9378(24)01196-7. doi: 10.1016/j.ajog.2024.12.019. Online ahead of print.ABSTRACTOBJECTIVE: To investigate whether nuclear magnetic resonance (NMR)-based metabolomic profiling of maternal blood can be used for first-trimester prediction of gestational diabetes mellitus (GDM).STUDY DESIGN: This was a prospective study of 20,000 women attending for routine pregnancy care at 11-13 weeks' gestation. Metabolic profiles were assessed using a high-throughput NMR metabolomics platform. To inform translational applications, we focused on a panel of 34 clinically validated biomarkers for detailed analysis and risk modelling. All biomarkers were used to generate a multivariable logistic regression model to predict GDM. Data were split using random seed into a 70%-30% training and validation set, respectively. Performance of the multivariable models was measured by receiver operating characteristic (ROC) curve analysis and detection rates (DRs) at fixed 10% and 20% false positive rates. Calibration for the combined risk model for all GDM was assessed visually through a figure showing the observed incidence against the predicted risk for GDM. A sensitivity analysis was carried out excluding the 64 women in our cohort who were diagnosed with GDM prior to 20 weeks' gestation.RESULTS: The concentration of several metabolomic biomarkers, including cholesterols, triglycerides, fatty acids, and amino acids, were different in the group that developed GDM, compared to those without GDM. Addition of biomarker profile improved the prediction of GDM provided by maternal demographic characteristics and elements of medical history alone (area under the receiver operating characteristics curve [AUROC] 0.790 and detection rate (DR) of 50%, 95%CI 44.3%-55.7%, at 10% false positive rate (FPR) and 63%, 95%CI 57.4%-68.3%, at 20% FPR, to 0.840, 56%, 95%CI 50.3%-61.6% and 73%, 95%CI 67.7%-77.8%, respectively). The performance of combined testing was better for GDM treated by insulin (ROC AUC 0.905, DR 76%, 95%CI 67.5%-83.2%, at 10% FPR and DR 85%, 95%CI 77.4%-90.9%, at 20%) than GDM treated by diet alone (ROC AUC 0.762, DR 47%, 95%CI 37.7%-56.5%, at 10% FPR and DR 64%, 95%CI 54.5%-72.7%, at 20% FPR). In the calibration plot there was good agreement between the observed incidence of GDM against that predicted from the combined risk model. In the sensitivity analysis excluding the women diagnosed with GDM prior to 20 weeks' gestation, there was a negligible difference in ROC AUC in comparison to the results from the entire cohort combined.CONCLUSIONS: Addition of NMR-based metabolomic profiling to risk factors can provide first-trimester prediction of GDM.PMID:39694165 | DOI:10.1016/j.ajog.2024.12.019

Cell Signal. 2024 Dec 16:111563. doi: 10.1016/j.cellsig.2024.111563. Online ahead of print.ABSTRACTDisulfiram/Cu(DSF) has a known pharmacokinetic and safety profile, exerting a strong antitumor effect. Oral tyrosine kinase inhibitors including lenvatinib are approved as first-line therapy for treating advanced unresectable hepatocellular carcinoma (HCC). These patients still have limited survival due to drug resistance. Disulfiram/Cu and lenvatinib are the promising antitumor treatments. In this study, we studied whether Disulfiram/Cu increased lenvatinib sensitivity in HCC cells. Moreover, the potential drug targets of Disulfiram/Cu and associated mechanisms were explored. We mainly investigated Autophagic flux was determined via immunofluorescence analysis and confocal microscopy. p-PI3K, p-AKT, p62, LC3B, FOXO6, and CHKA proteins associated with autophagy were detected by immunoblotting. In addition, antitumour activity of Disulfiram/Cu in combination with lenvatinib was examined in vivo through construction of the nude mouse transplant tumor model. Furthermore, our results show disulfiram/Cu combined with lenvatinib exerted the synergistic impact on treating HCC in vitro. Mechanistically, transcriptome combined with metabolome reveals Disulfiram/Cu targeting FOXO6 induction of autophagy mediated inhibits cell growth in hepatocellular carcinoma by downregulating CHKα for inhibiting AKT pathway activation while blocking choline metabolic reprogramming in HCC. These effects mostly explain the tumor-promoting effect of FOXO6 on HCC. In general, the results illustrate the mechanistic associations between metabolites and tumor cell malignant phenotype, contributing to developing new anti-HCC pharmacological treatments by Inhibiting FOXO6 for disrupting choline metabolic pathway.PMID:39694126 | DOI:10.1016/j.cellsig.2024.111563

