Metabolites

15 pages, 1576 KiB

Open AccessEditor’s ChoiceArticle

Accurate Prediction of ¹H NMR Chemical Shifts of Small Molecules Using Machine Learning

by Tanvir Sajed, Zinat Sayeeda, Brian L. Lee, Mark Berjanskii, Fei Wang, Vasuk Gautam and David S. Wishart

Metabolites 2024, 14(5), 290; https://doi.org/10.3390/metabo14050290 - 19 May 2024

Cited by 3 | Viewed by 2045

Abstract

NMR is widely considered the gold standard for organic compound structure determination. As such, NMR is routinely used in organic compound identification, drug metabolite characterization, natural product discovery, and the deconvolution of metabolite mixtures in biofluids (metabolomics and exposomics). In many cases, compound [...] Read more.

NMR is widely considered the gold standard for organic compound structure determination. As such, NMR is routinely used in organic compound identification, drug metabolite characterization, natural product discovery, and the deconvolution of metabolite mixtures in biofluids (metabolomics and exposomics). In many cases, compound identification by NMR is achieved by matching measured NMR spectra to experimentally collected NMR spectral reference libraries. Unfortunately, the number of available experimental NMR reference spectra, especially for metabolomics, medical diagnostics, or drug-related studies, is quite small. This experimental gap could be filled by predicting NMR chemical shifts for known compounds using computational methods such as machine learning (ML). Here, we describe how a deep learning algorithm that is trained on a high-quality, “solvent-aware” experimental dataset can be used to predict ¹H chemical shifts more accurately than any other known method. The new program, called PROSPRE (PROton Shift PREdictor) can accurately (mean absolute error of <0.10 ppm) predict ¹H chemical shifts in water (at neutral pH), chloroform, dimethyl sulfoxide, and methanol from a user-submitted chemical structure. PROSPRE (pronounced “prosper”) has also been used to predict ¹H chemical shifts for >600,000 molecules in many popular metabolomic, drug, and natural product databases. Full article

(This article belongs to the Special Issue Metabolomics and Machine Learning for Improved Diagnostics and as a Tool to Accelerate Drug Development)

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17 pages, 1844 KiB

Open AccessEditor’s ChoiceArticle

Long-Term Consumption of Purified Water Altered Amino Acid, Fatty Acid and Energy Metabolism in Livers of Rats

by Jia Wang, Zhiqun Qiu, Hui Zeng, Yao Tan, Yujing Huang, Jiaohua Luo and Weiqun Shu

Metabolites 2024, 14(5), 289; https://doi.org/10.3390/metabo14050289 - 19 May 2024

Viewed by 1815

Abstract

The consumption of low-mineral water has been increasing worldwide. Drinking low-mineral water is associated with cardiovascular disease, osteopenia, and certain neurodegenerative diseases. However, the specific mechanism remains unclear. The liver metabolic alterations in rats induced by drinking purified water for 3 months were [...] Read more.

The consumption of low-mineral water has been increasing worldwide. Drinking low-mineral water is associated with cardiovascular disease, osteopenia, and certain neurodegenerative diseases. However, the specific mechanism remains unclear. The liver metabolic alterations in rats induced by drinking purified water for 3 months were investigated with a metabolomics-based strategy. Compared with the tap water group, 74 metabolites were significantly changed in the purified water group (6 increased and 68 decreased), including 29 amino acids, 11 carbohydrates, 10 fatty acids, 7 short chain fatty acids (SCFAs), and 17 other biomolecules. Eight metabolic pathways were significantly changed, namely aminoacyl–tRNA biosynthesis; nitrogen metabolism; alanine, aspartate and glutamate metabolism; arginine and proline metabolism; histidine metabolism; biosynthesis of unsaturated fatty acids; butanoate metabolism; and glycine, serine and threonine metabolism. These changes suggested that consumption of purified water induced negative nitrogen balance, reduced expression of some polyunsaturated fatty acids and SCFAs, and disturbed energy metabolism in rats. These metabolic disturbances may contribute to low-mineral-water-associated health risks. The health risk of consuming low-mineral water requires attention. Full article

(This article belongs to the Section Animal Metabolism)

