PubMed

Mol Nutr Food Res. 2024 Dec 17:e202400726. doi: 10.1002/mnfr.202400726. Online ahead of print.ABSTRACTInflammatory bowel disease (IBD) is a chronic condition characterized by gut inflammation causing persistent diarrhea and abdominal pain. Despite the nutritional benefits of wolfberry honey (from Lycium barbarum L.), its potential to alleviate IBD remains underexplored. This study evaluated the protective effects of wolfberry honey and its extract (wolfberry honey extract [WHE]) against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) using in vivo and in vitro models. Mice pretreated with wolfberry honey showed significant symptom improvement in DSS-induced UC, linked to reduced expression of proinflammatory markers (Il-1β, Il-6, Tnf-α, and Mcp-1) and increased antioxidant genes (Nrf2, Sod2). Increased Occludin levels indicated improved intestinal barrier function. In vitro, WHE protected DSS-treated Caco-2 cells by lowering reactive oxygen species (ROS), stabilizing mitochondrial membrane potential, and inhibiting TLR4/NF-κB signaling. It enhanced the expression of antioxidant genes and tight junction proteins (ZO-1, Occludin, and Claudin-1). Metabolomic analysis revealed that WHE modulated glycerophospholipid metabolism, increasing phosphatidylcholine and choline levels and decreasing lysophosphatidylcholine levels. These results highlight the potential of wolfberry honey and its extract as nutraceuticals for managing UC through their effects on inflammation, oxidative stress, and intestinal barrier function. Further research is warranted to elucidate their mechanisms of action and assess their long-term therapeutic benefits in IBD management.PMID:39690893 | DOI:10.1002/mnfr.202400726

J Agric Food Chem. 2024 Dec 17. doi: 10.1021/acs.jafc.4c11116. Online ahead of print.ABSTRACTPassion fruit is one of the most famous fruit crops in tropical and subtropical regions due to its high edible, medicinal, and ornamental value. Flavonoids, a class of plant secondary metabolites, have important health-related roles. In this study, a total of 151 flavonoid metabolites were identified, of which 25 key metabolites may be the main contributors to the purple phenotype. Using RNA sequencing, 11,180 differentially expressed genes (DEGs) were identified. Among these, 48 flavonoid biosynthesis genes (PAL, 4CL, C4H, CHS, CHI, F3H, DFR, ANS, and UFGT) and 123 transcription factors were identified. Furthermore, 12 distinct modules were identified through weighted gene coexpression network analysis, of which the brown module displays a robust positive correlation with numerous flavonoid metabolites. Overexpression of PeMYB114 significantly promoted flavonoids accumulation in tobacco leaves. Our study provided a key candidate gene for molecular breeding to improve color traits in passion fruit.PMID:39690798 | DOI:10.1021/acs.jafc.4c11116

J Am Chem Soc. 2024 Dec 17. doi: 10.1021/jacs.4c12607. Online ahead of print.ABSTRACTNMR is a central tool in the field of metabolomics, thanks to its ability to provide valuable structural and quantitative information with high precision. Most NMR-based metabolomics studies rely on 1D 1H detection, which is heavily limited by strong peak overlap. 13C NMR benefits from a wider spectral dispersion and narrower signal line width but is barely used in metabolomics due to its low sensitivity. Dissolution dynamic nuclear polarization (d-DNP) offers an opportunity to improve 13C NMR sensitivity by several orders of magnitude. Here, we show that this emerging hyperpolarized metabolomics approach can provide meaningful information about clinical samples. Achieving sub-mM limits of detection with 13C at natural abundance in urine samples was made possible by a meticulous design of the experimental workflow. The analysis of human urine samples from patients with different stages of chronic kidney disease (CKD) was performed using 13C d-DNP NMR and benchmarked to conventional 1H NMR metabolomics at a high magnetic field to explore the complementarity between the two methods. Multivariate analysis of the d-DNP 13C NMR dataset provided a statistical model able to distinguish patients with CKD from control patients. Moreover, 13C d-DNP NMR spectra highlighted several biomarkers known to be biologically relevant. Some of them were in agreement with those obtained with conventional 1H NMR, and the results also highlighted the complementarity of biomarker coverage between hyperpolarized and conventional NMR metabolomics. In particular, 13C hyperpolarized NMR allowed the annotation of two biomarkers that could not be detected by 1H NMR because of peak overlap (i.e., guanine and guanidoacetate).PMID:39690120 | DOI:10.1021/jacs.4c12607

