Metabolites

18 pages, 2333 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of the Metabolite Profile of Fish Oil Omega-3 Fatty Acids (n-3 FAs) in Micellar and Enteric-Coated Forms—A Randomized, Cross-Over Human Study

by Afoke Ibi, Chuck Chang, Yun Chai Kuo, Yiming Zhang, Min Du, Yoon Seok Roh, Roland Gahler, Mary Hardy and Julia Solnier

Metabolites 2024, 14(5), 265; https://doi.org/10.3390/metabo14050265 - 7 May 2024

Viewed by 1476

Abstract

This study evaluated the differences in the metabolite profile of three n-3 FA fish oil formulations in 12 healthy participants: (1) standard softgels (STD) providing 600 mg n-3 FA; (2) enteric-coated softgels (ENT) providing 600 mg n-3 FA; (3) a new micellar formulation [...] Read more.

This study evaluated the differences in the metabolite profile of three n-3 FA fish oil formulations in 12 healthy participants: (1) standard softgels (STD) providing 600 mg n-3 FA; (2) enteric-coated softgels (ENT) providing 600 mg n-3 FA; (3) a new micellar formulation (LMF) providing 374 mg n-3 FA. The pharmacokinetics (PKs), such as the area under the plot of plasma concentration (AUC), and the peak blood concentration (C_max) of the different FA metabolites including HDHAs, HETEs, HEPEs, RvD1, RvD5, RvE1, and RvE2, were determined over a total period of 24 h. Blood concentrations of EPA (26,920.0 ± 10,021.0 ng/mL·h) were significantly higher with respect to AUC_0-24 following LMF treatment vs STD and ENT; when measured incrementally, blood concentrations of total n-3 FAs (EPA/DHA/DPA3) up to 11 times higher were observed for LMF vs STD (iAUC _0-24: 16,150.0 ± 5454.0 vs 1498.9 ± 443.0; p ≤ 0.0001). Significant differences in n-3 metabolites including oxylipins were found between STD and LMF with respect to 12-HEPE, 9-HEPE, 12-HETE, and RvD1; 9-HEPE levels were significantly higher following the STD vs. ENT treatment. Furthermore, within the scope of this study, changes in blood lipid levels (i.e., cholesterol, triglycerides, LDL, and HDL) were monitored in participants for up to 120 h post-treatment; a significant decrease in serum triglycerides was detected in participants (~20%) following the LMF treatment; no significant deviations from the baseline were detected for all the other lipid biomarkers in any of the treatment groups. Despite a lower administered dose, LMF provided higher blood concentrations of n-3 FAs and certain anti-inflammatory n-3 metabolites in human participants—potentially leading to better health outcomes. Full article

(This article belongs to the Section Nutrition and Metabolism)

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19 pages, 2911 KiB

Open AccessEditor’s ChoiceArticle

Predicting the Pathway Involvement of Metabolites Based on Combined Metabolite and Pathway Features

by Erik D. Huckvale and Hunter N. B. Moseley

Metabolites 2024, 14(5), 266; https://doi.org/10.3390/metabo14050266 - 7 May 2024

Cited by 3 | Viewed by 1284

Abstract

A major limitation of most metabolomics datasets is the sparsity of pathway annotations for detected metabolites. It is common for less than half of the identified metabolites in these datasets to have a known metabolic pathway involvement. Trying to address this limitation, machine [...] Read more.

A major limitation of most metabolomics datasets is the sparsity of pathway annotations for detected metabolites. It is common for less than half of the identified metabolites in these datasets to have a known metabolic pathway involvement. Trying to address this limitation, machine learning models have been developed to predict the association of a metabolite with a “pathway category”, as defined by a metabolic knowledge base like KEGG. Past models were implemented as a single binary classifier specific to a single pathway category, requiring a set of binary classifiers for generating the predictions for multiple pathway categories. This past approach multiplied the computational resources necessary for training while diluting the positive entries in the gold standard datasets needed for training. To address these limitations, we propose a generalization of the metabolic pathway prediction problem using a single binary classifier that accepts the features both representing a metabolite and representing a pathway category and then predicts whether the given metabolite is involved in the corresponding pathway category. We demonstrate that this metabolite–pathway features pair approach not only outperforms the combined performance of training separate binary classifiers but demonstrates an order of magnitude improvement in robustness: a Matthews correlation coefficient of 0.784 ± 0.013 versus 0.768 ± 0.154. Full article

(This article belongs to the Special Issue Machine Learning Applications in Metabolomics Analysis)

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14 pages, 869 KiB

Open AccessEditor’s ChoiceReview

Nuclear Magnetic Resonance (NMR) Metabolomics: Current Applications in Equine Health Assessment

by Fulvio Laus, Marilena Bazzano, Andrea Spaterna, Luca Laghi and Andrea Marchegiani

Metabolites 2024, 14(5), 269; https://doi.org/10.3390/metabo14050269 - 7 May 2024

Cited by 1 | Viewed by 2396

Abstract

Metabolomics can allow for the comprehensive identification of metabolites within biological systems, at given time points, in physiological and pathological conditions. In the last few years, metabolomic analysis has gained popularity both in human and in veterinary medicine, showing great potential for novel [...] Read more.

Metabolomics can allow for the comprehensive identification of metabolites within biological systems, at given time points, in physiological and pathological conditions. In the last few years, metabolomic analysis has gained popularity both in human and in veterinary medicine, showing great potential for novel applications in clinical activity. The aim of applying metabolomics in clinical practice is understanding the mechanisms underlying pathological conditions and the influence of certain stimuli (i.e., drugs, nutrition, exercise) on body systems, in the attempt of identifying biomarkers that can help in the diagnosis of diseases. Proton Nuclear Magnetic Resonance spectroscopy (¹H-NMR) is well tailored to be used as an analytical platform for metabolites’ detection at the base of metabolomics studies, due to minimal sample preparation and high reproducibility. In this mini-review article, the scientific production of NMR metabolomic applications to equine medicine is examined. The research works are very different in methodology and difficult to compare. Studies are mainly focused on exercise, reproduction, and nutrition, other than respiratory and musculoskeletal diseases. The available information on this topic is still scant, but a greater collection of data could allow researchers to define new reliable markers to be used in clinical practice for diagnostic and therapeutical purposes. Full article

(This article belongs to the Special Issue Metabolomic Profiling in Equine Medicine and Reproduction)

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18 pages, 5035 KiB

Open AccessEditor’s ChoiceArticle

Depth of Interbreed Difference in Postmortem Bovine Muscle Determined by CE-FT/MS and LC-FT/MS Metabolomics

by Susumu Muroya, Yuta Horiuchi, Kazuki Iguchi, Takuma Higuchi, Shuji Sakamoto, Koichi Ojima and Kazutsugu Matsukawa

Metabolites 2024, 14(5), 261; https://doi.org/10.3390/metabo14050261 - 1 May 2024

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Abstract

Japanese Brown (JBR) cattle have moderately marbled beef compared to the highly marbled beef of Japanese Black (JBL) cattle; however, their skeletal muscle properties remain poorly characterized. To unveil interbreed metabolic differences over the previous results, we explored the metabolome network changes before [...] Read more.

Japanese Brown (JBR) cattle have moderately marbled beef compared to the highly marbled beef of Japanese Black (JBL) cattle; however, their skeletal muscle properties remain poorly characterized. To unveil interbreed metabolic differences over the previous results, we explored the metabolome network changes before and after postmortem 7-day aging in the trapezius muscle of the two cattle breeds by employing a deep and high-coverage metabolomics approach. Using both capillary electrophoresis (CE) and ultra-high-performance liquid chromatography (UHPLC)–Fourier transform mass spectrometry (FT/MS), we detected 522 and 384 annotated peaks, respectively, across all muscle samples. The CE-based results showed that the cattle were clearly separated by breed and postmortem age in multivariate analyses. The metabolism related to glutathione, glycolysis, vitamin K, taurine, and arachidonic acid was enriched with differentially abundant metabolites in aged muscles, in addition to amino acid (AA) metabolisms. The LC-based results showed that the levels of bile-acid-related metabolites, such as tauroursodeoxycholic acid (TUDCA), were high in fresh JBR muscle and that acylcarnitines were enriched in aged JBR muscle, compared to JBL muscle. Postmortem aging resulted in an increase in fatty acids and a decrease in acylcarnitine in the muscles of both cattle breeds. In addition, metabolite set enrichment analysis revealed that JBR muscle was distinctive in metabolisms related to pyruvate, glycerolipid, cardiolipin, and mitochondrial energy production, whereas the metabolisms related to phosphatidylethanolamine, nucleotide triphosphate, and AAs were characteristic of JBL. This suggests that the interbreed differences in postmortem trapezius muscle are associated with carnitine/acylcarnitine transport, β-oxidation, tricarboxylic acid cycle, and mitochondrial membrane stability, in addition to energy substrate and AA metabolisms. These interbreed differences may characterize beef quality traits such as the flavor intensity and oxidative stability. Full article

(This article belongs to the Special Issue Muscle Metabolic Response and Adaptation to Exercise, Diet, and Environment)

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18 pages, 15365 KiB

Open AccessEditor’s ChoiceArticle

Prediction of Myocardial Infarction Using a Combined Generative Adversarial Network Model and Feature-Enhanced Loss Function

by Shixiang Yu, Siyu Han, Mengya Shi, Makoto Harada, Jianhong Ge, Xuening Li, Xiang Cai, Margit Heier, Gabi Karstenmüller, Karsten Suhre, Christian Gieger, Wolfgang Koenig, Wolfgang Rathmann, Annette Peters and Rui Wang-Sattler

Metabolites 2024, 14(5), 258; https://doi.org/10.3390/metabo14050258 - 30 Apr 2024

Viewed by 1252

Abstract

Accurate risk prediction for myocardial infarction (MI) is crucial for preventive strategies, given its significant impact on global mortality and morbidity. Here, we propose a novel deep-learning approach to enhance the prediction of incident MI cases by incorporating metabolomics alongside clinical risk factors. [...] Read more.

Accurate risk prediction for myocardial infarction (MI) is crucial for preventive strategies, given its significant impact on global mortality and morbidity. Here, we propose a novel deep-learning approach to enhance the prediction of incident MI cases by incorporating metabolomics alongside clinical risk factors. We utilized data from the KORA cohort, including the baseline S4 and follow-up F4 studies, consisting of 1454 participants without prior history of MI. The dataset comprised 19 clinical variables and 363 metabolites. Due to the imbalanced nature of the dataset (78 observed MI cases and 1376 non-MI individuals), we employed a generative adversarial network (GAN) model to generate new incident cases, augmenting the dataset and improving feature representation. To predict MI, we further utilized multi-layer perceptron (MLP) models in conjunction with the synthetic minority oversampling technique (SMOTE) and edited nearest neighbor (ENN) methods to address overfitting and underfitting issues, particularly when dealing with imbalanced datasets. To enhance prediction accuracy, we propose a novel GAN for feature-enhanced (GFE) loss function. The GFE loss function resulted in an approximate 2% improvement in prediction accuracy, yielding a final accuracy of 70%. Furthermore, we evaluated the contribution of each clinical variable and metabolite to the predictive model and identified the 10 most significant variables, including glucose tolerance, sex, and physical activity. This is the first study to construct a deep-learning approach for producing 7-year MI predictions using the newly proposed loss function. Our findings demonstrate the promising potential of our technique in identifying novel biomarkers for MI prediction. Full article

(This article belongs to the Special Issue Machine Learning in Metabolic Diseases)

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18 pages, 2004 KiB

Open AccessEditor’s ChoiceArticle

Harnessing Metabolites as Serum Biomarkers for Liver Graft Pathology Prediction Using Machine Learning

by Cristina Baciu, Soumita Ghosh, Sara Naimimohasses, Arya Rahmani, Elisa Pasini, Maryam Naghibzadeh, Amirhossein Azhie and Mamatha Bhat

Metabolites 2024, 14(5), 254; https://doi.org/10.3390/metabo14050254 - 27 Apr 2024

Viewed by 1271

Abstract

Graft injury affects over 50% of liver transplant (LT) recipients, but non-invasive biomarkers to diagnose and guide treatment are currently limited. We aimed to develop a biomarker of graft injury by integrating serum metabolomic profiles with clinical variables. Serum from 55 LT recipients [...] Read more.

Graft injury affects over 50% of liver transplant (LT) recipients, but non-invasive biomarkers to diagnose and guide treatment are currently limited. We aimed to develop a biomarker of graft injury by integrating serum metabolomic profiles with clinical variables. Serum from 55 LT recipients with biopsy confirmed metabolic dysfunction-associated steatohepatitis (MASH), T-cell mediated rejection (TCMR) and biliary complications was collected and processed using a combination of LC-MS/MS assay. The metabolomic profiles were integrated with clinical information using a multi-class Machine Learning (ML) classifier. The model’s efficacy was assessed through the Out-of-Bag (OOB) error estimate evaluation. Our ML model yielded an overall accuracy of 79.66% with an OOB estimate of the error rate at 19.75%. The model exhibited a maximum ability to distinguish MASH, with an OOB error estimate of 7.4% compared to 22.2% for biliary and 29.6% for TCMR. The metabolites serine and serotonin emerged as the topmost predictors. When predicting binary outcomes using three models: Biliary (biliary vs. rest), MASH (MASH vs. rest) and TCMR (TCMR vs. rest); the AUCs were 0.882, 0.972 and 0.896, respectively. Our ML tool integrating serum metabolites with clinical variables shows promise as a non-invasive, multi-class serum biomarker of graft pathology. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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13 pages, 3523 KiB

Open AccessEditor’s ChoiceArticle

Direct Infusion Mass Spectrometry to Rapidly Map Metabolic Flux of Substrates Labeled with Stable Isotopes

by Nils W. F. Meijer, Susan Zwakenberg, Johan Gerrits, Denise Westland, Arif I. Ardisasmita, Sabine A. Fuchs, Nanda M. Verhoeven-Duif, Judith J. M. Jans and Fried J. T. Zwartkruis

Metabolites 2024, 14(5), 246; https://doi.org/10.3390/metabo14050246 - 25 Apr 2024

Viewed by 1569

Abstract

Direct infusion–high-resolution mass spectrometry (DI-HRMS) allows for rapid profiling of complex mixtures of metabolites in blood, cerebrospinal fluid, tissue samples and cultured cells. Here, we present a DI-HRMS method suitable for the rapid determination of metabolic fluxes of isotopically labeled substrates in cultured [...] Read more.

