PubMed

Environ Toxicol Chem. 2022 Nov 8. doi: 10.1002/etc.5517. Online ahead of print.ABSTRACTPer- and polyfluoroalkyl substances (PFAS) are a class of persistent organic pollutants used in industrial applications due to their physicochemical properties that results in their ubiquitous presence across environmental matrices. To date, legacy PFAS have been well-studied, however, the concentration of alternative PFAS may exceed the concentration of legacy pollutants and more information is needed regarding the sub-lethal toxicity at the molecular-level of aquatic model organisms, such as Daphnia magna. Perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorohexanesulfonic acid (PFHxS), and perfluorononanoic acid (PFNA), are four widely detected PFAS alternatives of varying chain length and polar functionality that are quantified in aquatic environments. This study examines the metabolic perturbations of PFAS with varying chemistries to D. magna using targeted mass spectrometry -based metabolomics. Daphnia were acutely exposed to sub-lethal concentrations of PFBA, PFHxA, PFHxS, and PFNA before the polar metabolite profile was extracted from single organisms. Multivariate analysis demonstrated significant separation between the sub-lethal concentrations of PFHxA, PFHxS, and PFNA relative to the controls; in sum, longer chain lengths demonstrated greater overall perturbations to the extracted metabolic profiles. Univariate statistics revealed significant perturbations in the concentrations of several amino acids, nucleotides/nucleosides, and neurotransmitters with exposure to PFAS. These metabolic perturbations are consistent with disruptions in energy metabolism (pantothenate and Coenzyme A metabolism, histidine metabolism) and protein synthesis (aminoacyl-tRNA biosynthesis and amino acid metabolism) which were identified through biochemical pathway analysis. These results provide evidence that while PFAS chemistry (chain length and polar functional group) invokes unique metabolic responses there is also an underlying toxic mode of action that is common with select PFAS exposure. Overall, this work highlights the capabilities of environmental metabolomics to elucidate the molecular-level perturbations of pollutants within the same chemical class to model aquatic organisms which can be used to prioritize risk assessment of substituted PFAS alternatives. This article is protected by copyright. All rights reserved. Environ Toxicol Chem 2022;00:0-0. © 2022 SETAC.PMID:36345965 | DOI:10.1002/etc.5517

Heliyon. 2022 Oct 29;8(11):e11340. doi: 10.1016/j.heliyon.2022.e11340. eCollection 2022 Nov.ABSTRACTBACKGROUND: Hematological malignancies are the most common cancers in the pediatric population, and T-cell acute lymphocytic leukemia (T-ALL) is the most common hematological malignancy in children. Bloodstream infection (BSI) is a commonly occurring complication in leukemia due to underlying conditions and therapy-induced neutropenia. Several studies identified the gut microbiome as a major source of BSI due to bacterial translocation. This study aimed to investigate changes in the intestinal and fecal microbiome, and their roles in the pathophysiology of BSI in a pediatric T-ALL mouse model using high-throughput shotgun metagenomics sequencing, and metabolomics.RESULTS: Our results show that BSI in ALL is characterized by an increase of a mucin degrading bacterium (Akkermansia muciniphila) and a decrease of butyrate producer Clostridia spp., along with a decrease in short-chain fatty acid (SCFA) concentrations and differential expression of tight junction proteins in the small intestine. Functional analysis of the small intestinal microbiome indicated a reduced capability of SCFA synthesis, while SCFA supplementation ameliorated the development of BSI in ALL.CONCLUSIONS: Our data indicates that changes in the microbiome, and the resulting changes in levels of SCFAs contribute significantly to the pathogenesis of bloodstream infection in ALL. Our study provides tailored preventive or therapeutic approaches to reduce BSI-associated mortality in ALL.PMID:36345525 | PMC:PMC9636473 | DOI:10.1016/j.heliyon.2022.e11340

