PubMed

Mol Neurobiol. 2024 May 30. doi: 10.1007/s12035-024-04223-3. Online ahead of print.ABSTRACTBacopa monnieri (L.) Wettst and Centella asiatica (L.) Urb., two nootropics, are recognized in Indian Ayurvedic texts. Studies have attempted to understand their action as memory enhancers and neuroprotectants, but many molecular aspects remain unknown. We propose that Bacopa monnieri (L.) Wettst and Centella asiatica (L.) Urb. share common neuroprotective mechanisms. Mass spectrometry-based untargeted metabolomics and network pharmacology approach were used to identify potential protein targets for the metabolites from each extract. Phytochemical analyses and cell culture validation studies were also used to assess apoptosis and ROS activity using aqueous extracts prepared from both herbal powders. Further, docking studies were also performed using the LibDock protocol. Untargeted metabolomics and network pharmacology approach unveiled 2751 shared metabolites and 3439 and 2928 non-redundant metabolites from Bacopa monnieri and Centella asiatica extracts, respectively, suggesting a potential common neuroprotective mechanism among these extracts. Protein-target prediction highlighted 92.4% similarity among the proteins interacting with metabolites for these extracts. Among them, kinases mapped to MAPK, mTOR, and PI3K-AKT signaling pathways represented a predominant population. Our results highlight a significant similarity in the metabolome of Bacopa monnieri (L.) Wettst and Centella asiatica (L.) Urb., and their potential protein targets may be attributed to their common neuroprotective functions.PMID:38814535 | DOI:10.1007/s12035-024-04223-3

J Nat Prod. 2024 May 30. doi: 10.1021/acs.jnatprod.4c00376. Online ahead of print.ABSTRACTBiofilms commonly develop in immunocompromised patients, which leads to persistent infections that are difficult to treat. In the biofilm state, bacteria are protected against both antibiotics and the host's immune system; currently, there are no therapeutics that target biofilms. In this study, we screened a chemical fraction library representing the natural product capacity of the microbiota of marine egg masses, namely, the moon snail egg collars. This led to the identification of active fractions targeting both Pseudomonas aeruginosa and Staphylococcus aureus biofilms. Subsequent analysis revealed that a subset of these fractions were capable of eradicating preformed biofilms, all against S. aureus. Bioassay-guided isolation led us to identify pseudochelin A, a known siderophore, as a S. aureus biofilm inhibitor with an IC50 of 88.5 μM. Mass spectrometry-based metabolomic analyses revealed widespread production of pseudochelin A among fractions possessing S. aureus antibiofilm properties. In addition, a key biosynthetic gene involved in producing pseudochelin A was detected on 30% of the moon snail egg collars and pseudochelin A is capable of inhibiting the formation of biofilms (IC50 50.6 μM) produced by ecologically relevant bacterial strains. We propose that pseudochelin A may have a role in shaping the microbiome or protecting the egg collars from microbiofouling.PMID:38814458 | DOI:10.1021/acs.jnatprod.4c00376

Mol Cell Biochem. 2024 May 30. doi: 10.1007/s11010-024-05041-w. Online ahead of print.ABSTRACTCancer due to its heterogeneous nature and large prevalence has tremendous socioeconomic impacts on populations across the world. Therefore, it is crucial to discover effective panels of biomarkers for diagnosing cancer at an early stage. Cancer leads to alterations in cell growth and differentiation at the molecular level, some of which are very unique. Therefore, comprehending these alterations can aid in a better understanding of the disease pathology and identification of the biomolecules that can serve as effective biomarkers for cancer diagnosis. Metabolites, among other biomolecules of interest, play a key role in the pathophysiology of cancer whose levels are significantly altered while 'reprogramming the energy metabolism', a cellular condition favored in cancer cells which is one of the hallmarks of cancer. Metabolomics, an emerging omics technology has tremendous potential to contribute towards the goal of investigating cancer metabolites or the metabolic alterations during the development of cancer. Diverse metabolites can be screened in a variety of biofluids, and tumor tissues sampled from cancer patients against healthy controls to capture the altered metabolism. In this review, we provide an overview of different metabolomics approaches employed in cancer research and the potential of metabolites as biomarkers for cancer diagnosis. In addition, we discuss the challenges associated with metabolomics-driven cancer research and gaze upon the prospects of this emerging field.PMID:38814423 | DOI:10.1007/s11010-024-05041-w