Nutr Metab Cardiovasc Dis. 2024 Nov 9:103789. doi: 10.1016/j.numecd.2024.103789. Online ahead of print.ABSTRACTAIMS: Atherosclerosis is a life-threatening disease that develops when a plaque builds up inside an artery and progresses silently. Identifying the early pathological changes and the biomarkers of atherosclerosis deserves attention. We aimed to systematically study and integrate the various metabolites of atherosclerosis in the level of disease to provide more evidences to support early prevention and treatment of atherosclerosis.DATA SYNTHESIS: The protocol was registered with PROPSERO (CRD42023441845). We searched 14,985 records via EMBASE, PubMed, Web of Science, WanFang data, VIP data, and CNKI databases. The collected metabolites were for qualitative and quantitative meta-analysis. The I2 statistic estimated heterogeneity, with over 50 % considered to adopt the random-effects model. A total of 49 articles were included in the meta-analysis. We finally integrated 83 and 16 metabolites presented more than two times in inclusion studies, respectively in blood (plasma and serum) and urine. Among them, the level of citric acid (SMD = -10.35 [95%CI -15.03, -5.67], p < 0.001), lactic acid (SMD = 6.32 [95%CI 0.12, 12.52], p < 0.001) and TMAO (SMD = 1.40 [95%CI 0.27, 2.53], p < 0.001) had significant differences between atherosclerosis and controls. And we observed blood stasis syndrome of atherosclerosis patients present arterial ischemia and energy disorder obviously.CONCLUSIONS: The study provides an in-depth understanding of the roles of metabolites on atherosclerosis progression and prediction primarily in Chinese population, which contributing to development of prevention and therapeutic potential in the future.PMID:39690044 | DOI:10.1016/j.numecd.2024.103789

Comp Biochem Physiol C Toxicol Pharmacol. 2024 Dec 15:110111. doi: 10.1016/j.cbpc.2024.110111. Online ahead of print.ABSTRACTThe toxic effects of long-term exposure to low doses of chlorpyrifos (CPF) on Eriocheir sinensis were evaluated using acute toxicity tests, transcriptome analyses, and metabolome profiling. Four groups (three replicates per group, 60 crabs)-control (no CPF exposure), high exposure (0.12 mg/L CPF), medium exposure (0.036 mg/L), and low exposure (0.012 mg/L)-were subjected to CPF for 21 days. Tissue damage, antioxidant enzyme activity, transcriptional changes, and metabolic alterations in E. sinensis were analyzed. The results demonstrated that CPF disrupted the regulatory networks of transcription and metabolism in crabs under the experimental concentration conditions, with the severity of effects increasing as the duration of exposure lengthened despite the crabs' efforts to activate key defense mechanisms, such as upregulation of cholinesterase 1-like gene expression, to counteract organophosphorus toxicity and adapt to CPF presence in their environment. Even at low concentrations (0.012 mg/L), neurobehavioral development and the antioxidant kinase system in crabs were impaired, leading to hepatopancreatic tissue lesions that negatively affect their growth and survival rates. Additionally, E. sinensis accumulates significant levels of CPF, which may pose food safety concerns when humans consume them. Therefore, ensuring the rational use of CPF requires maintaining appropriate water concentrations to minimize direct harm to aquatic organisms and indirect impacts on food safety associated with this pesticide.PMID:39689750 | DOI:10.1016/j.cbpc.2024.110111