PeerJ. 2022 Nov 2;10:e14172. doi: 10.7717/peerj.14172. eCollection 2022.ABSTRACTBACKGROUND: Platycladus orientalis, as an important plant for ecological protection, is a pioneer tree species for afforestation in arid and barren mountainous areas. Lignin has the functions of water and soil conservation, strengthening plant mechanical strength and resisting adverse environmental effects and plays an important role in the ecological protection benefits of P. orientalis.METHODS: In this study, annual dynamic observations of the lignin content in roots, stems and leaves of one-year-old seedlings of a P. orientalis half-sib family were carried out, and combined transcriptome and metabolome analyses were carried out during three key stages of P. orientalis stem development.RESULTS: The lignin contents in roots, stems and leaves of P. orientalis showed extremely significant spatiotemporal differences. In the stems, lignin was mainly distributed in the cell walls of the pith, xylem, phloem, pericyte, and epidermis, with differences in different periods. A total of 226 metabolites were detected in the stem of P. orientalis, which were divided into seven categories, including 10 synthetic precursor compounds containing lignin. Among them, the content of coniferyl alcohol was the highest, accounting for 12.27% of the total content, and caffeyl alcohol was the lowest, accounting for 7.05% only. By annotating the KEGG functions, a large number of differentially expressed genes and differential metabolites were obtained for the comparison combinations, and seven key enzymes and 24 related genes involved in the process of lignin synthesis in P. orientalis were selected.CONCLUSIONS: Based on the results of the metabolic mechanism of lignin in P. orientalis by biochemical, anatomical and molecular biological analyzes, the key regulatory pathways of lignin in P. orientalis were identified, which will be of great significance for regulating the lignin content of P. orientalis and improving the adaptability and resistance of this plant.PMID:36345485 | PMC:PMC9636869 | DOI:10.7717/peerj.14172

Transl Pediatr. 2022 Oct;11(10):1704-1716. doi: 10.21037/tp-22-105.ABSTRACTBACKGROUND AND OBJECTIVE: Traditional targeted metabolomic investigations identify a pre-defined list of analytes in samples and have been widely used for decades in the diagnosis and monitoring of inborn errors of metabolism (IEMs). Recent technological advances have resulted in the development and maturation of untargeted metabolomics: a holistic, unbiased, analytical approach to detecting metabolic disturbances in human disease. We aim to provide a summary of untargeted metabolomics [focusing on tandem mass spectrometry (MS-MS)] and its application in the field of IEMs.METHODS: Data for this review was identified through a literature search using PubMed, Google Scholar, and personal repositories of articles collected by the authors. Findings are presented within several sections describing the metabolome, the current use of targeted metabolomics in the diagnostic pathway of patients with IEMs, the more recent integration of untargeted metabolomics into clinical care, and the limitations of this newly employed analytical technique.KEY CONTENT AND FINDINGS: Untargeted metabolomic investigations are increasingly utilized in screening for rare disorders, improving understanding of cellular and subcellular physiology, discovering novel biomarkers, monitoring therapy, and functionally validating genomic variants. Although the untargeted metabolomic approach has some limitations, this "next generation metabolic screening" platform is becoming increasingly affordable and accessible.CONCLUSIONS: When used in conjunction with genomics and the other promising "-omic" technologies, untargeted metabolomics has the potential to revolutionize the diagnostics of IEMs (and other rare disorders), improving both clinical and health economic outcomes.PMID:36345452 | PMC:PMC9636448 | DOI:10.21037/tp-22-105

Neuropsychiatr Dis Treat. 2022 Nov 1;18:2485-2496. doi: 10.2147/NDT.S377982. eCollection 2022.ABSTRACTPURPOSE: Tryptophan metabolism is involved in the etiology and exacerbation of depressive disorders. Kai-Xin-San (KXS), a traditional Chinese medicine formula, has been widely used to treat depression and modulate serotonin simultaneously, but how it regulates depressive-like behavior by shifting the balance of the tryptophan-serotonin metabolism and kynurenine pathway remains vague.PATIENTS AND METHODS: Ten participants with mild to moderate depression treated with KXS (KXS preparation) were analyzed in this study. Depression rating scale score and the concentration of serum tryptophan, 5-hydroxytryptophan and kynurenine was measured at baseline and the endpoint of KXS treatment. To explore the specific regulatory mechanism of KXS in tryptophan metabolism, the chronic restraint stress (CRS) was used to induce depressive-like syndrome in rats and the hippocampus level of tryptophan, 5-hydroxytryptophan, kynurenine with downstream metabolites (kynurenic acid, quinolinic acid) and key enzymes (indoleamine 2,3-dioxygenase, kynurenine 3-monooxygenase, kynurenine aminotransferase) were analyzed by liquid chromatography-electros pray ionization tandem mass spectrometry, high performance liquid chromatography and enzyme-linked immunosorbent assay respectively.RESULTS: KXS significantly decreased depression rating scale scores and increased the serum tryptophan and kynurenine concentration in depressive patients compared to baseline. Also, it alleviated the depressive behavior in CRS rats obviously. Comparing with CRS group, KXS increased tryptophan, 5-hydroxytryptophan, kynurenine level in rat hippocampus. Furthermore, in kynurenine pathway, KXS decreased the expression of indoleamine 2,3-dioxygenase, increased kynurenic acid by upregulating the expression of kynurenine aminotransferase while decreased quinolinic acid level in hippocampus, which suggested that KXS more favored improving serotonin pathway, and neuroprotective kynurenic acid branch in the tryptophan metabolism.CONCLUSION: This is the first tryptophan metabolomic study of patients with depression undergoing KXS treatment. Combining these clinical results with CRS induced rat model studies, it verified that KXS achieves an excellent antidepressant effect and balances tryptophan-kynurenine metabolic pathways by regulating some key metabolic products and enzymes.PMID:36345420 | PMC:PMC9636882 | DOI:10.2147/NDT.S377982