Cancer Chemother Pharmacol. 2024 May 30. doi: 10.1007/s00280-024-04680-6. Online ahead of print.ABSTRACTBACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity.METHODS: Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm.RESULTS: In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (β = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (β = 0.54 [0.19, 0.89], p = 0.002), tyrosine (β = 0.57 [0.23, 0.91], p = 0.001), and valine (β = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality.CONCLUSIONS: This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged.PMID:38814343 | DOI:10.1007/s00280-024-04680-6

J Endocrinol. 2024 May 1:JOE-24-0051. doi: 10.1530/JOE-24-0051. Online ahead of print.ABSTRACTGlucagon plays a central role in amino acid (AA) homeostasis. The dog is an established model of glucagon biology and recently metabolomic changes in people associated with glucagon infusions has been reported. Glucagon also has effects on the kidney; however, changes in urinary AA concentrations associated with glucagon remain under investigated. Therefore, we aimed to fill these gaps in the canine model by determining the effects of glucagon on the canine plasma metabolome and measuring urine AA concentrations. Employing two constant rate glucagon infusions (CRI) - low-dose (CRI-LO: 3 ng/kg/min) and high-dose (CRI-HI: 50 ng/kg/min) on five research beagles, we monitored interstitial glucose and conducted untargeted liquid chromatography tandem mass spectrometry (LC-MS/MS) on plasma samples and urine AA concentrations collected pre- and post-infusion. The CRI-HI induced a transient glucose peak (90-120 min), returning near baseline by infusion end, while only the CRI-LO resulted in 372 significantly altered plasma metabolites, primarily reductions (333). Similarly, CRI-HI affected 414 metabolites, with 369 reductions, evidenced by distinct clustering post-infusion via data reduction (PCA and sPLS-DA). CRI-HI notably decreased circulating AA levels, impacting various AA-related and energy generating metabolic pathways. Urine analysis revealed increased 3-methyl-L-histidine and glutamine, and decreased alanine concentrations post-infusion. These findings demonstrate glucagon's glucose-independent modulation of the canine plasma metabolome and highlight the dog's relevance as a translational model for glucagon biology. Understanding these effects contributes to managing dysregulated glucagon conditions and informs treatments impacting glucagon homeostasis.PMID:38814331 | DOI:10.1530/JOE-24-0051

Cell Mol Biol (Noisy-le-grand). 2024 May 27;70(5):248-252. doi: 10.14715/cmb/2024.70.5.45.ABSTRACTCataract (CAT) has a very high incidence rate among the middle-aged and elderly, with most patients complicated by branch retinal vein occlusion (BRVO), a key cause of blindness. In this study, through metabolomic analysis of aqueous humor samples from CAT patients with BRVO, a total of 319 different metabolites were found, most of which belonged to the categories of carboxylic acids and derivatives, fatty acyls, and organooxygen compounds. The most typical metabolites were 3-methylhistidine and biliverdin, which were up-regulated, as well as the down-regulated beta-glycerophosphoric acid. Tricosanoic acid showed the most significant correlation with CAT+BRVO. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the most commonly related keywords for differentially expressed metabolites were biosynthesis of unsaturated fatty acids and synaptic vesicle cycle. These results can not only help to further understand the pathogenesis of CAT complicated by BRVO in clinical practice, but also provide some new therapeutic research directions.PMID:38814207 | DOI:10.14715/cmb/2024.70.5.45