Direct infusion–high-resolution mass spectrometry (DI-HRMS) allows for rapid profiling of complex mixtures of metabolites in blood, cerebrospinal fluid, tissue samples and cultured cells. Here, we present a DI-HRMS method suitable for the rapid determination of metabolic fluxes of isotopically labeled substrates in cultured cells and organoids. We adapted an automated annotation pipeline by selecting labeled adducts that best represent the majority of ¹³C and/or ¹⁵N-labeled glycolytic and tricarboxylic acid cycle intermediates as well as a number of their derivatives. Furthermore, valine, leucine and several of their degradation products were included. We show that DI-HRMS can determine anticipated and unanticipated alterations in metabolic fluxes along these pathways that result from the genetic alteration of single metabolic enzymes, including pyruvate dehydrogenase (PDHA1) and glutaminase (GLS). In addition, it can precisely pinpoint metabolic adaptations to the loss of methylmalonyl-CoA mutase in patient-derived liver organoids. Our results highlight the power of DI-HRMS in combination with stable isotopically labeled compounds as an efficient screening method for fluxomics. Full article

(This article belongs to the Special Issue Advances in Metabolic Profiling of Biological Samples 2nd Edition)

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16 pages, 2107 KiB

Open AccessEditor’s ChoiceArticle

The Metabolic and Lipidomic Fingerprint of Torin1 Exposure in Mouse Embryonic Fibroblasts Using Untargeted Metabolomics

by Rani Robeyns, Angela Sisto, Elias Iturrospe, Katyeny Manuela da Silva, Maria van de Lavoir, Vincent Timmerman, Adrian Covaci, Sigrid Stroobants and Alexander L. N. van Nuijs

Metabolites 2024, 14(5), 248; https://doi.org/10.3390/metabo14050248 - 25 Apr 2024

Viewed by 1476

Abstract

Torin1, a selective kinase inhibitor targeting the mammalian target of rapamycin (mTOR), remains widely used in autophagy research due to its potent autophagy-inducing abilities, regardless of its unspecific properties. Recognizing the impact of mTOR inhibition on metabolism, our objective was to develop a [...] Read more.

Torin1, a selective kinase inhibitor targeting the mammalian target of rapamycin (mTOR), remains widely used in autophagy research due to its potent autophagy-inducing abilities, regardless of its unspecific properties. Recognizing the impact of mTOR inhibition on metabolism, our objective was to develop a reliable and thorough untargeted metabolomics workflow to study torin1-induced metabolic changes in mouse embryonic fibroblast (MEF) cells. Crucially, our quality assurance and quality control (QA/QC) protocols were designed to increase confidence in the reported findings by reducing the likelihood of false positives, including a validation experiment replicating all experimental steps from sample preparation to data analysis. This study investigated the metabolic fingerprint of torin1 exposure by using liquid chromatography—high resolution mass spectrometry (LC-HRMS)-based untargeted metabolomics platforms. Our workflow identified 67 altered metabolites after torin1 exposure, combining univariate and multivariate statistics and the implementation of a validation experiment. In particular, intracellular ceramides, diglycerides, phosphatidylcholines, phosphatidylethanolamines, glutathione, and 5′-methylthioadenosine were downregulated. Lyso-phosphatidylcholines, lyso-phosphatidylethanolamines, glycerophosphocholine, triglycerides, inosine, and hypoxanthine were upregulated. Further biochemical pathway analyses provided deeper insights into the reported changes. Ultimately, our study provides a valuable workflow that can be implemented for future investigations into the effects of other compounds, including more specific autophagy modulators. Full article

(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics and Lipidomics for Biomarker Discovery and Drug Development)

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17 pages, 2604 KiB

Open AccessEditor’s ChoiceArticle

A Data-Driven Approach to Sugarcane Breeding Programs with Agronomic Characteristics and Amino Acid Constituent Profiling

by Chiaki Ishikawa, Yasuhiro Date, Makoto Umeda, Yusuke Tarumoto, Megumi Okubo, Yasujiro Morimitsu, Yasuaki Tamura, Yoichi Nishiba and Hiroshi Ono

Metabolites 2024, 14(4), 243; https://doi.org/10.3390/metabo14040243 - 21 Apr 2024

Viewed by 1499

Abstract

Sugarcane (Saccharum spp. hybrids) and its processed products have supported local industries such as those in the Nansei Islands, Japan. To improve the sugarcane quality and productivity, breeders select better clones by evaluating agronomic characteristics, such as commercially recoverable sugar and cane [...] Read more.

Sugarcane (Saccharum spp. hybrids) and its processed products have supported local industries such as those in the Nansei Islands, Japan. To improve the sugarcane quality and productivity, breeders select better clones by evaluating agronomic characteristics, such as commercially recoverable sugar and cane yield. However, other constituents in sugarcane remain largely unutilized in sugarcane breeding programs. This study aims to establish a data-driven approach to analyze agronomic characteristics from breeding programs. This approach also determines a correlation between agronomic characteristics and free amino acid composition to make breeding programs more efficient. Sugarcane was sampled in clones in the later stage of breeding selection and cultivars from experimental fields on Tanegashima Island. Principal component analysis and hierarchical cluster analysis using agronomic characteristics revealed the diversity and variability of each sample, and the data-driven approach classified cultivars and clones into three groups based on yield type. A comparison of free amino acid constituents between these groups revealed significant differences in amino acids such as asparagine and glutamine. This approach dealing with a large volume of data on agronomic characteristics will be useful for assessing the characteristics of potential clones under selection and accelerating breeding programs. Full article

(This article belongs to the Special Issue Metabolomic Technology in Quality and Safety of Agricultural Products and Foods)

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19 pages, 2039 KiB

Open AccessEditor’s ChoiceArticle

Comparative Lipidomics of Oral Commensal and Opportunistic Bacteria

by Paul L. Wood, Annie Le and Dominic L. Palazzolo

Metabolites 2024, 14(4), 240; https://doi.org/10.3390/metabo14040240 - 20 Apr 2024

Cited by 3 | Viewed by 1760

Abstract

The oral cavity contains a vast array of microbes that contribute to the balance between oral health and disease. In addition, oral bacteria can gain access to the circulation and contribute to other diseases and chronic conditions. There are a limited number of [...] Read more.

The oral cavity contains a vast array of microbes that contribute to the balance between oral health and disease. In addition, oral bacteria can gain access to the circulation and contribute to other diseases and chronic conditions. There are a limited number of publications available regarding the comparative lipidomics of oral bacteria and fungi involved in the construction of oral biofilms, hence our decision to study the lipidomics of representative oral bacteria and a fungus. We performed high-resolution mass spectrometric analyses (<2.0 ppm mass error) of the lipidomes from five Gram-positive commensal bacteria: Streptococcus oralis, Streptococcus intermedius, Streptococcus mitis, Streptococcus sanguinis, and Streptococcus gordonii; five Gram-positive opportunistic bacteria: Streptococcus mutans, Staphylococcus epidermis, Streptococcus acidominimus, Actinomyces viscosus, and Nanosynbacter lyticus; seven Gram-negative opportunistic bacteria: Porphyromonas gingivalis. Prevotella brevis, Proteus vulgaris, Fusobacterium nucleatum, Veillonella parvula, Treponema denticola, and Alkermansia muciniphila; and one fungus: Candida albicans. Our mass spectrometric analytical platform allowed for a detailed evaluation of the many structural modifications made by microbes for the three major lipid scaffolds: glycerol, sphingosine and fatty acyls of hydroxy fatty acids (FAHFAs). Full article

(This article belongs to the Special Issue Lipidomics in Health and Disease)

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15 pages, 1228 KiB

Open AccessEditor’s ChoiceArticle

Vitamin D and Ceramide Metabolomic Profile in Acute Myocardial Infarction

by Melania Gaggini, Federica Marchi, Nataliya Pylypiv, Alessandra Parlanti, Simona Storti, Umberto Paradossi, Sergio Berti and Cristina Vassalle

Metabolites 2024, 14(4), 233; https://doi.org/10.3390/metabo14040233 - 18 Apr 2024

Viewed by 1431

Abstract

Sphingolipids (SLs) influence several cellular pathways, while vitamin D exerts many extraskeletal effects in addition to its traditional biological functions, including the modulation of calcium homeostasis and bone health. Moreover, Vitamin D and SLs affect the regulation of each others’ metabolism; hence, this [...] Read more.

Sphingolipids (SLs) influence several cellular pathways, while vitamin D exerts many extraskeletal effects in addition to its traditional biological functions, including the modulation of calcium homeostasis and bone health. Moreover, Vitamin D and SLs affect the regulation of each others’ metabolism; hence, this study aims to evaluate the relationship between the levels of 25(OH)D and ceramides in acute myocardial infarction (AMI). In particular, the blood abundance of eight ceramides and 25(OH)D was evaluated in 134 AMI patients (aged 68.4 ± 12.0 years, 72% males). A significant inverse correlation between 25(OH)D and both Cer(d18:1/16:0) and Cer(d18:1/18:0) was found; indeed, patients with severe hypovitaminosis D (<10 ng/mL) showed the highest levels of the two investigated ceramides. Moreover, diabetic/dyslipidemic patients with suboptimal levels of 25(OH)D (<30 ng/mL) had higher levels of both the ceramides when compared with the rest of the population. On the other hand, 25(OH)D remained an independent determinant for Cer(d18:1/16:0) (STD Coeff −0.18, t-Value −2, p ≤ 0.05) and Cer(d18:1/18:0) (−0.2, −2.2, p < 0.05). In light of these findings, the crosstalk between sphingolipids and vitamin D may unravel additional mechanisms by which these molecules can influence CV risk in AMI. Full article

(This article belongs to the Special Issue Lipid Metabolism and Cardiometabolic Diseases: Latest Advances and Prospects)

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15 pages, 3312 KiB

Open AccessEditor’s ChoiceArticle

Discrimination of Lipogenic or Glucogenic Diet Effects in Early-Lactation Dairy Cows Using Plasma Metabolite Abundances and Ratios in Combination with Machine Learning

by Xiaodan Wang, Sanjeevan Jahagirdar, Wouter Bakker, Carolien Lute, Bas Kemp, Ariette van Knegsel and Edoardo Saccenti

Metabolites 2024, 14(4), 230; https://doi.org/10.3390/metabo14040230 - 17 Apr 2024

Viewed by 1273

Abstract

During early lactation, dairy cows have a negative energy balance since their energy demands exceed their energy intake: in this study, we aimed to investigate the association between diet and plasma metabolomics profiles and how these relate to energy unbalance of course in [...] Read more.

During early lactation, dairy cows have a negative energy balance since their energy demands exceed their energy intake: in this study, we aimed to investigate the association between diet and plasma metabolomics profiles and how these relate to energy unbalance of course in the early-lactation stage. Holstein-Friesian cows were randomly assigned to a glucogenic (n = 15) or lipogenic (n = 15) diet in early lactation. Blood was collected in week 2 and week 4 after calving. Plasma metabolite profiles were detected using liquid chromatography–mass spectrometry (LC-MS), and a total of 39 metabolites were identified. Two plasma metabolomic profiles were available every week for each cow. Metabolite abundance and metabolite ratios were used for the analysis using the XGboost algorithm to discriminate between diet treatment and lactation week. Using metabolite ratios resulted in better discrimination performance compared with the metabolite abundances in assigning cows to a lipogenic diet or a glucogenic diet. The quality of the discrimination of performance of lipogenic diet and glucogenic diet effects improved from 0.606 to 0.753 and from 0.696 to 0.842 in week 2 and week 4 (as measured by area under the curve, AUC), when the metabolite abundance ratios were used instead of abundances. The top discriminating ratios for diet were the ratio of arginine to tyrosine and the ratio of aspartic acid to valine in week 2 and week 4, respectively. For cows fed the lipogenic diet, choline and the ratio of creatinine to tryptophan were top features to discriminate cows in week 2 vs. week 4. For cows fed the glucogenic diet, methionine and the ratio of 4-hydroxyproline to choline were top features to discriminate dietary effects in week 2 or week 4. This study shows the added value of using metabolite abundance ratios to discriminate between lipogenic and glucogenic diet and lactation weeks in early-lactation cows when using metabolomics data. The application of this research will help to accurately regulate the nutrition of lactating dairy cows and promote sustainable agricultural development. Full article

(This article belongs to the Collection Advances in Metabolomics)

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41 pages, 14139 KiB

Open AccessEditor’s ChoiceReview

Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective

by Yansong Fu, Zhipeng Wang and Hong Qin

Metabolites 2024, 14(4), 218; https://doi.org/10.3390/metabo14040218 - 12 Apr 2024

Cited by 2 | Viewed by 1958

Abstract

Metabolic-associated fatty liver disease (MAFLD), characterized primarily by hepatic steatosis, has become the most prevalent liver disease worldwide, affecting approximately two-fifths of the global population. The pathogenesis of MAFLD is extremely complex, and to date, there are no approved therapeutic drugs for clinical [...] Read more.

