Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Mechanism of Inhibiting the Growth and Aflatoxin B<sub>1</sub> Biosynthesis of <em>Aspergillus flavus</em> by Phenyllactic Acid

Tue, 27/06/2023 - 12:00
Toxins (Basel). 2023 Jun 1;15(6):370. doi: 10.3390/toxins15060370.ABSTRACTPhenyllactic acid (PLA), a promising food preservative, is safe and effective against a broad spectrum of food-borne pathogens. However, its mechanisms against toxigenic fungi are still poorly understood. In this study, we applied physicochemical, morphological, metabolomics, and transcriptomics analyses to investigate the activity and mechanism of PLA inhibition of a typical food-contaminating mold, Aspergillus flavus. The results showed that PLA effectively inhibited the growth of A. flavus spores and reduced aflatoxin B1 (AFB1) production by downregulating key genes associated with AFB1 biosynthesis. Propidium iodide staining and transmission electron microscopy analysis demonstrated a dose-dependent disruption of the integrity and morphology of the A. flavus spore cell membrane by PLA. Multi-omics analyses showed that subinhibitory concentrations of PLA induced significant changes in A. flavus spores at the transcriptional and metabolic levels, as 980 genes and 30 metabolites were differentially expressed. Moreover, KEGG pathway enrichment analysis indicated PLA-induced cell membrane damage, energy-metabolism disruption, and central-dogma abnormality in A. flavus spores. The results provided new insights into the anti-A. flavus and -AFB1 mechanisms of PLA.PMID:37368671 | DOI:10.3390/toxins15060370

Serum factors mediate changes in mitochondrial bioenergetics associated with diet and exercise interventions

Tue, 27/06/2023 - 12:00
Geroscience. 2023 Jun 27. doi: 10.1007/s11357-023-00855-w. Online ahead of print.ABSTRACTMitochondrial improvements resulting from behavioral interventions, such as diet and exercise, are systemic and apparent across multiple tissues. Here, we test the hypothesis that factors present in serum, and therefore circulating throughout the body, can mediate changes in mitochondrial function in response to intervention. To investigate this, we used stored serum from a clinical trial comparing resistance training (RT) and RT plus caloric restriction (RT + CR) to examine effects of blood borne circulating factors on myoblasts in vitro. We report that exposure to dilute serum is sufficient to mediate bioenergetic benefits of these interventions. Additionally, serum-mediated bioenergetic changes can differentiate between interventions, recapitulate sex differences in bioenergetic responses, and is linked to improvements in physical function and inflammation. Using metabolomics, we identified circulating factors associated with changes in mitochondrial bioenergetics and the effects of interventions. This study provides new evidence that circulating factors play a role in the beneficial effects of interventions that improve healthspan among older adults. Understanding the factors that drive improvements in mitochondrial function is a key step towards predicting intervention outcomes and developing strategies to countermand systemic age-related bioenergetic decline.PMID:37368157 | DOI:10.1007/s11357-023-00855-w

Coordinated Regulation of Central Carbon Metabolism in Pyroligneous Acid-Treated Tomato Plants under Aluminum Stress

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 20;13(6):770. doi: 10.3390/metabo13060770.ABSTRACTAluminum (Al) toxicity is a major threat to global crop production in acidic soils, which can be mitigated by natural substances such as pyroligneous acid (PA). However, the effect of PA in regulating plant central carbon metabolism (CCM) under Al stress is unknown. In this study, we investigated the effects of varying PA concentrations (0, 0.25 and 1% PA/ddH2O (v/v)) on intermediate metabolites involved in CCM in tomato (Solanum lycopersicum L., 'Scotia') seedlings under varying Al concentrations (0, 1 and 4 mM AlCl3). A total of 48 differentially expressed metabolites of CCM were identified in the leaves of both control and PA-treated plants under Al stress. Calvin-Benson cycle (CBC) and pentose phosphate pathway (PPP) metabolites were considerably reduced under 4 mM Al stress, irrespective of the PA treatment. Conversely, the PA treatment markedly increased glycolysis and tricarboxylic acid cycle (TCA) metabolites compared to the control. Although glycolysis metabolites in the 0.25% PA-treated plants under Al stress were comparable to the control, the 1% PA-treated plants exhibited the highest accumulation of glycolysis metabolites. Furthermore, all PA treatments increased TCA metabolites under Al stress. Electron transport chain (ETC) metabolites were higher in PA-treated plants alone and under 1 mM, Al but were reduced under a higher Al treatment of 4 mM. Pearson correlation analysis revealed that CBC metabolites had a significantly strong positive (r = 0.99; p < 0.001) association with PPP metabolites. Additionally, glycolysis metabolites showed a significantly moderate positive association (r = 0.76; p < 0.05) with TCA metabolites, while ETC metabolites exhibited no association with any of the determined pathways. The coordinated association between CCM pathway metabolites suggests that PA can stimulate changes in plant metabolism to modulate energy production and biosynthesis of organic acids under Al stress conditions.PMID:37367927 | DOI:10.3390/metabo13060770

