Metabolomics最新文献

Introduction: The placenta plays influential role in the fetal development of mammals. But how the metabolic need of the fetal organs is related to that of the placenta, and whether this relationship is influenced by the sex of the fetus remain poorly understood.

Objectives: This study used pigs to investigate metabolomic signatures of male and female fetal organs, and determine the relevance of gene expression of the placenta and brain to the metabolism of peripheral organs.

Methods: Untargeted metabolomics analysis was performed with the day-45 placenta, kidney, heart, liver, lung and brain of male and female pig fetuses to model sex differences in the metabolism of the peripheral organs relative to that of the brain and placenta. Transcriptomic analysis was performed to investigate the expression of metabolic genes in the placenta and fetal brain of both sexes.

Results: The results of this study show that the fetoplacental metabolic regulation was not only influenced by the fetal sex but also dependent on the metabolic requirement of  the individual organs of the fetus. Neural network modeling of metabolomics data revealed differential relationship of the metabolic changes of the peripheral organs with the placenta and fetal brain between males and females. RNA sequencing further showed that genes associated with the metabolism of the peripheral organs were differentially expressed in the placenta and fetal brain.

Conclusion: The findings of this study suggest a regulatory role of the fetal brain and placenta axis in the sex-bias metabolism of the peripheral organs.

Background: The global incidence of hypertension, a condition of elevated blood pressure, is rising alarmingly. According to the World Health Organization's Qatar Hypertension Profile for 2023, around 33% of adults are affected by hypertension. This is a significant public health concern that can lead to serious health complications if left untreated. Metabolic dysfunction is a primary cause of hypertension. By studying key biomarkers, we can discover new treatments to improve the lives of those with high blood pressure.

Aims: This study aims to use explainable artificial intelligence (XAI) to interpret novel metabolite biosignatures linked to hypertension in Qatari Population.

Methods: The study utilized liquid chromatography-mass spectrometry (LC/MS) method to profile metabolites from biosamples of Qatari nationals diagnosed with stage 1 hypertension (n = 224) and controls (n = 554). Metabolon platform was used for the annotation of raw metabolite data generated during the process. A comprehensive series of analytical procedures, including data trimming, imputation, undersampling, feature selection, and biomarker discovery through explainable AI (XAI) models, were meticulously executed to ensure the accuracy and reliability of the results.

Results: Elevated Vanillylmandelic acid (VMA) levels are markedly associated with stage 1 hypertension compared to controls. Glycerophosphorylcholine (GPC), N-Stearoylsphingosine (d18:1/18:0)*, and glycine are critical metabolites for accurate hypertension prediction. The light gradient boosting model yielded superior results, underscoring the potential of our research in enhancing hypertension diagnosis and treatment. The model's classification metrics: accuracy (78.13%), precision (78.13%), recall (78.13%), F1-score (78.13%), and AUROC (83.88%) affirm its efficacy. SHapley Additive exPlanations (SHAP) further elucidate the metabolite markers, providing a deeper understanding of the disease's pathology.

Conclusion: This study identified novel metabolite biomarkers for precise hypertension diagnosis using XAI, enhancing early detection and intervention in the Qatari population.

Introduction: Breast Cancer (BC) is one of the most diagnosed malignancies among women and the second leading cause of cancer related death in North America. Triple Negative BC (TNBC), one of the most severe subtypes of BC, is extremely aggressive and has a higher chance of occurrence in women under 50 years of age. Due to a lack of regular mammographic testing in women under 50, many individuals with TNBC are diagnosed late which can decrease their survival rate. Currently, liquid biopsy is being investigated as a potentially less-invasive alternative to traditional breast tissue biopsy, but this approach is not completely reliable. Blood contains extracellular vesicles (EVs), which carry biomolecular cargo and play a role in BC progression and metastasis. Examination of small EVs could potentially yield metabolite biomarkers for early BC diagnosis.

