PubMed

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

Environ Res. 2022 Oct 28;216(Pt 3):114648. doi: 10.1016/j.envres.2022.114648. Online ahead of print.ABSTRACTEpidemiological and animal studies have shown that maternal fine particulate matters (PM2.5) exposure correlates with various adverse pregnancy outcomes such as low birth weight (LBW) of offspring. However, the underlying biological mechanisms have not been fully understood. In this study, female C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during pregestational and gestational periods, and metabolomics was performed to analyze the metabolic features in maternal serum and placenta by liquid chromatography-mass spectrometry (LC-MS). The partial least squares discriminate analysis (PLS-DA) displayed evident clustering of FA- and CAP-exposed samples for both maternal serum and placenta. In addition, pathway analysis identified that vitamin digestion and absorption was perturbed in maternal serum, while metabolic pathways including arachidonic acid metabolism, serotonergic synapse, 2-oxocarboxylic acid metabolism and cAMP signaling pathway were perturbed in placenta. Further analysis indicated that CAP exposure influenced the nutrient transportation capacity of placenta, by not only changing the ratios of some critical metabolites in placenta to maternal serum but also significantly altering the expressions of nutrition transporters in placenta. These findings reaffirm the importance of protecting women from PM2.5 exposure, and also advance our understanding of the toxic actions of ambient PM2.5.PMID:36341790 | DOI:10.1016/j.envres.2022.114648

Analyst. 2022 Nov 7. doi: 10.1039/d2an01520j. Online ahead of print.ABSTRACTLameness is a major challenge in the dairy cattle industry in terms of animal welfare and economic implications. Better understanding of metabolic alteration associated with lameness could lead to early diagnosis and effective treatment, there-fore reducing its prevalence. To determine whether metabolic signatures associated with lameness could be discovered with untargeted metabolomics, we developed a novel workflow using direct infusion-tandem mass spectrometry to rapidly analyse (2 min per sample) dried milk spots (DMS) that were stored on commercially available Whatman® FTA® DMPK cards for a prolonged period (8 and 16 days). An orthogonal partial least squares-discriminant analysis (OPLS-DA) method validated by triangulation of multiple machine learning (ML) models and stability selection was employed to reliably identify important discriminative metabolites. With this approach, we were able to differentiate between lame and healthy cows based on a set of lipid molecules and several small metabolites. Among the discriminative molecules, we identified phosphatidylglycerol (PG 35:4) as the strongest and most sensitive lameness indicator based on stability selection. Overall, this untargeted metabolomics workflow is found to be a fast, robust, and discriminating method for determining lameness in DMS samples. The DMS cards can be potentially used as a convenient and cost-effective sample matrix for larger scale research and future routine screening for lameness.PMID:36341756 | DOI:10.1039/d2an01520j

Food Funct. 2022 Nov 7. doi: 10.1039/d2fo02739a. Online ahead of print.ABSTRACTTreatment of anxiety and depression predominantly centres around pharmacological interventions, which have faced criticism for their associated side effects, lack of efficacy and low tolerability. Saffron, which is reportedly well tolerated in humans, has been recognised for its antidepressant and anti-anxiety properties. Indeed, we previously reported upon the efficacy of saffron extract supplementation in healthy adults with subclinical anxiety. However, the molecular aetiology remains unclear. In a rodent model of low-grade chronic inflammation, we explored the impact of a saffron extract (Safr'Inside™) supplemented at a physiological dose, which equated to 22 ± 1.2 mg per day human equivalent dose for a person of 60 kg. Behavioural tests (Open Field task, Y maze, Novel object recognition), caecal 16S rRNA microbial sequencing, caecal 1H NMR metabolomic analysis and 2DE brain proteomic analyses were completed to probe gut-brain axis interactions. Time occupying the centre of the Open Field maze (OF) was increased by 62% in saffron supplemented animals. This improvement in anxiety-related behaviour coincided with gut microbial shifts, notably Akkermansia, Muribaculaceae, Christensenellacae and Alloprevotella which significantly increased in response to saffron supplementation. Akkermansia and Muribaculaceae abundance negatively correlated with the neurotoxic metabolite dimethylamine which was reduced in saffron supplemented animals. Brain proteomic analysis highlighted several significantly altered proteins including ketimine reductase mu-crystallin which also correlated with dimethylamine concentration. Both dimethylamine and ketimine reductase mu-crystallin were associated with OF performance. This may be indicative of a novel interaction across the gut-brain axis which contributes to anxiety-related disorders.PMID:36341693 | DOI:10.1039/d2fo02739a