J Chromatogr A. 2022 Oct 30;1685:463626. doi: 10.1016/j.chroma.2022.463626. Online ahead of print.ABSTRACTHILIC is a separation technique increasingly used for the study of polar metabolites. However, HILIC suffers of a drawback related to the solvents used for these analyses: acetonitrile as sample solvent leads to the best chromatographic peaks, but it is not capable to extract/dissolve the most polar compounds. In this work we evaluated the use of several strategies for the extraction of polar compounds from plasma samples and, although methanol was the ideal solvent for analyte extraction, distorted peaks were obtained in the chromatography. Different strategies were tested included changing the solvent after extraction or modifying the injection volume and type. Finally, the best solution was using the lowest injection volume possible and to employ a simple sandwich injection including acetonitrile during the injection of the sample. This remarkably improves the peak shape when methanol is used in the sample. We evaluated and applied two HILIC-MS methods, in positive and negative ionization modes, on plasma samples from pigs with pulmonary hypertension produced by aorto-pulmonary shunting to identify metabolic signatures underlying damage to the right heart. Our analyses revealed altered relevant metabolic pathways, suggestive of oxidative stress and reduced energy demands.PMID:36345071 | DOI:10.1016/j.chroma.2022.463626

Behav Genet. 2022 Nov 7. doi: 10.1007/s10519-022-10126-7. Online ahead of print.ABSTRACTThis study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42%) and independent clinical data (N = 142, cases = 45%) ranged from 43 to 57%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.PMID:36344863 | DOI:10.1007/s10519-022-10126-7

Sci Rep. 2022 Nov 7;12(1):18883. doi: 10.1038/s41598-022-20461-8.ABSTRACTPine wilt disease (PWD) is a destructive vector-borne forest disease caused by the nematode Bursaphelenchus xylophilus. To date, several options are available for the management of pine wilt disease; however constant development and search for natural products with potential nematicidal activity are imperative to diversify management options and to cope with the possible future emergence of resistance in parasitic nematodes. Here, a combined metabolomics and genomics approach was employed to investigate the chemical repertoire and biosynthetic potential of the bacterial endophyte Peribacillus frigoritolerans BE93, previously characterized to exhibit nematicidal activity against B. xylophilus. Feature-based molecular networking revealed the presence of diverse secondary metabolites. A cyclic imine heptapeptide, koranimine, was found to be among the most abundant secondary metabolites produced. Genome mining displayed the presence of several putative biosynthetic gene clusters (BGCs), including a dedicated non-ribosomal peptide synthase (NRPS) BGC for koranimine. Given the non-ribosomal peptide nature of koranimine, in silico molecular docking analysis was conducted to investigate its potential nematicidal activity against the target receptor ivermectin-sensitive invertebrate α glutamate-gated chloride channel (GluCl). Results revealed the binding of koranimine at the allosteric site of the channel-the ivermectin binding site. Moreover, the ligand-receptor interactions observed were mostly shared between koranimine and ivermectin when bound to the α GluCl receptor thus, suggesting a possibly shared mechanism of potential nematicidal activity. This study highlights the efficiency of combined metabolomics and genomics approach in the identification of candidate compounds.PMID:36344604 | DOI:10.1038/s41598-022-20461-8