Novel Metabolomic Approach for Identifying Pathology-Specific Biomarkers in Rare Diseases: A Case Study in Oculopharyngeal Muscular Dystrophy (OPMD)

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 19;13(6):769. doi: 10.3390/metabo13060769.ABSTRACTThe identification of metabolomic biomarkers relies on the analysis of large cohorts of patients compared to healthy controls followed by the validation of markers in an independent sample set. Indeed, circulating biomarkers should be causally linked to pathology to ensure that changes in the marker precede changes in the disease. However, this approach becomes unfeasible in rare diseases due to the paucity of samples, necessitating the development of new methods for biomarker identification. The present study describes a novel approach that combines samples from both mouse models and human patients to identify biomarkers of OPMD. We initially identified a pathology-specific metabolic fingerprint in murine dystrophic muscle. This metabolic fingerprint was then translated into (paired) murine serum samples and then to human plasma samples. This study identified a panel of nine candidate biomarkers that could predict muscle pathology with a sensitivity of 74.3% and specificity of 100% in a random forest model. These findings demonstrate that the proposed approach can identify biomarkers with good predictive performance and a higher degree of confidence in their relevance to pathology than markers identified in a small cohort of human samples alone. Therefore, this approach has a high potential utility for identifying circulating biomarkers in rare diseases.PMID:37367926 | DOI:10.3390/metabo13060769

A GC-MS Chemotaxonomic Study on Lipophilic Compounds in the Bark of <em>S. aucuparia</em> subsp. <em>sibirica</em> Trees from the Population Growing in Akademgorodok, Novosibirsk (Russia)

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 19;13(6):768. doi: 10.3390/metabo13060768.ABSTRACTDetermination of chemotypes and of their role in the polymorphism of populations is an important field in the research on secondary metabolites of plants. In the present study, by gas chromatography coupled with mass spectrometry, the composition of bark extracts from rowan S. aucuparia subsp. sibirica was determined for 16 trees growing within Akademgorodok of Novosibirsk, with bark samples collected both in winter and summer. Among 101 fully or partially identified metabolites, there are alkanes, alkenes, linear alcohols, fatty acids and their derivatives, phenols and their derivatives, prunasin and its parent and derivative compounds, polyprenes and their derivatives, cyclic diterpenes, and phytosterols. These compounds were grouped according to their biosynthesis pathways. Cluster analysis revealed two groups among the bark samples collected in winter and three groups among bark samples collected in summer. The key determinants of this clustering are the biosynthesis of metabolites via the cyanogenic pathway (especially potentially toxic prunasin) and their formation via the phytosterol pathway (especially potentially pharmacologically useful lupeol). It follows from the results that the presence of chemotypes having sharply different profiles of metabolites in a population from a small geographic area invalidates the practice of general sampling to obtain averaged data when a population is described. From the standpoint of possible industrial use or plant selection based on metabolomic data, it is possible to select specific sets of samples containing a minimal amount of potentially toxic compounds and the largest amount of potentially useful substances.PMID:37367925 | DOI:10.3390/metabo13060768

Untargeted Metabolomics Approach for the Differentiation between <em>Panax vietnamensis</em> var. <em>vietnamensis</em> and <em>Panax vietnamensis</em> var. <em>fuscidiscus</em>