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12 pages, 1620 KiB

Open AccessArticle

Adipose Tissue Insulin Resistance in South Asian and Nordic Women after Gestational Diabetes Mellitus

by Ahalya Anita Suntharalingam Kvist, Archana Sharma, Christine Sommer, Elisabeth Qvigstad, Hanne Løvdal Gulseth, Stina Therese Sollid, Ingrid Nermoen, Naveed Sattar, Jason Gill, Tone Møller Tannæs, Kåre Inge Birkeland and Sindre Lee-Ødegård

Metabolites 2024, 14(5), 288; https://doi.org/10.3390/metabo14050288 - 18 May 2024

Viewed by 1634

Abstract

South Asians (SAs) have a higher risk of developing type 2 diabetes (T2D) than white Europeans, especially following gestational diabetes mellitus (GDM). Despite similar blood glucose levels post-GDM, SAs exhibit more insulin resistance (IR) than Nordics, though the underlying mechanisms are unclear. This [...] Read more.

South Asians (SAs) have a higher risk of developing type 2 diabetes (T2D) than white Europeans, especially following gestational diabetes mellitus (GDM). Despite similar blood glucose levels post-GDM, SAs exhibit more insulin resistance (IR) than Nordics, though the underlying mechanisms are unclear. This study aimed to assess markers of adipose tissue (AT) IR and liver fat in SA and Nordic women post-GDM. A total of 179 SA and 108 Nordic women in Norway underwent oral glucose tolerance tests 1–3 years post-GDM. We measured metabolic markers and calculated the AT IR index and non-alcoholic fatty liver disease liver fat (NAFLD-LFS) scores. Results showed that normoglycaemic SAs had less non-esterified fatty acid (NEFA) suppression during the test, resembling prediabetes/T2D responses, and higher levels of plasma fetuin-A, CRP, and IL-6 but lower adiponectin, indicating AT inflammation. Furthermore, normoglycaemic SAs had higher NAFLD-LFS scores, lower insulin clearance, and higher peripheral insulin than Nordics, indicating increased AT IR, inflammation, and liver fat in SAs. Higher liver fat markers significantly contributed to the ethnic disparities in glucose metabolism, suggesting a key area for intervention to reduce T2D risk post-GDM in SAs. Full article

(This article belongs to the Special Issue Glucose Metabolism in Pregnancy)

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17 pages, 2112 KiB

Open AccessReview

The Role of Exerkines in Obesity-Induced Disruption of Mitochondrial Homeostasis in Thermogenic Fat

by Hui Shao, Huijie Zhang and Dandan Jia

Metabolites 2024, 14(5), 287; https://doi.org/10.3390/metabo14050287 - 17 May 2024

Viewed by 1713

Abstract

There is a notable correlation between mitochondrial homeostasis and metabolic disruption. In this review, we report that obesity-induced disruption of mitochondrial homeostasis adversely affects lipid metabolism, adipocyte differentiation, oxidative capacity, inflammation, insulin sensitivity, and thermogenesis in thermogenic fat. Elevating mitochondrial homeostasis in thermogenic [...] Read more.

There is a notable correlation between mitochondrial homeostasis and metabolic disruption. In this review, we report that obesity-induced disruption of mitochondrial homeostasis adversely affects lipid metabolism, adipocyte differentiation, oxidative capacity, inflammation, insulin sensitivity, and thermogenesis in thermogenic fat. Elevating mitochondrial homeostasis in thermogenic fat emerges as a promising avenue for developing treatments for metabolic diseases, including enhanced mitochondrial function, mitophagy, mitochondrial uncoupling, and mitochondrial biogenesis. The exerkines (e.g., myokines, adipokines, batokines) released during exercise have the potential to ameliorate mitochondrial homeostasis, improve glucose and lipid metabolism, and stimulate fat browning and thermogenesis as a defense against obesity-associated metabolic diseases. This comprehensive review focuses on the manifold benefits of exercise-induced exerkines, particularly emphasizing their influence on mitochondrial homeostasis and fat thermogenesis in the context of metabolic disorders associated with obesity. Full article

(This article belongs to the Special Issue Exploring Pathological Mechanisms in Obesity, Diabetes, and Metabolic Syndrome)