Trends Endocrinol Metab. 2022 Nov 4:S1043-2760(22)00178-3. doi: 10.1016/j.tem.2022.09.003. Online ahead of print.ABSTRACTThyroid hormones are essential metabolic and developmental regulators that exert a huge variety of effects in different organs. Triiodothyronine (T3) and thyroxine (T4) are synthesized in the thyroid gland and constitute unique iodine-containing hormones that are constantly regulated by a homeostatic feedback mechanism. T3/T4 activity in cells is mainly determined by specific transporters, cytosolic binding proteins, deiodinases (DIOs), and nuclear receptors. Modulation of intracellular T3/T4 level contributes to the maintenance of this regulatory feedback. μ-Crystallin (CRYM) is an important intracellular high-affinity T3-binding protein that buffers the amount of T3 freely available in the cytosol, thereby controlling its action. In this review, we focus on the molecular and pathological properties of CRYM in thyroid hormone signaling, with emphasis on its critical role in malignancies.PMID:36344381 | DOI:10.1016/j.tem.2022.09.003

Harmful Algae. 2022 Nov;119:102320. doi: 10.1016/j.hal.2022.102320. Epub 2022 Oct 7.ABSTRACTThis paper summarizes the research conducted by the partners of the EU co-funded CoCliME project to ascertain the ecological, human health and economic impacts of Ostreopsis (mainly O. cf. ovata) blooms in the NW Mediterranean coasts of France, Monaco and Spain. This knowledge is necessary to design strategies to prevent, mitigate and, if necessary, adapt to the impacts of these events in the future and in other regions. Ostreopsis proliferations in the Mediterranean have been related to massive mortalities of benthic organisms and to symptoms of respiratory and cutaneous irritation in humans. A six-year epidemiologic study in a Ostreopsis hot spot in Catalonia and the accumulated experience of the French Mediterranean National Ostreopsis Surveillance Network confirm the main effects of these blooms on human health in the NW Mediterranean. The impacts are associated to direct exposure to seawater with high Ostreopsis cell concentrations and to inhalation of aerosols containing unknown irritative chemicals produced under certain circumstances during the blooms. A series of mild acute symptoms, affecting the entire body as well as the ophthalmic, digestive, respiratory and dermatologic systems have been identified. A main remaining challenge is to ascertain the effects of the chronic exposure to toxic Ostreopsis blooms. Still, the mechanisms involved in the deletereous effects of Ostreopsis blooms are poorly understood. Characterizing the chemical nature of the harmful compounds synthesized by Ostreopsis as well as the role of the mucus by which cells attach to benthic surfaces, requires new technical approaches (e.g., metabolomics) and realistic and standardized ecotoxicology tests. It is also necessary to investigate how palytoxin analogues produced by O. cf. ovata could be transferred through the marine food webs, and to evaluate the real risk of seafood poisonings in the area. On the other hand, the implementation of beach monitoring and surveillance systems in the summer constitutes an effective strategy to prevent the impacts of Ostreopsis on human health. In spite of the confirmed noxious effects, a survey of tourists and residents in Nice and Monaco to ascertain the socioeconomic costs of Ostreopsis blooms indicated that the occurrence of these events and their impacts are poorly known by the general public. In relationship with a plausible near future increase of Ostreopsis blooms in the NW Mediterranean coast, this survey showed that a substantial part of the population might continue to go to the beaches during Ostreopsis proliferations and thus could be exposed to health risks. In contrast, some people would not visit the affected areas, with the potential subsequent negative impacts on coastal recreational and touristic activities. However, at this stage, it is too early to accurately assess all the economic impacts that a potentially increasing frequency and biogeographic expansion of the events might cause in the future.PMID:36344192 | DOI:10.1016/j.hal.2022.102320