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 19;13(6):763. doi: 10.3390/metabo13060763.ABSTRACTPanax vietnamensis var. vietnamensis (PVV) and Panax vietnamensis var. fuscidiscus (PVF) both belong to Panax vietnamensis species and are chemically and morphologically similar, making it hard to distinguish for the consumer. Herein, 42 PVF and 12 PVV samples were collected in Quang Nam and Lai Chau Province, respectively, and subsequently characterized by ITSr-DNA sequence data to verify their origins. Next, untargeted metabolomics combined with multivariate statistical analysis was developed to differentiate PVV and PVF. The metabolic profiles of PVV and PVF were found to be distinct and classified well using Partial Least-Squares Discriminant Analysis (PLS-DA) in the training set. Among them, seven ginsenosides were of high abundance in PVV, while six were of high abundance in PVF. Next, the test set was used to validate 13 putative differential markers found in the training set, illustrating a complete match with the expression patterns of these ginsenosides in the training set. Finally, PLS-DA and linear Support Vector Machine models both indicated distinct ginsenoside profiles of PVV and PVF without misclassification in the test set. Conclusively, the developed untargeted metabolomics approach might serve as a powerful tool for the authentication of PVV and PVF at the metabolome level.PMID:37367920 | DOI:10.3390/metabo13060763

Non-Targeted Metabolomic Study of Fetal Growth Restriction

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 17;13(6):761. doi: 10.3390/metabo13060761.ABSTRACTWe aimed to explore the differential metabolites in amniotic fluid and its cells from fetuses with fetal growth restriction (FGR). A total of 28 specimens of amniotic fluid were collected, including 18 with FGR and 10 controls. Differential metabolites in all samples were detected by chromatography-mass spectrometry. Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) were used to analyze the differences in metabolic spectra between the FGR and control groups through multidimensional and single-dimensional statistical analysis. The KEGG database was used for metabolic pathway enrichment analysis. Both PCA and OPLS-DA models showed a clear separation trend between FGR and control groups. We identified 27 differentially expressed metabolites in the amniotic fluid supernatant of the two groups (p < 0.05), of which 14 metabolites were up-regulated in the FGR group, and 13 metabolites, such as glutamate, phenylalanine, valine and leucine, were down-regulated. We also identified 20 differentially expressed metabolites in the amniotic fluid cell (p < 0.05), of which 9 metabolites, including malic acid, glycolic acid and D-glycerate, were up-regulated significantly and 11 metabolites, including glyceraldehyde, were down-regulated. Pathway analysis showed that most of the identified differential metabolites were involved in tricarboxylic acid cycle (TCA cycle), ABC transport, amino acid metabolism pathways and so on. The results indicated that many metabolic changes associated with FGR, which are mainly manifested by abnormal metabolism of amino acid in amniotic fluid and abnormal glucose metabolism including TCA cycle in amniotic fluid cells, respectively. Our findings provide more data for exploring the mechanism of FGR and the potential therapy targets.PMID:37367917 | DOI:10.3390/metabo13060761

Maternal and Cord Blood Serum Metabolite Associations with Childhood Adiposity and Body Composition Outcomes

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 13;13(6):749. doi: 10.3390/metabo13060749.ABSTRACTMaternal metabolites influence the size of newborns independently of maternal body mass index (BMI) and glycemia, highlighting the importance of maternal metabolism on offspring outcomes. This study examined associations of maternal metabolites during pregnancy with childhood adiposity, and cord blood metabolites with childhood adiposity using phenotype and metabolomic data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study. The maternal metabolites analyses included 2324 mother-offspring pairs, while the cord blood metabolites analyses included 937 offspring. Multiple logistic and linear regression were used to examine associations between primary predictors, maternal or cord blood metabolites, and childhood adiposity outcomes. Multiple maternal fasting and 1 hr metabolites were significantly associated with childhood adiposity outcomes in Model 1 but were no longer significant after adjusting for maternal BMI and/or maternal glycemia. In the fully adjusted model, fasting lactose levels were negatively associated with child BMI z-scores and waist circumference, while fasting urea levels were positively associated with waist circumference. One-hour methionine was positively associated with fat-free mass. There were no significant associations between cord blood metabolites and childhood adiposity outcomes. Few metabolites were associated with childhood adiposity outcomes after adjusting for maternal BMI and glucose, suggesting that maternal BMI accounts for the association between maternal metabolites and childhood adiposity.PMID:37367907 | DOI:10.3390/metabo13060749

