PubMed

Int J Antimicrob Agents. 2023 Nov 4:107028. doi: 10.1016/j.ijantimicag.2023.107028. Online ahead of print.ABSTRACTVoriconazole-associated hepatotoxicity, generally manifesting as elevated liver enzymes, is commonly observed and may lead to drug discontinuation, thus necessitating careful monitoring. However, specific plasma biomarkers for identifying voriconazole-associated hepatotoxicity are still lacking. Metabolomics has emerged as a promising technique for investigating biomarkers associated with drug-induced toxicity. This study aimed to use targeted metabolomics to evaluate seven previously identified endogenous metabolites as potential biomarkers of voriconazole-associated hepatotoxicity. Patients undergoing therapeutic drug monitoring of voriconazole were classified into hepatotoxicity group (18 patients) and control group (153 patients). Plasma samples were analyzed using ultra-high-performance liquid chromatography coupled to mass spectrometry. The metabolite concentrations were compared between the two groups. Areas under the receiver operating characteristic (AUROC) curves generated from logistic regressions were used to correlate the concentrations of these seven metabolites with the voriconazole trough concentrations and conventional liver biochemistry tests. Glycocholate and α-ketoglutarate levels were significantly higher in the hepatotoxicity group compared to the control group (false discovery rate-corrected p < 0.001 and p = 0.024, respectively). The metabolites glycocholate (AUROC = 0.795) and α-ketoglutarate (AUROC = 0.696) outperformed voriconazole trough concentrations (AUROC = 0.555) and approached the performance of alkaline phosphatase (AUROC = 0.876) and total bilirubin (AUROC = 0.815). A panel of glycocholate combined with voriconazole trough concentrations (AUROC = 0.827) substantially improved the performance of voriconazole trough concentrations alone in predicting hepatotoxicity. We conclude that the panel integrating glycocholate with voriconazole trough concentrations may have a great potential in identifying voriconazole-associated hepatotoxicity.PMID:37931850 | DOI:10.1016/j.ijantimicag.2023.107028

Sci Total Environ. 2023 Nov 4:168338. doi: 10.1016/j.scitotenv.2023.168338. Online ahead of print.ABSTRACTThe ubiquitous existence of various pharmaceuticals in the marine environment has received global attention for their risk assessment. However, rather little is known thus far regarding the natural attenuation (e.g., photolysis)-induced product/mixture toxicity of these pharmaceuticals on marine organisms. In this study, the photodegradation behavior, product formation, and risks of two representative pharmaceuticals (i.e., ciprofloxacin, CIP; diclofenac, DCF) were explored in the simulated estuary water. It was noted that both pharmaceuticals can be completely photolyzed within 1 h, and five products of CIP and three products of DCF were identified by a high-resolution liquid chromatography-mass spectrometer. Accordingly, their photodecomposition pathways were tentatively proposed. The in silico prediction suggested that the formed transformation products maintained the persistence, bioaccumulation potential, and multi-endpoint toxic effects such as genotoxicity, developmental toxicity, and acute/chronic toxicity on different aquatic species. Particularly, the non-targeted metabolomics first elucidated that DCF and its photolytic mixtures can significantly affect the antioxidant status of marine algae (Heterosigma akashiwo), triggering oxidative stress and damage to cellular components. It is very alarming that the complete photolyzed DCF sample induced more serious oxidative stress than DCF itself, which called for more concern about the photolysis-driven ecological risks. Overall, this investigation first uncovered the overlooked but serious toxicity of the transformation products of prevalent pharmaceuticals during natural attenuation on marine species.PMID:37931817 | DOI:10.1016/j.scitotenv.2023.168338

Fitoterapia. 2023 Nov 4:105717. doi: 10.1016/j.fitote.2023.105717. Online ahead of print.ABSTRACTThe relevance of oxylipins as biomarkers of oxidative stress has been established in recent years. Phytoprostanes and phytofurans are plant metabolites derived from peroxidation of α-linolenic acid (ALA) induced by ROS. Previous findings have suggested new valuable biological properties for these new active compounds in the frame of diverse pathophysiological situations and health constraints. Lipidomic profiling of different aerial parts of the same Acacia cyanophylla Lindl. specimen, was evaluated for the first time here, using LC-MS/MS technology. Analysis revealed the existence of six PhytoPs and three PhytoFs. Stems have the highest amount of these metabolites with 179.35 ng/g and 320.79 ng/g respectively. This first complete profile paves the way to explore Acacia cyanophylla Lindl. as a source of plant oxylipins for therapeutic or pharmaceutical uses.PMID:37931720 | DOI:10.1016/j.fitote.2023.105717