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17 pages, 1190 KiB

Open AccessArticle

Targeted Analysis of Plasma Polar Metabolites in Postmenopausal Depression

by Maria Fernanda Naufel, Amanda Paula Pedroso, Adriana Pereira de Souza, Valter Tadeu Boldarine, Lila Missae Oyama, Edson Guimarães Lo Turco, Helena Hachul, Eliane Beraldi Ribeiro and Mônica Marques Telles

Metabolites 2024, 14(5), 286; https://doi.org/10.3390/metabo14050286 - 16 May 2024

Viewed by 1116

Abstract

Depression will be the disease with the highest incidence worldwide by 2030. Data indicate that postmenopausal women have a higher incidence of mood disorders, and this high vulnerability seems to be related to hormonal changes and weight gain. Although research evaluating the profile [...] Read more.

Depression will be the disease with the highest incidence worldwide by 2030. Data indicate that postmenopausal women have a higher incidence of mood disorders, and this high vulnerability seems to be related to hormonal changes and weight gain. Although research evaluating the profile of metabolites in mood disorders is advancing, further research, maintaining consistent methodology, is necessary to reach a consensus. Therefore, the objective of the present study was to carry out an exploratory analysis of the plasma polar metabolites of pre- and postmenopausal women to explore whether the profile is affected by depression. The plasma analysis of 50 polar metabolites was carried out in a total of 67 postmenopausal women, aged between 50 and 65 years, either without depression (n = 25) or with depression symptoms (n = 42), which had spontaneous onset of menopause and were not in use of hormone replacement therapy, insulin, or antidepressants; and in 42 healthy premenopausal women (21 without depression and 21 with depression symptoms), aged between 40 and 50 years and who were not in use of contraceptives, insulin, or antidepressants. Ten metabolites were significantly affected by depression symptoms postmenopause, including adenosine (FDR = 3.778 × 10⁻¹⁴), guanosine (FDR = 3.001 × 10⁻¹⁴), proline (FDR = 1.430 × 10⁻⁶), citrulline (FDR = 0.0001), lysine (FDR = 0.0004), and carnitine (FDR = 0.0331), which were down-regulated, and dimethylglycine (FDR = 0.0022), glutathione (FDR = 0.0048), creatine (FDR = 0.0286), and methionine (FDR = 0.0484) that were up-regulated. In premenopausal women with depression, oxidized glutathione (FDR = 0.0137) was down-regulated, and dimethylglycine (FDR = 0.0406) and 4-hydroxyproline (FDR = 0.0433) were up-regulated. The present study provided new data concerning the consequences of depression on plasma polar metabolites before and after the establishment of menopause. The results demonstrated that the postmenopausal condition presented more alterations than the premenopausal period and may indicate future measures to treat the disturbances involved in both menopause and depression. Full article

(This article belongs to the Special Issue Metabolomics Meets Neuropsychiatry)

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16 pages, 18541 KiB

Open AccessArticle

Changes in Metabolite Profiles of Chinese Soy Sauce at Different Time Durations of Fermentation Studied by ¹H-NMR-Based Metabolomics

by Jalal Uddin, Samra Yasmin, Ghulam Mustafa Kamal, Mufarreh Asmari, Muhammad Saqib and Heyu Chen

Metabolites 2024, 14(5), 285; https://doi.org/10.3390/metabo14050285 - 15 May 2024

Cited by 1 | Viewed by 1167

Abstract

Fermentation parameters, especially the duration, are important in imparting a peculiar taste and flavor to soy sauce. The main purpose of this research was to monitor metabolic changes occurring during the various time intervals of the fermentation process. NMR-based metabolomics was used to [...] Read more.