Dietary Inflammatory and Insulinemic Potentials, Plasma Metabolome and Risk of Colorectal Cancer

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 12;13(6):744. doi: 10.3390/metabo13060744.ABSTRACTThe inflammatory and insulinemic potentials of diets have been associated with colorectal cancer risk. However, it is unknown whether the plasma metabolite profiles related to inflammatory diets, or to insulinemic diets, underlie this association. The aim of this study was to evaluate the association between metabolomic profile scores related to the food-based empirical dietary inflammatory patterns (EDIP), the empirical dietary index for hyperinsulinemia (EDIH), and plasma inflammation (CRP, IL-6, TNFα-R2, adiponectin) and insulin (C-peptide) biomarkers, and colorectal cancer risk. Elastic net regression was used to derive three metabolomic profile scores for each dietary pattern among 6840 participants from the Nurses' Health Study and Health Professionals Follow-up Study, and associations with CRC risk were examined using multivariable-adjusted logistic regression, in a case-control study of 524 matched pairs nested in both cohorts. Among 186 known metabolites, 27 were significantly associated with both the EDIP and inflammatory biomarkers, and 21 were significantly associated with both the EDIH and C-peptide. In men, odds ratios (ORs) of colorectal cancer, per 1 standard deviation (SD) increment in metabolomic score, were 1.91 (1.31-2.78) for the common EDIP and inflammatory-biomarker metabolome, 1.12 (0.78-1.60) for EDIP-only metabolome, and 1.65 (1.16-2.36) for the inflammatory-biomarkers-only metabolome. However, no association was found for EDIH-only, C-peptide-only, and the common metabolomic signatures in men. Moreover, the metabolomic signatures were not associated with colorectal cancer risk among women. Metabolomic profiles reflecting pro-inflammatory diets and inflammation biomarkers were associated with colorectal cancer risk in men, while no association was found in women. Larger studies are needed to confirm our findings.PMID:37367904 | DOI:10.3390/metabo13060744

Metabolomic Analysis in Neurocritical Care Patients

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 11;13(6):745. doi: 10.3390/metabo13060745.ABSTRACTMetabolomics is the analytical study of metabolites in biological matrices using high-throughput profiling. Traditionally, the metabolome has been studied to identify various biomarkers for the diagnosis and pathophysiology of disease. Over the last decade, metabolomic research has grown to include the identification of prognostic markers, the development of novel treatment strategies, and the prediction of disease severity. In this review, we summarized the available evidence on the use of metabolome profiling in neurocritical care populations. Specifically, we focused on aneurysmal subarachnoid hemorrhage, traumatic brain injury, and intracranial hemorrhage to identify the gaps in the current literature and to provide direction for future studies. A primary literature search of the Medline and EMBASE databases was conducted. Upon removing duplicate studies, abstract screening and full-text screening were performed. We screened 648 studies and extracted data from 17 studies. Based on the current evidence, the utility of metabolomic profiling has been limited due to inconsistencies amongst studies and a lack of reproducible data. Studies identified various biomarkers for diagnosis, prognosis, and treatment modification. However, studies evaluated and identified different metabolites, resulting in an inability to compare the study results. Future research towards addressing the gaps in the current literature, including reproducing data on the use of specific metabolite panels, is needed.PMID:37367902 | DOI:10.3390/metabo13060745

Metabolomics and Transcriptomics Revealed a Comprehensive Understanding of the Biochemical and Genetic Mechanisms Underlying the Color Variations in Chrysanthemums