Appl Environ Microbiol. 2024 May 30:e0066524. doi: 10.1128/aem.00665-24. Online ahead of print.ABSTRACTAsh dieback, caused by the fungal pathogen Hymenoscyphus fraxineus (Helotiales, Ascomycota), is threatening the existence of the European ash, Fraxineus excelsior. During our search for biological control agents for this devastating disease, endophytic fungi were isolated from healthy plant tissues and co-cultivated with H. fraxineus to assess their antagonistic potential. Among the strains screened, Penicillium cf. manginii DSM 104493 most strongly inhibited the pathogen. Initially, DSM 104493 showed promise in planta as a biocontrol agent. Inoculation of DSM 104493 into axenically cultured ash seedlings greatly decreased the development of disease symptoms in seedlings infected with H. fraxineus. The fungus was thus cultivated on a larger scale in order to obtain sufficient material to identify active metabolites that accounted for the antibiosis observed in dual culture. We isolated PF1140 (1) and identified it as the main active compound in the course of a bioassay-guided isolation strategy. Furthermore, its derivative 2, the mycotoxin citreoviridin (3), three tetramic acids of the vancouverone type (4-6), and penidiamide (7) were isolated by preparative chromatography. The structures were elucidated mainly by NMR spectroscopy and high-resolution mass spectrometry (HRMS), of which compounds 2 and 6 represent novel natural products. Of the compounds tested, not only PF1140 (1) strongly inhibited H. fraxineus in an agar diffusion assay but also showed phytotoxic effects in a leaf puncture assay. Unfortunately, both the latent virulent attributes of DSM 104493 observed subsequent to these experiments in planta and the production of mycotoxins exclude strain Penicillium cf. manginii DSM 104493 from further development as a safe biocontrol agent.IMPORTANCEEnvironmentally friendly measures are urgently needed to control the causative agent of ash dieback, Hymenoscyphus fraxineus. Herein, we show that the endophyte DSM 104493 exhibits protective effects in vitro and in planta. We traced the activity of DSM 104493 to the antifungal natural product PF1140, which unfortunately also showed phytotoxic effects. Our results have important implications for understanding plant-fungal interactions mediated by secondary metabolites, not only in the context of ash dieback but also generally in plant-microbial interactions.PMID:38814060 | DOI:10.1128/aem.00665-24

Elife. 2024 May 30;13:e81875. doi: 10.7554/eLife.81875. Online ahead of print.ABSTRACTGermline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to growth and developmental changes in mouse offspring. In this study, we show that offspring from mouse oocytes lacking the PRC2 protein Embryonic Ectoderm Development (EED) were initially developmentally delayed, characterised by low blastocyst cell counts and substantial growth delay in mid-gestation embryos. This initial developmental delay was resolved as offspring underwent accelerated fetal development and growth in late gestation resulting in offspring that were similar stage and weight to controls at birth. The accelerated development and growth in offspring from Eed-null oocytes was associated with remodelling of the placenta, which involved an increase in fetal and maternal tissue size, conspicuous expansion of the glycogen enriched cell population and delayed parturition. Despite placental remodelling and accelerated offspring fetal growth and development, placental efficiency and fetal blood glucose levels were low, and the fetal blood metabolome was unchanged. Moreover, while expression of the H3K27me3-imprinted gene and amino acid transporter Slc38a4 was increased, fetal blood levels of individual amino acids were similar to controls, indicating that placental amino acid transport was not enhanced. Genome-wide analyses identified extensive transcriptional dysregulation and DNA methylation changes in affected placentas, including a range of imprinted and non-imprinted genes. Together, while deletion of Eed in growing oocytes resulted in fetal growth and developmental delay and placental hyperplasia, our data indicate a remarkable capacity for offspring fetal growth to be normalised despite inefficient placental function and the loss of H3K27me3-dependent genomic imprinting.PMID:38813868 | DOI:10.7554/eLife.81875

Dis Aquat Organ. 2024 May 30;158:143-155. doi: 10.3354/dao03790.ABSTRACTPerkinsus olseni and P. marinus are classified as notifiable pathogens by the World Organisation for Animal Health and are known to cause perkinsosis in a variety of molluscs globally. Mass mortalities due to these parasites in farms and in the wild have been a recurrent issue. Diagnosis for these protozoans is currently done using Ray's fluid thioglycollate medium method followed by optical microscopy or molecular assays. Both require a high level of skill and are time-consuming. An immunoassay method would make the diagnosis of perkinsosis quicker and cheaper. The present study used mass spectrometry-based proteomics to investigate common hypothetical surface peptides between different geographical isolates of P. olseni, which could be used to develop immunoassays in the future. Two peptides were identified: POLS_08089, which is a 42.7 kDa peptide corresponding to the 60S ribosomal subunit protein L4; and POLS_15916, which is a conserved hypothetical protein of 55.6 kDa. The identification of peptides may allow the development of immunoassays through a more targeted approach.PMID:38813855 | DOI:10.3354/dao03790