Objective: We aim to study metabolites in small EVs to find biomarkers for BC diagnosis.

Methods: In this work, an untargeted nano-LC MS/MS metabolomics approach was used to analyze metabolites from small EVs derived from metastatic MDA-MB-231 and compare it with a non-cancerous MCF10A cell line.

Results: Two metabolites, LysoPC 22:6/0:0 and N-acetyl-L-Phenylalanine, unique to sEVs of MDA-MB-231, were identified, validated, and proposed as potential BC biomarkers.

Conclusion: Metabolites from sEVs may be used for BC diagnosis.

Background: Chronic kidney disease (CKD) is common in patients with diabetes mellitus (DM). Volatile organic compounds (VOCs) are widespread pollutants that may impact DM development.

Objective: This study aims to explore the association between urinary VOC metabolites and CKD in patients with DM.

Methods: Adult National Health and Nutrition Examination Survey (NHANES) 2011 to 2018 participants with DM were included in this study. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² or urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g. Multivariable regression models were used to analyze the associations between urinary VOC metabolites and CKD.

Results: A total of 1,295 participants with DM and a mean age of 59 years were included. After adjustment for demographic and clinical characteristics, elevated levels of N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA) (tertile 2: adjusted odds ratio (aOR)  =   1.81, 95% confidence interval (CI): 1.15-2.85, p  =  0.012), N-acetyl-S-(N-methylcarbamoyl)-L-cysteine (AMCC) (tertile 2: aOR   =  1.84, 95% CI: 1.10-3.08, p  =  0.021), DHBMA (tertile 3: aOR  =  1.93, 95% CI: 1.12-3.35, p  =   0.020), and phenylglyoxylic acid (PGA) (tertile 3: aOR   =  1.71, 95% CI: 1.11-2.63, p  =  0.017) were significantly associated with increased likelihood of CKD.

Conclusion: Specific urinary VOC metabolite levels are positively associated with an increased risk of CKD in patients with DM. These findings suggest that monitoring urinary VOC metabolites could be important for the prevention and management of CKD in this population. Future longitudinal studies should focus on establishing causality and elucidating the underlying mechanisms of these associations.

Introduction and objectives: Since the use of a bio stimulant should provide a response to a problem that depends on the production system implemented (crops, plant model, soil, climate, the farmer's practices…), the agricultural sector is facing concomitant challenges of choosing the best bio stimulant that suits their needs. Thus, understanding bio stimulant-plant interactions, at molecular level, using metabolomics approaches is a prerequisite, for the development of a bio stimulant, leading to an effective exploration and application of formulations in agriculture. AGRO-K®, is commercialized as a plant-based bio stimulant that improve vigor and enhance resistance to lodging in cereal crops. A recent previous untargeted metabolomics study has demonstrated the ability of this bio stimulant to improve wheat resistance to lodging, in real open-field conditions. However, the reproducibility of the impact of this bio stimulant in other filed crops is not yet investigated.

Methods: Therefore, the present study aimed to assess the changes in primary and secondary metabolites in the roots, stems, and leaves of fiber flax (Linum usitatissimum L), treated with the bio stimulant, using NMR and LC-MS-based untargeted metabolomics approach.

Results and conclusions: In addition to the previous result conducted in wheat, the present analysis seemed to show that this bio stimulant led to a similar pathway enhancement in flax. The pathways which seem to be reproducibly impacted are hydroxycinnamic acid amides (HCAAs), phenylpropanoids and flavonoids. Impacting these pathways enhance root growth and elongation and cell wall lignification, which can aid in preventing crop lodging. These results confirm that HCAAs, flavonoids, and phenylpropanoids could serve as signatory biomarkers of the impact of AGRO-K® on improving lodging resistance across various plant species.