J Adv Res. 2023 Nov 4:S2090-1232(23)00328-4. doi: 10.1016/j.jare.2023.11.005. Online ahead of print.ABSTRACTINTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA)-caused infections greatly threaten public health. The discovery of natural-product-based anti-MRSA agents for treating infectious diseases has become one of the current research focuses.OBJECTIVES: This study aims to identify promising anti-MRSA agents with a clear mechanism based on natural norharmane modified by quaternization or dimerization.METHODS: A total of 32 norharmane analogues were prepared and characterized. Their antibacterial activities and resistance development propensity were tested by the broth double-dilution method. Cell counting kit-8 and hemolysis experiments were used to assess their biosafety. The plasma stability, bactericidal mode, and biofilm disruption effects were examined by colony counting and crystal violet staining assays. Fluorescence microscopy, metabolomic analysis, docking simulation and spectra titration revealed its anti-MRSA mechanisms. The mouse skin infection model was used to investigate the in vivo efficacy.RESULTS: Compound 5a was selected as a potential anti-MRSA agent, which exhibited potent anti-MRSA activity in vitro and in vivo, low cytotoxicity and hemolysis under an effective dose. Moreover, compound 5a showed good stability in 50% plasma, a low tendency of resistance development and capabilities to disrupt bacterial biofilms. The mechanism studies revealed that compound 5a could inhibit the biosynthesis of bacteria cell walls, damage the membrane, disturb energy metabolism and amino acid metabolism pathways, and interfere with protein synthesis and nucleic acid function.CONCLUSIONS: These results suggested that compound 5a is a promising candidate for combating MRSA infections, providing valuable information for further exploiting a new generation of therapeutic antibiotics.PMID:37931657 | DOI:10.1016/j.jare.2023.11.005

Biomed Pharmacother. 2023 Nov 4;168:115840. doi: 10.1016/j.biopha.2023.115840. Online ahead of print.ABSTRACTBACKGROUND: Hypothalamic neuroinflammation is associated with disorders of lipid metabolism. Considering the anti-neuroinflammation effects of sodium-glucose cotransporter 2(SGLT2) inhibitors, a central administration of Dapagliflozin is postulated to provide hypothalamic protection and change lipid metabolism in kidney against diabetic kidney disease (DKD).METHODS: Blood samples of DKD patients were collected. Male Sprague-Dawley (SD) rats with 30 mg/kg streptozotocin and a high-fat diet, db/db mice and palmitic acid (PA)-stimulated BV2 microglia were used for study models. 0.28 mg/3ul dapagliflozin was injected into the lateral ventricle in db/db mice. Genes and protein expression levels were determined by qPCR, western blotting, immunofluorescence, and immunohistochemistry staining. Secreted IL-1β and IL-6 were quantified by ELISA. Oil red O staining, lipidomic, and non-targeted metabolomics were performed to evaluate abnormal lipid metabolism in kidney.RESULTS: The decrease of serum MCPIP1 was an independent risk factor for renal progression in DKD patients (OR=1.22, 95 %CI: 1.02-1.45, P = 0.033). Higher microglia marker IBA1 and lower MCPIP1 in the hypothalamus, as well as lipid droplet deposition increasing in the kidney were observed in DKD rats. Central dapagliflozin could reduce the blood sugar, hypothalamic inflammatory cytokines, lipid droplet deposition in renal tubular. Lipidomics and metabolomics results showed that dapagliflozin changed 37 lipids and 19 metabolites considered on promoting lipolysis. These lipid metabolism changes were attributed to dapagliflozin by upregulating MCPIP1, and inhibiting cytokines in the microglia induced by PA.CONCLUSIONS: Central administrated Dapagliflozin elicits an anti-inflammatory effect by upregulating MCPIP1 levels in microglia and changes lipid metabolism in kidney of DKD.PMID:37931516 | DOI:10.1016/j.biopha.2023.115840