Nat Prod Res. 2024 May 30:1-14. doi: 10.1080/14786419.2024.2360150. Online ahead of print.ABSTRACTLichens contain different types of chemical compounds with multiple biological activities that demonstrate their potential pharmacological use. This research aims to report the metabolomic identification of the ethanolic extracts of P. antarcticum and P. hypnorum, their antioxidant, enzyme inhibitory, and their cytoprotection activity. Sixteen metabolites were identified in P. antarcticum and twelve in P. hypnorum; the extracts reported variable antioxidant activity with IC50 >350 µg/mL in DPPH·, values >18 µmol Trolox/g in ORAC and >40 µmol Trolox/g in FRAP and a phenolic compound content >10 mg GAE/g, as well as significant results in cholinesterases, α-glucosidase, pancreatic lipase, α-amylase, and tyrosinase enzyme inhibition activities with IC50 ranging from 18 to 510 µg/mL, and which were complemented by molecular docking experiments. Both extracts showed improved cytoprotection at the concentrations of 0.5 to 1.0 μg/mL. This study contributes to the knowledge of the chemical diversity of Antarctic lichen extracts and their effectiveness in the evaluation of biological activities related to neurodegenerative diseases and metabolic syndrome.PMID:38813688 | DOI:10.1080/14786419.2024.2360150

Rapid Commun Mass Spectrom. 2024 Aug 15;38(15):e9832. doi: 10.1002/rcm.9832.ABSTRACTRATIONALE: Silver doping of electrospray is known to increase the abundance of olefinic compounds detected by mass spectrometry. While demonstrated in targeted experiments, this has yet to be investigated in an untargeted study. Utilizing infrared matrix-assisted laser desorption electrospray ionization mass spectrometry imaging (IR-MALDESI-MSI), an untargeted lipidomics experiment on mouse liver was performed to evaluate the advantages of silver-doped electrospray.METHODS: 10 ppm silver nitrate was doped into the IR-MALDESI solvent consisting of 60% acetonitrile and 0.2% formic acid. Using an Orbitrap mass spectrometer in positive ionization mode, MSI was performed, analyzing from m/z 150 to m/z 2000 to capture all lipids with potential silver adducts. The lipids detected in the control and silver-doped electrosprays were compared by annotating using the LIPID MAPS Structural Database and eliminating false positives using the metabolite annotation confidence score.RESULTS: Silver-doped electrospray allowed for the detection of such ions of lipid molecules as [M + H]+ or [M + NH4]+ and as [M + Ag]+. Among the ions seen as [M + H]+ or [M + NH4]+, the signal was comparable between the control and silver-doped electrosprays. The silver-doped electrospray led to a 10% increase in the number of detected lipids, all of which contained a bay region increasing the interaction between silver and alkenes. Silver preferentially interacted with lipids that did not contain hard bases such as phosphates.CONCLUSIONS: Silver-doped electrospray enabled detection of 10% more olefinic lipids, all containing bay regions in their putative structures. This technique is valuable for detecting previously unobserved lipids that have the potential to form bay regions, namely fatty acyls, glycerolipids, prenol lipids, and polyketides.PMID:38813623 | DOI:10.1002/rcm.9832

Front Public Health. 2024 May 15;12:1384544. doi: 10.3389/fpubh.2024.1384544. eCollection 2024.ABSTRACTINTRODUCTION: Extreme heat events caused by occupational exposure and heat waves are becoming more common. However, the molecular changes underlying the response to heat exposure in humans remain to be elucidated.METHODS: This study used longitudinal multi-omics profiling to assess the impact of acute heat exposure (50°C for 30 min) in 24 subjects from a mine rescue team. Intravenous blood samples were collected before acute heat exposure (baseline) and at 5 min, 30 min, 1 h, and 24 h after acute heat exposure (recovery). In-depth multi-omics profiling was performed on each sample, including plasma proteomics (untargeted) and metabolomics (untargeted).RESULTS: After data curation and annotation, the final dataset contained 2,473 analytes, including 478 proteins and 1995 metabolites. Time-series analysis unveiled an orchestrated molecular choreography of changes involving the immune response, coagulation, acid-base balance, oxidative stress, cytoskeleton, and energy metabolism. Further analysis through protein-protein interactions and network analysis revealed potential regulators of acute heat exposure. Moreover, novel blood-based analytes that predicted change in cardiopulmonary function after acute heat exposure were identified.CONCLUSION: This study provided a comprehensive investigation of the dynamic molecular changes that underlie the complex physiological processes that occur in human males who undergo heat exposure. Our findings will help health impact assessment of extreme high temperature and inspire future mechanistic and clinical studies.PMID:38813424 | PMC:PMC11135052 | DOI:10.3389/fpubh.2024.1384544