FEMS Microbiol Ecol. 2022 Nov 7:fiac129. doi: 10.1093/femsec/fiac129. Online ahead of print.ABSTRACTWith the increasing reliance on intensive arable agriculture, analysis of the problems associated with continuous cropping has become a global research focus. Here, high-throughput sequencing and non-targeted metabolomics were used to evaluate the responses of soil microbial community structure and soil metabolic function to continuous cucumber cultivation (from one to 18 years of continuous cultivation) in greenhouses. Continuous cucumber cropping resulted in increased soil nutrient concentrations but decreased concentrations of available nutrients. The abundance of several bacterial genera associated with nutrient cycling, such as Bacillus and Sphingomonas, was reduced by continuous cucumber cultivation. The abundance of several beneficial fungal genera, including pathogen antagonists (e.g. Chaetomium, Mortierella, Aspergillus, and Penicillium), were found to gradually decrease in response to the increased duration of continuous cropping. 3-amino-2-naphthoic acid and L-valine increased initially and then decreased as the cropping continued, which were related to fatty acid metabolism and amino acid biosynthesis. We also confirmed a close association between microbial community structure and soil metabolites. This study linked the changes in microbial community structure and metabolites in the rhizosphere soil and provided new insights into soil-microbial interactions in continuous cucumber culture systems.PMID:36341539 | DOI:10.1093/femsec/fiac129

EMBO Mol Med. 2022 Nov 7:e15200. doi: 10.15252/emmm.202115200. Online ahead of print.ABSTRACTLeukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL.PMID:36341492 | DOI:10.15252/emmm.202115200

Front Immunol. 2022 Jul 11;13:936106. doi: 10.3389/fimmu.2022.936106. eCollection 2022.ABSTRACTSevere acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection triggers inflammatory clinical stages that affect the outcome of patients with coronavirus disease 2019 (COVID-19). Disease severity may be associated with a metabolic imbalance related to amino acids, lipids, and energy-generating pathways. The aim of this study was to characterize the profile of amino acids and acylcarnitines in COVID-19 patients. A multicenter, cross-sectional study was carried out. A total of 453 individuals were classified by disease severity. Levels of 11 amino acids, 31 acylcarnitines, and succinylacetone in serum samples were analyzed by electrospray ionization-triple quadrupole tandem mass spectrometry. Different clusters were observed in partial least squares discriminant analysis, with phenylalanine, alanine, citrulline, proline, and succinylacetone providing the major contribution to the variability in each cluster (variable importance in the projection >1.5). In logistic models adjusted by age, sex, type 2 diabetes mellitus, hypertension, and nutritional status, phenylalanine was associated with critical outcomes (odds ratio=5.3 (95% CI 3.16-9.2) in the severe vs. critical model, with an area under the curve of 0.84 (95% CI 0.77-0.90). In conclusion the metabolic imbalance in COVID-19 patients might affect disease progression. This work shows an association of phenylalanine with critical outcomes in COVID-19 patients, highlighting phenylalanine as a potential metabolic biomarker of disease severity.PMID:36341434 | PMC:PMC9634751 | DOI:10.3389/fimmu.2022.936106