J Hazard Mater. 2024 Dec 14;485:136886. doi: 10.1016/j.jhazmat.2024.136886. Online ahead of print.ABSTRACTTetrabromobisphenol A (TBBPA) poses significant ecological risks owing to its toxicity; however, its specific effects on toxin-producing cyanobacteria in aquatic environments remain poorly understood. This study systematically investigated the effects of TBBPA at concentrations ranging from 100 ng/L to 100 mg/L on Microcystis aeruginosa (M. aeruginosa) by examining growth, photosynthesis, toxin production, antioxidant responses, and molecular-level changes. The results indicated that low levels of TBBPA (0.1-1000 μg/L) induced stimulatory effects on the growth and microcystin-leucine-arginine (MC-LR) production of M. aeruginosa. Metabolomic analysis revealed that low levels of TBBPA significantly upregulated metabolites associated with energy metabolism, xenobiotic biodegradation, oxidative stress responses, and protein biosynthesis in M. aeruginosa, potentially contributing to the observed hormetic effect. Conversely, higher doses (40-100 mg/L) inhibited growth and significantly increased MC-LR release by compromising cellular structural integrity. Proteomic analysis revealed that toxic levels of TBBPA significantly affected the expression of proteins associated with energy harvesting and utilization. Specifically, TBBPA disrupted electron flow in oxidative phosphorylation and the photosynthetic system (PS) by targeting PSI, PSII, and Complex I, impairing energy acquisition and causing oxidative damage, ultimately leading to algal cell death. Additionally, proteins involved in the biosynthesis and metabolism of cysteine, methionine, phenylalanine, tyrosine, and tryptophan were upregulated, potentially enhancing M. aeruginosa resistance to TBBPA-induced stress. This study offers insights into the effects of TBBPA on M. aeruginosa and its potential risks to aquatic ecosystems.PMID:39689566 | DOI:10.1016/j.jhazmat.2024.136886

Anal Bioanal Chem. 2024 Dec 18. doi: 10.1007/s00216-024-05688-w. Online ahead of print.ABSTRACTFolate, serving as a crucial micronutrient, plays an important role in promoting human growth and supporting transformations to a variety of metabolic pathways including one-carbon, pyrimidine, purine, and homocysteine metabolism. The 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme is pivotal in the folate metabolic pathway. Polymorphism in the MTHFR gene, especially C677T, was associated with decreased enzyme activity and disturbance of folate metabolism, which is linked to various diseases including birth defects in newborns and neural tube abnormalities. However, the detailed metabolic disturbance induced by MTHFR C677T polymorphism is still elusive. In this study, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the precise quantification of 93 metabolites from six important metabolic pathways related to folate metabolism. The method characteristics demonstrated high accuracy and precision, with r2 values ranging from 0.981 to 1.000 for all metabolites. Then the impact of the MTHFR C677T polymorphism on folate metabolism was further investigated, revealing a significant reduction in the level of 5-methyltetrahydrofolate and abnormal levels of metabolites associated with DNA synthesis pathways in individuals carrying the mutation. These data highlight the pivotal role of folic acid supplementation for individuals with the MTHFR C677T polymorphism to mitigate health risks and show the value of precision measurement of folate-related metabolites.PMID:39690314 | DOI:10.1007/s00216-024-05688-w

World J Microbiol Biotechnol. 2024 Dec 18;41(1):11. doi: 10.1007/s11274-024-04224-3.ABSTRACTPeriodontal disease is characterized by bacterial toxins within the oral biofilm surrounding the teeth, leading to gingivitis and the gradual dissolution of the alveolar bone, which supports the teeth. Notably, symptoms in the early stages of the disease are often absent. Similarly, dental caries occurs when oral bacteria metabolize dietary sugars, producing acids that dissolve tooth enamel and dentin. These bacteria are commonly present in the oral cavity of most individuals. Metabolomics, a relatively recent addition to the "omics" research landscape, involves the comprehensive analysis of metabolites in vivo to elucidate pathological mechanisms and accelerate drug discovery. Meanwhile, the term "microbiome" refers to the collection of microorganisms within a specific environmental niche or their collective genomes. The human microbiome plays a critical role in health and disease, influencing a wide array of physiological and pathological processes. Recent advances in microbiome research have identified numerous bacteria implicated in dental caries and periodontal disease. Additionally, studies have uncovered various pathogenic factors associated with these microorganisms. This review focuses on recent findings in metabolomics and the microbiome, specifically targeting oral bacteria linked to dental caries and periodontal disease. We acknowledge the limitation of relying exclusively on the MEDLINE database via PubMed, while excluding other sources such as gray literature, conference proceedings, and clinical practice guidelines.PMID:39690257 | DOI:10.1007/s11274-024-04224-3