Front Genet. 2024 May 15;15:1392622. doi: 10.3389/fgene.2024.1392622. eCollection 2024.ABSTRACTIntroduction: Circulating metabolites act as biomarkers of dysregulated metabolism and may inform disease pathophysiology. A portion of the inter-individual variability in circulating metabolites is influenced by common genetic variation. We evaluated whether a genetics-based "virtual" metabolomics approach can identify novel metabolite-disease associations. Methods: We examined the association between polygenic scores for 724 metabolites with 1,247 clinical phenotypes in the BioVU DNA biobank, comprising 57,735 European ancestry and 15,754 African ancestry participants. We applied Mendelian randomization (MR) to probe significant relationships and validated significant MR associations using independent GWAS of candidate phenotypes. Results and Discussion: We found significant associations between 336 metabolites and 168 phenotypes in European ancestry and 107 metabolites and 56 phenotypes in African ancestry. Of these metabolite-disease pairs, MR analyses confirmed associations between 73 metabolites and 53 phenotypes in European ancestry. Of 22 metabolitephenotype pairs evaluated for replication in independent GWAS, 16 were significant (false discovery rate p < 0.05). These included associations between bilirubin and X-21796 with cholelithiasis, phosphatidylcholine (16:0/22:5n3,18:1/20:4) and arachidonate with inflammatory bowel disease and Crohn's disease, and campesterol with coronary artery disease and myocardial infarction. These associations may represent biomarkers or potentially targetable mediators of disease risk.PMID:38812968 | PMC:PMC11133605 | DOI:10.3389/fgene.2024.1392622

Front Nutr. 2024 May 15;11:1376889. doi: 10.3389/fnut.2024.1376889. eCollection 2024.ABSTRACTBACKGROUND: Hemorrhagic stroke (HS), a leading cause of death and disability worldwide, has not been clarified in terms of the underlying biomolecular mechanisms of its development. Circulating metabolites have been closely associated with HS in recent years. Therefore, we explored the causal association between circulating metabolomes and HS using Mendelian randomization (MR) analysis and identified the molecular mechanisms of effects.METHODS: We assessed the causal relationship between circulating serum metabolites (CSMs) and HS using a bidirectional two-sample MR method supplemented with five ways: weighted median, MR Egger, simple mode, weighted mode, and MR-PRESSO. The Cochran Q-test, MR-Egger intercept test, and MR-PRESSO served for the sensitivity analyses. The Steiger test and reverse MR were used to estimate reverse causality. Metabolic pathway analyses were performed using MetaboAnalyst 5.0, and genetic effects were assessed by linkage disequilibrium score regression. Significant metabolites were further synthesized using meta-analysis, and we used multivariate MR to correct for common confounders.RESULTS: We finally recognized four metabolites, biliverdin (OR 0.62, 95% CI 0.40-0.96, PMVMR = 0.030), linoleate (18. 2n6) (OR 0.20, 95% CI 0.08-0.54, PMVMR = 0.001),1-eicosadienoylglycerophosphocholine* (OR 2.21, 95% CI 1.02-4.76, PMVMR = 0.044),7-alpha-hydroxy-3 -oxo-4-cholestenoate (7-Hoca) (OR 0.27, 95% CI 0.09-0.77, PMVMR = 0.015) with significant causal relation to HS.CONCLUSION: We demonstrated significant causal associations between circulating serum metabolites and hemorrhagic stroke. Monitoring, diagnosis, and treatment of hemorrhagic stroke by serum metabolites might be a valuable approach.PMID:38812939 | PMC:PMC11133746 | DOI:10.3389/fnut.2024.1376889