Metabolic-associated fatty liver disease (MAFLD), characterized primarily by hepatic steatosis, has become the most prevalent liver disease worldwide, affecting approximately two-fifths of the global population. The pathogenesis of MAFLD is extremely complex, and to date, there are no approved therapeutic drugs for clinical use. Considerable evidence indicates that various metabolic disorders play a pivotal role in the progression of MAFLD, including lipids, carbohydrates, amino acids, and micronutrients. In recent years, the medicinal properties of natural products have attracted widespread attention, and numerous studies have reported their efficacy in ameliorating metabolic disorders and subsequently alleviating MAFLD. This review aims to summarize the metabolic-associated pathological mechanisms of MAFLD, as well as the natural products that regulate metabolic pathways to alleviate MAFLD. Full article

(This article belongs to the Special Issue Advances in Dietary Nutrition Intervention on Metabolic Diseases)

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13 pages, 1058 KiB

Open AccessEditor’s ChoiceArticle

Accumulation of Non-Pathological Liver Fat Is Associated with the Loss of Glyoxalase I Activity in Humans

by Andreas Peter, Erwin Schleicher, Elisabeth Kliemank, Julia Szendroedi, Alfred Königsrainer, Hans-Ulrich Häring, Peter P. Nawroth and Thomas Fleming

Metabolites 2024, 14(4), 209; https://doi.org/10.3390/metabo14040209 - 7 Apr 2024

Viewed by 1787

Abstract

The underlying molecular mechanisms for the development of non-alcoholic fatty liver (NAFL) and its progression to advanced liver diseases remain elusive. Glyoxalase 1 (Glo1) loss, leading to elevated methylglyoxal (MG) and dicarbonyl stress, has been implicated in various diseases, including obesity-related conditions. This [...] Read more.

The underlying molecular mechanisms for the development of non-alcoholic fatty liver (NAFL) and its progression to advanced liver diseases remain elusive. Glyoxalase 1 (Glo1) loss, leading to elevated methylglyoxal (MG) and dicarbonyl stress, has been implicated in various diseases, including obesity-related conditions. This study aimed to investigate changes in the glyoxalase system in individuals with non-pathological liver fat. Liver biopsies were obtained from 30 individuals with a narrow range of BMI (24.6–29.8 kg/m²). Whole-body insulin sensitivity was assessed using HOMA-IR. Liver biopsies were analyzed for total triglyceride content, Glo1 and Glo2 mRNA, protein expression, and activity. Liquid chromatography–tandem mass spectrometry determined liver dicarbonyl content and oxidation and glycation biomarkers. Liver Glo1 activity showed an inverse correlation with HOMA-IR and liver triglyceride content, but not BMI. Despite reduced Glo1 activity, no associations were found with elevated liver dicarbonyls or glycation markers. A sex dimorphism was observed in Glo1, with females exhibiting significantly lower liver Glo1 protein expression and activity, and higher liver MG-H1 content compared to males. This study demonstrates that increasing liver fat, even within a non-pathological range, is associated with reduced Glo1 activity. Full article

(This article belongs to the Special Issue Metabolic Syndrome and Non-Alcoholic Liver Disease)

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20 pages, 1583 KiB

Open AccessEditor’s ChoiceArticle

Identifying Predictive Biomarkers of Subclinical Mastitis in Dairy Cows through Urinary Metabotyping

by Grzegorz Zwierzchowski, Klevis Haxhiaj, Roman Wójcik, David S. Wishart and Burim N. Ametaj

Metabolites 2024, 14(4), 205; https://doi.org/10.3390/metabo14040205 - 4 Apr 2024

Viewed by 2136

Abstract

Mastitis is a significant infectious disease in dairy cows, resulting in milk yield loss and culling. Early detection of mastitis-prone cows is crucial for implementing effective preventive measures before disease onset. Current diagnosis of subclinical mastitis (SCM) relies on somatic cell count assessment [...] Read more.

Mastitis is a significant infectious disease in dairy cows, resulting in milk yield loss and culling. Early detection of mastitis-prone cows is crucial for implementing effective preventive measures before disease onset. Current diagnosis of subclinical mastitis (SCM) relies on somatic cell count assessment post-calving, lacking predictive capabilities. This study aimed to identify metabolic changes in pre-SCM cows through targeted metabolomic analysis of urine samples collected 8 wks and 4 wks before calving, using mass spectrometry. A nested case-control design was employed, involving a total of 145 multiparous dairy cows, with disease occurrence monitored pre- and postpartum. Among them, 15 disease-free cows served as healthy controls (CON), while 10 cows exclusively had SCM, excluding those with additional diseases. Urinary metabolite profiling revealed multiple alterations in acylcarnitines, amino acids, and organic acids in pre-SCM cows. Metabotyping identified 27 metabolites that distinguished pre-SCM cows from healthy CON cows at both 8 and 4 wks before parturition. However, only four metabolites per week showed significant alterations (p < 0.005). Notably, a panel of four serum metabolites (asymmetric dimethylarginine, proline, leucine, and homovanillate) at 8 wks prepartum, and another panel (asymmetric dimethylarginine, methylmalonate, citrate, and spermidine) at 4 wks prepartum, demonstrated predictive ability as urinary biomarkers for SCM risk (AUC = 0.88; p = 0.02 and AUC = 0.88; p = 0.03, respectively). In conclusion, our findings indicate that metabolite testing can identify cows at risk of SCM as early as 8 and 4 wks before parturition. Validation of the two identified metabolite panels is warranted to implement these predictive biomarkers, facilitate early intervention strategies, and improve dairy cow management to mitigate the impact of SCM. Further research is needed to confirm the efficacy and applicability of these biomarkers in practical farm settings. Full article

(This article belongs to the Section Animal Metabolism)

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14 pages, 1057 KiB

Open AccessEditor’s ChoiceReview

Challenges in the Metabolomics-Based Biomarker Validation Pipeline

by Shenghan Li, Nikita Looby, Vinod Chandran and Vathany Kulasingam

Metabolites 2024, 14(4), 200; https://doi.org/10.3390/metabo14040200 - 3 Apr 2024

Cited by 3 | Viewed by 1921

Abstract

As end-products of the intersection between the genome and environmental influences, metabolites represent a promising approach to the discovery of novel biomarkers for diseases. However, many potential biomarker candidates identified by metabolomics studies fail to progress beyond analytical validation for routine implementation in [...] Read more.

As end-products of the intersection between the genome and environmental influences, metabolites represent a promising approach to the discovery of novel biomarkers for diseases. However, many potential biomarker candidates identified by metabolomics studies fail to progress beyond analytical validation for routine implementation in clinics. Awareness of the challenges present can facilitate the development and advancement of innovative strategies that allow improved and more efficient applications of metabolite-based markers in clinical settings. This minireview provides a comprehensive summary of the pre-analytical factors, required analytical validation studies, and kit development challenges that must be resolved before the successful translation of novel metabolite biomarkers originating from research. We discuss the necessity for strict protocols for sample collection, storage, and the regulatory requirements to be fulfilled for a bioanalytical method to be considered as analytically validated. We focus especially on the blood as a biological matrix and liquid chromatography coupled with tandem mass spectrometry as the analytical platform for biomarker validation. Furthermore, we examine the challenges of developing a commercially viable metabolomics kit for distribution. To bridge the gap between the research lab and clinical implementation and utility of relevant metabolites, the understanding of the translational challenges for a biomarker panel is crucial for more efficient development of metabolomics-based precision medicine. Full article

(This article belongs to the Special Issue Challenges and Opportunities in Application of Mass Spectrometry for Metabolomics and Lipidomics)

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15 pages, 4025 KiB

Open AccessEditor’s ChoiceArticle

Time-Course Metabolomic Analysis: Production of Betaine Structural Analogs by Fungal Fermentation of Seaweed

by Nao Inoue, Keisuke Tsuge, Teruyoshi Yanagita, Akira Oikawa and Koji Nagao

Metabolites 2024, 14(4), 201; https://doi.org/10.3390/metabo14040201 - 3 Apr 2024

Cited by 2 | Viewed by 1364

Abstract

Betaine structural analogs are compounds characterized by the presence of positive and negative charges in a single molecule and have been reported to have physiological properties, such as anti-inflammatory activities. In this study, we performed a metabolomic analysis of metabolite composition changes during [...] Read more.

Betaine structural analogs are compounds characterized by the presence of positive and negative charges in a single molecule and have been reported to have physiological properties, such as anti-inflammatory activities. In this study, we performed a metabolomic analysis of metabolite composition changes during the fermentation of Neopyropia yezoensis, an edible red alga, with Aspergillus oryzae for 72 h. The results indicated that three specific betaine structural analogs (betaine, stachydrine, and carnitine) exhibited significant changes in production by the end of the 72 h fermentation period. Time-course analysis suggested that betaine was generated from the precursor choline at 12–24 h during the late stage of fungal growth, while stachydrine was generated from the precursor-related compound glutamic acid at 48–72 h during the sporulation stage. However, the contribution of the precursor lysine to the increased production of carnitine during the 12–72 h period was unclear. This study provides useful information on the efficient production of betaine structural analogs by the fungal fermentation of seaweed as well as various other food materials. Full article

(This article belongs to the Special Issue Emerging Applications of Metabolomics in Fermented Food)

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15 pages, 1170 KiB

Open AccessEditor’s ChoiceArticle

Grape/Blueberry Anthocyanins and Their Gut-Derived Metabolites Attenuate LPS/Nigericin-Induced Inflammasome Activation by Inhibiting ASC Speck Formation in THP-1 Monocytes

by Inken Behrendt, Isabella Röder, Frank Will, Gabriela Michel, Elvira Friedrich, Daniela Grote, Zoe Martin, Hanna Pauline Dötzer, Mathias Fasshauer, Martin Speckmann and Sabine Kuntz

Metabolites 2024, 14(4), 203; https://doi.org/10.3390/metabo14040203 - 3 Apr 2024

Cited by 2 | Viewed by 1427

Abstract

Inflammasomes are multi-protein complexes, which are formed in response to tissue injury, infections, and metabolic stress. However, aberrant inflammasome activation has been linked to several inflammatory diseases. Anthocyanins have been reported to attenuate NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, but the [...] Read more.

Inflammasomes are multi-protein complexes, which are formed in response to tissue injury, infections, and metabolic stress. However, aberrant inflammasome activation has been linked to several inflammatory diseases. Anthocyanins have been reported to attenuate NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, but the influence of grape/blueberry anthocyanins and especially their gut-derived metabolites on NLRP3 inflammasome activation in human monocytes remains unclear. Therefore, human leukemic monocytes (THP-1 cells, Tohoku Hospital Pediatrics-1 cells) were preincubated with different concentrations of grape/blueberry anthocyanins, homovanillyl alcohol, or 2,4,6-trihydroxybenzaldehyde (THBA) before the NLRP3 inflammasome was activated by lipopolysaccharide and/or nigericin. Apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, as well as ASC and NLRP3 protein expression, were determined using flow cytometry. Caspase-1 activity was measured in cultured cells, and pro-inflammatory cytokine secretion was determined using enzyme-linked immunosorbent assays. Anthocyanins and their metabolites had no effect on ASC or NLRP3 protein expression. However, THBA significantly inhibited ASC speck formation in primed and unprimed THP-1 monocytes, while caspase-1 activity was significantly declined by grape/blueberry anthocyanins. Furthermore, reduced inflammasome activation resulted in lower pro-inflammatory cytokine secretion. In conclusion, our results show for the first time that grape/blueberry anthocyanins and their gut-derived metabolites exert anti-inflammatory effects by attenuating NLRP3 inflammasome activation in THP-1 monocytes. Full article

(This article belongs to the Special Issue Role of Gut-Derived Metabolites in Health and Disease)

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26 pages, 3539 KiB

Open AccessEditor’s ChoiceArticle

Lipidome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys with Metabolic Dysfunction-Associated Steatotic Liver Disease

by Helaina E. Huneault, Chih-Yu Chen, Catherine C. Cohen, Xueyun Liu, Zachery R. Jarrell, Zhulin He, Karla E. DeSantos, Jean A. Welsh, Kristal M. Maner-Smith, Eric A. Ortlund, Jeffrey B. Schwimmer and Miriam B. Vos

Metabolites 2024, 14(4), 191; https://doi.org/10.3390/metabo14040191 - 28 Mar 2024

Cited by 1 | Viewed by 1948

Abstract

Little is known about lipid changes that occur in the setting of metabolic-dysfunction-associated steatotic liver disease (MASLD) regression. We previously reported improvements in hepatic steatosis, de novo lipogenesis (DNL), and metabolomic profiles associated with oxidative stress, inflammation, and selected lipid metabolism in 40 [...] Read more.

Little is known about lipid changes that occur in the setting of metabolic-dysfunction-associated steatotic liver disease (MASLD) regression. We previously reported improvements in hepatic steatosis, de novo lipogenesis (DNL), and metabolomic profiles associated with oxidative stress, inflammation, and selected lipid metabolism in 40 adolescent boys (11–16 y) with hepatic steatosis ≥5% (98% meeting the definition of MASLD). Participants were randomized to a low-free-sugar diet (LFSD) (n = 20) or usual diet (n = 20) for 8 weeks. Here, we employed untargeted/targeted lipidomics to examine lipid adaptations associated with the LFSD and improvement of hepatic steatosis. Our LC-MS/MS analysis revealed decreased triglycerides (TGs), diacylglycerols (DGs), cholesteryl esters (ChE), lysophosphatidylcholine (LPC), and phosphatidylcholine (PC) species with the diet intervention (p < 0.05). Network analysis demonstrated significantly lower levels of palmitate-enriched TG species post-intervention, mirroring the previously shown reduction in DNL in response to the LFSD. Targeted oxylipins analysis revealed a decrease in the abundance of 8-isoprostane and 14,15-DiHET and an increase in 8,9-DiHET (p < 0.05). Overall, we observed reductions in TGs, DGs, ChE, PC, and LPC species among participants in the LFSD group. These same lipids have been associated with MASLD progression; therefore, our findings may indicate normalization of key biological processes, including lipid metabolism, insulin resistance, and lipotoxicity. Additionally, our targeted oxylipins assay revealed novel changes in eicosanoids, suggesting improvements in oxidative stress. Future studies are needed to elucidate the mechanisms of these findings and prospects of these lipids as biomarkers of MASLD regression. Full article

(This article belongs to the Section Lipid Metabolism)

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19 pages, 15378 KiB

Open AccessEditor’s ChoiceArticle

Sex-Specific Effects of Polystyrene Microplastic and Lead(II) Co-Exposure on the Gut Microbiome and Fecal Metabolome in C57BL/6 Mice

by Weishou Shen, Meng Zhao, Weichen Xu, Xiaochun Shi, Fangfang Ren, Pengcheng Tu, Nan Gao, Jinjun Shan and Bei Gao

Metabolites 2024, 14(4), 189; https://doi.org/10.3390/metabo14040189 - 27 Mar 2024

Cited by 2 | Viewed by 1991

Abstract

The wide spread of microplastics has fueled growing public health concern globally. Due to their porous structure and large surface area, microplastics can serve as carriers for other environmental pollutants, including heavy metals. Although the toxic effects of microplastics or heavy metals have [...] Read more.