Mol Metab. 2024 Dec 16:102083. doi: 10.1016/j.molmet.2024.102083. Online ahead of print.ABSTRACTOBJECTIVE: Antagonism of the muscarinic acetylcholine type 1 receptor (M1R) promotes sensory axon repair and is protective in peripheral neuropathy, however, the mechanism remains elusive. We investigated the role of the heat-sensing transient receptor potential melastatin-3 (TRPM3) cation channel in M1R antagonism-mediated nerve regeneration and explored the potential of TRPM3 activation to facilitate axonal plasticity.METHODS: Dorsal root ganglion (DRG) neurons from adult control or diabetic rats were cultured and treated with TRPM3 agonists (CIM0216, pregnenolone sulfate) and M1R antagonists pirenzepine (PZ) or muscarinic toxin 7 (MT7). Ca2+ transients, mitochondrial respiration, AMP-activated protein kinase (AMPK) expression, and mitochondrial inner membrane potential were analyzed. The effect of M1R activation or blockade on TRPM3 activity mediated by phosphatidylinositol 4,5-bisphosphate (PIP2) was studied. Metabolic profiling of DRG neurons and human neuroblastoma SY-SY5Y cells was conducted.RESULTS: M1R antagonism induced by PZ or MT7 increased Ca2+ influx in DRG neurons and was inhibited by TRPM3 antagonists or in the absence of extracellular Ca2+. TRPM3 agonists elevated Ca2+ levels, augmented mitochondrial respiration, AMPK activation and neurite outgrowth. M1R antagonism stimulated TRPM3 channel activity through inhibition of PIP2 hydrolysis to activate Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK, leading to augmented mitochondrial function and neuronal metabolism. DRG neurons with AAV-mediated shRNA knockdown of TRPM3 exhibited suppressed antimuscarinic drug-induced neurite outgrowth. TRPM3 agonists increased glycolysis and TCA cycle metabolites, indicating enhanced metabolism in DRG neurons and SH-SY5Y cells.CONCLUSION: Activation of the TRPM3/CaMKKβ/AMPK pathway promoted collateral sprouting of sensory axons, positioning TRPM3 as a promising therapeutic target for peripheral neuropathy.PMID:39694091 | DOI:10.1016/j.molmet.2024.102083

Bioorg Chem. 2024 Dec 10;154:108046. doi: 10.1016/j.bioorg.2024.108046. Online ahead of print.ABSTRACTThe Pseudomonas aeruginosa LasR quorum sensing system (QSS) is central to regulating the expression of several pathogenicity factors. Also, while seed- and/or plant-derived products have been investigated as QSS regulators, the impact of Helianthus annuus (Pannar sunflower seed cultivars) extracts and metabolites as LasR modulators remain underexplored. Thus, this study focused on the untargeted metabolomic profiling (Liquid Chromatography-Mass Spectrometry), in vitro and in silico (docking, pharmacokinetics, dynamic simulation) bioprospection of Pannar seed cultivars' extracts and metabolites as LasR modulators. The extracts showed significant QS modulating properties (motility, violacein, biofilm, cell attachment, pyocyanin inhibition) with the PAN 7102 CLP seed cultivar (74.3 %) being the most potent, compared to azithromycin (65 %) and cinnamaldehyde (62 %). Chemometric principal component analysis (PCA) analysis showed distinct metabolite signatures with 52.5 % variance across the six cultivars that was driven by aqueous and ethanolic extracts of PAN 7102, 7160, and 7156 cultivars. The presence of methoxymellein, hydroxytetradecanedioic acid, koninginin G, geoside, pinellic acid and methylpicraquassioside A were reported for the first time. The profiled metabolites were subjected to a 100-ns molecular dynamics simulation following molecular docking. Binding free energy (ΔGbind) calculations revealed obolactone (-48.26 kcal/mol), 1,4-bis(phenylglyoxaloyl)benzene (-45.06 kcal/mol), cyclocanaliculatin (-43.41 kcal/mol), 5-hydroxy-7-methoxy-2-phenylchroman-4-one (-39.18 kcal/mol) and lonchocarpin (-33.78 kcal/mol) as first-time putative leads relative to azithromycin (-32.09 kcal/mol). All lead metabolites also conformed to Lipinski's rule of 5 (Ro5), and their LasR bound complexes were thermodynamically stable and compact given their strong bond interactions. Findings indicate that metabolomic profiling remain key to identifying new compounds from underexplored species. H. annuus lead metabolites and extracts may also play key roles as LasR modulators. Further structural modification of the 5 leads could aid their development into novel, oral therapeutics targeting LasR to mitigate resistant P. aeruginosa infections.PMID:39693924 | DOI:10.1016/j.bioorg.2024.108046