Fermentation parameters, especially the duration, are important in imparting a peculiar taste and flavor to soy sauce. The main purpose of this research was to monitor metabolic changes occurring during the various time intervals of the fermentation process. NMR-based metabolomics was used to monitor the compositional changes in soy sauce during fermentation. The ¹H-NMR spectra of the soy sauce samples taken from the fermentation tanks at 0 to 8 months were analyzed using ¹H-NMR spectroscopy, and the obtained spectra were analyzed by multivariate statistical analysis. The Principal Component Analysis (PCA) and Partial Least Square Discriminate analysis (PLSDA) revealed the separation of samples fermented for various time durations under identical conditions. Key metabolites shown by corresponding loading plots exhibited variations in amino acids (lysine, threonine, isoleucine, etc.), acetate, glucose, fructose, sucrose, ethanol, glycerol, and others. The levels of ethanol in soy sauce increased with longer fermentation durations, which can be influenced by both natural fermentation and the intentional addition of ethanol as a preservative. The study shows that the variation in metabolite can be very efficiently monitored using ¹H-NMR-based metabolomics, thus suggestion to optimize the time duration to get the soy sauce product with the desired taste and flavor. Full article

(This article belongs to the Special Issue Application of Metabolomics in Food Fermentation)

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15 pages, 5213 KiB

Open AccessEditor’s ChoiceArticle

Desorption Electrospray Ionization Mass Spectrometry Imaging Techniques Depict a Reprogramming of Energy and Purine Metabolism in the Core Brain Regions of Chronic Social Defeat Stress Mice

by Yulong Song, Fan Xiao, Jiye Aa and Guangji Wang

Metabolites 2024, 14(5), 284; https://doi.org/10.3390/metabo14050284 - 15 May 2024

Viewed by 1372

Abstract

Depression is associated with pathological changes and metabolic abnormalities in multiple brain regions. The simultaneous comprehensive and in situ detection of endogenous molecules in all brain regions is essential for a comprehensive understanding of depression pathology, which is described in this paper. A [...] Read more.

Depression is associated with pathological changes and metabolic abnormalities in multiple brain regions. The simultaneous comprehensive and in situ detection of endogenous molecules in all brain regions is essential for a comprehensive understanding of depression pathology, which is described in this paper. A method based on desorption electrospray ionization mass spectrometry imaging (DESI-MSI) technology was developed to classify mouse brain regions using characteristic lipid molecules and to detect the metabolites in mouse brain tissue samples simultaneously. The results showed that characteristic lipid molecules can be used to clearly distinguish each subdivision of the mouse brain, and the accuracy of this method is higher than that of the conventional staining method. The cerebellar cortex, medial prefrontal cortex, hippocampus, striatum, nucleus accumbens-core, and nucleus accumbens-shell exhibited the most significant differences in the chronic social defeat stress model. An analysis of metabolic pathways revealed that 13 kinds of molecules related to energy metabolism and purine metabolism exhibited significant changes. A DESI-MSI method was developed for the detection of pathological brain sections. We found, for the first time, that there are characteristic changes in the energy metabolism in the cortex and purine metabolism in the striatum, which is highly important for obtaining a deeper and more comprehensive understanding of the pathology of depression and discovering regulatory targets. 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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28 pages, 5902 KiB

Open AccessReview

Deleterious Effects of Heat Stress on the Tomato, Its Innate Responses, and Potential Preventive Strategies in the Realm of Emerging Technologies

by Qaisar Khan, Yixi Wang, Gengshou Xia, Hui Yang, Zhengrong Luo and Yan Zhang

Metabolites 2024, 14(5), 283; https://doi.org/10.3390/metabo14050283 - 15 May 2024

Cited by 1 | Viewed by 2115

Abstract

The tomato is a fruit vegetable rich in nutritional and medicinal value grown in greenhouses and fields worldwide. It is severely sensitive to heat stress, which frequently occurs with rising global warming. Predictions indicate a 0.2 °C increase in average surface temperatures per [...] Read more.