The wide spread of microplastics has fueled growing public health concern globally. Due to their porous structure and large surface area, microplastics can serve as carriers for other environmental pollutants, including heavy metals. Although the toxic effects of microplastics or heavy metals have been reported previously, investigations into the sex-differential health effects of combined exposure to microplastics and heavy metals are lacking. In the present study, the effects of polystyrene microplastics and lead(II) co-exposure on the gut microbiome, intestinal permeability, and fecal metabolome were examined in both male and female mice. Combined exposure of polystyrene microplastics and lead(II) increased intestinal permeability in both male and female mice. Sex-specific responses to the co-exposure were found in gut bacteria, fungi, microbial metabolic pathways, microbial genes encoding antibiotic resistance and virulence factors, as well as fecal metabolic profiles. In particular, Shannon and Simpson indices of gut bacteria were reduced by the co-exposure only in female mice. A total of 34 and 13 fecal metabolites were altered in the co-exposure group in female and male mice, respectively, among which only three metabolites were shared by both sexes. These sex-specific responses to the co-exposure need to be taken into consideration when investigating the combined toxic effects of microplastics and heavy metals on the gut microbiota. Full article

(This article belongs to the Section Microbiology and Ecological Metabolomics)

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14 pages, 3618 KiB

Open AccessEditor’s ChoiceArticle

Poly(ADP-Ribose) Polymerases-Inhibitor Talazoparib Inhibits Muscle Atrophy and Fatty Infiltration in a Tendon Release Infraspinatus Sheep Model: A Pilot Study

by Maurits G. L. Olthof, Anita Hasler, Paola Valdivieso, Martin Flück, Christian Gerber, Rieke Gehrke, Karina Klein, Brigitte von Rechenberg, Jess G. Snedeker and Karl Wieser

Metabolites 2024, 14(4), 187; https://doi.org/10.3390/metabo14040187 - 26 Mar 2024

Viewed by 1513

Abstract

Structural muscle changes, including muscle atrophy and fatty infiltration, follow rotator cuff tendon tear and are associated with a high repair failure rate. Despite extensive research efforts, no pharmacological therapy is available to successfully prevent both muscle atrophy and fatty infiltration after tenotomy [...] Read more.

Structural muscle changes, including muscle atrophy and fatty infiltration, follow rotator cuff tendon tear and are associated with a high repair failure rate. Despite extensive research efforts, no pharmacological therapy is available to successfully prevent both muscle atrophy and fatty infiltration after tenotomy of tendomuscular unit without surgical repair. Poly(ADP-ribose) polymerases (PARPs) are identified as a key transcription factors involved in the maintenance of cellular homeostasis. PARP inhibitors have been shown to influence muscle degeneration, including mitochondrial hemostasis, oxidative stress, inflammation and metabolic activity, and reduced degenerative changes in a knockout mouse model. Tenotomized infraspinatus were assessed for muscle degeneration for 16 weeks using a Swiss Alpine sheep model (n = 6). All sheep received daily oral administration of 0.5 mg Talazoparib. Due to animal ethics, the treatment group was compared with three different controls from prior studies of our institution. To mitigate potential batch heterogeneity, PARP-I was evaluated in comparison with three distinct control groups (n = 6 per control group) using the same protocol without treatment. The control sheep were treated with an identical study protocol without Talazoparib treatment. Muscle atrophy and fatty infiltration were evaluated at 0, 6 and 16 weeks post-tenotomy using DIXON-MRI. The controls and PARP-I showed a significant (control p < 0.001, PARP-I p = 0.01) decrease in muscle volume after 6 weeks. However, significantly less (p = 0.01) atrophy was observed in PARP-I after 6 weeks (control 1: 76.6 ± 8.7%; control 2: 80.3 ± 9.3%, control 3: 73.8 ± 6.7% vs. PARP-I: 90.8 ± 5.1% of the original volume) and 16 weeks (control 1: 75.7 ± 9.9; control 2: 74.2 ± 5.6%; control 3: 75.3 ± 7.4% vs. PARP-I 93.3 ± 10.6% of the original volume). All experimental groups exhibited a statistically significant (p < 0.001) augmentation in fatty infiltration following a 16-week period when compared to the initial timepoint. However, the PARP-I showed significantly less fatty infiltration (p < 0.003) compared to all controls (control 1: 55.6 ± 6.7%, control 2: 53.4 ± 9.4%, control 3: 52.0 ± 12.8% vs. PARP-I: 33.5 ± 8.4%). Finally, a significantly (p < 0.04) higher proportion and size of fast myosin heavy chain-II fiber type was observed in the treatment group. This study shows that PARP-inhibition with Talazoparib inhibits the progression of both muscle atrophy and fatty infiltration over 16 weeks in retracted sheep musculotendinous units. Full article

(This article belongs to the Special Issue Skeletal Muscle Fiber Phenotype as Determinant of Metabolism and Function in Health and Disease)

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13 pages, 1392 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Profiling of SH-SY5Y and Neuro2A Cells in Relation to Fetal Calf Serum (FCS) Concentration in Culture Media

by Lys Kronenberger, Janine Mett, Jessica Hoppstädter and Uli Müller

Metabolites 2024, 14(4), 188; https://doi.org/10.3390/metabo14040188 - 26 Mar 2024

Viewed by 1392

Abstract

The neuroblastoma cell lines SH-SY5Y and Neuro2A are commonly utilized models in neurobiological research. DMEM supplemented with different nutrients and 5–10% Fetal Calf Serum (FCS) is typically used for culturing these cell lines. During special treatments, a reduced FCS content is often deployed [...] Read more.

The neuroblastoma cell lines SH-SY5Y and Neuro2A are commonly utilized models in neurobiological research. DMEM supplemented with different nutrients and 5–10% Fetal Calf Serum (FCS) is typically used for culturing these cell lines. During special treatments, a reduced FCS content is often deployed to reduce cellular proliferation or the content of bioactive compounds. The impact of the reduction of FCS in culture media on the metabolic profile of SH-SY5Y and Neuro2A cells is currently unknown. Using an Amplex Red Assay, this study showed that the consumption of L-glutamine decreased after FCS reduction. Glucose and pyruvate consumption increased in both cell lines after the reduction of FCS. Thus, lactate production also increased with reduced FCS concentration. The reduction of FCS in the cell culture medium resulted in a reduced aerobic ATP production for SH-SY5Y cells and a complete shut down of aerobic ATP production for Neuro2A cells, measured using the Seahorse XF Real-Time ATP Rate Assay. Utilizing the Seahorse XF Glutamine Oxidation Stress Test, Neuro2A cells showed an increased utilization of L-glutamine oxidation after reduction of FCS. These results indicate that changes in FCS concentration in culture media have an impact on the different energy production strategies of SH-SY5Y and Neuro2A cells which must be considered when planning special treatments. Full article

(This article belongs to the Section Cell Metabolism)

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14 pages, 934 KiB

Open AccessEditor’s ChoiceArticle

Metabolomic Profiles and Pathways in Osteoarthritic Human Cartilage: A Comparative Analysis with Healthy Cartilage

by Hope D. Welhaven, Avery H. Welfley, Priyanka Brahmachary, Annika R. Bergstrom, Eden Houske, Matthew Glimm, Brian Bothner, Alyssa K. Hahn and Ronald K. June

Metabolites 2024, 14(4), 183; https://doi.org/10.3390/metabo14040183 - 25 Mar 2024

Cited by 3 | Viewed by 1696

Abstract

Osteoarthritis (OA) is a chronic joint disease with heterogenous metabolic pathology. To gain insight into OA-related metabolism, metabolite extracts from healthy (n = 11) and end-stage osteoarthritic cartilage (n = 35) were analyzed using liquid chromatography–mass spectrometry metabolomic profiling. Specific metabolites and metabolic [...] Read more.

Osteoarthritis (OA) is a chronic joint disease with heterogenous metabolic pathology. To gain insight into OA-related metabolism, metabolite extracts from healthy (n = 11) and end-stage osteoarthritic cartilage (n = 35) were analyzed using liquid chromatography–mass spectrometry metabolomic profiling. Specific metabolites and metabolic pathways, including lipid and amino acid pathways, were differentially regulated in osteoarthritis-derived and healthy cartilage. The detected alterations in amino acids and lipids highlighted key differences in bioenergetic resources, matrix homeostasis, and mitochondrial alterations in OA-derived cartilage compared to healthy cartilage. Moreover, the metabolomic profiles of osteoarthritic cartilage separated into four distinct endotypes, highlighting the heterogenous nature of OA metabolism and the diverse landscape within the joint in patients. The results of this study demonstrate that human cartilage has distinct metabolomic profiles in healthy and end-stage OA patients. By taking a comprehensive approach to assess metabolic differences between healthy and osteoarthritic cartilage and within osteoarthritic cartilage alone, several metabolic pathways with distinct regulation patterns were detected. Additional investigation may lead to the identification of metabolites that may serve as valuable indicators of disease status or potential therapeutic targets. Full article

(This article belongs to the Section Cell Metabolism)

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35 pages, 1971 KiB

Open AccessEditor’s ChoiceReview

Determination of Bile Acids in Canine Biological Samples: Diagnostic Significance

by Krisztián Németh, Ágnes Sterczer, Dávid Sándor Kiss, Réka Katalin Lányi, Vivien Hemző, Kriszta Vámos, Tibor Bartha, Anna Buzás and Katalin Lányi

Metabolites 2024, 14(4), 178; https://doi.org/10.3390/metabo14040178 - 22 Mar 2024

Cited by 2 | Viewed by 2630

Abstract

The comprehensive examination of bile acids is of paramount importance across various fields of health sciences, influencing physiology, microbiology, internal medicine, and pharmacology. While enzymatic reaction-based photometric methods remain fundamental for total BA measurements, there is a burgeoning demand for more sophisticated techniques [...] Read more.

The comprehensive examination of bile acids is of paramount importance across various fields of health sciences, influencing physiology, microbiology, internal medicine, and pharmacology. While enzymatic reaction-based photometric methods remain fundamental for total BA measurements, there is a burgeoning demand for more sophisticated techniques such as liquid chromatography–tandem mass spectrometry (LC-MS/MS) for comprehensive BA profiling. This evolution reflects a need for nuanced diagnostic assessments in clinical practice. In canines, a BA assessment involves considering factors, such as food composition, transit times, and breed-specific variations. Multiple matrices, including blood, feces, urine, liver tissue, and gallbladder bile, offer insights into BA profiles, yet interpretations remain complex, particularly in fecal analysis due to sampling challenges and breed-specific differences. Despite ongoing efforts, a consensus regarding optimal matrices and diagnostic thresholds remains elusive, highlighting the need for further research. Emphasizing the scarcity of systematic animal studies and underscoring the importance of ap-propriate sampling methodologies, our review advocates for targeted investigations into BA alterations in canine pathology, promising insights into pathomechanisms, early disease detection, and therapeutic avenues. Full article

(This article belongs to the Special Issue Nutrient Metabolism Studies in Companion Animals)

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16 pages, 4416 KiB

Open AccessEditor’s ChoiceArticle

Elucidation and Regulation of Tyrosine Kinase Inhibitor Resistance in Renal Cell Carcinoma Cells from the Perspective of Glutamine Metabolism

by Kento Morozumi, Yoshihide Kawasaki, Tomonori Sato, Masamitsu Maekawa, Shinya Takasaki, Shuichi Shimada, Takanari Sakai, Shinichi Yamashita, Nariyasu Mano and Akihiro Ito

Metabolites 2024, 14(3), 170; https://doi.org/10.3390/metabo14030170 - 19 Mar 2024

Cited by 1 | Viewed by 1620

Abstract

Tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of advanced renal cell carcinoma (RCC). However, there is a lack of useful biomarkers for assessing treatment efficacy. Through urinary metabolite analysis, we identified the metabolites and pathways involved in TKI resistance [...] Read more.

Tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of advanced renal cell carcinoma (RCC). However, there is a lack of useful biomarkers for assessing treatment efficacy. Through urinary metabolite analysis, we identified the metabolites and pathways involved in TKI resistance and elucidated the mechanism of TKI resistance. To verify the involvement of the identified metabolites obtained from urine metabolite analysis, we established sunitinib-resistant RCC cells and elucidated the antitumor effects of controlling the identified metabolic pathways in sunitinib-resistant RCC cells. Through the analysis of VEGFR signaling, we aimed to explore the mechanisms underlying the antitumor effects of metabolic control. Glutamine metabolism has emerged as a significant pathway in urinary metabolite analyses. In vitro and in vivo studies have revealed the antitumor effects of sunitinib-resistant RCC cells via knockdown of glutamine transporters. Furthermore, this antitumor effect is mediated by the control of VEGFR signaling via PTEN. Our findings highlight the involvement of glutamine metabolism in the prognosis and sunitinib resistance in patients with advanced RCC. Additionally, the regulating glutamine metabolism resulted in antitumor effects through sunitinib re-sensitivity in sunitinib-resistant RCC. Our results are expected to contribute to the more effective utilization of TKIs with further improvements in prognosis through current drug therapies. Full article

(This article belongs to the Special Issue Drug Metabolism and New Drug Development for Cancers)

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14 pages, 1926 KiB

Open AccessEditor’s ChoiceArticle

Serum Uric Acid/Serum Creatinine Ratio and Cardiovascular Mortality in Diabetic Individuals—The Uric Acid Right for Heart Health (URRAH) Project

by Lanfranco D’Elia, Maria Masulli, Pietro Cirillo, Agostino Virdis, Edoardo Casiglia, Valerie Tikhonoff, Fabio Angeli, Carlo Maria Barbagallo, Michele Bombelli, Federica Cappelli, Rosario Cianci, Michele Ciccarelli, Arrigo F. G. Cicero, Massimo Cirillo, Raffaella Dell’Oro, Giovambattista Desideri, Claudio Ferri, Loreto Gesualdo, Cristina Giannattasio, Guido Grassi, Guido Iaccarino, Luciano Lippa, Francesca Mallamaci, Alessandro Maloberti, Stefano Masi, Alberto Mazza, Alessandro Mengozzi, Maria Lorenza Muiesan, Pietro Nazzaro, Paolo Palatini, Gianfranco Parati, Roberto Pontremoli, Fosca Quarti-Trevano, Marcello Rattazzi, Gianpaolo Reboldi, Giulia Rivasi, Elisa Russo, Massimo Salvetti, Giuliano Tocci, Andrea Ungar, Paolo Verdecchia, Francesca Viazzi, Massimo Volpe, Claudio Borghi and Ferruccio Galletti Show full author list Hide full author list

Metabolites 2024, 14(3), 164; https://doi.org/10.3390/metabo14030164 - 14 Mar 2024

Cited by 1 | Viewed by 1930

Abstract

Several studies have detected a direct association between serum uric acid (SUA) and cardiovascular (CV) risk. In consideration that SUA largely depends on kidney function, some studies explored the role of the serum creatinine (sCr)-normalized SUA (SUA/sCr) ratio in different settings. Previously, the [...] Read more.

Several studies have detected a direct association between serum uric acid (SUA) and cardiovascular (CV) risk. In consideration that SUA largely depends on kidney function, some studies explored the role of the serum creatinine (sCr)-normalized SUA (SUA/sCr) ratio in different settings. Previously, the URRAH (URic acid Right for heArt Health) Study has identified a cut-off value of this index to predict CV mortality at 5.35 Units. Therefore, given that no SUA/sCr ratio threshold for CV risk has been identified for patients with diabetes, we aimed to assess the relationship between this index and CV mortality and to validate this threshold in the URRAH subpopulation with diabetes; the URRAH participants with diabetes were studied (n = 2230). The risk of CV mortality was evaluated by the Kaplan–Meier estimator and Cox multivariate analysis. During a median follow-up of 9.2 years, 380 CV deaths occurred. A non-linear inverse association between baseline SUA/sCr ratio and risk of CV mortality was detected. In the whole sample, SUA/sCr ratio > 5.35 Units was not a significant predictor of CV mortality in diabetic patients. However, after stratification by kidney function, values > 5.35 Units were associated with a significantly higher mortality rate only in normal kidney function, while, in participants with overt kidney dysfunction, values of SUA/sCr ratio > 7.50 Units were associated with higher CV mortality. The SUA/sCr ratio threshold, previously proposed by the URRAH Study Group, is predictive of an increased risk of CV mortality in people with diabetes and preserved kidney function. While, in consideration of the strong association among kidney function, SUA, and CV mortality, a different cut-point was detected for diabetics with impaired kidney function. These data highlight the different predictive roles of SUA (and its interaction with kidney function) in CV risk, pointing out the difference in metabolic- and kidney-dependent SUA levels also in diabetic individuals. Full article

(This article belongs to the Special Issue Exploring Uric Acid and Beyond)

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9 pages, 1796 KiB

Open AccessEditor’s ChoiceCommunication

Evaluation of Oil-Absorbing Film for Imprint Desorption Electrospray Ionization Mass Spectrometry Imaging (IDESI-MSI) on Biological Samples

by Jiedong Li, Ruolun Wei, Yifan Meng and Richard N. Zare

Metabolites 2024, 14(3), 160; https://doi.org/10.3390/metabo14030160 - 11 Mar 2024

Viewed by 1669

Abstract

Imprint Desorption Electrospray Ionization Mass Spectrometry Imaging (IDESI-MSI) has proven to be a robust and reliable tool for chemically imaging biological samples such as fungi, animal tissues, and plants, but the choice of the imprint substrate is crucial. It must effectively transfer maximum [...] Read more.

Imprint Desorption Electrospray Ionization Mass Spectrometry Imaging (IDESI-MSI) has proven to be a robust and reliable tool for chemically imaging biological samples such as fungi, animal tissues, and plants, but the choice of the imprint substrate is crucial. It must effectively transfer maximum amounts of species from the sample while preserving the original spatial distribution of detected molecules. In this study, we explored the potential of utilizing an oil-absorbing film, known for its soft nature and excellent lipophilicity, as an imprint substrate for IDESI-MSI on biological samples. To assess the transfer efficiency of the amounts of molecules and molecular patterns, we conducted experiments using mouse brain tissue. The result shows that more than 90% of the analytes can be transferred to the oil-absorbing film from the original tissue. A comparison of IDESI-MSI results between the oil-absorbing film and the original tissue demonstrates the material’s capability to transfer most molecules from the original tissue and retain images of different analytes with high spatial fidelity. We extended our investigation to plant imaging, where we applied IDESI-MSI to a cross-section of okra. The oil-absorbing film exhibited promise in this context as well. These findings suggest that IDESI-MSI utilizing the oil-absorbing film holds potential across various research fields, including biological metabolism, chemistry, and clinical research, making this technique widely applicable. Full article

(This article belongs to the Special Issue Mass Spectrometry Imaging: Theory, Methods and Applications in Biochemical and Pharmaceutical Research)

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19 pages, 1443 KiB

Open AccessEditor’s ChoiceReview

Integrative Multiomics Approach to Skin: The Sinergy between Individualised Medicine and Futuristic Precision Skin Care?

by Angelica Dessì, Roberta Pintus, Vassilios Fanos and Alice Bosco

Metabolites 2024, 14(3), 157; https://doi.org/10.3390/metabo14030157 - 7 Mar 2024

Cited by 1 | Viewed by 2490

Abstract

The skin is a complex ecosystem colonized by millions of microorganisms, the skin microbiota, which are crucial in regulating not only the physiological functions of the skin but also the metabolic changes underlying the onset of skin diseases. The high microbial colonization together [...] Read more.

The skin is a complex ecosystem colonized by millions of microorganisms, the skin microbiota, which are crucial in regulating not only the physiological functions of the skin but also the metabolic changes underlying the onset of skin diseases. The high microbial colonization together with a low diversity at the phylum level and a high diversity at the species level of the skin is very similar to that of the gastrointestinal tract. Moreover, there is an important communication pathway along the gut–brain–skin axis, especially associated with the modulation of neurotransmitters by the microbiota. Therefore, it is evident that the high complexity of the skin system, due not only to the genetics of the host but also to the interaction of the host with resident microbes and between microbe and microbe, requires a multi-omics approach to be deeply understood. Therefore, an integrated analysis, with high-throughput technologies, of the consequences of microbial interaction with the host through the study of gene expression (genomics and metagenomics), transcription (transcriptomics and meta-transcriptomics), and protein production (proteomics and meta-proteomics) and metabolite formation (metabolomics and lipidomics) would be useful. Although to date very few studies have integrated skin metabolomics data with at least one other ‘omics’ technology, in the future, this approach will be able to provide simple and fast tests that can be routinely applied in both clinical and cosmetic settings for the identification of numerous skin diseases and conditions. It will also be possible to create large archives of multi-omics data that can predict individual responses to pharmacological treatments and the efficacy of different cosmetic products on individual subjects by means of specific allotypes, with a view to increasingly tailor-made medicine. In this review, after analyzing the complexity of the skin ecosystem, we have highlighted the usefulness of this emerging integrated omics approach for the analysis of skin problems, starting with one of the latest ‘omics’ sciences, metabolomics, which can photograph the expression of the genome during its interaction with the environment. Full article

(This article belongs to the Special Issue Preclinical and Clinical Application of Metabolomics in Medicine)

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20 pages, 4688 KiB

Open AccessEditor’s ChoiceArticle

Integrative Analysis of Cytokine and Lipidomics Datasets Following Mild Traumatic Brain Injury in Rats

by Alexis N. Pulliam, Alyssa F. Pybus, David A. Gaul, Samuel G. Moore, Levi B. Wood, Facundo M. Fernández and Michelle C. LaPlaca

Metabolites 2024, 14(3), 133; https://doi.org/10.3390/metabo14030133 - 21 Feb 2024

Cited by 3 | Viewed by 2225

Abstract

Traumatic brain injury (TBI) is a significant source of disability in the United States and around the world and may lead to long-lasting cognitive deficits and a decreased quality of life for patients across injury severities. Following the primary injury phase, TBI is [...] Read more.

Traumatic brain injury (TBI) is a significant source of disability in the United States and around the world and may lead to long-lasting cognitive deficits and a decreased quality of life for patients across injury severities. Following the primary injury phase, TBI is characterized by complex secondary cascades that involve altered homeostasis and metabolism, faulty signaling, neuroinflammation, and lipid dysfunction. The objectives of the present study were to (1) assess potential correlations between lipidome and cytokine changes after closed-head mild TBI (mTBI), and (2) examine the reproducibility of our acute lipidomic profiles following TBI. Cortices from 54 Sprague Dawley male and female rats were analyzed by ultra-high-performance liquid chromatography mass spectrometry (LC-MS) in both positive and negative ionization modes and multiplex cytokine analysis after single (smTBI) or repetitive (rmTBI) closed-head impacts, or sham conditions. Tissue age was a variable, given that two cohorts (n = 26 and n = 28) were initially run a year-and-a-half apart, creating inter-batch variations. We annotated the lipidome datasets using an in-house data dictionary based on exact masses of precursor and fragment ions and removed features with statistically significant differences between sham control batches. Our results indicate that lipids with high-fold change between injury groups moderately correlate with the cytokines eotaxin, IP-10, and TNF-α. Additionally, we show a significant decrease in the pro-inflammatory markers IL-1β and IP-10, TNF-α, and RANTES in the rmTBI samples relative to the sham control. We discuss the major challenges in correlating high dimensional lipidomic data with functional cytokine profiles and the implications for understanding the biological significance of two related but disparate analysis modes in the study of TBI, an inherently heterogeneous neurological disorder. Full article

(This article belongs to the Special Issue Challenges and Opportunities in Application of Mass Spectrometry for Metabolomics and Lipidomics)

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13 pages, 2106 KiB

Open AccessEditor’s ChoiceArticle

metabCombiner 2.0: Disparate Multi-Dataset Feature Alignment for LC-MS Metabolomics

by Hani Habra, Jennifer L. Meijer, Tong Shen, Oliver Fiehn, David A. Gaul, Facundo M. Fernández, Kaitlin R. Rempfert, Thomas O. Metz, Karen E. Peterson, Charles R. Evans and Alla Karnovsky

Metabolites 2024, 14(2), 125; https://doi.org/10.3390/metabo14020125 - 15 Feb 2024

Cited by 1 | Viewed by 2248

Abstract

Liquid chromatography–high-resolution mass spectrometry (LC-HRMS), as applied to untargeted metabolomics, enables the simultaneous detection of thousands of small molecules, generating complex datasets. Alignment is a crucial step in data processing pipelines, whereby LC-MS features derived from common ions are assembled into a unified [...] Read more.

Liquid chromatography–high-resolution mass spectrometry (LC-HRMS), as applied to untargeted metabolomics, enables the simultaneous detection of thousands of small molecules, generating complex datasets. Alignment is a crucial step in data processing pipelines, whereby LC-MS features derived from common ions are assembled into a unified matrix amenable to further analysis. Variability in the analytical factors that influence liquid chromatography separations complicates data alignment. This is prominent when aligning data acquired in different laboratories, generated using non-identical instruments, or between batches from large-scale studies. Previously, we developed metabCombiner for aligning disparately acquired LC-MS metabolomics datasets. Here, we report significant upgrades to metabCombiner that enable the stepwise alignment of multiple untargeted LC-MS metabolomics datasets, facilitating inter-laboratory reproducibility studies. To accomplish this, a “primary” feature list is used as a template for matching compounds in “target” feature lists. We demonstrate this workflow by aligning four lipidomics datasets from core laboratories generated using each institution’s in-house LC-MS instrumentation and methods. We also introduce batchCombine, an application of the metabCombiner framework for aligning experiments composed of multiple batches. metabCombiner is available as an R package on Github and Bioconductor, along with a new online version implemented as an R Shiny App. Full article

(This article belongs to the Special Issue Open-Source Software in Metabolomics)

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18 pages, 3450 KiB

Open AccessEditor’s ChoiceArticle

Metabolomics Reveals Antioxidant Metabolites in Colored Rice Grains

by Jinyan Zhu, Ruizhi Wang, Yu Zhang, Yanyao Lu, Shuo Cai and Qiangqiang Xiong

Metabolites 2024, 14(2), 120; https://doi.org/10.3390/metabo14020120 - 11 Feb 2024

Cited by 5 | Viewed by 1781

Abstract

Colored rice is richer in nutrients and contains more nutrients and bioactive substances than ordinary white rice. Moderate consumption of black (purple) rice has a variety of physiological effects, such as antioxidant effects, blood lipid regulation, and blood sugar control. Therefore, we utilized [...] Read more.