BMJ Open. 2022 Nov 7;12(11):e065839. doi: 10.1136/bmjopen-2022-065839.ABSTRACTINTRODUCTION: Hepatocellular carcinoma (HCC) is a common cause of cancer-related death, often detected in the intermediate stage. The standard of care for intermediate-stage HCC is transarterial chemoembolisation (TACE), where idarubicin (IDA) is a promising drug. Despite the fact that TACE has been used for several decades, treatment success is unpredictable. This clinical trial has been designed believing that further improvement might be achieved by increasing the understanding of interactions between local pharmacology, tumour targeting, HCC pathophysiology, metabolomics and molecular mechanisms of drug resistance.METHODS AND ANALYSIS: The study population of this single-centre clinical trial consists of adults with intermediate-stage HCC. Each tumour site will receive TACE with two different IDA doses, 10 and 15 mg, on separate occasions. Before and after each patient's first TACE blood samples, tissue and liquid biopsies, and positron emission tomography (PET)/MRI will be performed. Blood samples will be used for pharmacokinetics (PK) and liver function evaluation. Tissue biopsies will be used for histopathology analyses, and culturing of primary organoids of tumour and non-tumour tissue to measure cell viability, drug response, multiomics and gene expression. Multiomics analyses will also be performed on liquid biopsies. PET/MRI will be used to evaluate tumour viability and liver metabolism. The two doses of IDA will be compared regarding PK, antitumour effects and safety. Imaging, molecular biology and multiomics data will be used to identify HCC phenotypes and their relation to drug uptake and metabolism, treatment response and survival.ETHICS AND DISSEMINATION: Participants give informed consent. Personal data are deidentified. A patient will be withdrawn from the study if considered medically necessary, or if it is the wish of the patient. The study has been approved by the Swedish Ethical Review Authority (Dnr. 2021-01928) and by the Medical Product Agency, Uppsala, Sweden.TRIAL REGISTRATION NUMBER: EudraCT number: 2021-001257-31.PMID:36343995 | DOI:10.1136/bmjopen-2022-065839

Mol Metab. 2022 Nov 4:101629. doi: 10.1016/j.molmet.2022.101629. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Ependymin-Related Protein 1 (EPDR1) was recently identified as a secreted human batokine regulating mitochondrial respiration linked to thermogenesis in brown fat. Despite that EPDR1 is expressed in human pancreatic β-cells and that glucose-stimulated mitochondrial metabolism is critical for stimulus-secretion coupling in β-cells, the role of EPDR1 in β-cell metabolism and function has not been investigated.MATERIALS AND METHODS: EPDR1 mRNA levels in human pancreatic islets from non-diabetic (ND) and type 2 diabetes (T2D) subjects were assessed. Human islets, EndoC-βH1 and INS1 832/13 cells were transfected with scramble (control) and EPDR1 siRNAs (EPDR1-KD) or treated with human EPDR1 protein, and glucose-stimulated insulin secretion (GSIS) assessed by ELISA. Mitochondrial metabolism was investigated by extracellular flux analyzer, confocal microscopy and mass spectrometry-based metabolomics analysis.RESULTS: EPDR1 mRNA expression was upregulated in human islets from T2D and obese donors and positively correlated to BMI of donors. In T2D donors, EPDR1 mRNA levels negatively correlated with HbA1c and positively correlated with GSIS. EPDR1 silencing in human islets and β-cell lines reduced GSIS whereas treatment with human EPDR1 protein increased GSIS. Epdr1 silencing in INS1 832/13 cells reduced glucose- and pyruvate- but not K+-stimulated insulin secretion. Metabolomics analysis in Epdr1-KD INS1 832/13 cells suggests diversion of glucose-derived pyruvate to lactate production and decreased malate-aspartate shuttle and the tricarboxylic acid (TCA) cycle activity. The glucose-stimulated rise in mitochondrial respiration and ATP/ADP-ratio was impaired in Epdr1-deficient cells.CONCLUSION: These results suggests that to maintain glucose homeostasis in obese people, upregulation of EPDR1 may improve β-cell function via channelling glycolysis-derived pyruvate to the mitochondrial TCA cycle.PMID:36343918 | DOI:10.1016/j.molmet.2022.101629