J Ethnopharmacol. 2024 Dec 15:119249. doi: 10.1016/j.jep.2024.119249. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Cordycepin, the main active component of Cordyceps militaris, exhibits various pharmacological activities, including anti-tumor and antioxidant effects. However, its antidepressant effect and the underlying mechanisms remain unclear.AIM OF REVIEW: This study aimed to explore the antidepressant effect of cordycepin and elucidate the potential molecular mechanisms.MATERIALS AND METHODS: Chronic unpredictable mild stress (CUMS) rat model was established to assess antidepressant effect of cordycepin. Gas chromatography-mass spectrometry (GC-MS) metabolomics with integrated network pharmacology were used to find differential metabolites in serum, brain, and cerebrospinal fluid of rats and identify potential target by cordycepin. Western blot and Real-time PCR were applied to validate the signaling pathway.RESULTS: Cordycepin alleviated CUMS-induced depression-like behaviors by weight gain, sucrose preference increment, immobility time reduction, total travelling distance extension and serum corticosterone levels reduction. Metabolomics showed that cordycepin reversed CUMS-induced metabolic disturbances through alanine and TCA cycle metabolism pathways. Network pharmacology identified GSK3β as a potential target. Cordycepin increased protein levels of p-GSK3β, β-catenin and nuclear β-catenin, and enhanced transcription of downstream genes PKM, LDHA, Cyclin D1 and C-myc in brains of CUMS-induced rats.CONCLUSIONS: This study indicated that cordycepin exerted antidepressant effect by modulating GSK3β/β-catenin pathway, suggesting its potential as a candidate agent for depression.PMID:39689748 | DOI:10.1016/j.jep.2024.119249

J Ethnopharmacol. 2024 Dec 15:119241. doi: 10.1016/j.jep.2024.119241. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Chronic fatigue syndrome (CFS), as a complex, multisystemic, and multisystemic disorder affecting multiple organs and systems, often accompanies by symptoms such as post-exercise discomfort, sleep disorders, cognitive difficulties, and orthostatic intolerance. Jingfang Granule (JFG) is a traditional Chinese medicine that have significant protective effects on CFS, but the mechanism is still vague.AIM OF STUDY: This study was designed to evaluate the protective mechanism of JFG on mice with CFS.MATERIALS AND METHODS: The combined stimuli method was used to establish the mice CFS model, and JFG was orally administered. The body weight, exhaustion swimming training and tail suspension test were assayed every 7 days to evaluate the improvement of JFG on CFS. Lactic acid, adenosine triphosphate (ATP), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), IL-1β, TNF-α, IL-6 in serum and liver glycogen, muscle glycogen in muscle were analyzed. Transmission electron microscopy was used to detect mitochondrial morphology. The regulatory networks were investigated by proteomics and central carbon metabolomics, which were verified by western blot.RESULTS: JFG reversed the loss of weight and reduce of exhaust swimming time (P < 0.05) induced by CFS in mice, and increased the tail suspension time (P < 0.05), indicating that JFG has an improving effect on CFS. Meanwhile, JFG increased the spleen index (P < 0.05), decreased the thymus index (P < 0.05) and cardiac index (P < 0.05), inhibited the secretion of Lactic acid (P < 0.05), and increased the content of liver glycogen (P < 0.05), muscle glycogen (P < 0.05), and ATP (P < 0.05), and improved mitochondrial morphology in mice with CFS. JFG also inhibited the release of TNF-α (P < 0.05), IL-1β (P < 0.05) and IL-6 (P < 0.05) in serum by inhibiting TLR4/NF-κB signaling pathway and NLRP3 inflammasome signaling pathway, and inhibited oxidative stress by activating Nrf2/HO-1/NQO1 axis. Integrated central carbon metabolomics, proteomics and western blot showed that JFG intervened in CFS by increasing the expression of Idh1 (P < 0.05) and Idh2 (P < 0.01) to promote tricarboxylic acid (TCA) cycle.CONCLUSIONS: This study confirmed that JFG promoted the TCA cycle by increasing the expression of Idh1 and Idh2, and then inhibited inflammation and oxidative stress to prevent CFS injury, which provided a potential drug candidate for CFS treatment.PMID:39689747 | DOI:10.1016/j.jep.2024.119241