Biochem Biophys Res Commun. 2023 Oct 29;687:149161. doi: 10.1016/j.bbrc.2023.149161. Online ahead of print.ABSTRACTEvidence from mice with global deletion of fatty-acid transport protein4 (FATP4) indicates its role on β-oxidation and triglycerides (TG) metabolism. We reported that plasma glycerol and free fatty acids (FA) were increased in liver-specific Fatp4 deficient (L-FATP4-/-) mice under dietary stress. We hypothesized that FATP4 may mediate hepatocellular TG lipolysis. Here, we demonstrated that L-FATP4-/- mice showed an increase in these blood lipids, liver TG, and subcutaneous fat weights. We therefore studied TG metabolism in response to oleate treatment in two experimental models using FATP4-knockout HepG2 (HepKO) cells and L-FATP4-/- hepatocytes. Both FATP4-deificient liver cells showed a significant decrease in β-oxidation products by ∼30-35% concomitant with marked upregulation of CD36, FATP2, and FATP5 as well as lipoprotein microsomal-triglyceride-transfer protein genes. By using 13C3D5-glycerol, HepKO cells displayed an increase in metabolically labelled TG species which were further increased with oleate treatment. This increase was concomitant with a step-wise elevation of TG in cells and supernatants as well as the secretion of cholesterol very low-density and high-density lipoproteins. Upon analyzing TG lipolytic enzymes, both mutant liver cells showed marked upregulated expression of hepatic lipase, while that of hormone-sensitive lipase and adipose-triglyceride lipase was downregulated. Lipolysis measured by extracellular glycerol and free FA was indeed increased in mutant cells, and this event was exacerbated by oleate treatment. Taken together, FATP4 deficiency in liver cells led to a metabolic shift from β-oxidation towards lipolysis-directed TG and lipoprotein secretion, which is in line with an association of FATP4 polymorphisms with blood lipids.PMID:37931418 | DOI:10.1016/j.bbrc.2023.149161

Anal Chem. 2023 Nov 6. doi: 10.1021/acs.analchem.3c02693. Online ahead of print.ABSTRACTAccurate identification between alkyl- and plasmenyl-phosphatidylcholine (PC(O-) and PC(P-)) isomers is a major analytical challenge in lipidomics studies due to a lack of structure-specific ions in conventional tandem mass spectrometry (MS/MS) methods and the absence of universal retention time (RT) references. Given the importance of PC(O-) and PC(P-), an easy-to-apply method for current research is urgently needed. In this study, we present a quadratic RT-XLOGP3SM regression model that uses endogenous sphingomyelin (SM) species in blood samples as retention time (RT) indicators to predict the RTs of PC(O-) and PC(P-) species by coupling their calculated partition coefficients based on XLOGP3. The prediction results were obtained with a root-mean-square error (RMSE) of 0.12 min (1.3%) for the RRHD (rapid resolution high definition) nonlinear LC condition. A lipidomic analysis with RT-XLOGP3SM regression was used to study lipid regulation in coronary artery disease (CAD) outpatient plasma samples, and we found that the types of exhibited regulation were highly dependent on the lipid subclasses in comparison to the healthy control group. In conclusion, given that the quadratic RT-XLOGP3SM regression model predicts the RTs of PC species based on the relative value of XLOGP3 and the RTs of endogenous SM species, it can be expected that most of the C18-based lipidomics analyses could apply this method to increase the identification ability of the PC(O-) and PC(P-) subclasses and to improve the understanding of their physiological functions.PMID:37931321 | DOI:10.1021/acs.analchem.3c02693