Front Physiol. 2024 May 15;15:1378565. doi: 10.3389/fphys.2024.1378565. eCollection 2024.ABSTRACTExtracellular vesicles mediate intercellular communication by transporting biologically active macromolecules. Our prior studies have demonstrated that the nuclear factor of activated T cell cytoplasmic member 3 (NFATc3) is activated in mouse pulmonary macrophages in response to lipopolysaccharide (LPS). Inhibition of NFATc3 activation by a novel cell-permeable calcineurin peptide inhibitor CNI103 mitigated the development of acute lung injury (ALI) in LPS-treated mice. Although pro-inflammatory lipid mediators are known contributors to lung inflammation and injury, it remains unclear whether the calcineurin-NFATc pathway regulates extracellular vesicle (EV) lipid content and if this content contributes to ALI pathogenesis. In this study, EVs from mouse bronchoalveolar lavage fluid (BALF) were analyzed for their lipid mediators by liquid chromatography in conjunction with mass spectrometry (LC-MS/MS). Our data demonstrate that EVs from LPS-treated mice contained significantly higher levels of arachidonic acid (AA) metabolites, which were found in low levels by prior treatment with CNI103. The catalytic activity of lung tissue cytoplasmic phospholipase A2 (cPLA2) increased during ALI, correlating with an increased amount of arachidonic acid (AA) in the EVs. Furthermore, ALI is associated with increased expression of cPLA2, cyclooxygenase 2 (COX2), and lipoxygenases (5-LOX, 12-LOX, and 15-LOX) in lung tissue, and pretreatment with CNI103 inhibited the catalytic activity of cPLA2 and the expression of cPLA2, COX, and LOX transcripts. Furthermore, co-culture of mouse pulmonary microvascular endothelial cell (PMVEC) monolayer and NFAT-luciferase reporter macrophages with BALF EVs from LPS-treated mice increased the pulmonary microvascular endothelial cell (PMVEC) monolayer barrier permeability and luciferase activity in macrophages. However, EVs from CNI103-treated mice had no negative impact on PMVEC monolayer barrier integrity. In summary, BALF EVs from LPS-treated mice carry biologically active NFATc-dependent, AA-derived lipids that play a role in regulating PMVEC monolayer barrier function.PMID:38812883 | PMC:PMC11133699 | DOI:10.3389/fphys.2024.1378565

Front Endocrinol (Lausanne). 2024 May 15;15:1386265. doi: 10.3389/fendo.2024.1386265. eCollection 2024.ABSTRACTINTRODUCTION: Prader-Willi syndrome (PWS) is a rare disease, which shows a peculiar clinical phenotype, including obesity, which is different from essential obesity (EOB). Metabolomics might represent a valuable tool to reveal the biochemical mechanisms/pathways underlying clinical differences between PWS and EOB. The aim of the present (case-control, retrospective) study was to determine the metabolomic profile that characterizes PWS compared to EOB.METHODS: A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to measure a total of 188 endogenous metabolites in plasma samples of 32 patients with PWS (F/M = 23/9; age: 31.6 ± 9.2 years; body mass index [BMI]: 42.1 ± 7.0 kg/m2), compared to a sex-, age- and BMI-matched group of patients with EOB (F/M = 23/9; age: 31.4 ± 6.9 years; BMI: 43.5 ± 3.5 kg/m2).RESULTS: Body composition in PWS was different when compared to EOB, with increased fat mass and decreased fat-free mass. Glycemia and HDL cholesterol were higher in patients with PWS than in those with EOB, while insulinemia was lower, as well as heart rate. Resting energy expenditure was lower in the group with PWS than in the one with EOB, a difference that was missed after fat-free mass correction. Carrying out a series of Tobit multivariable linear regressions, adjusted for sex, diastolic blood pressure, and C reactive protein, a total of 28 metabolites was found to be associated with PWS (vs. non-PWS, i.e., EOB), including 9 phosphatidylcholines (PCs) ae, 5 PCs aa, all PCs aa, 7 lysoPCs a, all lysoPCs, 4 acetylcarnitines, and 1 sphingomyelin, all of which were higher in PWS than EOB.CONCLUSIONS: PWS exhibits a specific metabolomic profile when compared to EOB, suggesting a different regulation of some biochemical pathways, fundamentally related to lipid metabolism.PMID:38812813 | PMC:PMC11133515 | DOI:10.3389/fendo.2024.1386265

Front Microbiol. 2024 May 15;15:1402654. doi: 10.3389/fmicb.2024.1402654. eCollection 2024.ABSTRACTINTRODUCTION: Folate supplementation is crucial for the human body, and the chemically synthesized folic acid might have undesirable side effects. The use of molecular breeding methods to modify the genes related to the biosynthesis of folate by probiotics to increase folate production is currently a focus of research.METHODS: In this study, the folate-producing strain of Limosilactobacillus reuteri B1-28 was isolated from human breast milk, and the difference between B1-28 and folA gene deletion strain ΔFolA was investigated by phenotyping, in vitro probiotic evaluation, metabolism and transcriptome analysis.RESULTS: The results showed that the folate producted by the ΔFolA was 2-3 folds that of the B1-28. Scanning electron microscope showed that ΔFolA had rougher surface, and the acid-producing capacity (p = 0.0008) and adhesion properties (p = 0.0096) were significantly enhanced than B1-28. Transcriptomic analysis revealed that differentially expressed genes were mainly involved in three pathways, among which the biosynthesis of ribosome and aminoacyl-tRNA occurred in the key metabolic pathways. Metabolomics analysis showed that folA affected 5 metabolic pathways, involving 89 different metabolites.DISCUSSION: In conclusion, the editing of a key gene of folA in folate biosynthesis pathway provides a feasible pathway to improve folate biosynthesis in breast milk-derived probiotics.PMID:38812695 | PMC:PMC11133606 | DOI:10.3389/fmicb.2024.1402654

