PubMed

Curr Opin Chem Biol. 2022 Nov 5;71:102226. doi: 10.1016/j.cbpa.2022.102226. Online ahead of print.ABSTRACTMetabolites are the end products of cellular vital activities and can reflect the state of cellular to a certain extent. Rapid change of metabolites and the low abundance of signature metabolites cause difficulties in single-cell detection, which is a great challenge in single-cell metabolomics analysis. Mass spectrometry (MS) is a powerful tool that uniquely suited to detect intracellular small-molecule metabolites and has shown good application in single-cell metabolite analysis. In this mini-review, we describe three types of emerging technologies for MS-based single-cell metabolic analysis in recent years, including nano-ESI-MS based single-cell metabolomics analysis, high-throughput analysis via flow cytometry, and cellular metabolic imaging analysis. These techniques provide a large amount of single-cell metabolic data, allowing the potential of MS in single-cell metabolic analysis is gradually being explored and is of great importance in disease and life science research.PMID:36347197 | DOI:10.1016/j.cbpa.2022.102226

Hear Res. 2022 Nov 2;426:108645. doi: 10.1016/j.heares.2022.108645. Online ahead of print.ABSTRACTThe cochlear nucleus receives numerous inputs from auditory and nonauditory systems. This extensive innervation of the cochlear nucleus is involved in sound source localization and the integration of auditory signals with other sensory modalities. The dorsal cochlear nucleus may also have an important role in tinnitus. Although its gross anatomy and function have been extensively studied, the metabolome of the cochlear nucleus remains poorly understood, particularly at different stages of auditory maturity. Here, we present a protocol for untargeted metabolomics analysis of the rat cochlear nucleus, then discuss differences in the metabolome of the rat cochlear nucleus between postnatal day (PD) 14 (hearing onset) and PD60 (hearing maturation). Cochlear nucleus samples collected from rats at PD14 or PD60 were analyzed by liquid chromatography-tandem mass spectrometry (LCMS). In total, 344 metabolites were identified. Principal component analysis and orthogonal partial least-square discriminant analysis showed that the metabolic profiles at these two stages had distinct distribution patterns. Moreover, 91 significantly differential metabolites (62 upregulated and 29 downregulated) were identified at PD60 vs. PD14. N-acetylaspartylglutamic acid (NAAG), γ-aminobutyric acid (GABA), taurine, adenosine monophosphate (AMP), and choline were significantly upregulated at PD60. Pathway enrichment analysis suggested that alanine, aspartate, and glutamate metabolism; glycine, serine, and threonine metabolism; the mammalian target of rapamycin (mTOR) signaling pathway; and the AMP-activated protein kinase (AMPK) signaling pathway may be involved in key developmental events during maturation of the cochlear nucleus. Taken together, the metabolic profiles identified in this study could lead to the identification and understanding of specific key biomarkers and metabolic pathways involved in the maturation of hearing. Moreover, LC-MS-based metabolomics provides an alternative approach for the characterization of auditory maturation and auditory diseases.PMID:36347123 | DOI:10.1016/j.heares.2022.108645

Blood Transfus. 2022 Oct 21. doi: 10.2450/2022.0172-22. Online ahead of print.ABSTRACTBACKGROUND: The Red blood cell (RBC) storage lesion results in decreased circulation and function of transfused RBCs. Elevated oxidant stress and impaired energy metabolism are a hallmark of the storage lesion in both human and murine RBCs. Although human studies don't suffer concerns that findings may not translate, they do suffer from genetic and environmental variability amongst subjects. Murine models can control for genetics, environment, and much interventional experimentation can be carried out in mice that is neither technically feasible nor ethical in humans. However, murine models are only useful to the extent that they have similar biology to humans. Hypoxic storage has been shown to mitigate the storage lesion in human RBCs, but has not been investigated in mice.MATERIALS AND METHODS: RBCs from a C57BL6/J mouse strain were stored under normoxic (untreated) or hypoxic conditions (SO2 ~ 26%) for 1h, 7 and 12 days. Samples were tested for metabolomics at steady state, tracing experiments with 1,2,3-13C3-glucose, proteomics and end of storage post transfusion recovery.RESULTS: Hypoxic storage improved post-transfusion recovery and energy metabolism, including increased steady state and 13C3-labeled metabolites from glycolysis, high energy purines (adenosine triphosphate) and 2,3-diphospholgycerate. Hypoxic storage promoted glutaminolysis, increased glutathione pools, and was accompanied by elevation in the levels of free fatty acids and acyl-carnitines.DISCUSSION: This study isolates hypoxia, as a single independent variable, and shows similar effects as seen in human studies. These findings also demonstrate the translatability of murine models for hypoxic RBC storage and provide a pre-clinical platform for ongoing study.PMID:36346885 | DOI:10.2450/2022.0172-22