Microbiol Spectr. 2023 Oct 16:e0170523. doi: 10.1128/spectrum.01705-23. Online ahead of print.ABSTRACTGenome-scale metabolic (GEM) models are knowledge bases of the reactions and metabolites of a particular organism. These GEM models allow for the simulation of the metabolism, for example, calculating growth and production yields-based on the stoichiometry, reaction directionality, and uptake rates of the metabolic network. Over the years, several extensions have been added to take into account other actors in metabolism, going beyond pure stoichiometry. One such extension is enzyme-constrained models, which enable the integration of proteomics data into GEM models containing the necessary k cat values for their enzymes. Given its relatively recent formulation, there are still challenges in standardization and data reconciliation between the model and the experimental measurements. In this work, we present geckopy 3.0 (genome-scale model with enzyme constraints, using Kinetics and Omics in Python), an actualization from scratch of the previous Python implementation of the same name. This update tackles the aforementioned challenges, to reach maturity in enzyme-constrained modeling. With the new geckopy, proteins are typed in the Systems Biology Markup Language (SBML) document, taking advantage of the SBML Groups extension, in compliance with community standards. In addition, a suite of relaxation algorithms-in the form of linear and mixed-integer linear programming problems-has been added to facilitate the reconciliation of raw proteomics data with the metabolic model. Several functionalities to integrate experimental data were implemented, including an interface layer with pytfa for the usage of thermodynamics and metabolomics constraints. Finally, the relaxation algorithms were benchmarked against public proteomics data sets in Escherichia coli for different conditions, revealing targets for improving the enzyme-constrained model and/or the proteomics pipeline. IMPORTANCE The metabolism of biological cells is an intricate network of reactions that interconvert chemical compounds, gathering energy, and using that energy to grow. The static analysis of these metabolic networks can be turned into a computational model that can efficiently output the distribution of fluxes in the network. With the inclusion of enzymes in the network, we can also interpret the role and concentrations of the metabolic proteins. However, the models and the experimental data often clash, resulting in a network that cannot grow. Here, we tackle this situation with a suite of relaxation algorithms in a package called geckopy. Geckopy also integrates with other software to allow for adding thermodynamic and metabolomic constraints. In addition, to ensure that enzyme-constrained models follow the community standards, a format for the proteins is postulated. We hope that the package and algorithms presented here will be useful for the constraint-based modeling community.PMID:37931133 | DOI:10.1128/spectrum.01705-23

Environ Sci Technol. 2023 Nov 6. doi: 10.1021/acs.est.3c03401. Online ahead of print.ABSTRACTWe assessed phthalate-hormone associations in 382 pregnant women of the new-generation SEPAGES cohort (2014-2017, France) using improved exposure and outcome assessments. Metabolites from seven phthalate compounds and the replacement di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (≈21 samples/trimester). Metabolites from five steroid hormones were measured in maternal hair samples collected at delivery, reflecting cumulative levels over the previous weeks to months. Adjusted linear regression and Bayesian weighted quantile sum (BWQS) mixture models were performed. Each doubling in third-trimester urinary mono-benzyl phthalate (MBzP) concentrations was associated with an average increase of 13.3% (95% CI: 2.65, 24.9) for ∑cortisol, 10.0% (95% CI: 0.26, 20.7) for ∑cortisone, 17.3% (95% CI: 1.67, 35.4) for 11-dehydrocorticosterone, and 16.2% (95% CI: 2.20, 32.1) for testosterone, together with a suggestive 10.5% (95% CI: -1.57, 24.1) increase in progesterone levels. Each doubling in second-trimester urinary di-isononyl phthalate (DiNP) concentrations was inversely associated with testosterone levels ( -11.6%; 95% CI: -21.6, -0.31). For most hormones, a nonsignificant trend toward a positive phthalate mixture effect was observed in the third but not in the second trimester. Our study showed that exposure to some phthalate metabolites, especially MBzP, may affect adrenal and reproductive hormone levels during pregnancy.PMID:37931007 | DOI:10.1021/acs.est.3c03401

Cell Rep. 2023 Nov 5;42(11):113381. doi: 10.1016/j.celrep.2023.113381. Online ahead of print.ABSTRACTOncogene-induced senescence (OIS) is a persistent anti-proliferative response that acts as a barrier against malignant transformation. During OIS, cells undergo dynamic remodeling, which involves alterations in protein and organelle homeostasis through autophagy. Here, we show that ribosomes are selectively targeted for degradation by autophagy during OIS. By characterizing senescence-dependent alterations in the ribosomal interactome, we find that the deubiquitinase USP10 dissociates from the ribosome during the transition to OIS. This release of USP10 leads to an enhanced ribosome ubiquitination, particularly of small subunit proteins, including lysine 275 on RPS2. Both reinforcement of the USP10-ribosome interaction and mutation of RPS2 K275 abrogate ribosomal delivery to lysosomes without affecting bulk autophagy. We show that the selective recruitment of ubiquitinated ribosomes to autophagosomes is mediated by the p62 receptor. While ribophagy is not required for the establishment of senescence per se, it contributes to senescence-related metabolome alterations and facilitates the senescence-associated secretory phenotype.PMID:37930887 | DOI:10.1016/j.celrep.2023.113381