Sci Total Environ. 2022 Nov 4:159932. doi: 10.1016/j.scitotenv.2022.159932. Online ahead of print.ABSTRACT>80 % of applied pesticides in agriculture will enter the soil and be exposed to soil animals. Little is known about the stereoselective metabolic effects of epoxiconazole (EPO) on soil animals. In this study, EPO-mediated stereoselective enrichment, biotransformation, oxidative stress, detoxification, and global metabolic profiles in earthworms were investigated by exposure to EPO and its enantiomers at 1 mg/kg and 10 mg/kg doses. Preferential enrichment of (-)-EPO was observed, and the five transformation products (TPs) exhibited the chemically specific stereoselective accumulation with inconsistent configurations. Biochemical markers related to reactive oxygen species (ROS) and detoxification (·OH- content, SOD, CAT, GST, and CYP450 enzymes) showed a significant stereoselective activation overall at the low-level exposure (p-value <0.05). Based on untargeted metabolomic analysis, the steroid biosynthesis and ROS-related biotransformation, glutathione metabolism, TCA cycle, amino acid metabolism, purine and pyrimidine metabolism of earthworms were significantly interfered with by EPO and its enantiomer exposure. More pronounced stereoselectivity was observed at the level of the global metabolic profile, while comparable levels of metabolic perturbations were identified at the individual metabolite level. This study provides novel insights into the stereoselective effects of the chiral fungicide EPO, and valuable evidence for soil environmental risk assessments.PMID:36343825 | DOI:10.1016/j.scitotenv.2022.159932

Sci Total Environ. 2022 Nov 4:159978. doi: 10.1016/j.scitotenv.2022.159978. Online ahead of print.ABSTRACTPseudotargeted metabolomics is achieved by introducing an algorithm designed to choose ions for selected ion monitoring from identified metabolites. This method integrates the advantages of both untargeted and targeted metabolomics. In this study,environmental pseudotargeted metabolomics was established to analyze the soil metabolites, based on microwave assisted derivatization followed by gas chromatography-mass spectrometry analysis. The method development included the optimization of extraction factors and derivatization conditions, evaluation of silylation reagent types and matrix-dependent behaviors. Under the optimal conditions, the microwave oximation and silylation were completed in 5 min and 9 min. A total of 184 metabolites from 26 chemical classifications were identified in soil matrices. The method validation demonstrated excellent performance in terms of linearity (correlation coefficient > 0.99), repeatability (relative standard deviation (RSD) < 20 %), reproducibility (RSD < 25 %), stability (relative difference < 10 % within 18 h), and sensitivity (16-110 times higher signal-to-noise ratio). This developed method was applied to characterize the metabolite compositions and metabolic profiling in a 1000-year paddy soil chronosequence. The relative abundance of trehalose was highest in 6-(40.3 %), 60-(55.8 %), 300-(67.7 %)and 1000-(61.7 %)years paddy soil, respectively, but long-chain fatty acids were most abundant in marine sediment (57.4 %). Forty-two characteristic metabolites were considered as primarily responsible for discriminating and characterizing the paddy soil chronosequences development and seven major metabolic pathways were altered. In addition, GC-MS metabolite profile presented better discriminating power in paddy soil ecosystem changes than phospholipid fatty acids (PLFAs). Overall, environmental pseudotargeted metabolomics can provide a high throughout and wide coverage approach for performing metabolic profiling in the soil research.PMID:36343812 | DOI:10.1016/j.scitotenv.2022.159978

Phytomedicine. 2022 Oct 28;108:154529. doi: 10.1016/j.phymed.2022.154529. Online ahead of print.ABSTRACTBACKGROUND: Previous studies have shown that the anti-cholestatic effect of oleanolic acid (OA) is associated with FXR and NRF2. However, how the two signaling pathways cooperate to regulate the anti-cholestatic effect of OA remains unclear.PURPOSE: This study aimed to further demonstrate the effect of OA on alpha-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury and the interaction mechanism between NRF2 and FXR signaling pathways in maintaining bile acid homeostasis.METHODS: Gene knockout animals and cell models, metabolomics analysis, and co-immunoprecipitation were used to investigate the mechanism of OA against cholestatic liver injury.RESULTS: The effect of OA against ANIT-induced liver injury in rats was dramatically reduced after Nrf2 gene knockdown. With the silencing of Fxr, the hepatoprotective effect of OA was weakened, but it still effectively alleviated cholestatic liver injury in rats. In L02 cells, OA can up-regulate the levels of NRF2, FXR, BSEP and UGT1A1, and reduce the expression of CYP7A1. Silencing of NRF2 or FXR significantly attenuated the protective effect of OA on ANIT-induced L02 cell injury and its regulation on downstream target genes, and the influence of NRF2 gene silencing on OA appeared to be greater. The NRF2 activator sulforaphane, and the FXR activator GW4064 both remarkably promoted NRF2 binding to P300 and FXR to RXRα, but reduced β-catenin binding to P300 and β-catenin binding to FXR.CONCLUSION: The effect of OA on cholestatic liver injury is closely related to the simultaneous activation of NRF2 and FXR dual signaling pathways, in which NRF2 signaling pathway plays a more important role. The dual signaling pathways of NRF2 and FXR cooperatively regulate bile acid metabolic homeostasis through the interaction mechanism with β-catenin/P300.PMID:36343550 | DOI:10.1016/j.phymed.2022.154529