Colored rice is richer in nutrients and contains more nutrients and bioactive substances than ordinary white rice. Moderate consumption of black (purple) rice has a variety of physiological effects, such as antioxidant effects, blood lipid regulation, and blood sugar control. Therefore, we utilized nontargeted metabolomics, quantitative assays for flavonoid and phenolic compounds, and physiological and biochemical data to explore the correlations between metabolites and the development of antioxidant characteristics in pigmented rice seeds. The findings indicated that, among Yangjinnuo 818 (YJN818), Hongnuo (HN), Yangchannuo 1 hao (YCN1H), and Yangzi 6 hao (YZ6H), YZ6H exhibited the highest PAL activity, which was 2.13, 3.08, and 3.25 times greater than those of YJN818, HN, and YCN1H, respectively. YZ6H likewise exhibited the highest flavonoid content, which was 3.8, 7.06, and 35.54 times greater than those of YJN818, HN, and YCN1H, respectively. YZ6H also had the highest total antioxidant capacity, which was 2.42, 3.76, and 3.77 times greater than those of YJN818, HN, and YCN1H, respectively. Thus, purple rice grains have stronger antioxidant properties than other colored rice grains. Receiver operating characteristic (ROC) curve analysis revealed that trans-3,3′,4′,5,5′,7-hexahydroxyflavanone, phorizin, and trilobatin in the YZ6H, HN, and YCN1H comparison groups all had area under the curve (AUC) values of 1. Phlorizin, trans-3,3′,4′,5,5′,7-hexahydroxyflavanone, and trilobatin were recognized as indices of antioxidant capability in colored rice in this research. This research adds to the understanding of antioxidant compounds in pigmented rice, which can increase the nutritional value of rice and promote the overall well-being of individuals. This type of information is of immense importance in maintaining a balanced and healthy diet. Full article

(This article belongs to the Section Plant Metabolism)

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18 pages, 3547 KiB

Open AccessEditor’s ChoiceArticle

Longitudinal Profiling of Fasting Plasma Metabolome in Response to Weight-Loss Interventions in Patients with Morbid Obesity

by Mingjing Chen, Guanhong Miao, Zhiguang Huo, Hao Peng, Xiaoxiao Wen, Stephen Anton, Dachuan Zhang, Gang Hu, Ricky Brock, Phillip J. Brantley and Jinying Zhao

Metabolites 2024, 14(2), 116; https://doi.org/10.3390/metabo14020116 - 10 Feb 2024

Viewed by 1843

Abstract

It is well recognized that patients with severe obesity exhibit remarkable heterogeneity in response to different types of weight-loss interventions. Those who undergo Roux-en-Y gastric bypass (RYGB) usually exhibit more favorable glycemic outcomes than those who receive adjustable gastric banding (BAND) or intensive [...] Read more.

It is well recognized that patients with severe obesity exhibit remarkable heterogeneity in response to different types of weight-loss interventions. Those who undergo Roux-en-Y gastric bypass (RYGB) usually exhibit more favorable glycemic outcomes than those who receive adjustable gastric banding (BAND) or intensive medical intervention (IMI). The molecular mechanisms behind these observations, however, remain largely unknown. To identify the plasma metabolites associated with differential glycemic outcomes induced by weight-loss intervention, we studied 75 patients with severe obesity (25 each in RYGB, BAND, or IMI). Using untargeted metabolomics, we repeatedly measured 364 metabolites in plasma samples at baseline and 1-year after intervention. Linear regression was used to examine whether baseline metabolites or changes in metabolites are associated with differential glycemic outcomes in response to different types of weight-loss intervention, adjusting for sex, baseline age, and BMI as well as weight loss. Network analyses were performed to identify differential metabolic pathways involved in the observed associations. After correction for multiple testing (q < 0.05), 33 (RYGB vs. IMI) and 28 (RYGB vs. BAND) baseline metabolites were associated with changes in fasting plasma glucose (FPG) or glycated hemoglobin (HbA1c). Longitudinal changes in 38 (RYGB vs. IMI) and 38 metabolites (RYGB vs. BAND) were significantly associated with changes in FPG or HbA1c. The identified metabolites are enriched in pathways involved in the biosynthesis of aminoacyl-tRNA and branched-chain amino acids. Weight-loss intervention evokes extensive changes in plasma metabolites, and the altered metabolome may underlie the differential glycemic outcomes in response to different types of weight-loss intervention, independent of weight loss itself. Full article

(This article belongs to the Special Issue Analytical Advances and Applications in Clinical Metabolomics)

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16 pages, 1418 KiB

Open AccessEditor’s ChoiceTechnical Note

Implementation of FAIR Practices in Computational Metabolomics Workflows—A Case Study

by Mahnoor Zulfiqar, Michael R. Crusoe, Birgitta König-Ries, Christoph Steinbeck, Kristian Peters and Luiz Gadelha

Metabolites 2024, 14(2), 118; https://doi.org/10.3390/metabo14020118 - 10 Feb 2024

Viewed by 1903

Abstract

Scientific workflows facilitate the automation of data analysis tasks by integrating various software and tools executed in a particular order. To enable transparency and reusability in workflows, it is essential to implement the FAIR principles. Here, we describe our experiences implementing the FAIR [...] Read more.

Scientific workflows facilitate the automation of data analysis tasks by integrating various software and tools executed in a particular order. To enable transparency and reusability in workflows, it is essential to implement the FAIR principles. Here, we describe our experiences implementing the FAIR principles for metabolomics workflows using the Metabolome Annotation Workflow (MAW) as a case study. MAW is specified using the Common Workflow Language (CWL), allowing for the subsequent execution of the workflow on different workflow engines. MAW is registered using a CWL description on WorkflowHub. During the submission process on WorkflowHub, a CWL description is used for packaging MAW using the Workflow RO-Crate profile, which includes metadata in Bioschemas. Researchers can use this narrative discussion as a guideline to commence using FAIR practices for their bioinformatics or cheminformatics workflows while incorporating necessary amendments specific to their research area. Full article

(This article belongs to the Special Issue Open-Source Software in Metabolomics)

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21 pages, 3360 KiB

Open AccessEditor’s ChoiceArticle

Data-Driven Characterization of Metabolome Reprogramming during Early Development of Sorghum Seedlings

by Ian A. Dubery, Lerato P. Nephali, Fidele Tugizimana and Paul A. Steenkamp

Metabolites 2024, 14(2), 112; https://doi.org/10.3390/metabo14020112 - 7 Feb 2024

Viewed by 1944

Abstract

Specialized metabolites are produced via discrete metabolic pathways. These small molecules play significant roles in plant growth and development, as well as defense against environmental stresses. These include damping off or seedling blight at a post-emergence stage. Targeted metabolomics was followed to gain [...] Read more.

Specialized metabolites are produced via discrete metabolic pathways. These small molecules play significant roles in plant growth and development, as well as defense against environmental stresses. These include damping off or seedling blight at a post-emergence stage. Targeted metabolomics was followed to gain insights into metabolome changes characteristic of different developmental stages of sorghum seedlings. Metabolites were extracted from leaves at seven time points post-germination and analyzed using ultra-high performance liquid chromatography coupled to mass spectrometry. Multivariate statistical analysis combined with chemometric tools, such as principal component analysis, hierarchical clustering analysis, and orthogonal partial least squares–discriminant analysis, were applied for data exploration and to reduce data dimensionality as well as for the selection of potential discriminant biomarkers. Changes in metabolome patterns of the seedlings were analyzed in the early, middle, and late stages of growth (7, 14, and 29 days post-germination). The metabolite classes were amino acids, organic acids, lipids, cyanogenic glycosides, hormones, hydroxycinnamic acid derivatives, and flavonoids, with the latter representing the largest class of metabolites. In general, the metabolite content showed an increase with the progression of the plant growth stages. Most of the differential metabolites were derived from tryptophan and phenylalanine, which contribute to innate immune defenses as well as growth. Quantitative analysis identified a correlation of apigenin flavone derivatives with growth stage. Data-driven investigations of these metabolomes provided new insights into the developmental dynamics that occur in seedlings to limit post-germination mortality. Full article

(This article belongs to the Special Issue Metabolomics and Plant Defence)

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14 pages, 1158 KiB

Open AccessEditor’s ChoiceArticle

Blood-Derived Metabolic Signatures as Biomarkers of Injury Severity in Traumatic Brain Injury: A Pilot Study

by Elani A. Bykowski, Jamie N. Petersson, Sean P. Dukelow, Chester Ho, Chantel T. Debert, Tony Montina and Gerlinde A. S. Metz

Metabolites 2024, 14(2), 105; https://doi.org/10.3390/metabo14020105 - 2 Feb 2024

Viewed by 2062

Abstract

Metabolomic biomarkers hold promise in aiding the diagnosis and prognostication of traumatic brain injury. In Canada, over 165,000 individuals annually suffer from a traumatic brain injury (TBI), making it one of the most prevalent neurological conditions. In this pilot investigation, we examined blood-derived [...] Read more.

Metabolomic biomarkers hold promise in aiding the diagnosis and prognostication of traumatic brain injury. In Canada, over 165,000 individuals annually suffer from a traumatic brain injury (TBI), making it one of the most prevalent neurological conditions. In this pilot investigation, we examined blood-derived biomarkers as proxy measures that can provide an objective approach to TBI diagnosis and monitoring. Using a ¹H nuclear magnetic resonance (NMR)-based quantitative metabolic profiling approach, this study determined whether (1) blood-derived metabolites change during recovery in male participants with mild to severe TBI; (2) biological pathway analysis reflects mechanisms that mediate neural damage/repair throughout TBI recovery; and (3) changes in metabolites correlate to initial injury severity. Eight male participants with mild to severe TBI (with intracranial lesions) provided morning blood samples within 1–4 days and again 6 months post-TBI. Following NMR analysis, the samples were subjected to multivariate statistical and machine learning-based analyses. Statistical modelling displayed metabolic changes during recovery through group separation, and eight significant metabolic pathways were affected by TBI. Metabolic changes were correlated to injury severity. L-alanine (R= −0.63, p < 0.01) displayed a negative relationship with the Glasgow Coma Scale. This study provides pilot data to support the feasibility of using blood-derived metabolites to better understand changes in biochemistry following TBI. Full article

(This article belongs to the Special Issue Innovation and Development in NMR-Based Metabolomics for Disease Diagnostics)

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15 pages, 2534 KiB

Open AccessEditor’s ChoiceArticle

New Implications of Metabolites and Free Fatty Acids in Quality Control of Crossbred Wagyu Beef during Wet Aging Cold Storage

by Shuji Ueda, Yuka Yoshida, Biniam Kebede, Chiaki Kitamura, Ryo Sasaki, Masakazu Shinohara, Itsuko Fukuda and Yasuhito Shirai

Metabolites 2024, 14(2), 95; https://doi.org/10.3390/metabo14020095 - 29 Jan 2024

Cited by 1 | Viewed by 2118

Abstract

Efficient cold-chain delivery is essential for maintaining a sustainable global food supply. This study used metabolomic analysis to examine meat quality changes during the “wet aging” of crossbred Wagyu beef during cold storage. The longissimus thoracic (Loin) and adductor muscles (Round) of hybrid [...] Read more.

Efficient cold-chain delivery is essential for maintaining a sustainable global food supply. This study used metabolomic analysis to examine meat quality changes during the “wet aging” of crossbred Wagyu beef during cold storage. The longissimus thoracic (Loin) and adductor muscles (Round) of hybrid Wagyu beef, a cross between the Japanese Black and Holstein–Friesian breeds, were packaged in vacuum film and refrigerated for up to 40 days. Sensory evaluation indicated an increase in the umami and kokumi taste owing to wet aging. Comprehensive analysis using gas chromatography-mass spectrometry identified metabolite changes during wet aging. In the Loin, 94 metabolites increased, and 24 decreased; in the Round, 91 increased and 18 decreased. Metabolites contributing to the umami taste of the meat showed different profiles during wet aging. Glutamic acid increased in a cold storage-dependent manner, whereas creatinine and inosinic acid degraded rapidly even during cold storage. In terms of lipids, wet aging led to an increase in free fatty acids. In particular, linoleic acid, a polyunsaturated fatty acid, increased significantly among the free fatty acids. These results provide new insight into the effects of wet aging on Wagyu-type beef, emphasizing the role of free amino acids, organic acids, and free fatty acids generated during cold storage. Full article

(This article belongs to the Section Food Metabolomics)

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16 pages, 2967 KiB

Open AccessEditor’s ChoiceArticle

Advancing Glucose Conjugated Gibberellins Discovery: A Structure–Oriented Screening and Identification Method for Unraveling Gibberellin Metabolites in Plants

by Chen Zeng, Wen-Jing Cai, Liu-Cheng Jiang, Tiantian Ye and Yu-Qi Feng

Metabolites 2024, 14(2), 96; https://doi.org/10.3390/metabo14020096 - 29 Jan 2024

Viewed by 1474

Abstract

Gibberellins (GAs) play a pivotal role in modulating plant growth and development. Glucose–conjugated gibberellins (Glc–GAs), a prevalent conjugated form of GAs, regulate intracellular GA levels by the coupling and decoupling of glucose groups. However, the diversity of Glc–GAs identified within individual species remains [...] Read more.

Gibberellins (GAs) play a pivotal role in modulating plant growth and development. Glucose–conjugated gibberellins (Glc–GAs), a prevalent conjugated form of GAs, regulate intracellular GA levels by the coupling and decoupling of glucose groups. However, the diversity of Glc–GAs identified within individual species remains limited, hinting at a multitude of yet undiscovered gibberellin metabolites. This lacuna poses considerable impediments to research efforts dedicated to comprehensively delineating the GA metabolic pathway. In this study, we developed a structure–oriented screening and identification method for Glc–GAs in plant species by employing LC–MS/MS coupled with chemical derivatization. Through the application of chemical derivatization technique, carboxyl groups on Glc–GAs were labeled which effectively enhanced the sensitivity and selectivity of mass spectrometry detection for these compounds. Concurrently, the integration of mass spectrometry fragmentation and chromatographic retention behavior facilitated the efficient screening and identification of potential Glc–GAs. With this strategy, we screened and identified 12 potential Glc–GAs from six plant species. These findings expand the Glc–GA diversity in plants and contribute to understanding GA metabolic pathways. Full article

(This article belongs to the Section Plant Metabolism)

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12 pages, 816 KiB

Open AccessEditor’s ChoiceArticle

Associations of the Single Bovine Embryo Growth Media Metabolome with Successful Pregnancy

by Elina Tsopp, Kalle Kilk, Egon Taalberg, Pille Pärn, Anni Viljaste-Seera, Ants Kavak and Ülle Jaakma

Metabolites 2024, 14(2), 89; https://doi.org/10.3390/metabo14020089 - 26 Jan 2024

Viewed by 1760

Abstract

This study investigated whether metabolomic fingerprints of bovine embryo growth media improve the prediction of successful embryo implantation. In this prospective cohort study, the metabolome from in vitro-produced day 7 blastocysts with successful implantation (n = 11), blastocysts with failed implantation ( [...] Read more.