Nucleic Acids Res. 2023 Nov 1:gkad978. doi: 10.1093/nar/gkad978. Online ahead of print.ABSTRACTModern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.PMID:37930845 | DOI:10.1093/nar/gkad978

Am J Chin Med. 2023 Nov 4:1-26. doi: 10.1142/S0192415X23500945. Online ahead of print.ABSTRACTCoptis chinensis Franch (RC), has historically been used for the treatment of "Xiao Ke" and "Xia Li" symptoms in China. "Xia Li" is characterized by abdominal pain and diarrhea, which are similar to the clinical symptoms of ulcerative colitis (UC). For the first time, this study aims to compare the anti-colitis effects of berberine (BBR) and total RC alkaloids (TRCA) and investigate the underlying metabolites and gut microbiota biomarkers. Metabolomics results showed that several colitis-related biomarkers, including lysophosphatidyl ethanolamine, lysophosphatidylcholine, scopolamine-methyl-bromide, N1-methyl-2-pyridone-5-carboxamide, 4-hydroxyretinoic acid, and malic acid, were significantly improved in model mice after BBR and TRCA treatments. High-dose BBR and TRCA treatments reversed the mouse colon shortening caused by dextran sodium sulfate (DSS), alleviated bowel wall swelling, and reduced inflammatory cell infiltration. BBR and TRCA restored the damaged mucosa integrity in colitis mice by upregulating claudin 1 and occludin, preventing colon epithelium apoptosis by inhibiting the cleavage of caspase 3. Additionally, BBR and TRCA significantly decreased the richness of the pathogenic bacteria Bacteroides acidifaciens but increased the abundance of the probiotic Lactobacillus spp. Notably, TRCA exhibited superior anti-colitis effects to those of BBR. Thus, this agent warrants further study and application in the treatment of inflammatory bowel disease in the clinic.PMID:37930330 | DOI:10.1142/S0192415X23500945

Microbiol Spectr. 2023 Nov 6:e0032723. doi: 10.1128/spectrum.00327-23. Online ahead of print.ABSTRACTMelatonin (MLT) can affect the microbial community structure and its metabolites by releasing cellular regulatory factors. Intestinal bacteria recognize and respond to MLT signals from the intestine through MLT binding sites and further activate the function of intestinal immune cells. However, the signal transduction pathway of MLT in the intestine has not been clearly elucidated yet. The effect of MLT on rumen bacterial metabolism was studied by simulating rumen fermentation in vitro. The test was divided into three groups: artificial saliva+standard MLT solution (CK0 group), artificial saliva+rumen juice (CK1 group), and artificial saliva+rumen juice+standard MLT solution (MLT group). The fermentation broth was collected after 24 h of simulated culture in vitro. The results showed that the addition of MLT significantly increased the contents of propionic acid, butyric acid, valeric acid, and total volatile fatty acids (P < 0.05). The analysis of the differences in flora found that at the genus level, Alistipes, Veillonellaceae_UCG-001, Selenomonas, Lachnospiraceae_NK4A136_group, and Succinivibrio were significantly increased, whereas Acinetobacter and Prevotella were significantly decreased (P < 0.05). The analysis of differential metabolites showed that compared with the CK1 group, the relative contents of glutathione, spermidine, indole, 3-methyl indole, phenylpyruvate, and other metabolites were increased significantly in the MLT group (P < 0.05). The results of enzyme activity on the enrichment pathway showed that MLT could significantly enhance the activities of genes such as GST, SPDS, DAHP, AS, TS, TPH, AANAT, ASMT, and IDO. Therefore, melatonin had certain regulatory effects on rumen microorganisms and their metabolic pathways.IMPORTANCEIn in vitro studies, it has been found that the effects of MLT on rumen microorganisms and metabolites can change the rumen flora structure, significantly inhibit the relative abundance of harmful Acinetobacter, and improve the relative abundance of beneficial bacteria. MLT may regulate the "arginine-glutathione" pathway, "phenylalanine, tyrosine and tryptophan biosynthesis-tryptophan generation" branch, "tryptophan-kynurenine" metabolism, and "tryptophan-tryptamine-serotonin" pathway through microorganisms.PMID:37929993 | DOI:10.1128/spectrum.00327-23