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 10;13(6):742. doi: 10.3390/metabo13060742.ABSTRACTFlower color is an important characteristic of ornamental plants and is determined by various chemical components, including anthocyanin. In the present study, combined metabolomics and transcriptomics analysis was used to explore color variations in the chrysanthemums of three cultivars, of which the color of JIN is yellow, FEN is pink, and ZSH is red. A total of 29 different metabolites, including nine anthocyanins, were identified in common in the three cultivars. Compared with the light-colored cultivars, all of the nine anthocyanin contents were found to be up-regulated in the dark-colored ones. The different contents of pelargonidin, cyanidin, and their derivates were found to be the main reason for color variations. Transcriptomic analysis showed that the color difference was closely related to anthocyanin biosynthesis. The expression level of anthocyanin structural genes, including DFR, ANS, 3GT, 3MaT1, and 3MaT2, was in accordance with the flower color depth. This finding suggests that anthocyanins may be a key factor in color variations among the studied cultivars. On this basis, two special metabolites were selected as biomarkers to assist in chrysanthemum breeding for color selection.PMID:37367900 | DOI:10.3390/metabo13060742

Widely Targeted HPLC-MS/MS Metabolomics Analysis Reveals Natural Metabolic Insights in Insects

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 8;13(6):735. doi: 10.3390/metabo13060735.ABSTRACTInsect metabolites play vital roles in regulating the physiology, behavior, and numerous adaptations of insects, which has contributed to them becoming the largest class of Animalia. However, systematic metabolomics within the insects is still unclear. The present study performed a widely targeted metabolomics analysis based on the HPLC-MS/MS technology to construct a novel integrated metabolic database presenting comprehensive multimetabolite profiles from nine insect species across three metamorphosis types. A total of 1442 metabolites were identified, including amino acids and their metabolites, organic acids and their derivatives, fatty acids (FAs), glycerophospholipids (GPs), nucleotides and their metabolites, and benzene and its substituted derivatives. Among them, 622 metabolites were used to generate a 0 and 1 matrix based on their presence or absence, and these metabolites were enriched in arachidonic acid metabolism, tyrosine metabolism, phenylalanine metabolism, and insect hormone biosynthesis pathways. Our study revealed that there is a high coincidence between the evolutionary relationships of the species and the hierarchical cluster based on the types of metabolites, while the quantities of the metabolites show a high diversity among species. The metabolome of the nine representative insects provides an important platform for implementing the analysis of insect systemic metabolites and biological events at the metabolic level.PMID:37367893 | DOI:10.3390/metabo13060735

Lipidomic Profiles of Lipid Biosynthesis in Oil Palm during Fruit Development

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 6;13(6):727. doi: 10.3390/metabo13060727.ABSTRACTThe fruit of the oil palm (Elaeis guineensis Jacq.) has fleshy mesocarpic tissue rich in lipids. This edible vegetable oil is economically and nutritionally significant across the world. The core concepts of oil biosynthesis in oil palms remain to be researched as the knowledge of oil biosynthesis in plants improves. In this study, we utilized a metabolite approach and mass spectral analysis to characterize metabolite changes and identify the sequences of protein accumulation during the physiological processes that regulate oil synthesis during oil palm fruit ripening. Here, we performed a comprehensive lipidomic data analysis in order to understand the role of lipid metabolism in oil biosynthesis mechanisms. The experimental materials were collected from the mesocarp of oil palm (Tenera) at 95 days (early accumulation of fatty acid, first stage), 125 days (rapid growth of fatty acid accumulation, second stage), and 185 days (stable period of fatty acid accumulation, third stage) after pollination. To gain a clear understanding of the lipid changes that occurred during the growth of the oil palm, the metabolome data were found using principal component analysis (PCA). Furthermore, the accumulations of diacylglycerols, ceramides, phosphatidylethanolamine, and phosphatidic acid varied between the developmental stages. Differentially expressed lipids were successfully identified and functionally classified using KEGG analysis. Proteins related to the metabolic pathway, glycerolipid metabolism, and glycerphospholipid metabolism were the most significantly changed proteins during fruit development. In this study, LC-MS analysis and evaluation of the lipid profile in different stages of oil palm were performed to gain insight into the regulatory mechanisms that enhance fruit quality and govern differences in lipid composition and biosynthesis.PMID:37367885 | DOI:10.3390/metabo13060727