Bioorg Chem. 2024 Dec 13;154:108059. doi: 10.1016/j.bioorg.2024.108059. Online ahead of print.ABSTRACTPsoriasis (PSO) is a common inflammatory skin disease caused by multiple factors. Magnolia officinalis is an important medicinal plant in China, with various values such as ecology, medicine, food, and daily chemicals. However, its diverse application potential has not been fully explored. Magnolol (MGO) is the main active compound of Magnolia officinalis with significant anti-inflammatory effect. To investigate the application potential of MGO in inflammatory skin disease, the effects and underlying mechanisms of topical MGO treating psoriasis were explored in this study. Network pharmacology and molecular docking firstly predicted that topical MGO may treat psoriasis by regulating pyroptosis pathway and acting on caspase-1 (CASP1). In vitro experiments then demonstrated that MGO could inhibit the level of inflammatory cytokines and the key protein expression of NOD-like receptor protein 3 (NLRP3)/Caspase-1 pathway in lipopolysaccharide (LPS)-stimulated phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells. Meanwhile, MGO could inhibit CuSO4-induced neutrophils migration in Tg (mpx:EGFP) zebrafish by suppressing inflammation and pyroptosis. This study further indicated that topical application of MGO ameliorated imiquimod (IMQ)-induced psoriasis-like dermatitis by reducing the release of inflammatory factors and decreasing the key protein expression of pyroptosis-related NLRP3/Caspase-1 pathway. Metabolomics analysis revealed that topical application of MGO could significantly regulate tryptophan metabolism and affect the level of tryptophan in skin lesions. Tryptophan could also regulate inflammation-related genes and inhibit pyroptosis-related NLRP3/Caspase-1 pathway in LPS-stimulated PMA-differentiated THP-1 cells. In conclusion, this study suggested that topical MGO may ameliorate psoriasis-like dermatitis by inhibiting NLRP3/Caspase-1 pathway and regulating tryptophan metabolism.PMID:39693920 | DOI:10.1016/j.bioorg.2024.108059

Food Chem. 2024 Dec 9;468:142420. doi: 10.1016/j.foodchem.2024.142420. Online ahead of print.ABSTRACTThis study examines the impact of the complex microbiota from long-term fermented kimchi, used as a backslop, on fermentation dynamics. The fermentation was conducted with autoclaved (group A) and non-autoclaved (NA) starter cultures. Bacterial and fungal communities were analyzed with 16S rRNA gene V4 and ITS2 region, respectively, and metabolites were profiled using gas chromatography-mass spectrometry. In the group NA, Levilactobacillus dominated at 64.3 % by day 5, while Pediococcus reached 57.4 % by day 50. Principal coordinate analysis showed that bacterial communities in both the starter culture and samples of the group NA became similar by the end of the fermentation (day 100); however, no significant differences were found in fungal community. Principal component analysis revealed distinct metabolite profiles, explaining 68.7 % of variability on PC1, with each group clustered separately by day 100. These results suggest that inoculating with microbiota from long-term fermentation can rapidly produce foods with desirable characteristics.PMID:39693884 | DOI:10.1016/j.foodchem.2024.142420