Proc Natl Acad Sci U S A. 2022 Nov 15;119(46):e2212406119. doi: 10.1073/pnas.2212406119. Epub 2022 Nov 8.ABSTRACTDefense against ultraviolet (UV) radiation exposure is essential for survival, especially in high-elevation species. Although some specific genes involved in UV response have been reported, the full view of UV defense mechanisms remains largely unexplored. Herein, we used integrated approaches to analyze UV responses in the highest-elevation frog, Nanorana parkeri. We show less damage and more efficient antioxidant activity in skin of this frog than those of its lower-elevation relatives after UV exposure. We also reveal genes related to UV defense and a corresponding temporal expression pattern in N. parkeri. Genomic and metabolomic analysis along with large-scale transcriptomic profiling revealed a time-dependent coordinated defense mechanism in N. parkeri. We also identified several microRNAs that play important regulatory roles, especially in decreasing the expression levels of cell cycle genes. Moreover, multiple defense genes (i.e., TYR for melanogenesis) exhibit positive selection with function-enhancing substitutions. Thus, both expression shifts and gene mutations contribute to UV adaptation in N. parkeri. Our work demonstrates a genetic framework for evolution of UV defense in a natural environment.PMID:36346846 | DOI:10.1073/pnas.2212406119

Sci Signal. 2022 Nov 8;15(759):eabj4220. doi: 10.1126/scisignal.abj4220. Epub 2022 Nov 8.ABSTRACTThe role of metabolites exchanged in the tumor microenvironment is largely thought of as fuels to drive the increased biosynthetic and bioenergetic demands of growing tumors. However, this view is shifting as metabolites are increasingly shown to function as signaling molecules that directly regulate oncogenic pathways. Combined with our growing understanding of the essential role of stromal cells, this shift has led to increased interest in how the collective and interconnected metabolome of the tumor microenvironment can drive malignant transformation, epithelial-to-mesenchymal transition, drug resistance, immune evasion, and metastasis. In this review, we discuss how metabolite exchange between tumors and various cell types in the tumor microenvironment-such as fibroblasts, adipocytes, and immune cells-can activate signaling pathways that drive cancer progression.PMID:36346837 | DOI:10.1126/scisignal.abj4220

Sci China Life Sci. 2022 Nov 4. doi: 10.1007/s11427-022-2198-5. Online ahead of print.ABSTRACTAlthough crop domestication has greatly aided human civilization, the sequential domestication and regulation of most quality traits remain poorly understood. Here, we report the stepwise selection and regulation of major fruit quality traits that occurred during watermelon evolution. The levels of fruit cucurbitacins and flavonoids were negatively selected during speciation, whereas sugar and carotenoid contents were positively selected during domestication. Interestingly, fruit malic acid and citric acid showed the opposite selection trends during the improvement. We identified a novel gene cluster (CGC1, cucurbitacin gene cluster on chromosome 1) containing both regulatory and structural genes involved in cucurbitacin biosynthesis, which revealed a cascade of transcriptional regulation operating mechanisms. In the CGC1, an allele caused a single nucleotide change in ClERF1 binding sites (GCC-box) in the promoter of ClBh1, which resulted in reduced expression of ClBh1 and inhibition of cucurbitacin synthesis in cultivated watermelon. Functional analysis revealed that a rare insertion of 244 amino acids, which arose in C. amarus and became fixed in sweet watermelon, in ClOSC (oxidosqualene cyclase) was critical for the negative selection of cucurbitacins during watermelon evolution. This research provides an important resource for metabolomics-assisted breeding in watermelon and for exploring metabolic pathway regulation mechanisms.PMID:36346547 | DOI:10.1007/s11427-022-2198-5