Proteomics. 2023 Nov 6:e2200533. doi: 10.1002/pmic.202200533. Online ahead of print.ABSTRACTWith the emergence of next-generation nucleotide sequencing and mass spectrometry-based proteomics and metabolomics tools, we have comprehensive and scalable methods to analyze the genes, transcripts, proteins, and metabolites of a multitude of biological systems. Despite the fascinating new molecular insights at the genome, transcriptome, proteome and metabolome scale, we are still far from fully understanding cellular organization, cell cycles and biology at the molecular level. Significant advances in sensitivity and depth for both sequencing as well as mass spectrometry-based methods allow the analysis at the single cell and single molecule level. At the same time, new tools are emerging that enable the investigation of molecular interactions throughout the central dogma of molecular biology. In this review, we provide an overview of established and recently developed mass spectrometry-based tools to probe metabolite-protein interactions-from individual interaction pairs to interactions at the proteome-metabolome scale. This article is protected by copyright. All rights reserved.PMID:37929699 | DOI:10.1002/pmic.202200533

Front Vet Sci. 2023 Oct 20;10:1238064. doi: 10.3389/fvets.2023.1238064. eCollection 2023.ABSTRACTFermented distiller's grains (FDG)-based diets are nutritious and can improve the growth and intestinal immunity in livestock. However, there is limited research examining the effect of feeding FDG-based diets on changes in intestinal metabolites and related pathways in livestock. In this study, nine Guanling crossbred cattle (Guizhou Guanling Yellow cattle × Simmental cattle) were selected and randomly divided into a basal diet (BD) group and two experimental groups fed with FDG replacing 15% and 30% of the daily ration concentrates (FDG-Case A and FDG-Case B), respectively, with three cattle in each group. Fresh jejunum (J) and cecum (C) tissues were collected for metabolomic analysis. Differential metabolites and metabolic pathways were explored by means of univariate and multivariate statistical analysis. Compared with the J-BD group, 30 and 100 differential metabolites (VIP > 1, p < 0.05) were obtained in the J-FDG-Case A group and J-FDG-Case B group, respectively, and the J-FDG-Case B vs. J-FDG-Case A comparison revealed 63 significantly differential metabolites, which were mainly divided into superclasses including lipids and lipid-like molecules, organoheterocyclic compounds, and organic acids and derivatives. Compared with the C-BD, 3 and 26 differential metabolites (VIP > 1, p < 0.05) were found in the C-FDG-Case A group and C-FDG-Case B group, respectively, and the C-FDG-Case B vs. C-FDG-Case A comparison revealed 21 significantly different metabolites, which were also mainly divided into superclasses including lipids and lipid-like molecules, organoheterocyclic compounds, and organic acids and derivatives. A total of 40 metabolic pathways were identified, with a significance threshold set at p < 0.05. Among them, 2, 14, and 18 metabolic pathways were significantly enriched in the J-FDG-Case A vs. J-BD, J-FDG-Case B vs. J-BD, and J-FDG-Case B vs. J-FDG-Case A comparisons, respectively. Meanwhile, 1, 2, and 3 metabolic pathways were obtained in the C-FDG-Case A vs. C-BD, C-FDG-Case B vs. C-BD, and C-FDG-Case B vs. C-FDG-Case A comparisons, respectively. Furthermore, four significant metabolic pathways, namely insulin resistance, biosynthesis of unsaturated fatty acids, linoleic acid metabolism, and primary bile acid biosynthesis, were significantly enriched in Guanling crossbred cattle fed FDG diets. These results suggest that feeding FDG diets may promote the growth and intestinal immunity of Guanling crossbred cattle by regulating metabolic patterns of lipid compounds and related metabolic pathways. This study sheds light on the potential metabolic regulatory mechanisms of FDG diets and offers some references for their use in livestock feed.PMID:37929280 | PMC:PMC10622970 | DOI:10.3389/fvets.2023.1238064