Food Chem. 2024 Dec 11;468:142241. doi: 10.1016/j.foodchem.2024.142241. Online ahead of print.ABSTRACTFermentation is a key process in Congou black tea, but there is limited research on the changes in flavor factors and their interrelationships during different fermentation stages under industrial production. This study applies sensory evaluation and metabolomics techniques to explore the interactions between flavors. Sensory evaluation indicated that the 4-h fermented sample exhibited the best overall performance. The experiment of adding aroma substances further revealed the significant effects of sweet aroma and green odor on taste of sweetness and astringency. Additionally, 532 flavor compounds were identified using high-resolution liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Moreover, significant differences were observed in the volatile compounds derived from flavonoids, amino acids, and fatty acids of samples with different fermentation degrees. Furthermore, weighted co-expression network analysis of flavor compounds showed that the oxidation of polyphenols, especially catechins, plays an important regulatory role in content changes of volatile and other non-volatile compounds during fermentation.PMID:39689488 | DOI:10.1016/j.foodchem.2024.142241

Food Chem. 2024 Dec 10;468:142447. doi: 10.1016/j.foodchem.2024.142447. Online ahead of print.ABSTRACTLactiplantibacillus plantarum NUC08, a novel probiotic strain, has demonstrated potential for synergistic fermentation with starter cultures. This study investigates its functional properties in fermented milk and examines how mulberry fruit extract (MFE), rich in bioactive compounds, may influence its fermentation performance. MFE significantly boosted LAB growth, improved texture and rheological properties, and enhanced antioxidant capacity in the probiotic yogurt. GC-MS analysis revealed that MFE enriched the flavor profile by increasing key flavor-related metabolites, contributing to superior sensory qualities. Furthermore, the combination of L. plantarum NUC08 and MFE led to distinct shifts in metabolic pathways, as shown by LC-MS analysis, amplifying the regulatory effects on antioxidant activity. These findings demonstrate the synergy between MFE and L. plantarum NUC08, where MFE enhances the growth and functionality of L. plantarum NUC08, improving the yogurt's physicochemical properties, antioxidant capacity, and flavor, with potential for functional dairy product development.PMID:39689487 | DOI:10.1016/j.foodchem.2024.142447

Appl Radiat Isot. 2024 Nov 20;217:111597. doi: 10.1016/j.apradiso.2024.111597. Online ahead of print.ABSTRACTSugarcane is an economically important polyploid crop whose genetic complexity and limited fertility poses a challenge for crop improvement programs. Gamma radiation-induced mutagenesis is an alternate approach for generating a diverse array of agronomically useful mutants, accelerating varietal development in a long-duration crop like sugarcane. To develop agronomically useful mutants of a commercial sugarcane genotype Co 99004, gamma ray induced in vitro mutagenesis was carried out. The phenotypic variants of Co 99004 in V1 generation could be categorized into five distinct phenotypically scorable classes, including three chlorophyll mutants (albina, chlorina and chlorina pigmented) and two green mutants like wild type control. SRAP marker analyses indicated distinct genomic variation among the phenotypic mutants and control plants, with the polymorphic information content (PIC) ranging from 0 to 0.472. Further, the phylogenetic dendrogram derived from the SRAP marker data grouped the mutants into four distinct clusters clearly differentiating the phenotypic classification. Sequencing of selected SRAP amplicons indicated deletion/insertion of gene specific fragments. Interestingly, the loss of chlorophyll in albina and chlorina mutants showed gamma irradiation-induced deletions in the gene encoding FAR1-RELATED SEQUENCE 5-like protein, which is involved in chlorophyll biosynthesis. GC-MS based metabolome profiling showed alteration in tetrapyrrole biosynthesis, MEP (Methylerythritol Phosphate), and fatty acid biosynthesis pathways, indicating a significant metabolic variation in the chlorophyll mutants. Further characterization of the genetically distinct, non-lethal green wild type mutants can lead to the identification of agronomically useful mutants. In addition, the loss-of-function chlorophyll mutants can serve as a good source for comparative genomics studies aimed at gene-trait association.PMID:39689483 | DOI:10.1016/j.apradiso.2024.111597