Epilepsy Behav. 2022 Nov 4;137(Pt A):108964. doi: 10.1016/j.yebeh.2022.108964. Online ahead of print.ABSTRACTINTRODUCTION: Acetate has been shown to have neuroprotective and anti-inflammatory effects. It is oxidized by astrocytes and can thus provide auxiliary energy to the brain in addition to glucose. Therefore, we hypothesized that it may protect against seizures, which is investigated here by feeding glyceryl triacetate (GTA), to provide high amounts of acetate without raising sodium or acid levels.METHOD: CD1 male mice were fed controlled diets with or without GTA for up to three weeks. Body weights, blood glucose levels, plasma short-chain fatty acid levels, and other hematological parameters were monitored. Seizure thresholds were determined in 6 Hz and maximal electroshock seizure threshold (MEST) tests. Antioxidant capacities were evaluated in the cerebral cortex and plasma using a ferric reducing antioxidant power (FRAP) assay and Trolox equivalent antioxidant capacity assay.RESULTS: Body weight gain was similar with both diets with and without GTA in two experiments. Glyceryl triacetate-fed groups showed 2-3- and 1.6-fold increased acetate and propionate levels in plasma, respectively. Glucose levels were unaltered in blood collected from the tail tip but increased in trunk blood. No differences were found in the activity of cerebral cortex acetyl-CoA synthetase. In the 6 Hz threshold test, seizure thresholds were lower by 3 mA and 2.4 mA after 8 and 14 days, respectively, in the GTA compared to the control diet-fed group, but showed no difference on day 16, showing that GTA has small, but inconsistent proconvulsant effects in this model. In MEST tests, a slightly increased seizure threshold (1 mA) was found on day 19 in the GTA-fed group, but not in another experiment on day 21. There were no differences in antioxidant capacity in plasma or cortex between the two groups.CONCLUSION: Glyceryl triacetate feeding showed no antioxidant effects nor beneficial changes in acute electrical seizure threshold mouse models, despite its ability to increase plasma acetate levels.PMID:36343532 | DOI:10.1016/j.yebeh.2022.108964

Biomed Chromatogr. 2022 Nov 7:e5546. doi: 10.1002/bmc.5546. Online ahead of print.ABSTRACTPanax ginseng, an essential component of traditional medicine and often referred to as the king of herbs, has played a pivotal role in medicine globally for several millennia. Previously, traditional phytochemical methods were mainly used for quality evaluation and pharmacological mechanism studies of ginseng, resulting in the lack of systematicness and innovation and hindering the development and utilization of ginseng resources. Since the beginning of the new century, systems biology technology represented by metabolomics has shown unique advantages in the modernization and internationalization of herbal medicine, establishing a bridge for communication between traditional medicine and modern medicine. P. ginseng, a special herb used in medicine and food, is one of the main research objects for qualitative and quantitative analysis of metabolomics and has gradually become the focus of researchers globally. Here, we conducted a comprehensive summary and analysis of numerous studies published in ginseng metabolomics. This review aims to provide more novel ideas for the quality evaluation, development and clinical application of ginseng in the future and offer more useful technical references for the modernization and internationalization of herbal medicine based on metabolomics.PMID:36342761 | DOI:10.1002/bmc.5546