A Distinctive Metabolomics Profile and Potential Biomarkers for Very Long Acylcarnitine Dehydrogenase Deficiency (VLCADD) Diagnosis in Newborns

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 5;13(6):725. doi: 10.3390/metabo13060725.ABSTRACTVery long-chain acylcarnitine dehydrogenase deficiency (VLCADD) is a rare inherited metabolic disorder associated with fatty acid β-oxidation and characterized by genetic mutations in the ACADVL gene and accumulations of acylcarnitines. VLCADD, developed in neonates or later adults, can be diagnosed using newborn bloodspot screening (NBS) or genetic sequencing. These techniques have limitations, such as a high false discovery rate and variants of uncertain significance (VUS). As a result, an extra diagnostic tool is needed to deliver improved performance and health outcomes. As VLCADD is linked with metabolic disturbance, we postulated that newborn patients with VLCADD could display a distinct metabolomics pattern compared to healthy newborns and other disorders. Herein, we applied an untargeted metabolomics approach using liquid chromatography-high resolution mass spectrometry (LC-HRMS) to measure the global metabolites in dried blood spot (DBS) cards collected from VLCADD newborns (n = 15) and healthy controls (n = 15). Two hundred and six significantly dysregulated endogenous metabolites were identified in VLCADD, in contrast to healthy newborns. Fifty-eight and one hundred and eight up- and down-regulated endogenous metabolites were involved in several pathways such as tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, amino sugar and nucleotide sugar metabolism, pyrimidine metabolism and pantothenate, and CoA biosynthesis. Furthermore, biomarker analyses identified 3,4-Dihydroxytetradecanoylcarnitine (AUC = 1), PIP (20:1)/PGF1alpha) (AUC = 0.982), and PIP2 (16:0/22:3) (AUC = 0.978) as potential metabolic biomarkers for VLCADD diagnosis. Our findings showed that compared to healthy newborns, VLCAADD newborns exhibit a distinctive metabolic profile, and identified potential biomarkers that can be used for early diagnosis, which improves the identification of the affected patients earlier. This allows for the timely administration of proper treatments, leading to improved health. However, further studies with large independent cohorts of VLCADD patients with different ages and phenotypes need to be studied to validate our potential diagnostic biomarkers and their specificity and accuracy during early life.PMID:37367883 | DOI:10.3390/metabo13060725

Predicting Valproate-Induced Liver Injury Using Metabolomic Analysis of Ex Ovo Chick Embryo Allantoic Fluid

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 2;13(6):721. doi: 10.3390/metabo13060721.ABSTRACTThe use of sensitive animals in toxicological studies tends to be limited. Even though cell culture is an attractive alternative, it has some limitations. Therefore, we investigated the potential of the metabolomic profiling of the allantoic fluid (AF) from ex ovo chick embryos to predict the hepatotoxicity of valproate (VPA). To this end, the metabolic changes occurring during embryo development and following exposure to VPA were assessed using 1H-NMR spectroscopy. During embryonic development, our findings indicated a metabolism progressively moving from anaerobic to aerobic, mainly based on lipids as the energy source. Next, liver histopathology of VPA-exposed embryos revealed abundant microvesicles indicative of steatosis and was metabolically confirmed via the determination of lipid accumulation in AF. VPA-induced hepatotoxicity was further demonstrated by (i) lower glutamine levels, precursors of glutathione, and decreased β-hydroxybutyrate, an endogenous antioxidant; (ii) changes in lysine levels, a precursor of carnitine, which is essential in the transport of fatty acids to the mitochondria and whose synthesis is known to be reduced by VPA; and (iii) choline accumulation that promotes the export of hepatic triglycerides. In conclusion, our results support the use of the ex ovo chick embryo model combined with the metabolomic assessment of AF to rapidly predict drug-induced hepatotoxicity.PMID:37367880 | DOI:10.3390/metabo13060721

Effect of Genetically Reduced Maternal Myostatin on Late Gestation Maternal, Fetal, and Placental Metabolomes in Mice