Metabolomics. 2022 Nov 8;18(11):90. doi: 10.1007/s11306-022-01951-2.ABSTRACTINTRODUCTION: Adult sea lamprey (Petromyzon marinus) cease feeding and migrate to spawning streams where males build nests, undergo final sexual maturation, and subsequently produce and release large quantities of bile acid pheromones that attract mature females. These animals are predicted to rearrange their metabolic pathways drastically to support their reproductive strategies, presenting advantageous opportunities to examine how sex and the maturation processes affect metabolism.OBJECTIVES: The objective is to investigate the metabolic differences between sexes and maturation states in sea lamprey that support changes in physiological functions.METHODS: We compared plasma metabolomes of spawning and prespawning sea lamprey in both sexes using both non-targeted and targeted metabolomics approaches using UPLC/MS-MS with electrospray ionization in both positive and negative modes. The data were processed using Progenesis QI, Compound Discoverer and XCMS softwares for alignment, peak picking, and deconvolution of the peaks. Principle component analyses (PCA) and partial least squares discriminant analyses (PLS-DA) were performed using SIMCA and Metaboanalyst softwares to identify discriminating features, followed by fragmentation matching with extensive database search and pathway mapping.RESULTS: The pheromonal bile acid biosynthesis was upregulated significantly in males compared to females. Spermiating males further upregulated bile acid biosynthesis by altering amino acid metabolisms, upregulating cofactors and nucleotide metabolisms, but downregulating carbohydrate and energy metabolisms.CONCLUSION: Plasma metabolomes are sex- and maturation-dependent and reflect the special metabolic demands at each life stage and reproductive strategy.PMID:36346466 | DOI:10.1007/s11306-022-01951-2

Sleep. 2022 Nov 8:zsac268. doi: 10.1093/sleep/zsac268. Online ahead of print.NO ABSTRACTPMID:36346440 | DOI:10.1093/sleep/zsac268

J Neurosci Nurs. 2022 Nov 8. doi: 10.1097/JNN.0000000000000682. Online ahead of print.ABSTRACTOBJECTIVE: The aim of this study was to identify a signature lipid profile from cerebral thrombi in acute ischemic stroke (AIS) patients at the time of ictus. METHODS: We performed untargeted lipidomics analysis using liquid chromatography-mass spectrometry on cerebral thrombi taken from a nonprobability, convenience sampling of adult subjects (≥18 years old, n = 5) who underwent thrombectomy for acute cerebrovascular occlusion. The data were classified using random forest, a machine learning algorithm. RESULTS: The top 10 metabolites identified from the random forest analysis were of the glycerophospholipid species and fatty acids. CONCLUSION: Preliminary analysis demonstrates feasibility of identification of lipid metabolomic profiling in cerebral thrombi retrieved from AIS patients. Recent advances in omic methodologies enable lipidomic profiling, which may provide insight into the cellular metabolic pathophysiology caused by AIS. Understanding of lipidomic changes in AIS may illuminate specific metabolite and lipid pathways involved and further the potential to develop personalized preventive strategies.PMID:36346351 | DOI:10.1097/JNN.0000000000000682