Metabolomics. 2022 Nov 7;18(11):89. doi: 10.1007/s11306-022-01935-2.ABSTRACTINTRODUCTION: The 2,6-dichloro-1,4-benzoquinone (DCBQ) and its derivative 2,6-dichloro-3-hydroxy-1,4-benzoquinone (DCBQ-OH) are disinfection by-products (DBPs) and emerging pollutants in the environment. They are considered to be of particular importance as they have a high potential of toxicity and they are likely to be carcinogenic.OBJECTIVES: In this study, human epidermal keratinocyte cells (HaCaT) were exposed to the DCBQ and its derivative DCBQ-OH, at concentrations equivalent to their IC20 and IC50, and a study of the metabolic phenotype of cells was performed.METHODS: The perturbations induced in cellular metabolites and their relative content were screened and evaluated through a metabolomic study, using 1H-NMR and MS spectroscopy.RESULTS: Changes in the metabolic pathways of HaCaT at concentrations corresponding to IC20 and IC50 of DCBQ-OH involved the activation of cell membrane α-linolenic acid, biotin, and glutathione and deactivation of glycolysis/gluconeogenesis at IC50. The changes in metabolic pathways at IC20 and IC50 of DCBQ were associated with the activation of inositol phosphate, pertaining to the transfer of messages from the receptors of the membrane to the interior as well as with riboflavin. Deactivation of biotin metabolism was recorded, among others. The cells exposed to DCBQ exhibited a concentration-dependent decrease in saccharide concentrations. The concentration of steroids increased when cells were exposed to IC20 and decreased at IC50. Although both chemical factors stressed the cells, DCBQ led to the activation of transporting messages through phosphorylated derivatives of inositol.CONCLUSION: Our findings provided insights into the impact of the two DBPs on human keratinocytes. Both chemical factors induced energy production perturbations, oxidative stress, and membrane damage.PMID:36342571 | DOI:10.1007/s11306-022-01935-2

Arch Immunol Ther Exp (Warsz). 2022 Nov 7;70(1):28. doi: 10.1007/s00005-022-00665-6.ABSTRACTMetabolomics is a new field of science dealing with the study and analysis of metabolites formed in living cells. The biological fluids used in this test method are: blood, blood plasma, serum, cerebrospinal fluid, saliva and urine. The most popular methods of assessing the composition of metabolites include nuclear magnetic resonance spectroscopy and mass spectrometry (MS) in combination with gas chromatography-MS or liquid chromatography-MS. Metabolomics is used in many areas of medicine. The variability of biochemical processes in neoplastic cells in relation to healthy cells is the starting point for this type of research. The aim of the research currently being carried out is primarily to find biomarkers for quick diagnosis of the disease, assessment of its advancement and treatment effectiveness. The development of metabolomics may also contribute to the individualization of treatment of patients, adjusting drugs depending on the metabolic profile, and thus may improve the effectiveness of therapy, reduce side effects and help to improve the quality of life of patients. Here, we review the current and potential applications of metabolomics, focusing on its use as a biomarker method for childhood leukemia.PMID:36342560 | DOI:10.1007/s00005-022-00665-6

G3 (Bethesda). 2022 Nov 7:jkac297. doi: 10.1093/g3journal/jkac297. Online ahead of print.ABSTRACTFlavonoids are rich in tea plants (Camellia sinensis), and responsible for the flavor and healthful benefits of tea beverage. The anthocyanin levels in the purple tender shoots are higher than in the general green leaves of tea plant, which provide special materials to search metabolic mechanisms of flavonoid enrichment in plant. In this work, flavonoid differences between purple and green shoots from tea cultivars 'Zijuan' (ZJ) and 'Yunkang10' (YK-10) were investigated through metabolomic analysis, and mechanisms for their difference were surveyed by comparative transcriptomic and proteomic analysis. Levels of 34 flavonoids were different between ZJ and YK-10 shoots. Among them, eight and six were marker metabolites in ZJ and YK-10, respectively. The differentially expressed genes (DEGs), proteins (DEPs) and different-level metabolites (DLMs) between ZJ and YK-10 were researched, respectively; and interactions including DEG-DLM, DEP-DLM, DEG-DEP and DEG-DEP-DLM were analyzed; the contents of 18 characteristic flavonoids in tea leaves and expressions of 34 flavonoid metabolic genes were measured to verify the omics results. Integrated above analyses, a proposed model of flavonoids biosynthesis in tea shoots were established. The differential expression of the leucoanthocyanidin reductase (LAR), anthocyanidin synthase (ANS), anthocyanidin reductase (ANR), UDPG-flavonoid glucosyltransferase (UGT) 75L12 and 94P1 at gene level, and the ANS, ANR and UGT78A15 at protein level, were closely associated with differences in flavonoids between ZJ and YK-10 shoot. Together, this study provides new information on the flavonoid accumulation mechanism in tea plant.PMID:36342187 | DOI:10.1093/g3journal/jkac297