Introduction and objectives: The application of untargeted metabolomics assays using ultra high performance liquid chromatography-mass spectrometry (UHPLC-MS) to study metabolism in biological systems including humans is rapidly increasing. In some of these studies there is a requirement to collect and analyse low sample volumes of biofluids (e.g. tear fluid) or low cell and tissue mass samples (e.g. tissue needle biopsies). The application of microflow, capillary or nano liquid chromatography (≤ 1.0 mm column internal diameter (i.d.)) theoretically should accomplish a higher assay sensitivity compared to analytical liquid chromatography (2.1-5.0 mm column internal diameter). To date, there has been limited research into microflow UHPLC-MS assays that can be applied to study samples of low volume or mass.

Methods: This paper presents three complementary UHPLC-MS assays (aqueous C₁₈ reversed-phase, lipidomics C₁₈ reversed-phase and Hydrophilic Interaction Liquid Chromatography (HILIC)) applying 1.0 mm internal diameter columns for untargeted metabolomics. Human plasma and urine samples were applied for the method development, with porcine plasma, urine and tear fluid used for method assessment. Data were collected and compared for columns of the same length, stationary phase and stationary phase particle size but with two different column internal diameters (2.1 mm and 1.0 mm).

Results and conclusions: All three assays showed an increase in peak areas and peak widths when applying the 1.0 mm i.d. assays. HILIC assays provide an advantage at lower sample dilutions whereas for reversed phase (RP) assays there was no benefit added. This can be seen in the validation study where a much higher number of compounds were detected in the HILIC assay. RP assays were still appropriate for small volume samples with hundreds of compounds being detected. In summary, the 1.0 mm i.d. column assays are applicable for small volume samples where dilution is required during sample preparation.

Introduction: Plant hormonal mutants, which do not produce or are insensitive to hormones, are often affected in their growth and development, but other metabolic rearrangements might be involved. A trade-off between growth and stress response is necessary for the plant survival.

Objectives: Here, we explore the metabolic profile and the pathogen resistance of a brassinosteroid-insensitive Hordeum vulgare L. semi-dwarf mutant, BW312.

Methods: We investigate BW312 metabolism through a chemical enrichment analysis, confirming a shifted metabolic profile towards pathogen resistance. The effective pathogen resistance of the mutant was tested in presence of Pyrenophora teres and Fusarium graminearum.

Results: Four compound families were increased in the mutant (pyrrolidines, basic amino acids, alkaloids, monounsaturated fatty acids), while two compound families were decreased (pyrrolidinones, anthocyanins). Dipeptides were also altered (increased and decreased). BW312 displayed a better resistance to Pyrenophora teres in the earliest stage of infection with a 21.5% decrease of the lesion length 10 days after infection. BW312 also exhibited a reduced lesion length (43.3%) and a reduced browning of the lesions (55.5%) when exposed to Fusarium graminearum at the seedling stage.

Conclusion: The observed metabolomic shift strongly suggests that the BW312 semi-dwarf mutant is in a primed state, resulting in a standby state of alertness to pathogens.

Introduction: There is a lack of biomarkers of clinically important diets, such as the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet.

Objectives: Our study explored serum metabolites associated with adherence to the MIND diet.

Methods: In 3,908 Atherosclerosis Risk in Communities (ARIC) study participants, we calculated a modified MIND diet score based on a 66-item self-reported food frequency questionnaire (FFQ). The modified score did not include berries and olive oil, as these items were not assessed in the FFQ. We used multivariable linear regression models in 2 subgroups of ARIC study participants and meta-analyzed results using fixed effects regression to identify significant metabolites after Bonferroni correction. We also examined associations between these metabolites and food components of the modified MIND diet. C-statistics evaluated the prediction of high modified MIND diet adherence using significant metabolites beyond participant characteristics.

Results: Of 360 metabolites analyzed, 27 metabolites (15 positive, 12 negative) were significantly associated with the modified MIND diet score (lipids, n = 13; amino acids, n = 5; xenobiotics, n = 3; cofactors and vitamins, n = 3; carbohydrates n = 2; nucleotide n = 1). The top 4 metabolites that improved the prediction of high dietary adherence to the modified MIND diet were 7-methylxanthine, theobromine, docosahexaenoate (DHA), and 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF).