Front Immunol. 2022 Oct 20;13:984408. doi: 10.3389/fimmu.2022.984408. eCollection 2022.ABSTRACTMetabolomic studies show that rheumatoid arthritis (RA) is associated with metabolic disruption. Metabolic changes in fibroblast-like synoviocytes (FLS) likely contribute to FLS abnormal response and strongly contribute to joint destruction. These changes often involve increased expression of nutrient transporters to meet a high demand for energy or biomolecules. The solute carrier (SLC) transporter families are nutrient transporters and serve as 'metabolic gates' for cells by mediating the transport of several different nutrients such as glucose, amino acids, vitamins, neurotransmitters, and inorganic/metal ions. In RA FLS SLC-mediated transmembrane transport was one pathway associated with different epigenetic landscape between RA and osteoarthritis (OA) FLS. These highlight that transporters from the SLC family offer unique targets for further research and offer the promise of future therapeutic targets for RA.PMID:36341411 | PMC:PMC9632162 | DOI:10.3389/fimmu.2022.984408

Front Immunol. 2022 Oct 20;13:1002536. doi: 10.3389/fimmu.2022.1002536. eCollection 2022.ABSTRACTBACKGROUND: Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. Dupilumab, a monoclonal antibody that targets the interleukin (IL)-4 and IL-13 receptors, has been widely used in AD because of its efficacy. However, metabolic changes occurring in patients with AD in response to dupilumab remains unknown. In this study, we integrated metabolomics and lipidomics analyses with clinical data to explore potential metabolic alterations associated with dupilumab therapeutic efficacy. In addition, we investigated whether the development of treatment side effects was linked to the dysregulation of metabolic pathways.METHODS: A total of 33 patients with AD were included in the current study, with serum samples collected before and after treatment with dupilumab. Comprehensive metabolomic and lipidomic analyses have previously been developed to identify serum metabolites (including lipids) that vary among treatment groups. An orthogonal partial least squares discriminant analysis model was established to screen for differential metabolites and metabolites with variable importance in projection > 1 and p < 0.05 were considered potential metabolic biomarkers. MetaboAnalyst 5.0 was used to identify related metabolic pathways. Patients were further classified into two groups, well responders (n = 19) and poor responders (n = 14), to identify differential metabolites between the two groups.RESULTS: The results revealed significant changes in serum metabolites before and after 16 weeks of dupilumab treatment. Variations in the metabolic profile were more significant in the well-responder group than in the poor-responder group. Pathway enrichment analysis revealed that differential metabolites derived from the well-responder group were mainly involved in glycerophospholipid metabolism, valine, leucine and isoleucine biosynthesis, the citrate cycle, arachidonic acid metabolism, pyrimidine metabolism, and sphingolipid metabolism.CONCLUSION: Serum metabolic profiles of patients with AD varied significantly after treatment with dupilumab. Differential metabolites and their related metabolic pathways may provide clues for understanding the effects of dupilumab on patient metabolism.PMID:36341398 | PMC:PMC9632449 | DOI:10.3389/fimmu.2022.1002536