EBioMedicine. 2024 Dec 17;111:105507. doi: 10.1016/j.ebiom.2024.105507. Online ahead of print.ABSTRACTBACKGROUND: Sleep is essential to maintaining health and wellbeing of individuals, influencing a variety of outcomes from mental health to cardiometabolic disease. This study aims to assess the relationships between various sleep-related phenotypes and blood metabolites.METHODS: Utilising data from the Hispanic Community Health Study/Study of Latinos, we performed association analyses between 40 sleep-related phenotypes, grouped in several domains (sleep disordered breathing (SDB), sleep duration, sleep timing, self-reported insomnia symptoms, excessive daytime sleepiness (EDS), and heart rate during sleep), and 768 metabolites measured via untargeted metabolomics profiling. Network analysis was employed to visualise and interpret the associations between sleep phenotypes and metabolites.FINDINGS: The patterns of statistically significant associations between sleep phenotypes and metabolites differed by superpathways, and highlighted subpathways of interest for future studies. For example, primary bile acid metabolism showed the highest cumulative percentage of statistically significant associations across all sleep phenotype domains except for SDB and EDS phenotypes. Several metabolites were associated with multiple sleep phenotypes, from a few domains. Glycochenodeoxycholate, vanillyl mandelate (VMA) and 1-stearoyl-2-oleoyl-GPE (18:0/18:1) were associated with the highest number of sleep phenotypes, while pregnenolone sulfate was associated with all sleep phenotype domains except for sleep duration. N-lactoyl amino acids such as N-lactoyl phenylalanine (lac-Phe), were associated with sleep duration, SDB, sleep timing and heart rate during sleep.INTERPRETATION: This atlas of sleep-metabolite associations will facilitate hypothesis generation and further study of the metabolic underpinnings of sleep health.FUNDING: R01HL161012, R35HL135818, R01AG80598.PMID:39693737 | DOI:10.1016/j.ebiom.2024.105507

Clin Sci (Lond). 2024 Dec 18:CS20242610. doi: 10.1042/CS20242610. Online ahead of print.ABSTRACTAdipose tissue dysfunction leads to abnormal lipid metabolism and high inflammation levels. This research aims to explore the role of Serpina3c, which is highly expressed in adipocytes, in obesity-related hypertriglyceridemia and metaflammation. Serpina3c global knockout (KO) mice, adipocyte-specific Serpina3c overexpressing mice, Serpina3c knockdown (KD) mice, and hypoxia-inducible factor 1 alpha (Hif1α) KD mice were fed a high-fat diet (HFD) for 16 weeks to generate obesity-related hypertriglyceridemia mice models. In the present study, Serpina3c KO mice and adipocyte-specific Serpina3c KD mice exhibited more severe obesity-related hypertriglyceridemia and metaflammation under HFD conditions. Serpina3c KO epididymal white adipose tissue (eWAT) primary stromal vascular fraction (SVF)-derived adipocytes exhibited higher lipid (triglyceride and non-esterified fatty acid) levels and higher fatty acid synthase expression after palmitic acid stimulation. Adipocyte-specific Serpina3c overexpression in KO mice prevented the KO group phenotype. The RNA-seq and in vitro validation revealed that Hif1α and the glycolysis pathways were upregulated in Serpina3c KD adipocytes, which were all validated by in vitro and in vivo reverse experiments. Co-immunoprecipitation (co-IP) provided evidence that Serpina3c bound nuclear factor erythroid 2-related factor 2 (Nrf2) to regulate Hif1α. Nrf2 KD reduced Hif1α and Fasn expression, decreased lipid content, and reduced the extracellular acidification rate in Serpina3c KO adipocytes. Metabolomics revealed that lactic acid (LD) levels in eWAT were responsible for adipose-associated macrophage inflammation. In summary, Serpina3c inhibits the Hif1α-glycolysis pathway and reduces de novo lipogenesis and LD secretion in adipocytes by binding to Nrf2, thereby improving HFD-induced lipid metabolism disorders and alleviating adipose tissue macrophage inflammation.PMID:39693610 | DOI:10.1042/CS20242610

Sci Adv. 2024 Dec 20;10(51):eads5466. doi: 10.1126/sciadv.ads5466. Epub 2024 Dec 18.ABSTRACTMetformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin's ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.PMID:39693440 | DOI:10.1126/sciadv.ads5466