This study investigated whether metabolomic fingerprints of bovine embryo growth media improve the prediction of successful embryo implantation. In this prospective cohort study, the metabolome from in vitro-produced day 7 blastocysts with successful implantation (n = 11), blastocysts with failed implantation (n = 10), and plain culture media without embryos (n = 5) were included. Samples were analyzed using an AbsoluteIDQ^® p180 Targeted Metabolomics Kit with LC-MS/MS, and a total of 189 metabolites were analyzed from each sample. Blastocysts that resulted in successful embryo implantation had significantly higher levels of methionine sulfoxide (p < 0.001), DOPA (p < 0.05), spermidine (p < 0.001), acetylcarnitine-to-free-carnitine ratio (p < 0.05), C2 + C3-to-free-carnitine ratio (p < 0.05), and lower levels of threonine (nep < 0.001) and phosphatidylcholine PC ae C30:0 (p < 0.001) compared to control media. However, when compared to embryos that failed to implant, only DOPA, spermidine, C2/C0, (C2 + C3)/C0, and PC ae C30:0 levels differentiated significantly. In summary, our study identifies a panel of differential metabolites in the culture media of bovine blastocysts that could act as potential biomarkers for the selection of viable blastocysts before embryo transfer. Full article

(This article belongs to the Section Animal Metabolism)

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16 pages, 4181 KiB

Open AccessEditor’s ChoiceArticle

Metabolomics Reveals Lysinibacillus capsici TT41-Induced Metabolic Shifts Enhancing Drought Stress Tolerance in Kimchi Cabbage (Brassica rapa L. subsp. pekinensis)

by Tae Jin Kim, Ye Ji Hwang, Young Jin Park, Jong Sung Lee, Jae Kwang Kim and Mi-Hwa Lee

Metabolites 2024, 14(2), 87; https://doi.org/10.3390/metabo14020087 - 25 Jan 2024

Viewed by 1655

Abstract

Climate change has increased variable weather patterns that affect plants. To address these issues, we developed a microbial biocontrol agent against drought stress in kimchi cabbage (Brassica rapa L. subsp. pekinensis). We selected three bacterial strains (Leifsonia sp. CS9, Bacillus [...] Read more.

Climate change has increased variable weather patterns that affect plants. To address these issues, we developed a microbial biocontrol agent against drought stress in kimchi cabbage (Brassica rapa L. subsp. pekinensis). We selected three bacterial strains (Leifsonia sp. CS9, Bacillus toyonensis TSJ7, and Lysinibacillus capsici TT41) because they showed a survival rate of up to 50% and good growth rate when treated with 30% PEG 6000. The three strains were treated with kimchi cabbage to confirm their enhanced drought stress resistance under non-watering conditions. Among the three strains, the TT41 treated group showed a significant increase in various plant parameters compared with the negative control on the 7th day. We performed extensive profiling of primary and secondary metabolites from kimchi cabbage and the TT41 strain. Multivariate and pathway analyses revealed that only the TT41 group clustered with the well-watered group and showed almost the same metabolome on the 7th day. When treated with TT41, lactic acid was identified as an indicator metabolite that significantly improved drought stress tolerance. Furthermore, lactic acid treatment effectively induced drought stress tolerance in kimchi cabbage, similar to that achieved with the TT41 strain. Full article

(This article belongs to the Section Plant Metabolism)

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16 pages, 3643 KiB

Open AccessEditor’s ChoiceArticle

Proteomics-Based Investigation of Different Live Prey Administered to Freshwater Dark Sleeper (Odontobutis potamophila): Examining the Effects on Glycolipids and Energy Metabolism

by Zihan Zhou, Qichen Jiang, You Zheng, Chen Hao, Shuyan Ding, Mengya Guo, Yunlong Zhao, Guoxing Liu and Shuyan Miao

Metabolites 2024, 14(2), 85; https://doi.org/10.3390/metabo14020085 - 24 Jan 2024

Viewed by 1630

Abstract

Live prey is characterized by balanced rich nutrients and high palatability and is widely used for the seedling cultivation of freshwater dark sleeper (Odontobutis potamophila) larvae. In this study, we evaluated the effects of four groups of paired feeding regimens (group [...] Read more.

Live prey is characterized by balanced rich nutrients and high palatability and is widely used for the seedling cultivation of freshwater dark sleeper (Odontobutis potamophila) larvae. In this study, we evaluated the effects of four groups of paired feeding regimens (group C (Daphnia magna), group L (Limnodrilus hoffmeisteri), group H (Hypophthalmichthys molitrix fry), and group M (mixed groups C, L, and H)) on glycolipid and energy metabolism in O. potamophila larvae. We observed that fatty acid synthase (FAS) and sterol-regulatory-element-binding protein-1 (SREBP-1) mRNA levels were significantly lower in group H when compared to mRNA levels in the other three groups (p < 0.05) and that carnitine palmitoyltransferase 1α (CPT1-α) mRNA levels were significantly lower in group L when compared to group M (p < 0.05). Relative glucokinase (GK) expression levels were significantly lower in group M when compared to the other three groups (p < 0.05). Using proteomics, we analyzed and compared groups H and L and identified 457 differentially expressed proteins (DEPs), of which 151 were significantly up-regulated and 306 were significantly down-regulated. In the comparison of group M with groups C, L, and H, we found significant enrichment in glycolytic processes, the endoplasmic reticulum lumen, NAD binding, intermediate filaments, and nutrient reservoir activity. Our results provide a theoretical guidance for bait selection during larvae cultivation stages in carnivorous fish. Full article

(This article belongs to the Special Issue Nutrition and Metabolism in Animals)

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15 pages, 1939 KiB

Open AccessEditor’s ChoiceArticle

Optimized Mass Spectrometry Detection of Thyroid Hormones and Polar Metabolites in Rodent Cerebrospinal Fluid

by Ryann M. Fame, Ilhan Ali, Maria K. Lehtinen, Naama Kanarek and Boryana Petrova

Metabolites 2024, 14(2), 79; https://doi.org/10.3390/metabo14020079 - 23 Jan 2024

Cited by 3 | Viewed by 2252

Abstract

Thyroid hormones (TH) are required for brain development and function. Cerebrospinal fluid (CSF), which bathes the brain and spinal cord, contains TH as free hormones or as bound to transthyretin (TTR). Tight TH level regulation in the central nervous system is essential for [...] Read more.

Thyroid hormones (TH) are required for brain development and function. Cerebrospinal fluid (CSF), which bathes the brain and spinal cord, contains TH as free hormones or as bound to transthyretin (TTR). Tight TH level regulation in the central nervous system is essential for developmental gene expression, which governs neurogenesis, myelination, and synaptogenesis. This integrated function of TH highlights the importance of developing precise and reliable methods for assessing TH levels in CSF. We report an optimized liquid chromatography–mass spectrometry (LC-MS)-based method to measure TH in rodent CSF and serum, applicable to both fresh and frozen samples. Using this new method, we find distinct differences in CSF TH in pregnant dams vs. non-pregnant adults and in embryonic vs. adult CSF. Further, targeted LC-MS metabolic profiling uncovers distinct central carbon metabolism in the CSF of these populations. TH detection and metabolite profiling of related metabolic pathways open new avenues of rigorous research into CSF TH and will inform future studies on metabolic alterations in CSF during normal development. Full article

(This article belongs to the Special Issue Mass Spectrometry: A Powerful Tool for Comprehensive Metabolomic Profiling of Cells and Tissues)

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14 pages, 2380 KiB

Open AccessEditor’s ChoiceArticle

Analysis of the Fecal Metabolomic Profile in Breast vs. Different Formula Milk Feeding in Late Preterm Infants

by Giuseppe De Bernardo, Gilda D’Urso, Simona Spadarella, Maurizio Giordano, Giuseppina Leone and Agostino Casapullo

Metabolites 2024, 14(1), 72; https://doi.org/10.3390/metabo14010072 - 22 Jan 2024

Cited by 1 | Viewed by 1914

Abstract

Human milk is the gold standard for infant nutrition, but when it is not available or insufficient to satisfy the needs of the infant, formula milk is proposed as an effective substitute. A prospective observational cohort study was conducted on late preterm infants [...] Read more.

Human milk is the gold standard for infant nutrition, but when it is not available or insufficient to satisfy the needs of the infant, formula milk is proposed as an effective substitute. A prospective observational cohort study was conducted on late preterm infants fed with breast and two different formula milks. On this basis, they were divided into three groups: group FMPB (fed with formula + postbiotic), group FM (fed with standard formula), and group BM (breastfed). Stool samples for a metabolomic study were collected at T0 (5–7 days after birth), T1 (30 days of life), and T2 (90 days of life), giving rise to 74 samples analyzed via liquid chromatography coupled with high-resolution mass spectrometry. The T0, T1, and T2 LC-MS raw data were processed for Partial Least Square Discriminant Analysis (PLS-DA), followed by a statistical analysis. This preliminary study highlighted a good overlapping between the fecal metabolome of breast and substitute feeding systems, confirming the efficacy of the formula preparations as breast milk substitutes. Moreover, several similarities were also detected between the FMPB and BM metabolome, highlighting that the addition of a postbiotic to standard formula milk could be more effective and considered a better alternative to breast milk. Full article

(This article belongs to the Section Advances in Metabolomics)

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17 pages, 931 KiB

Open AccessEditor’s ChoiceReview

Gut Microbiota–Gut Metabolites and Clostridioides difficile Infection: Approaching Sustainable Solutions for Therapy

by Bijay Gurung, Maranda Stricklin and Shaohua Wang

Metabolites 2024, 14(1), 74; https://doi.org/10.3390/metabo14010074 - 22 Jan 2024

Cited by 5 | Viewed by 3207

Abstract

Clostridioides difficile (C. difficile) infection (CDI) is the most common hospital-acquired infection. With the combination of a high rate of antibiotic resistance and recurrence, it has proven to be a debilitating public health threat. Current treatments for CDI include antibiotics and [...] Read more.

Clostridioides difficile (C. difficile) infection (CDI) is the most common hospital-acquired infection. With the combination of a high rate of antibiotic resistance and recurrence, it has proven to be a debilitating public health threat. Current treatments for CDI include antibiotics and fecal microbiota transplantation, which contribute to recurrent CDIs and potential risks. Therefore, there is an ongoing need to develop new preventative treatment strategies for CDI. Notably, gut microbiota dysbiosis is the primary risk factor for CDI and provides a promising target for developing novel CDI therapy approaches. Along with gut microbiota dysbiosis, a reduction in important gut metabolites like secondary bile acids and short-chain fatty acids (SCFAs) were also seen in patients suffering from CDI. In this review study, we investigated the roles and mechanisms of gut microbiota and gut microbiota-derived gut metabolites, especially secondary bile acids and SCFAs in CDI pathogenesis. Moreover, specific signatures of gut microbiota and gut metabolites, as well as different factors that can modulate the gut microbiota, were also discussed, indicating that gut microbiota modulators like probiotics and prebiotics can be a potential therapeutic strategy for CDI as they can help restore gut microbiota and produce gut metabolites necessary for a healthy gut. The understanding of the associations between gut microbiota–gut metabolites and CDI will allow for developing precise and sustainable approaches, distinct from antibiotics and fecal transplant, for mitigating CDI and other gut microbiota dysbiosis-related diseases. Full article

(This article belongs to the Section Advances in Metabolomics)

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11 pages, 2227 KiB

Open AccessEditor’s ChoiceArticle

Reliability of Time-Series Plasma Metabolome Data over 6 Years in a Large-Scale Cohort Study

by Atsuko Miyake, Sei Harada, Daisuke Sugiyama, Minako Matsumoto, Aya Hirata, Naoko Miyagawa, Ryota Toki, Shun Edagawa, Kazuyo Kuwabara, Tomonori Okamura, Asako Sato, Kaori Amano, Akiyoshi Hirayama, Masahiro Sugimoto, Tomoyoshi Soga, Masaru Tomita, Kazuharu Arakawa, Toru Takebayashi and Miho Iida

Metabolites 2024, 14(1), 77; https://doi.org/10.3390/metabo14010077 - 22 Jan 2024

Viewed by 1748

Abstract

Studies examining long-term longitudinal metabolomic data and their reliability in large-scale populations are limited. Therefore, we aimed to evaluate the reliability of repeated measurements of plasma metabolites in a prospective cohort setting and to explore intra-individual concentration changes at three time points over [...] Read more.