Tue, 27/06/2023 - 12:00
Metabolites. 2023 Jun 1;13(6):719. doi: 10.3390/metabo13060719.ABSTRACTMyostatin (gene symbol: Mstn) is an autocrine and paracrine inhibitor of muscle growth. Pregnant mice with genetically reduced levels of myostatin give birth to offspring with greater adult muscle mass and bone biomechanical strength. However, maternal myostatin is not detectable in fetal circulations. Fetal growth is dependent on the maternal environment, and the provisioning of nutrients and growth factors by the placenta. Thus, this study examined the effect of reduced maternal myostatin on maternal and fetal serum metabolomes, as well as the placental metabolome. Fetal and maternal serum metabolomes were highly distinct, which is consistent with the role of the placenta in creating a specific fetal nutrient environment. There was no effect from myostatin on maternal glucose tolerance or fasting insulin. In comparisons between pregnant control and Mstn+/- mice, there were more significantly different metabolite concentrations in fetal serum, at 50, than in the mother's serum at 33, confirming the effect of maternal myostatin reduction on the fetal metabolic milieu. Polyamines, lysophospholipids, fatty acid oxidation, and vitamin C, in fetal serum, were all affected by maternal myostatin reduction.PMID:37367877 | DOI:10.3390/metabo13060719

Development of a Urine Metabolomics Biomarker-Based Prediction Model for Preeclampsia during Early Pregnancy

Tue, 27/06/2023 - 12:00
Metabolites. 2023 May 31;13(6):715. doi: 10.3390/metabo13060715.ABSTRACTPreeclampsia (PE) is a condition that poses a significant risk of maternal mortality and multiple organ failure during pregnancy. Early prediction of PE can enable timely surveillance and interventions, such as low-dose aspirin administration. In this study, conducted at Stanford Health Care, we examined a cohort of 60 pregnant women and collected 478 urine samples between gestational weeks 8 and 20 for comprehensive metabolomic profiling. By employing liquid chromatography mass spectrometry (LCMS/MS), we identified the structures of seven out of 26 metabolomics biomarkers detected. Utilizing the XGBoost algorithm, we developed a predictive model based on these seven metabolomics biomarkers to identify individuals at risk of developing PE. The performance of the model was evaluated using 10-fold cross-validation, yielding an area under the receiver operating characteristic curve of 0.856. Our findings suggest that measuring urinary metabolomics biomarkers offers a noninvasive approach to assess the risk of PE prior to its onset.PMID:37367874 | DOI:10.3390/metabo13060715

Plant Secondary Metabolites: The Weapons for Biotic Stress Management

Tue, 27/06/2023 - 12:00
Metabolites. 2023 May 31;13(6):716. doi: 10.3390/metabo13060716.ABSTRACTThe rise in global temperature also favors the multiplication of pests and pathogens, which calls into question global food security. Plants have developed special coping mechanisms since they are sessile and lack an immune system. These mechanisms use a variety of secondary metabolites as weapons to avoid obstacles, adapt to their changing environment, and survive in less-than-ideal circumstances. Plant secondary metabolites include phenolic compounds, alkaloids, glycosides, and terpenoids, which are stored in specialized structures such as latex, trichomes, resin ducts, etc. Secondary metabolites help the plants to be safe from biotic stressors, either by repelling them or attracting their enemies, or exerting toxic effects on them. Modern omics technologies enable the elucidation of the structural and functional properties of these metabolites along with their biosynthesis. A better understanding of the enzymatic regulations and molecular mechanisms aids in the exploitation of secondary metabolites in modern pest management approaches such as biopesticides and integrated pest management. The current review provides an overview of the major plant secondary metabolites that play significant roles in enhancing biotic stress tolerance. It examines their involvement in both indirect and direct defense mechanisms, as well as their storage within plant tissues. Additionally, this review explores the importance of metabolomics approaches in elucidating the significance of secondary metabolites in biotic stress tolerance. The application of metabolic engineering in breeding for biotic stress resistance is discussed, along with the exploitation of secondary metabolites for sustainable pest management.PMID:37367873 | DOI:10.3390/metabo13060716