Sci Adv. 2024 Dec 20;10(51):eadp3743. doi: 10.1126/sciadv.adp3743. Epub 2024 Dec 18.ABSTRACTBiological aging clocks produce age estimates that can track with age-related health outcomes. This study aimed to benchmark machine learning algorithms, including regularized regression, kernel-based methods, and ensembles, for developing metabolomic aging clocks from nuclear magnetic resonance spectroscopy data. The UK Biobank data, including 168 plasma metabolites from up to N = 225,212 middle-aged and older adults (mean age, 56.97 years), were used to train and internally validate 17 algorithms. Metabolomic age (MileAge) delta, the difference between metabolite-predicted and chronological age, from a Cubist rule-based regression model showed the strongest associations with health and aging markers. Individuals with an older MileAge were frailer, had shorter telomeres, were more likely to suffer from chronic illness, rated their health worse, and had a higher all-cause mortality hazard (HR = 1.51; 95% CI, 1.43 to 1.59; P < 0.001). This metabolomic aging clock (MileAge) can be applied in research and may find use in health assessments, risk stratification, and proactive health tracking.PMID:39693428 | DOI:10.1126/sciadv.adp3743

Int J Cancer. 2024 Dec 18. doi: 10.1002/ijc.35295. Online ahead of print.ABSTRACTAnimal models of N-butyl-N-(4-hydroxy butyl) nitrosamine (BBN)-induced urothelial carcinoma (UC), particularly bladder cancer (BC), have long been established. However, the rare incidence of BBN-induced upper urinary tract UC (UTUC), which originates from the same urothelium as BC, remains elusive. The scarcity of animal models of UTUC has made it challenging to study the biology of UTUC. To address this problem, we tried to establish a novel mouse model of UTUC by treating multiple mice strains and sexes with BBN. The molecular consistency between the UTUC mouse model and human UTUC was confirmed using multi-omics analyses, including whole-exome, whole-transcriptome, and spatial transcriptome sequencing. 16S ribosomal RNA metagenome sequencing, metabolome analysis, and dietary interventions were employed to assess changes in the gut microbiome, metabolome, and carcinogenesis of UTUC. Of all treated mice, only female BALB/c mice developed UTUC over BC. Multi-omics analyses confirmed that the UTUC model reflected the molecular characteristics and heterogeneity of human UTUC with poor prognosis. Furthermore, the model exhibited increased Tnf-related inflammatory gene expression in the upper urinary tract and a low relative abundance of Parabacteroides distasonis in the gut. Dietary intervention, mainly without alanine, led to P. distasonis upregulation and successfully prevented UTUC, as well as suppressed Tnf-related inflammatory gene expression in the upper urinary tract despite the exposure to BBN. This is the first report to demonstrate a higher incidence of UTUC than BC in a non-engineered mouse model using BBN. Overall, this model could serve as a useful tool for comprehensively investigating UTUC in future studies.PMID:39693209 | DOI:10.1002/ijc.35295

Ann Med. 2025 Dec;57(1):2442070. doi: 10.1080/07853890.2024.2442070. Epub 2024 Dec 18.ABSTRACTBACKGROUND: Maternal colonization with Group B Streptococcus (GBS) disrupts the vaginal microbiota, potentially affecting infant microbiota assembly and growth. While the gut microbiota's importance in infant growth is recognized, the specific effects of maternal GBS on growth remain unclear. This study aimed to explore the effects of maternal vaginal GBS during pregnancy on early infant growth, microbiome, and metabolomics.METHODS: We recruited and classified 453 pregnant women from southern China into GBS or healthy groups based on GBS vaginal colonization. Their infants were categorized as GBS-exposed or GBS-unexposed groups. We comprehensively analyzed infant growth, gut microbiota, and metabolites during early life, along with maternal vaginal microbiota during pregnancy, using 16S rDNA sequencing and targeted metabolomics.RESULTS: GBS-exposed infants exhibited lower length-for-age z-scores (LAZ) than GBS-unexposed infants, especially at 2 months. Altered gut microbiota and metabolites in GBS-exposed infants correlated with growth, mediating the impact of maternal GBS on infant LAZ. Changes in the vaginal microbiota of the GBS group during the third trimester correlated with infant LAZ. Additionally, differences in neonatal gut microbiota, metabolites, and vaginal microbiota during pregnancy were identified between infants with overall LAZ<-1 within 8 months after birth and their counterparts, enhancing the discriminatory power of fundamental data for predicting the occurrence of LAZ<-1 during the first 8 months of life.CONCLUSIONS: GBS exposure is associated with decreased infant length growth, with altered microbiota and metabolites potentially mediating the effects of maternal GBS on offspring length growth, offering potential targets for predicting and addressing growth impairment.PMID:39693119 | DOI:10.1080/07853890.2024.2442070