Front Plant Sci. 2023 Oct 20;14:1156733. doi: 10.3389/fpls.2023.1156733. eCollection 2023.ABSTRACTPythium oligandrum is a soil-borne oomycete associated with rhizosphere and root tissues. Its ability to enhance plant growth, stimulate plant immunity and parasitize fungal and oomycete preys has led to the development of agricultural biocontrol products. Meanwhile, the effect of P. oligandrum on mutualistic interactions and more generally on root microbial communities has not been investigated. Here, we developed a biological system comprising P. oligandrum interacting with two legume plants, Medicago truncatula and Pisum sativum. P. oligandrum activity was investigated at the transcriptomics level through an RNAseq approach, metabolomics and finally metagenomics to investigate the impact of P. oligandrum on root microbiota. We found that P. oligandrum promotes plant growth in these two species and protects them against infection by the oomycete Aphanomyces euteiches, a devastating legume root pathogen. In addition, P. oligandrum up-regulated more than 1000 genes in M. truncatula roots including genes involved in plant defense and notably in the biosynthesis of antimicrobial compounds and validated the enhanced production of M. truncatula phytoalexins, medicarpin and formononetin. Despite this activation of plant immunity, we found that root colonization by P. oligandrum did not impaired symbiotic interactions, promoting the formation of large and multilobed symbiotic nodules with Ensifer meliloti and did not negatively affect the formation of arbuscular mycorrhizal symbiosis. Finally, metagenomic analyses showed the oomycete modifies the composition of fungal and bacterial communities. Together, our results provide novel insights regarding the involvement of P. oligandrum in the functioning of plant root microbiota.PMID:37929182 | PMC:PMC10625430 | DOI:10.3389/fpls.2023.1156733

ACS Omega. 2023 Oct 16;8(43):40212-40228. doi: 10.1021/acsomega.3c03861. eCollection 2023 Oct 31.ABSTRACTFour edible flowers commonly consumed in the Western Himalayan region, namely, Bauhinia variegata (Kachnar), Tropaeolum majus (Nasturtium), Matricaria chamomilla (Chamomile), and Tagetes erecta (Marigold), were characterized for their nutritional and phytochemical composition. Through the UHPLC-QTOF-IMS-based metabolomics approach, 131 compounds were tentatively identified consisting of phenolic acids, flavonoid glycosides, terpenoids, amino acids, and fatty acid derivatives. Kaempferol and quercetin glycosides for Kachnar, apigenin glycosides and caffeoylquinic acid derivatives for Chamomile, patulin and quercetin derivatives for Marigold, cyanidin and delphinidin glycosides for Nasturtium were the predicted marker metabolites identified through non-targeted metabolomics. Kachnar and Chamomile scored best in terms of macronutrients and essential micronutrients, respectively. Nasturtium contained high concentrations of α-linolenic acid, anthocyanins, and lutein. Kachnar contained the highest total phenolic acids (63.36 ± 0.38 mg GAE g-1), while Marigold contained the highest total flavonoids (118.90 ± 1.30 mg QUE g-1). Marigolds possessed excellent free radical scavenging and metal chelation activities. Chamomile exhibited strong α-glucosidase inhibition activity, followed by Nasturtium. The in vitro gastrointestinal digestibility of flower extracts indicated that the bioaccessibility of phenolic acids was higher than that of flavonoids. Polyphenols from Nasturtium and Chamomile showed the highest bioaccessibility. The study is an attempt to characterize traditionally consumed edible flowers and promote their wider utilization in gastronomy and nutraceuticals.PMID:37929082 | PMC:PMC10620890 | DOI:10.1021/acsomega.3c03861