Studies examining long-term longitudinal metabolomic data and their reliability in large-scale populations are limited. Therefore, we aimed to evaluate the reliability of repeated measurements of plasma metabolites in a prospective cohort setting and to explore intra-individual concentration changes at three time points over a 6-year period. The study participants included 2999 individuals (1317 men and 1682 women) from the Tsuruoka Metabolomics Cohort Study, who participated in all three surveys—at baseline, 3 years, and 6 years. In each survey, 94 plasma metabolites were quantified for each individual and quality control (QC) sample. The coefficients of variation of QC, intraclass correlation coefficients, and change rates of QC were calculated for each metabolite, and their reliability was classified into three categories: excellent, fair to good, and poor. Seventy-six percent (71/94) of metabolites were classified as fair to good or better. Of the 39 metabolites grouped as excellent, 29 (74%) in men and 26 (67%) in women showed significant intra-individual changes over 6 years. Overall, our study demonstrated a high degree of reliability for repeated metabolome measurements. Many highly reliable metabolites showed significant changes over the 6-year period, suggesting that repeated longitudinal metabolome measurements are useful for epidemiological studies. Full article

(This article belongs to the Section Advances in Metabolomics)

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17 pages, 3790 KiB

Open AccessEditor’s ChoiceArticle

Biomarkers of Metabolic Adaptation to High Dietary Fats in a Mouse Model of Obesity Resistance

by Fadia Milhem, Leah M. Hamilton, Emily Skates, Mickey Wilson, Suzanne D. Johanningsmeier and Slavko Komarnytsky

Metabolites 2024, 14(1), 69; https://doi.org/10.3390/metabo14010069 - 20 Jan 2024

Cited by 2 | Viewed by 1960

Abstract

Obesity-resistant (non-responder, NR) phenotypes that exhibit reduced susceptibility to developing obesity despite being exposed to high dietary fat are crucial in exploring the metabolic responses that protect against obesity. Although several efforts have been made to study them in mice and humans, the [...] Read more.

Obesity-resistant (non-responder, NR) phenotypes that exhibit reduced susceptibility to developing obesity despite being exposed to high dietary fat are crucial in exploring the metabolic responses that protect against obesity. Although several efforts have been made to study them in mice and humans, the individual protective mechanisms are poorly understood. In this exploratory study, we used a polygenic C57BL/6J mouse model of diet-induced obesity to show that NR mice developed healthier fat/lean body mass ratios (0.43 ± 0.05) versus the obesity-prone (super-responder, SR) phenotypes (0.69 ± 0.07, p < 0.0001) by upregulating gene expression networks that promote the accumulation of type 2a, fast-twitch, oxidative muscle tissues. This was achieved in part by a metabolic adaptation in the form of blood glucose sparing, thus aggravating glucose tolerance. Resistance to obesity in NR mice was associated with 4.9-fold upregulated mitoferrin 1 (Slc25a37), an essential mitochondrial iron importer. SR mice also showed fecal volatile metabolite signatures of enhanced short-chain fatty acid metabolism, including increases in detrimental methyl formate and ethyl propionate, and these effects were reversed in NR mice. Continued research into obesity-resistant phenotypes can offer valuable insights into the underlying mechanisms of obesity and metabolic health, potentially leading to more personalized and effective approaches for managing weight and related health issues. Full article

(This article belongs to the Special Issue Internal Medicine, Clinical Immunology and Metabolic Diseases)

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13 pages, 4926 KiB

Open AccessEditor’s ChoiceArticle

The Omics Dashboard for Interactive Exploration of Metabolomics and Multi-Omics Data

by Suzanne Paley and Peter D. Karp

Metabolites 2024, 14(1), 65; https://doi.org/10.3390/metabo14010065 - 19 Jan 2024

Cited by 1 | Viewed by 3320

Abstract

The Omics Dashboard is a software tool for interactive exploration and analysis of metabolomics, transcriptomics, proteomics, and multi-omics datasets. Organized as a hierarchy of cellular systems, the Dashboard at its highest level contains graphical panels for the full range of cellular systems, including [...] Read more.

The Omics Dashboard is a software tool for interactive exploration and analysis of metabolomics, transcriptomics, proteomics, and multi-omics datasets. Organized as a hierarchy of cellular systems, the Dashboard at its highest level contains graphical panels for the full range of cellular systems, including biosynthesis, energy metabolism, and response to stimulus. Thus, the Dashboard top level surveys the state of the cell across a broad range of key systems in a single screen. Each Dashboard panel contains a series of X–Y plots depicting the aggregated omics data values relevant to different subsystems of that panel, e.g., subsystems within the biosynthesis panel include amino acid biosynthesis, carbohydrate biosynthesis and cofactor biosynthesis. Users can interactively drill down to focus in on successively lower-level subsystems of interest. In this article, we present for the first time the metabolomics analysis capabilities of the Omics Dashboard, along with significant new extensions to better accommodate metabolomics datasets, enable analysis and visualization of multi-omics datasets, and provide new data-filtering options. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Metabolic Pathway Mapping and Enrichment)

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12 pages, 2356 KiB

Open AccessEditor’s ChoiceArticle

Thyroid Hormone Metabolites Quantified in Pup and Adult Rat Cerebellum, Cortex and Whole-Brain Samples Using an Automated Online SPE-LC-MS/MS Method

by Christiane Hindrichs, Tilmann Walk, Robert Landsiedel, Hennicke Kamp, Steffen Schneider, Stephanie Melching-Kollmuss and Dorothee Funk-Weyer

Metabolites 2024, 14(1), 61; https://doi.org/10.3390/metabo14010061 - 17 Jan 2024

Viewed by 1627

Abstract

Changes in thyroid hormone (TH) levels in rat brain at early developmental stages are correlated with adverse effects on offspring development. To characterize the ability of substances to interfere with the TH concentrations in, e.g., rat brain, it is essential to know the [...] Read more.

Changes in thyroid hormone (TH) levels in rat brain at early developmental stages are correlated with adverse effects on offspring development. To characterize the ability of substances to interfere with the TH concentrations in, e.g., rat brain, it is essential to know the mean TH concentrations in this tissue under control conditions. In this publication, an online solid-phase extraction (SPE) liquid chromatography (LC) tandem mass spectrometry (MS/MS) method was validated and used to measure TH metabolites (T4, T3, rT3, T2 and T1) in the brains of untreated rats. Data on TH concentrations in the whole brain and separate data from the cerebellum and the cortex are shown. The corresponding samples were gathered from young rats at postnatal days (PND) 4 and 21/22 and from adult rats. The results show inter alia the high accuracy and precision of the method, and LOQs of 0.02 ng/mL were determined for T1, T2 and rT3 and of 0.15 ng/mL for T3 and T4. Technical variability is low, as shown by the relative standard deviations of 7.5–20%. For our rat model, we found that T4, T3 and T2 concentrations rise from PND4 to PND21, whereas the rT3 concentration decreases; as well as there is no statistical difference between TH concentrations in the male and female rat brain. This method is suitable to analyze TH metabolites in the brain and build up a database of historical TH concentrations in control rats. Together, this yields a robust diagnostic tool to detect potentially adverse disturbances of TH homeostasis in the most vulnerable anatomic structure. Full article

(This article belongs to the Special Issue Metabolomics in Preclinical Drug Safety Assessment)

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21 pages, 6619 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Adaptations in Rapeseed: Hemin-Induced Resilience to NaCl Stress by Enhancing Growth, Photosynthesis, and Cellular Defense Ability

by Xutong Lu, Dianfeng Zheng, Naijie Feng, Guangsheng Zhou, Aaqil Khan, Huimin Zhao, Peng Deng, Hang Zhou, Feng Lin and Ziming Chen

Metabolites 2024, 14(1), 57; https://doi.org/10.3390/metabo14010057 - 15 Jan 2024

Cited by 1 | Viewed by 1580

Abstract

This study aimed to investigate whether presoaking with hemin (5 μmol·L⁻¹) could alleviate NaCl stress during rapeseed seedlings’ growth and its role in the regulation of photosynthesis. In this experiment, ‘HUAYOUZA 62 (HYZ 62)’ and ‘HUAYOUZA 158R (158R)’ were used as [...] Read more.

This study aimed to investigate whether presoaking with hemin (5 μmol·L⁻¹) could alleviate NaCl stress during rapeseed seedlings’ growth and its role in the regulation of photosynthesis. In this experiment, ‘HUAYOUZA 62 (HYZ 62)’ and ‘HUAYOUZA 158R (158R)’ were used as materials for pot experiments to study the morphology, photosynthetic characteristics, antioxidant activity, and osmoregulatory factors of seedlings under different salt concentrations, as well as the regulatory effects of hemin-presoaked seeds. Our findings revealed that, compared the control, NaCl stress inhibited the growth of two rapeseed varieties, decreased the seedling emergence rate, and increased the content of malondialdehyde (MDA), the electrolyte leakage rate (EL) and antioxidant enzyme activity. Hemin soaking alleviated the adverse effects of salt stress and increased plant height, root elongation and dry matter accumulation. Compared with all NaCl treatments, hemin significantly enhanced photosynthetic indexes, including a percent increase of 12.99–24.36% and 5.39–16.52% in net photosynthetic rate (Pn), 17.86–48.08% and 8.6–23.44% in stomatal conductivity (Gs), and 15.42–37.94% and 11.09–19.08% in transpiration rate (Tr) for HYZ62 and 158R, respectively. Moreover, hemin soaking also increased antioxidant enzyme activities, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX), reducing the malondialdehyde, and thus resulting in the alleviation of oxidative damage caused by NaCl stress. Furthermore, hemin stimulated the formation of soluble protein, which effectively regulated the osmo-protective qualities. The current findings strongly elucidate that hemin soaking could effectively alleviate the negative impacts of NaCl stress by regulating the morphological, photosynthetic, and antioxidant traits. This study provides a new idea regarding the effect of Hemin on the salt tolerance of rapeseed, and provides a basis for the practical application of Hemin in saline–alkali soil to improve the salt tolerance of cultivated rapeseed. Full article

(This article belongs to the Special Issue Effects of Biotic/Abiotic Stress on Plant Metabolism)

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15 pages, 8154 KiB

Open AccessEditor’s ChoiceArticle

The Effect of Yucca schidigera Extract on Serum Metabolites of Angus Crossbreed Steers with Metabolomics

by Ziqi Deng, Baoyun Wu, Xin Yi, Jinglei Ma, Yue Liu, Luiz Gustavo Nussio, Qingxiang Meng, Zhenming Zhou and Hao Wu

Metabolites 2024, 14(1), 58; https://doi.org/10.3390/metabo14010058 - 15 Jan 2024

Cited by 1 | Viewed by 1652

Abstract

This study was conducted to explore the potential effect of Yucca schidigera extract (YSE) on the metabolism of beef cattle. Thirty Angus crossbreed steers were selected, with an initial mean body weight of 506.6 ± 33.3 kg, and assigned to two treatments: a [...] Read more.

This study was conducted to explore the potential effect of Yucca schidigera extract (YSE) on the metabolism of beef cattle. Thirty Angus crossbreed steers were selected, with an initial mean body weight of 506.6 ± 33.3 kg, and assigned to two treatments: a diet with no additives (CON group) and a diet supplemented with 1.75 g/kg of YSE (YSE group) (on a dry matter basis). The experiment lasted for 104 days, with 14 days for adaptation. The results showed that adding YSE could significantly improve the average daily gain (ADG) from 1 to 59 d (15.38%) (p = 0.01) and 1 to 90 d (11.38%) (p < 0.01), as well as dry matter digestibility (DMD) (0.84%) (p < 0.05). The contents of alanine aminotransferase, aspartate aminotransferase, and bilirubin and the total antioxidant capacity were increased and blood urea was reduced in the YSE group, compared to the CON group (p < 0.05). Both the glycerophospholipids and bile acids, including phosphocholine, glycerophosphocholine, PC(15:0/18:2(9Z,12Z)), PE(18:0/20:3(5Z,8Z,11Z)), PE(18:3(6Z,9Z,12Z)/P-18:0), LysoPC(15:0), LysoPC(17:0), LysoPC(18:0), LysoPC(20:5(5Z,8Z,11Z,14Z,17Z)), deoxycholic acid, glycocholic acid, and cholic acid, were upregulated by the addition of YSE. In summary, YSE may improve the ADG by increasing the blood total antioxidant capacity and glycerophospholipid synthesis, maintaining steers under a healthy status that is beneficial for growth. Furthermore, YSE may also increase the expression of bile acid synthesis, thereby promoting DMD, which, in turn, offers more nutrients available for growth. Full article

(This article belongs to the Special Issue Advances in Metabolism and Nutrition Physiology)

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26 pages, 6562 KiB

Open AccessEditor’s ChoiceArticle

Metabolomic Signatures of Brainstem in Mice following Acute and Subchronic Hydrogen Sulfide Exposure

by Dong-Suk Kim, Cristina M. Santana Maldonado, Cecilia Giulivi and Wilson Kiiza Rumbeiha

Metabolites 2024, 14(1), 53; https://doi.org/10.3390/metabo14010053 - 14 Jan 2024

Cited by 1 | Viewed by 1909

Abstract

Hydrogen sulfide (H₂S) is an environmental toxicant of significant health concern. The brain is a major target in acute H₂S poisoning. This study was conducted to test the hypothesis that acute and subchronic ambient H₂S exposures alter [...] Read more.

Hydrogen sulfide (H₂S) is an environmental toxicant of significant health concern. The brain is a major target in acute H₂S poisoning. This study was conducted to test the hypothesis that acute and subchronic ambient H₂S exposures alter the brain metabolome. Male 7–8-week-old C57BL/6J mice were exposed by whole-body inhalation to 1000 ppm H₂S for 45 min and euthanized at 5 min or 72 h for acute exposure. For subchronic study, mice were exposed to 5 ppm H₂S 2 h/day, 5 days/week for 5 weeks. Control mice were exposed to room air. The brainstem was removed for metabolomic analysis. Enrichment analysis showed that the metabolomic profiles in acute and subchronic H₂S exposures matched with those of cerebral spinal fluid from patients with seizures or Alzheimer’s disease. Acute H₂S exposure decreased excitatory neurotransmitters, aspartate, and glutamate, while the inhibitory neurotransmitter, serotonin, was increased. Branched-chain amino acids and glucose were increased by acute H₂S exposure. Subchronic H₂S exposure within OSHA guidelines surprisingly decreased serotonin concentration. In subchronic H₂S exposure, glucose was decreased, while polyunsaturated fatty acids, inosine, and hypoxanthine were increased. Collectively, these results provide important mechanistic clues for acute and subchronic ambient H₂S poisoning and show that H₂S alters brainstem metabolome. Full article

(This article belongs to the Section Animal Metabolism)

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