Discov Oncol. 2024 Dec 18;15(1):779. doi: 10.1007/s12672-024-01662-1.ABSTRACTThe progressive globalization of sedentary lifestyles and diets rich in lipids and processed foods has caused two major public health hazards-diabetes and obesity. The strong interlink between obesity and type 2 diabetes mellitus and their combined burden encompass them into a single term 'Diabesity'. They have also been tagged as the drivers for the onset of cancer. The clinical association between diabetes, obesity, and several types of human cancer demands an assessment of vital junctions correlating the three. This review focuses on revisiting the molecular axis linking diabetes and obesity to cancer through pathways that get imbalanced owing to metabolic upheaval. We also attempt to describe the functional disruptions of DNA repair mechanisms due to overwhelming oxidative DNA damage caused by diabesity. Genomic instability, a known cancer hallmark results when DNA repair does not work optimally, and as will be inferred from this review the obtruded metabolic homeostasis in diabetes and obesity creates a favorable microenvironment supporting metabolic reprogramming and enabling malignancies. Altered molecular and hormonal landscapes in these two morbidities provide a novel connection between metabolomics and oncogenesis. Understanding various aspects of the tumorigenic process in diabesity-induced cancers might help in the discovery of new biomarkers and prompt targeted therapeutic interventions.PMID:39692821 | DOI:10.1007/s12672-024-01662-1

Aging Cell. 2024 Dec 18:e14442. doi: 10.1111/acel.14442. Online ahead of print.ABSTRACTCalorie restriction (CR) and physical exercise (EX) are well-established interventions known to extend health span and lifespan in animal models. However, their impact on human biological aging remains unclear. With recent advances in omics technologies and biological age (BioAge) metrics, it is now possible to assess the impact of these lifestyle interventions without the need for long-term follow-up. This study compared BioAge biomarkers in 41 middle-aged and older adult long-term CR practitioners, 41 age- and sex-matched endurance athletes (EX), and 35 sedentary controls consuming Western diets (WD), through PhenoAge: a composite score derived from nine blood-biomarkers. Additionally, a subset of participants (12 CR, 11 EX, and 12 WD) underwent multi-omic profiling, including DNA methylation and RNAseq of colon mucosa, blood metabolomics, and stool metagenomics. A group of six young WD subjects (yWD) served as a reference for BioAge calculation using Mahalanobis distance across six omic layers. The results demonstrated consistently lower BioAge biomarkers in both CR and EX groups compared to WD controls across all layers. CR participants exhibited lower BioAge in gut microbiome and blood-derived omics, while EX participants had lower BioAge in colon mucosa-derived epigenetic and transcriptomic markers, suggesting potential tissue-specific effects. Multi-omic pathway enrichment analyses suggested both shared and intervention-specific mechanisms, including oxidative stress and basal transcription as common pathways, with ether lipid metabolism uniquely enriched in CR. Despite limitations due to sample size, these findings contribute to the broader understanding of the potential anti-aging effects of CR and EX, offering promising directions for further research.PMID:39692728 | DOI:10.1111/acel.14442

Microb Biotechnol. 2024 Dec;17(12):e70058. doi: 10.1111/1751-7915.70058.ABSTRACTActinomycetota are unrivalled producers of bioactive natural products, with strains living in association with macroalgae representing a prolific-yet largely unexplored-source of specialised chemicals. In this work, we have investigated the bioactive potential of Actinomycetota from macroalgae through culture-dependent and -independent approaches. A bioprospecting pipeline was applied to a collection of 380 actinobacterial strains, recovered from two macroalgae species collected in the Portuguese northern shore-Codium tomentosum and Chondrus crispus-in order to explore their ability to produce antibacterial, antifungal, anticancer and lipid-reducing compounds. Around 43% of the crude extracts showed activity in at least one of the screenings performed: 111 presented antimicrobial activity at 1 mg/mL, 83 significantly decreased cancer cells viability at 15 μg/mL and 5 reduced lipid content in zebrafish > 60% at 15 ug/mL. Dereplication of active extracts unveiled the presence of compounds that could explain most of the recorded results, but also unknown molecules in the metabolome of several strains, highlighting the opportunity for discovery. The bioactive potential of the actinobacterial community from the same macroalgae specimens, which served as the source for the aforementioned Actinomycetota collection, was also explored through metagenomics analysis, allowing to obtain a broader picture of its functional diversity and novelty. A total of 133 biosynthetic gene clusters recovered from metagenomic contigs and metagenome assembled genomes (MAGs). These were grouped into 91 gene cluster families, 83 of which shared less than 30% of similarity to database entries. Our findings provided by culture-dependent and -independent approaches underscore the potential held by actinomycetes from macroalgae as reservoirs for novel bioactive natural products.PMID:39692706 | DOI:10.1111/1751-7915.70058