The tomato is a fruit vegetable rich in nutritional and medicinal value grown in greenhouses and fields worldwide. It is severely sensitive to heat stress, which frequently occurs with rising global warming. Predictions indicate a 0.2 °C increase in average surface temperatures per decade for the next three decades, which underlines the threat of austere heat stress in the future. Previous studies have reported that heat stress adversely affects tomato growth, limits nutrient availability, hammers photosynthesis, disrupts reproduction, denatures proteins, upsets signaling pathways, and damages cell membranes. The overproduction of reactive oxygen species in response to heat stress is toxic to tomato plants. The negative consequences of heat stress on the tomato have been the focus of much investigation, resulting in the emergence of several therapeutic interventions. However, a considerable distance remains to be covered to develop tomato varieties that are tolerant to current heat stress and durable in the perspective of increasing global warming. This current review provides a critical analysis of the heat stress consequences on the tomato in the context of global warming, its innate response to heat stress, and the elucidation of domains characterized by a scarcity of knowledge, along with potential avenues for enhancing sustainable tolerance against heat stress through the involvement of diverse advanced technologies. The particular mechanism underlying thermotolerance remains indeterminate and requires further elucidatory investigation. The precise roles and interplay of signaling pathways in response to heat stress remain unresolved. The etiology of tomato plants’ physiological and molecular responses against heat stress remains unexplained. Utilizing modern functional genomics techniques, including transcriptomics, proteomics, and metabolomics, can assist in identifying potential candidate proteins, metabolites, genes, gene networks, and signaling pathways contributing to tomato stress tolerance. Improving tomato tolerance against heat stress urges a comprehensive and combined strategy including modern techniques, the latest apparatuses, speedy breeding, physiology, and molecular markers to regulate their physiological, molecular, and biochemical reactions. Full article

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

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11 pages, 684 KiB

Open AccessArticle

Overweight, Obesity, Hypertriglyceridemia, and Insulin Resistance Are Positively Associated with High Serum Copper Levels in Mexican Adults

by Armando Ramírez-Cruz, María Judith Rios-Lugo, Jacqueline Soto-Sánchez, Cuauhtémoc Arturo Juárez-Pérez, Alejandro Cabello-López, Carmina Jiménez-Ramírez, Consuelo Chang-Rueda, Miguel Cruz, Héctor Hernández-Mendoza and Miguel Vazquez-Moreno

Metabolites 2024, 14(5), 282; https://doi.org/10.3390/metabo14050282 - 14 May 2024

Viewed by 1059

Abstract

Recently, the role of trace elements in the pathophysiology of obesity, insulin resistance (IR), and metabolic diseases has been explored. In this cross-sectional study, we aimed to assess the association of overweight, obesity, and cardiometabolic traits with serum copper (Cu) levels in 346 [...] Read more.

Recently, the role of trace elements in the pathophysiology of obesity, insulin resistance (IR), and metabolic diseases has been explored. In this cross-sectional study, we aimed to assess the association of overweight, obesity, and cardiometabolic traits with serum copper (Cu) levels in 346 Mexican adults. Serum Cu level was measured by inductively coupled plasma mass spectrometry (ICP-MS). Anthropometrical data were collected, and biochemical parameters were measured. The triglyceride-glucose (TyG) index was used as a surrogate marker to evaluate IR. Overweight and obesity status was positively associated with the serum Cu level (β = 19.434 ± 7.309, p = 0.008). Serum Cu level was observed to have a positive association with serum triglycerides level (β = 0.160 ± 0.045, p < 0.001) and TyG (β = 0.001 ± 0.001, p < 0.001). Additionally, high serum Cu level was positively associated with overweight and obesity status (odds ratio [OR] = 1.9, 95% confidence interval [95% CI] 1.1–3.4, p = 0.014), hypertriglyceridemia (OR = 3.0, 95% CI 1.7–5.3, p < 0.001), and IR (OR = 2.6, 95% CI 1.4–4.6, p = 0.001). In conclusion, our results suggest that overweight, obesity, hypertriglyceridemia, and IR are positively associated with serum Cu levels in Mexican adults. Full article

(This article belongs to the Special Issue Trace Metal Element Metabolism in Biological Systems)

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12 pages, 1605 KiB

Open AccessArticle

Volatile Organic Compounds in Cellular Headspace after Hyperbaric Oxygen Exposure: An In Vitro Pilot Study

by Feiko J. M. de Jong, Thijs A. Lilien, Dominic W. Fenn, Thijs T. Wingelaar, Pieter-Jan A. M. van Ooij, Anke H. Maitland-van der Zee, Markus W. Hollmann, Rob A. van Hulst and Paul Brinkman

Metabolites 2024, 14(5), 281; https://doi.org/10.3390/metabo14050281 - 13 May 2024

Viewed by 1126

Abstract

Volatile organic compounds (VOCs) might be associated with pulmonary oxygen toxicity (POT). This pilot study aims to identify VOCs linked to oxidative stress employing an in vitro model of alveolar basal epithelial cells exposed to hyperbaric and hyperoxic conditions. In addition, the feasibility [...] Read more.