PLoS Biol. 2024 Dec 17;22(12):e3002943. doi: 10.1371/journal.pbio.3002943. Online ahead of print.ABSTRACTRepeated antigen exposure leads to T-cell exhaustion, a transcriptionally and epigenetically distinct cellular state marked by loss of effector functions (e.g., cytotoxicity, cytokine production/release), up-regulation of inhibitory receptors (e.g., PD-1), and reduced proliferative capacity. Molecular pathways underlying T-cell exhaustion have been defined for CD8+ cytotoxic T cells, but which factors drive exhaustion in CD4+ T cells, that are also required for an effective immune response against a tumor or infection, remains unclear. Here, we utilize quantitative proteomic, phosphoproteomic, and metabolomic analyses to characterize the molecular basis of the dysfunctional cell state induced by chronic stimulation of CD4+ memory T cells. We identified a dynamic response encompassing both known and novel up-regulated cell surface receptors, as well as dozens of unexpected transcriptional regulators. Integrated causal network analysis of our combined data predicts the histone acetyltransferase p300 as a driver of aspects of this phenotype following chronic stimulation, which we confirmed via targeted small molecule inhibition. While our integrative analysis also revealed large-scale metabolic reprogramming, our independent investigation confirmed a global remodeling away from glycolysis to a dysfunctional fatty acid oxidation-based metabolism coincident with oxidative stress. Overall, these data provide both insights into the mechanistic basis of CD4+ T-cell exhaustion and serve as a valuable resource for future interventional studies aimed at modulating T-cell dysfunction.PMID:39689157 | DOI:10.1371/journal.pbio.3002943

PLoS One. 2024 Dec 17;19(12):e0315857. doi: 10.1371/journal.pone.0315857. eCollection 2024.ABSTRACTBroadly targeted metabolomics techniques were used to identify phenolic acid compounds in Polygonatum kingianum var. grandifolium (PKVG) rhizomes and retrieve anti-cancer/tumor active substance bases from them. We identified potential drug targets by constructing Venn diagrams of compound and disease targets. Further, KEGG pathway analysis was performed to reveal the relevant pathways for anti-cancer/tumor activity of PKVG. Finally, we performed molecular docking to determine whether the identified proteins were targets of phenolic acid compounds from PKVG rhizome parts. The study's results revealed 71 phenolic acid compounds in PKVG rhizomes. Among them, three active ingredients and 42 corresponding targets were closely related to the anticancer/tumor activities of PKVG rhizome site phenolic acids. We identified two essential compounds and eight important targets by constructing the compound-target pathway network. 2 essential compounds were androsin and chlorogenic acid; 8 key targets were MAPK1, EGFR, PRKCA, MAPK10, GSK3B, CASP3, CASP8, and MMP9. The analysis of the KEGG pathway identified 42 anti-cancer/tumor-related pathways. In order of degree, we performed molecular docking on two essential compounds and the top 4 targets, MAPK1, EGFR, PRKCA, and MAPK10, to further validate the network pharmacology screening results. The molecular docking results were consistent with the network pharmacology results. Therefore, we suggest that the phenolic acids in PKVG rhizomes may exert anti-cancer/tumor activity through a multi-component, multi-target, and multi-channel mechanism of action.PMID:39689118 | DOI:10.1371/journal.pone.0315857