Analysis of Metabolites and Metabolic Pathways of Three Chinese Jujube Cultivar

Tue, 27/06/2023 - 12:00
Metabolites. 2023 May 31;13(6):714. doi: 10.3390/metabo13060714.ABSTRACTMost studies on metabolites in jujube fruits focus on specific types of metabolites, but there are only a few comprehensive reports on the metabolites in jujube fruits. In order to understand the variance of metabolites in fruits of different jujube varieties. The objective of this study was to explore the metabolic components of jujube fruit by comparing three cultivars, namely Linyi LiZao (LZ), Jiaocheng SuantianZao (STZ), and Xianxian Muzao (MZ). The metabolites present in the fruits of these three cultivars were evaluated and compared. The results revealed the detection of 1059 metabolites across the three jujube varieties, with each cultivar exhibiting distinct metabolic characteristics. Notably, MZ exhibited a higher abundance of six metabolite classes, namely amino acids and derivatives, flavonoids, lipids, organic acids, phenolic acids, and terpenoids, compared to LZ. Conversely, LZ exhibited higher concentrations of alkaloids, lignans, coumarins, nucleotides, and their derivatives compared to the other two cultivars. In terms of STZ, its content of amino acids and derivatives, lignans and coumarins, organic acids, and phenolic acids was largely similar to that of LZ. However, the content of alkaloids, nucleotides, and their derivatives, and terpenoids was significantly higher in STZ compared to LZ. Additionally, STZ exhibited lower levels of flavonoids and lipids compared to LZ. Moreover, MZ was found to be less nutritionally rich than STZ, except for lignans and coumarins, as it displayed lower levels of all the metabolites. KEGG pathway enrichment analysis revealed six significantly different metabolic pathways (p < 0.05) between LZ and MZ, including arginine and proline metabolism, sphingolipid metabolism, flavonoid biosynthesis, glutathione metabolism, glycerophospholipid metabolism, and cysteine and methionine metabolism. The metabolites in STZ and MZ exhibited three significantly different pathways (p < 0.05), primarily associated with flavonoid biosynthesis, arginine and proline metabolism, and sphingolipid metabolism. The significantly differential metabolites between LZ and STZ were observed in the phenylpropionic acid biosynthesis pathway and the ubiquinone and other terpenoid-quinone biosynthesis pathways. LZ showed a closer relationship with STZ than with MZ. STZ and LZ exhibited higher medicinal values, while LZ had lower acidity and MZ displayed better antioxidant activity. This study presents the first thorough analysis of metabolites in LZ, STZ, and MZ cultivars, which can serve as a theoretical basis for quality analysis, functional research, and classification processing of jujube fruit.PMID:37367872 | DOI:10.3390/metabo13060714

A Cohort Study of Gastric Fluid and Urine Metabolomics for the Prediction of Survival in Severe Prematurity

Tue, 27/06/2023 - 12:00
Metabolites. 2023 May 30;13(6):708. doi: 10.3390/metabo13060708.ABSTRACTPredicting survival in very preterm infants is critical in clinical medicine and parent counseling. In this prospective cohort study involving 96 very preterm infants, we evaluated whether the metabolomic analysis of gastric fluid and urine samples obtained shortly after birth could predict survival in the first 3 and 15 days of life (DOL), as well as overall survival up to hospital discharge. Gas chromatography-mass spectrometry (GC-MS) profiling was used. Uni- and multivariate statistical analyses were conducted to evaluate significant metabolites and their prognostic value. Differences in several metabolites were identified between survivors and non-survivors at the time points of the study. Binary logistic regression showed that certain metabolites in gastric fluid, including arabitol, and succinic, erythronic and threonic acids, were associated with 15 DOL and overall survival. Gastric glyceric acid was also associated with 15 DOL survival. Urine glyceric acid could predict survival in the first 3 DOL and overall survival. In conclusion, non-surviving preterm infants exhibited a different metabolic profile compared with survivors, demonstrating significant discrimination with the use of GC-MS-based gastric fluid and urine analyses. The results of this study support the usefulness of metabolomics in developing survival biomarkers in very preterm infants.PMID:37367866 | DOI:10.3390/metabo13060708

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