Front Immunol. 2022 Oct 20;13:960709. doi: 10.3389/fimmu.2022.960709. eCollection 2022.ABSTRACTPorcine reproductive and respiratory syndrome virus (PRRSV) is a highly contagious disease that affects the global pig industry. To understand mechanisms of susceptibility/resistance to PRRSV, this study profiled the time-serial white blood cells transcriptomic and serum metabolomic responses to PRRSV in piglets from a crossbred population of PRRSV-resistant Tongcheng pigs and PRRSV-susceptible Large White pigs. Gene set enrichment analysis (GSEA) illustrated that PRRSV infection up-regulated the expression levels of marker genes of dendritic cells, monocytes and neutrophils and inflammatory response, but down-regulated T cells, B cells and NK cells markers. CIBERSORT analysis confirmed the higher T cells proportion in resistant pigs during PRRSV infection. Resistant pigs showed a significantly higher level of T cell activation and lower expression levels of monocyte surface signatures post infection than susceptible pigs, corresponding to more severe suppression of T cell immunity and inflammatory response in susceptible pigs. Differentially expressed genes between resistant/susceptible pigs during the course of infection were significantly enriched in oxidative stress, innate immunity and humoral immunity, cell cycle, biotic stimulated cellular response, wounding response and behavior related pathways. Fourteen of these genes were distributed in 5 different QTL regions associated with PRRSV-related traits. Chemokine CXCL10 levels post PRRSV infection were differentially expressed between resistant pigs and susceptible pigs and can be a promising marker for susceptibility/resistance to PRRSV. Furthermore, the metabolomics dataset indicated differences in amino acid pathways and lipid metabolism between pre-infection/post-infection and resistant/susceptible pigs. The majority of metabolites levels were also down-regulated after PRRSV infection and were significantly positively correlated to the expression levels of marker genes in adaptive immune response. The integration of transcriptome and metabolome revealed concerted molecular events triggered by the infection, notably involving inflammatory response, adaptive immunity and G protein-coupled receptor downstream signaling. This study has increased our knowledge of the immune response differences induced by PRRSV infection and susceptibility differences at the transcriptomic and metabolomic levels, providing the basis for the PRRSV resistance mechanism and effective PRRS control.PMID:36341362 | PMC:PMC9631489 | DOI:10.3389/fimmu.2022.960709

JIMD Rep. 2022 Aug 22;63(6):593-603. doi: 10.1002/jmd2.12323. eCollection 2022 Nov.ABSTRACTAdrenomyeloneuropathy (AMN), the slow progressive phenotype of adrenoleukodystrophy (ALD), has no clinical plasma biomarker for disease progression. This feasibility study aimed to determine whether metabolomics and micro-RNA in blood plasma provide a potential source of biomarkers for AMN disease severity. Metabolomics and RNA-seq were performed on AMN and healthy human blood plasma. Biomarker discovery and pathway analyses were performed using clustering, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and regression against patient's clinical Expanded Disability Status Score (EDSS). Fourteen AMN and six healthy control samples were analyzed. AMN showed strong disease-severity-specific metabolic and miRNA clustering signatures. Strong, significant clinical correlations were shown for 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-HOCA) (r 2 = 0.83, p < 0.00001), dehydroepiandrosterone sulfate (DHEA-S; r 2 = 0.82, p < 0.00001), hypoxanthine (r 2 = 0.82, p < 0.00001), as well as miRNA-432-5p (r 2 = 0.68, p < 0.00001). KEGG pathway comparison of mild versus severe disease identified affected downstream systems: GAREM, IGF-1, CALCRL, SMAD2&3, glutathione peroxidase, LDH, and NOS. This feasibility study demonstrates that miRNA and metabolomics are a source of potential plasma biomarkers for disease severity in AMN, providing both a disease signature and individual markers with strong clinical correlations. Network analyses of affected systems implicate differentially altered vascular, inflammatory, and oxidative stress pathways, suggesting disease-severity-specific mechanisms as a function of disease severity.PMID:36341174 | PMC:PMC9626672 | DOI:10.1002/jmd2.12323

STAR Protoc. 2022 Oct 29;3(4):101799. doi: 10.1016/j.xpro.2022.101799. eCollection 2022 Dec 16.ABSTRACTThis protocol describes CAROM, a computational tool that combines genome-scale metabolic networks (GEMs) and machine learning to identify enzyme targets of post-translational modifications (PTMs). Condition-specific enzyme and reaction properties are used to predict targets of phosphorylation and acetylation in multiple organisms. CAROM is influenced by the accuracy of GEMs and associated flux-balance analysis (FBA), which generate the inputs of the model. We demonstrate the protocol using multi-omics data from E. coli. For complete details on the use and execution of this protocol, please refer to Smith et al. (2022).PMID:36340881 | PMC:PMC9630780 | DOI:10.1016/j.xpro.2022.101799