PLoS One. 2024 Dec 17;19(12):e0314854. doi: 10.1371/journal.pone.0314854. eCollection 2024.ABSTRACTOBJECTIVE: To investigate metabolic markers linked to Mycobacterium tuberculosis (M. tb) in the cerebrospinal fluid (CSF) of a South African cohort of paediatric tuberculous meningitis (TBM).METHODS: Targeted proton magnetic resonance (1H-NMR) spectroscopy and two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) metabolomics approaches were used to evaluate M. tb-linked metabolites in the CSF of 21 definite cases of TBM and 25 control cases. Uni- and multivariate statistical analyses were performed.RESULTS: Four statistically significant metabolites were identified to discriminate TBM cases from controls. Mannose and arabinose were found at lower concentrations in the TBM group. Nonanoic acid and propanoic acid were found in higher concentrations in the definite TBM group.CONCLUSIONS: We identified the novel presence of nonanoic acid for the first time as a M. tb-linked marker in the CSF of cases of TBM, possibly as a degradation product of the M. tb cell wall. Propanoic acid can be related to perturbed brain neuro-energetics and neuro-inflammation in TBM cases and is likely a host-response metabolite. Mannose and arabinose-supposed surrogates for lipoarabinomannan, a component of the M. tb cell wall-were not reliable markers for M. tb. Further research should focus on the analysis of fatty acids in the CSF of patients with TBM.PMID:39689104 | DOI:10.1371/journal.pone.0314854

PLoS One. 2024 Dec 17;19(12):e0313090. doi: 10.1371/journal.pone.0313090. eCollection 2024.ABSTRACTThe experiments presented here are based on the reconfiguration of an ancient medicine, Lemnian Earth (LE) (terra sigillata, stamped earth, sphragis), an acclaimed therapeutic clay with a 2500-year history of use. Based on our hypothesis that LE was not a natural material but an artificially modified one involving a clay-fungus interaction, we present results from experiments involving the co-culture of a common fungus, Penicillium purpurogenum (Pp), with two separate clay slurries, smectite and kaolin, which are the principal constituents of LE. Our results show: (a) the leachate of the Pp+smectite co-culture is antibacterial in vitro, inhibiting the growth of both Gram-positive and Gram-negative bacteria; (b) in vivo, supplementation of regular mouse diet with leachates of Pp+smectite increases intestinal microbial diversity; (c) Pp+kaolin does not produce similar results; (d) untargeted metabolomics and analysis of bacterial functional pathways indicates that the Pp+smectite-induced microbiome amplifies production of short-chain fatty acids (SCFAs) and amino acid biosynthesis, known to modulate intestinal and systemic inflammation. Our results suggest that the combination of increased microbial diversity and SCFA production indicates beneficial effects on the host microbiome, thus lending support to the argument that the therapeutic properties of LE may have been based on the potential for modulating the gut microbiome. Our experiments involving reconfigured LE open the door to future research into small molecule-based sources for promoting gut health.PMID:39689103 | DOI:10.1371/journal.pone.0313090

Anesth Analg. 2024 Dec 17. doi: 10.1213/ANE.0000000000007350. Online ahead of print.ABSTRACTBACKGROUND: In elderly individuals, excessive lactate levels in the brain may be associated with the development of cognitive impairment after surgery, including delayed neurocognitive recovery (dNCR). Since the origin of this increased lactate is unknown, here we assessed associations between metabolic pathways and postoperative dNCR.METHODS: This study included 43 patients (≥60 years old) who had surgery under general anesthesia. We also used a mouse model in which 20-month-old mice were exposed to sevoflurane to induce postoperative dNCR, while control mice were exposed to 40% oxygen. Mice in the control group and anesthesia/surgery group were injected with fructose or glucose intracerebroventricularly, or fructose metabolism inhibitor intraperitoneally. Barnes maze test and Y maze were used to measure cognitive function in mice. Metabolomics was used to measure metabolites in the serum of patients and the brains of mice after anesthesia/surgery. Isotope labeling and metabolic flux were used to analyze flow and distribution of specific metabolites in metabolic pathways.RESULTS: Among 43 patients, 17 developed dNCR. Metabolomics showed significantly decreased postoperative serum fructose 1-phosphate levels in dNCR compared to nondNCR patients (mean difference [×104] = -0.164 ± 0.070; P = .024). Similar results were found in the brains of mice (mean difference = -1.669 ± 0.555; *P = .014). Isotope labeling and metabolic flux experiments in mice showed fructose but not glucose entered glycolysis, increasing lactate levels in the brain after anesthesia/surgery (P < .05). Administration of intraperitoneal fructose inhibitors to mice effectively inhibited increased lactate levels in the brain (mean difference =96.0 ± 4.36, P = .0237) and cognitive dysfunction after anesthesia/surgery (mean difference =69.0 ± 3.94, P = .0237). In a small subsample, we also found anesthesia/surgery increased interleukin-6 (IL-6) levels in the brains of mice (mean difference =88.3 ± 3.44, P = .0237) and that IL-6 may function upstream in fructose activation.CONCLUSIONS: These results suggest that anesthesia/surgery activates fructose metabolism, producing excessive lactate in the brain that is associated with postoperative cognitive impairment. Fructose metabolism is thus a potential therapeutic target for dNCR.PMID:39689012 | DOI:10.1213/ANE.0000000000007350