mSystems. 2024 Dec 18:e0124424. doi: 10.1128/msystems.01244-24. Online ahead of print.ABSTRACTMetabolic state-reprogramming approach was extended from Gram-negative bacteria to Gram-positive bacterium methicillin-resistant Staphylococcus aureus (MRSA) for identifying desired reprogramming metabolites to synergize existing antibiotic killing to MRSA. Metabolomics comparison between MRSA and methicillin-sensitive Staphylococcus aureus showed a depressed metabolic state in MRSA. Valine was identified as the most depressed metabolite/biomarker, and valine, leucine and isoleucine biosynthesis as the most enriched metabolic pathway. Thus, valine was used as a reprogramming metabolite to potentiate existing antibiotic killing to MRSA. Among the tested antibiotics, valine synergized cefoperazone-sulbactam (SCF) to produce the greatest killing effect. The combined effect of SCF and valine was demonstrated in clinical MRSA isolates and in mouse systemic and thigh infection models. Underlying mechanisms were attributed to valine-induced the activation of the pyruvate cycle/the TCA cycle and fatty acid biosynthesis. The activated pyruvate cycle/the TCA cycle elevated proton motive force by NADH and the activated fatty acid biosynthesis promoted membrane permeability by lauric acid. Both together increased cefoperazone uptake, which outpaces efflux action and thereby intracellular drug is elevated to effectively kill MRSA. These results provide the combination of valine and SCF to produce a new drug candidate effective against MRSA.IMPORTANCE: Methicillin-resistant Staphylococcus aureus (MRSA) is possibly the most infamous example of antibiotic resistance and new antibiotics are urgently needed to control it. The present study used metabolic state-reprogramming approach to identify an ideal biomarker as an antibiotic adjuvant for reversing the metabolic state of MRSA. The most repressed valine was identified as the adjuvant. Exogenous valine most effectively potentiated cefoperazone-sulbactam (SCF) to kill MRSA in vitro and in vivo. Viability of 18 clinical MRSA isolates was reduced by the top 276.64-fold in the presence of valine and SCF. In mouse models, lower bacterial load in liver, spleen, kidney, thigh, and higher survival were determined in the SCF + valine than valine or SCF alone. Valine promoted MRSA to increase SCF uptake that overcomes the efflux and enzymatic hydrolysis. It also extended the PAE of SCF. These occur because valine activates the pyruvate cycle to elevate proton motive force by NADH and increases membrane permeability by lauric acid. Therefore, the combination of valine and SCF is a new drug candidate effective against MRSA.PMID:39692510 | DOI:10.1128/msystems.01244-24

Antimicrob Agents Chemother. 2024 Dec 18:e0127224. doi: 10.1128/aac.01272-24. Online ahead of print.ABSTRACTHand, foot, and mouth disease (HFMD) is a serious pediatric infectious disease that causes immeasurable physical and mental health burdens. Currently, there is a lack of information on the mechanisms of HFMD severity and early diagnosis. We performed metabolomic profiling of sera from 84 Enterovirus A71 (EV-A71) infections and 45 control individuals. Targeted metabolomics assays were employed to further validate some of the differential metabolic molecules. We identified significant molecular changes in the sera of HFMD patients compared to healthy controls (HCs). A total of 54, 60, 35, and 62 differential metabolites were screened between mild cases and HCs, severe cases and HCs, severe cases and mild cases, and among the three groups, respectively. These differential metabolites implicated dysregulation of the tricarboxylic acid cycle, alanine, aspartate, and glutamate metabolism, and valine, leucine, and isoleucine biosynthesis. The diagnostic panel based on some overlapped differential metabolites could effectively discriminate severe cases from mild cases with an AUC of 0.912 (95% CI: 0.85-0.97) using the logistic regression model. Next, we found the elevation of serum sphingosine 1-phosphate (S1P) level in EV-A71 infection mice, which was similar to clinical observation. Importantly, after blocking the release of S1P by MK571, the clinical symptoms and survival of mice were significantly improved, involving the reduction of leukocyte infiltration in infected brain tissues. Collectively, our data provided a landscape view of metabolic alterations in EV-A71 infected children and revealed regulating S1P metabolism was an exploitable therapeutic target against EV-A71 infection.PMID:39692504 | DOI:10.1128/aac.01272-24