J Anal Toxicol. 2022 Nov 8:bkac087. doi: 10.1093/jat/bkac087. Online ahead of print.ABSTRACTHeadspace gas chromatography with a flame ionization detector (HS-GC-FID) is a well-established approach for determining blood alcohol concentration (BAC), including in cadaveric specimens. Although the integrity of blood specimens can be adequately guaranteed after the sampling, the quantification of ethanol in cadaveric blood can be affected by postmortem fermentative phenomena occurring between the time since death and the sampling of biofluids. Vitreous humor is less affected by putrefactive phenomena allowing compound determination and its use as an alternative biological matrix. The present work aimed to develop and validate a method using the salting-out effect and based on HS-GC-FID for the ethanol determination in vitreous humor. The reported analytical method is based on a simple VH pre-treatment consisting of a dilution (1:9) with a solution of 2.5 mol/L K2CO3 and 0.0012 mol/L tert-butanol (internal standard). After 1 minute of incubation, part of the specimen evaporated in the headspace (2000 µL) is injected into the chromatographic system and analyzed in isothermal mode (40°C), with a chromatographic time of 1.6 minutes. The method was validated in terms of selectivity, lowest limit of detection, intraday and total imprecision, and trueness (bias). The determination of ethanol in vitreous humor and blood was carried out in 75 cases. The correlation between the two matrices was confirmed in 61 cases. However, 14 vitreous humor specimens showed lower ethanol concentrations, and in the related blood specimens, it was possible to identify the signal of n-propanol, a typical product of postmortem microbial fermentation, that justifies the excess of ethanol in the blood specimens.PMID:36346343 | DOI:10.1093/jat/bkac087

J Exp Bot. 2022 Nov 8:erac442. doi: 10.1093/jxb/erac442. Online ahead of print.ABSTRACTPlants have evolved a two-layer immune system comprising pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) that is activated in response to pathogen invasion. Microbial patterns and pathogen effectors can be recognized by surface-localized pattern-recognition receptors (PRRs) and intracellularly localized nucleotide-binding leucine-rich repeat receptors (NLRs) to trigger PTI and ETI responses, respectively. At present, the metabolites activated by PTI and ETI and their roles and signaling pathways in plant immunity are not well understood. In this study, metabolomic analysis showed that ETI and PTI induced various flavonoids and amino acids and their derivatives to accumulate in plants. Interestingly, the contents of glutathione and neodiosmin were specifically upregulated by ETI and PTI, respectively, which significantly enhanced plant immunity. Further studies showed that glutathione and neodiosmin failed to induce a plant immune response in which PRRs/coreceptors were mutated. In addition, glutathione-reduced mutant gsh1 analysis showed that GSH1 is also required for PTI and ETI. Finally, we propose a possible model in which glutathione and neodiosmin are considered signature metabolites induced in the process of ETI and PTI activation in plants and further continuous enhancement of plant immunity in which PRRs/coreceptors are needed. This model is beneficial for the in-depth understanding of the closed-loop mode of the positive feedback regulation of PTI and ETI signals at the metabolic level.PMID:36346205 | DOI:10.1093/jxb/erac442

J Biol Rhythms. 2022 Nov 8:7487304221132088. doi: 10.1177/07487304221132088. Online ahead of print.ABSTRACTShift workers face an increased risk of metabolic health problems, but the direct metabolic response to working nights is not fully understood. The aim of this study was to investigate the effect of night shifts on the 24-h urinary metabolome of shift workers. Eleven police officers working rotating shifts completed two 24-h laboratory visits that took place before and after they worked 7 consecutive nights. Sleep and meals were scheduled on a day schedule in the first visit and then on a night schedule (i.e., sleep and meals shifted by approximately 12 h) in the second visit. Targeted metabolomic analysis was performed on urine samples collected throughout these laboratory visits. Differential rhythmicity analysis was used to compare 24-h rhythms in urinary metabolites in both conditions. Our results show that on the day schedule, 24-h rhythms are present in the urinary levels of the majority of metabolites, but that this is significantly reduced on the night schedule, partly due to loss of organic acid rhythmicity. Furthermore, misalignment of 24-h metabolite rhythms with the shifted behavioral cycles in the night schedule was observed in more than half of the metabolites that were rhythmic in both conditions (all acylcarnitines). These results show that working nights alters the daily rhythms of the urinary metabolome in rotating shift workers, with the most notable impact observed for acylcarnitines and organic acids, 2 metabolite classes involved in mitochondrial function. Further research is warranted to study how these changes relate to the increased metabolic risks associated with shift work.PMID:36346168 | DOI:10.1177/07487304221132088

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