Microbiol Spectr. 2024 Dec 17:e0113124. doi: 10.1128/spectrum.01131-24. Online ahead of print.ABSTRACTMediation analysis has emerged as a versatile tool for answering mechanistic questions in microbiome research because it provides a statistical framework for attributing treatment effects to alternative causal pathways. Using a series of linked regressions, this analysis quantifies how complementary data relate to one another and respond to treatments. Despite these advances, existing software's rigid assumptions often result in users viewing mediation analysis as a black box. We designed the multimedia R package to make advanced mediation analysis techniques accessible, ensuring that statistical components are interpretable and adaptable. The package provides a uniform interface to direct and indirect effect estimation, synthetic null hypothesis testing, bootstrap confidence interval construction, and sensitivity analysis, enabling experimentation with various mediator and outcome models while maintaining a simple overall workflow. The software includes modules for regularized linear, compositional, random forest, hierarchical, and hurdle modeling, making it well-suited to microbiome data. We illustrate the package through two case studies. The first re-analyzes a study of the microbiome and metabolome of Inflammatory Bowel Disease patients, uncovering potential mechanistic interactions between the microbiome and disease-associated metabolites, not found in the original study. The second analyzes new data about the influence of mindfulness practice on the microbiome. The mediation analysis highlights shifts in taxa previously associated with depression that cannot be explained indirectly by diet or sleep behaviors alone. A gallery of examples and further documentation can be found at https://go.wisc.edu/830110.IMPORTANCE: Microbiome studies routinely gather complementary data to capture different aspects of a microbiome's response to a change, such as the introduction of a therapeutic. Mediation analysis clarifies the extent to which responses occur sequentially via mediators, thereby supporting causal, rather than purely descriptive, interpretation. Multimedia is a modular R package with close ties to the wider microbiome software ecosystem that makes statistically rigorous, flexible mediation analysis easily accessible, setting the stage for precise and causally informed microbiome engineering.PMID:39688588 | DOI:10.1128/spectrum.01131-24

Orthod Craniofac Res. 2024 Dec 17. doi: 10.1111/ocr.12883. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to uncover the microbial and metabolic changes in dental plaque during orthodontic treatments with fixed appliances (FAs) and clear aligners (CAs).MATERIALS AND METHODS: Twenty participants were grouped by the treatment modality they received, with 10 participants each in the FA and CA groups. Supragingival plaques were collected before orthodontic treatment (T0), after 1-3 months (T1) and more than 6 months (T2) of orthodontic treatment. 16S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry were employed to analyse the plaque samples.RESULTS: No significant change was observed in the alpha and beta diversity at different time points and between the two treatment modalities. The relative abundance of genera Veillonella, Mogibacterium and unclassified_c__Actinobacteria, and species Actinomyces massiliensis, Prevotella pallens and Prevotella jejuni experienced the most significant changes. The most differential metabolites were amino acids, nucleosides and organoheterocyclic compounds. Compared to T0, downregulation of nucleotide metabolism at T1 and upregulation of amino acid metabolism at T2 were found in the FA group. Compared with the FA group, the CA group experienced metabolite enrichment in several immune pathways at T1, while linoleic acid metabolism, riboflavin metabolism and nucleotide metabolism were downregulated at T2 in the CA group. Significant correlations were identified between most differential plaque microorganisms and metabolites.CONCLUSION: This study implied that exposure to FAs for more than 6 months resulted in the accumulation of oral disease-related bacteria in dental plaque and a metabolic shift towards a cariogenic state, whereas CAs could lead to a transient proinflammatory state.PMID:39688160 | DOI:10.1111/ocr.12883