Conclusion: Twenty-seven metabolomic markers were correlated with the modified MIND diet. The biomarkers, if further validated, could be useful to objectively assess adherence to the MIND diet.

Background: Dopaminergic neurons from the substantia nigra pars compacta (SNc) have a higher susceptibility to aging-related degeneration, compared to midbrain dopaminergic cells present in the ventral tegmental area (VTA); the death of dopamine neurons in the SNc results in Parkinson´s disease (PD). In addition to increased loss by aging, dopaminergic neurons from the SNc are more prone to cell death when exposed to genetic or environmental factors, that either interfere with mitochondrial function, or cause an increase of oxidative stress. The oxidation of dopamine is a contributing source of reactive oxygen species (ROS), but this production is not enough to explain the differences in susceptibility to degeneration between SNc and VTA neurons.

Aim of review: In this review we aim to highlight the intrinsic differences between SNc and VTA dopamine neurons, in terms of gene expression, calcium oscillations, bioenergetics, and ROS responses. Also, to describe the changes in the pentose phosphate pathway and the induction of apoptosis in SNc neurons during aging, as related to the development of PD.

Key scientific concepts of review: Recent work showed that neurons from the SNc possess intrinsic characteristics that result in metabolic differences, related to their intricate morphology, that render them more susceptible to degeneration. In particular, these neurons have an elevated basal energy metabolism, that is required to fulfill the demands of the constant firing of action potentials, but at the same time, is associated to higher ROS production, compared to VTA cells. Finally, we discuss how mutations related to PD affect metabolic pathways, and the related mechanisms, as revealed by metabolomics.

Introduction: Over the past two decades, liquid chromatography-mass spectrometry (LC-MS)-based metabolomics has experienced significant growth, playing a crucial role in various scientific disciplines. However, despite these advance-ments, metabolite identification (MetID) remains a significant challenge. To address this, stringent MetID requirements were established, emphasizing the necessity of aligning experimental data with authentic reference standards using multiple criteria. Establishing dependable methods and corresponding libraries is crucial for instilling confidence in MetID and driving further progress in metabolomics.

Objective: The EMBL-MCF 2.0 LC-MS/MS method and public library was designed to facilitate both targeted and untargeted metabolomics with exclusive focus on endogenous, polar metabolites, which are known to be challenging to analyze due to their hydrophilic nature. By accompanying spectral data with robust retention times obtained from authentic standards and low-adsorption chromatography, high confidence MetID is achieved and accessible to the metabolomics community.

Methods: The library is built on hydrophilic interaction liquid chromatography (HILIC) and state-of-the-art low adsorption LC hardware. Both high-resolution tandem mass spectra and manually optimized multiple reaction monitoring (MRM) transitions were acquired on an Orbitrap Exploris 240 and a QTRAP 6500+, respectively.

Results: Implementation of biocompatible HILIC has facilitated the separation of isomeric metabolites with significant enhancements in both selectivity and sensitivity. The resulting library comprises a diverse collection of more than 250 biologically relevant metabolites. The methodology was successfully applied to investigate a variety of biological matrices, with exemplary findings showcased using murine plasma samples.

Conclusions: Our work has resulted in the development of the EMBL-MCF 2.0 library, a powerful resource for sensitive metabolomics analyses and high-confidence MetID. The library is freely accessible and available in the universal .msp file format under the CC-BY 4.0 license: mona.fiehnlab.ucdavis.edu https://mona.fiehnlab.ucdavis.edu/spectra/browse?query=exists(tags.text:%27EMBL-MCF_2.0_HRMS_Library%27) , EMBL-MCF 2.0 HRMS https://www.embl.org/groups/metabolomics/instrumentation-and-software/#MCF-library .