Volatile organic compounds (VOCs) might be associated with pulmonary oxygen toxicity (POT). This pilot study aims to identify VOCs linked to oxidative stress employing an in vitro model of alveolar basal epithelial cells exposed to hyperbaric and hyperoxic conditions. In addition, the feasibility of this in vitro model for POT biomarker research was evaluated. The hyperbaric exposure protocol, similar to the U.S. Navy Treatment Table 6, was conducted on human alveolar basal epithelial cells, and the headspace VOCs were analyzed using gas chromatography–mass spectrometry. Three compounds (nonane [p = 0.005], octanal [p = 0.009], and decane [p = 0.018]), of which nonane and decane were also identified in a previous in vivo study with similar hyperbaric exposure, varied significantly between the intervention group which was exposed to 100% oxygen and the control group which was exposed to compressed air. VOC signal intensities were lower in the intervention group, but cellular stress markers (IL8 and LDH) confirmed increased stress and injury in the intervention group. Despite the observed reductions in compound expression, the model holds promise for POT biomarker exploration, emphasizing the need for further investigation into the complex relationship between VOCs and oxidative stress. Full article

(This article belongs to the Section Environmental Metabolomics)

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18 pages, 5080 KiB

Open AccessEditor’s ChoiceArticle

Olaris Global Panel (OGP): A Highly Accurate and Reproducible Triple Quadrupole Mass Spectrometry-Based Metabolomics Method for Clinical Biomarker Discovery

by Masoumeh Dorrani, Jifang Zhao, Nihel Bekhti, Alessia Trimigno, Sangil Min, Jongwon Ha, Ahram Han, Elizabeth O’Day and Jurre J. Kamphorst

Metabolites 2024, 14(5), 280; https://doi.org/10.3390/metabo14050280 - 11 May 2024

Viewed by 1725

Abstract

Mass spectrometry (MS)-based clinical metabolomics is very promising for the discovery of new biomarkers and diagnostics. However, poor data accuracy and reproducibility limit its true potential, especially when performing data analysis across multiple sample sets. While high-resolution mass spectrometry has gained considerable popularity [...] Read more.

Mass spectrometry (MS)-based clinical metabolomics is very promising for the discovery of new biomarkers and diagnostics. However, poor data accuracy and reproducibility limit its true potential, especially when performing data analysis across multiple sample sets. While high-resolution mass spectrometry has gained considerable popularity for discovery metabolomics, triple quadrupole (QqQ) instruments offer several benefits for the measurement of known metabolites in clinical samples. These benefits include high sensitivity and a wide dynamic range. Here, we present the Olaris Global Panel (OGP), a HILIC LC-QqQ MS method for the comprehensive analysis of ~250 metabolites from all major metabolic pathways in clinical samples. For the development of this method, multiple HILIC columns and mobile phase conditions were compared, the robustness of the leading LC method assessed, and MS acquisition settings optimized for optimal data quality. Next, the effect of U-¹³C metabolite yeast extract spike-ins was assessed based on data accuracy and precision. The use of these U-¹³C-metabolites as internal standards improved the goodness of fit to a linear calibration curve from r² < 0.75 for raw data to >0.90 for most metabolites across the entire clinical concentration range of urine samples. Median within-batch CVs for all metabolite ratios to internal standards were consistently lower than 7% and less than 10% across batches that were acquired over a six-month period. Finally, the robustness of the OGP method, and its ability to identify biomarkers, was confirmed using a large sample set. Full article

(This article belongs to the Special Issue Metabolomics and Machine Learning for Improved Diagnostics and as a Tool to Accelerate Drug Development)

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16 pages, 2491 KiB

Open AccessEditor’s ChoiceArticle

Mass Spectrometric Analysis of Purine Intermediary Metabolism Indicates Cyanide Induces Purine Catabolism in Rabbits

by Jordan Morningstar, Jangwoen Lee, Sari Mahon, Matthew Brenner and Anjali K. Nath

Metabolites 2024, 14(5), 279; https://doi.org/10.3390/metabo14050279 - 10 May 2024

Cited by 1 | Viewed by 1282

Abstract

Purines are the building blocks of DNA/RNA, energy substrates, and cofactors. Purine metabolites, including ATP, GTP, NADH, and coenzyme A, are essential molecules in diverse biological processes such as energy metabolism, signal transduction, and enzyme activity. When purine levels increase, excess purines are [...] Read more.