Mol Carcinog. 2024 Dec 18. doi: 10.1002/mc.23869. Online ahead of print.ABSTRACTHepatocellular carcinoma (HCC) is viewed as a metabolism associated disease, and bile acid metabolism is reported to occupy a significant role in the progression of HCC. However, little is known about the association between gut microbes and bile acid metabolism in HCC. Our study was designed to clarify the role of bile acid metabolism and microbiome in the progression of HCC. We investigated the relationship between bile acid metabolism and prognosis and immune cells by mining GSE14520. We studied the microbial profiles and metabolic alterations between the low bile acid group and high bile acid group using 16S rRNA sequencing and metabolomics. HCC patients in the high bile acid metabolism group showed better survival outcome compared with those in the low bile acid metabolism. Immune analysis displayed the close correlation between low bile acid metabolism and infiltration of CD4 + T cells, and the close relationship between high bile acid metabolism and infiltration of CD8 + T cells, macrophage cells in HCC. 16S rRNA sequencing results demonstrated that Blautia, Ruminococcus_gnavus_group, Erysipelotrichaceae_UCG-003 were mostly enriched in the low bile acid group. Metabolomics of the 109 fecal samples showed that the most enriched metabolites in the low total bile acid group were dihydrocytochalasin B, cucurbic acid and 27-Norcholestanehexol. Finally, KEGG enrichment analysis identified secondary bile acid biosynthesis and endocrine resistance as the most significant metabolic pathways. High bile acid metabolism was associated with more infiltration of CD8 + T cells, macrophage cells, and better prognosis in HCC. Levels of bile acid were significantly associated with altered gut microbes and metabolites in HCC. Further research related to gut microbes and bile acid metabolism may provide a novel insight into the pathogenesis and therapeutic strategy of HCC.PMID:39692258 | DOI:10.1002/mc.23869

Allergy. 2024 Dec 18. doi: 10.1111/all.16434. Online ahead of print.ABSTRACTRATIONALE: Biologics are becoming increasingly important in the management of severe asthma. However, little is known about the systemic immunometabolic consequences of Th2 response blockage.OBJECTIVES: To provide a better immunometabolic understanding of the effects of mepolizumab and omalizumab treatments by identifying potential biomarkers for monitoring.METHODS: In this exploratory longitudinal study severe asthmatic patients were followed for 18 months after initiating mepolizumab (n = 36) or Omalizumab (n = 20) treatment. Serum samples were collected before, 6, and 18 months after treatment. Targeted omic approaches were performed to analyze inflammatory metabolites (n = 35) and proteins (n = 45). Multiomic integration was performed individually for each treatment applying supervised analysis Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) framework. Then, potential biomarkers were confirmed using multivariate ROC analyses and correlated with clinical variables along treatment.MEASUREMENTS AND MAIN RESULTS: Mepolizumab and omalizumab were both effective (improved clinical variables) and showed different and specific metabolic and protein profiles in severe asthmatic patients during treatment. Multiomic integration and multivariate ROC analyses identified specific biomarkers, such as arachidonic acid, palmitoleic acid, oleic acid, propionylcarnitine, bilirubin, CCL11, and TNFSF10, which can explain the differences observed with Mepolizumab treatment over 18 months and significantly correlate with clinical improvement. However, no significant biomolecules and no discriminative multivariate ROC curves were found for Omalizumab treatment.CONCLUSIONS: Our results provide a comprehensive insight into the differential effects of mepolizumab and omalizumab on the immunometabolic kinetics of the inflammatory response in severe asthma. We identified a set of biomolecules with potential for monitoring mepolizumab treatment which could be useful for personalized medicine.PMID:39692160 | DOI:10.1111/all.16434