Front Microbiol. 2024 May 15;15:1387498. doi: 10.3389/fmicb.2024.1387498. eCollection 2024.ABSTRACTProbiotic bacteria have been proposed as an alternative to antibiotics for the control of antimicrobial resistant enteric pathogens. The mechanistic details of this approach remain unclear, in part because pathogen reduction appears to be both strain and ecology dependent. Here we tested the ability of five probiotic strains, including some from common probiotic genera Lactobacillus and Bifidobacterium, to reduce binding of Salmonella enterica sv. Typhimurium to epithelial cells in vitro. Bifidobacterium longum subsp. infantis emerged as a promising strain; however, S. Typhimurium infection outcome in epithelial cells was dependent on inoculation order, with B. infantis unable to rescue host cells from preceding or concurrent infection. We further investigated the complex mechanisms underlying this interaction between B. infantis, S. Typhimurium, and epithelial cells using a multi-omics approach that included gene expression and altered metabolism via metabolomics. Incubation with B. infantis repressed apoptotic pathways and induced anti-inflammatory cascades in epithelial cells. In contrast, co-incubation with B. infantis increased in S. Typhimurium the expression of virulence factors, induced anaerobic metabolism, and repressed components of arginine metabolism as well as altering the metabolic profile. Concurrent application of the probiotic and pathogen notably generated metabolic profiles more similar to that of the probiotic alone than to the pathogen, indicating a central role for metabolism in modulating probiotic-pathogen-host interactions. Together these data imply crosstalk via small molecules between the epithelial cells, pathogen and probiotic that consistently demonstrated unique molecular mechanisms specific probiotic/pathogen the individual associations.PMID:38812689 | PMC:PMC11133690 | DOI:10.3389/fmicb.2024.1387498

Front Microbiol. 2024 May 15;15:1323765. doi: 10.3389/fmicb.2024.1323765. eCollection 2024.ABSTRACTINTRODUCTION: Pectobacterium betavasculorum is a member of the Pectobacerium genus that inhabits a variety of niches and is found in all climates. Bacteria from the Pectobacterium genus can cause soft rot disease on various plants due to the secretion of plant cell wall degrading enzymes (PCWDEs). The species P. betavasculorum is responsible for the vascular necrosis of sugar beet and soft rot of many vegetables. It also infects sunflowers and artichokes. The main sugar present in sugar beet is sucrose while xylose is one of the main sugars in artichoke and sunflower.METHODS: In our work, we applied metabolomic studies coupled with genomics to investigate the metabolism of P. betavasculorum in the presence of xylose and sucrose as the only carbon source. The ability of the strains to use various sugars as the only carbon source were confirmed by the polypyridyl complex of Ru(II) method in 96-well plates.RESULTS: Our studies provided information on the metabolic pathways active during the degradation of those substrates. It was observed that different metabolic pathways are upregulated in the presence of xylose in comparison to sucrose.DISCUSSION: The presence of xylose enhances extracellular metabolism of sugars and glycerol as well as stimulates EPS and IPS synthesis. In contrast, in the presence of sucrose the intensive extracellular metabolism of amines and amino acids is promoted.PMID:38812674 | PMC:PMC11133636 | DOI:10.3389/fmicb.2024.1323765

Oncoimmunology. 2024 May 27;13(1):2360230. doi: 10.1080/2162402X.2024.2360230. eCollection 2024.ABSTRACTTigilanol tiglate is an oncolytic small molecule that is undergoing clinical trials. A recent study revealed the capacity of this pyroptosis inducer to elicit hallmarks of immunogenic cell death. In addition, intratumoral injection of tigilanol tiglate can sensitize subcutaneous cancers to subsequent immune checkpoint inhibitors targeting CTLA-4 alone or in combination with PD-1.PMID:38812571 | PMC:PMC11135828 | DOI:10.1080/2162402X.2024.2360230