Front Endocrinol (Lausanne). 2023 Oct 20;14:1181064. doi: 10.3389/fendo.2023.1181064. eCollection 2023.ABSTRACTAIM/INTRODUCTION: The study aimed to determine the effectiveness of early antidiabetic therapy in reversing metabolic changes caused by high-fat and high-sucrose diet (HFHSD) in both sexes.METHODS: Elderly Sprague-Dawley rats, 45 weeks old, were randomized into four groups: a control group fed on the standard diet (STD), one group fed the HFHSD, and two groups fed the HFHSD along with long-term treatment of either metformin (HFHSD+M) or liraglutide (HFHSD+L). Antidiabetic treatment started 5 weeks after the introduction of the diet and lasted 13 weeks until the animals were 64 weeks old.RESULTS: Unexpectedly, HFHSD-fed animals did not gain weight but underwent significant metabolic changes. Both antidiabetic treatments produced sex-specific effects, but neither prevented the onset of prediabetes nor diabetes.CONCLUSION: Liraglutide vested benefits to liver and skeletal muscle tissue in males but induced signs of insulin resistance in females.PMID:37929025 | PMC:PMC10623428 | DOI:10.3389/fendo.2023.1181064

MedComm (2020). 2023 Nov 2;4(6):e393. doi: 10.1002/mco2.393. eCollection 2023 Dec.ABSTRACTFasting has been grown in popularity with multiple potential benefits. However, very few studies dynamically monitor physiological and pathological changes during long-term fasting using noninvasive methods. In the present study, we recruited 37 individuals with metabolic syndrome to engage in a 5-day water-only fasting regimen, and simultaneously captured the molecular alterations through urinary proteomics and metabolomics. Our findings reveal that water-only fasting significantly mitigated metabolic syndrome-related risk markers, such as body weight, body mass index, abdominal circumference, blood pressure, and fasting blood glucose levels in metabolic syndrome patients. Indicators of liver and renal function remained within the normal range, with the exception of uric acid. Notably, inflammatory response was inhibited during the water-only fasting period, as evidenced by a decrease in the human monocyte differentiation antigen CD14. Intriguingly, glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation underwent a sex-dependent reprogramming throughout the fasting period, whereby males exhibited a greater upregulation of carbohydrate metabolism-related enzymes than females. This disparity may be attributed to evolutionary pressures. Collectively, our study sheds light on the beneficial physiological effects and novel dynamic molecular features associated with fasting in individuals with metabolic syndrome using noninvasive methods.PMID:37929015 | PMC:PMC10622739 | DOI:10.1002/mco2.393

Front Psychiatry. 2023 Oct 2;14:1249578. doi: 10.3389/fpsyt.2023.1249578. eCollection 2023.ABSTRACTAutism Spectrum Disorder (ASD or autism) is a phenotypically and etiologically heterogeneous condition. Identifying biomarkers of clinically significant metabolic subtypes of autism could improve understanding of its underlying pathophysiology and potentially lead to more targeted interventions. We hypothesized that the application of metabolite-based biomarker techniques using decision thresholds derived from quantitative measurements could identify autism-associated subpopulations. Metabolomic profiling was carried out in a case-control study of 499 autistic and 209 typically developing (TYP) children, ages 18-48 months, enrolled in the Children's Autism Metabolome Project (CAMP; ClinicalTrials.gov Identifier: NCT02548442). Fifty-four metabolites, associated with amino acid, organic acid, acylcarnitine and purine metabolism as well as microbiome-associated metabolites, were quantified using liquid chromatography-tandem mass spectrometry. Using quantitative thresholds, the concentrations of 4 metabolites and 149 ratios of metabolites were identified as biomarkers, each identifying subpopulations of 4.5-11% of the CAMP autistic population. A subset of 42 biomarkers could identify CAMP autistic individuals with 72% sensitivity and 90% specificity. Many participants were identified by several metabolic biomarkers. Using hierarchical clustering, 30 clusters of biomarkers were created based on participants' biomarker profiles. Metabolic changes associated with the clusters suggest that altered regulation of cellular metabolism, especially of mitochondrial bioenergetics, were common metabolic phenotypes in this cohort of autistic participants. Autism severity and cognitive and developmental impairment were associated with increased lactate, many lactate containing ratios, and the number of biomarker clusters a participant displayed. These studies provide evidence that metabolic phenotyping is feasible and that defined autistic subgroups can lead to enhanced understanding of the underlying pathophysiology and potentially suggest pathways for targeted metabolic treatments.PMID:37928922 | PMC:PMC10622772 | DOI:10.3389/fpsyt.2023.1249578