Purines are the building blocks of DNA/RNA, energy substrates, and cofactors. Purine metabolites, including ATP, GTP, NADH, and coenzyme A, are essential molecules in diverse biological processes such as energy metabolism, signal transduction, and enzyme activity. When purine levels increase, excess purines are either recycled to synthesize purine metabolites or catabolized to the end product uric acid. Purine catabolism increases during states of low oxygen tension (hypoxia and ischemia), but this metabolic pathway is incompletely understood in the context of histotoxic hypoxia (i.e., inhibition of oxygen utilization despite normal oxygen tension). In rabbits exposed to cyanide—a classical histotoxic hypoxia agent—we demonstrated significant increases in several concordant metabolites in the purine catabolic pathway (including plasma levels of uric acid, xanthosine, xanthine, hypoxanthine, and inosine) via mass spectrometry-based metabolite profiling. Pharmacological inhibition of the purine catabolic pathway with oxypurinol mitigated the deleterious effects of cyanide on skeletal muscle cytochrome c oxidase redox state, measured by non-invasive diffuse optical spectroscopy. Finally, plasma uric acid levels correlated strongly with those of lactic acid, an established clinical biomarker of cyanide exposure, in addition to a tissue biomarker of cyanide exposure (skeletal muscle cytochrome c oxidase redox state). Cumulatively, these findings not only shed light on the in vivo role(s) of cyanide but also have implications in the field of medical countermeasure (MCM) development. Full article

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

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16 pages, 1281 KiB

Open AccessEditor’s ChoiceArticle

A Chemical Structure and Machine Learning Approach to Assess the Potential Bioactivity of Endogenous Metabolites and Their Association with Early Childhood Systemic Inflammation

by Mario Lovrić, Tingting Wang, Mads Rønnow Staffe, Iva Šunić, Kristina Časni, Jessica Lasky-Su, Bo Chawes and Morten Arendt Rasmussen

Metabolites 2024, 14(5), 278; https://doi.org/10.3390/metabo14050278 - 10 May 2024

Viewed by 1703

Abstract

Metabolomics has gained much attention due to its potential to reveal molecular disease mechanisms and present viable biomarkers. This work uses a panel of untargeted serum metabolomes from 602 children from the COPSAC2010 mother–child cohort. The annotated part of the metabolome consists of [...] Read more.

Metabolomics has gained much attention due to its potential to reveal molecular disease mechanisms and present viable biomarkers. This work uses a panel of untargeted serum metabolomes from 602 children from the COPSAC2010 mother–child cohort. The annotated part of the metabolome consists of 517 chemical compounds curated using automated procedures. We created a filtering method for the quantified metabolites using predicted quantitative structure–bioactivity relationships for the Tox21 database on nuclear receptors and stress response in cell lines. The metabolites measured in the children’s serums are predicted to affect specific targeted models, known for their significance in inflammation, immune function, and health outcomes. The targets from Tox21 have been used as targets with quantitative structure–activity relationships (QSARs). They were trained for ~7000 structures, saved as models, and then applied to the annotated metabolites to predict their potential bioactivities. The models were selected based on strict accuracy criteria surpassing random effects. After application, 52 metabolites showed potential bioactivity based on structural similarity with known active compounds from the Tox21 set. The filtered compounds were subsequently used and weighted by their bioactive potential to show an association with early childhood hs-CRP levels at six months in a linear model supporting a physiological adverse effect on systemic low-grade inflammation. Full article

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

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21 pages, 2508 KiB

Open AccessEditor’s ChoiceReview

Salivary Metabolites Produced by Oral Microbes in Oral Diseases and Oral Squamous Cell Carcinoma: A Review

by Bina Kashyap and Arja Kullaa

Metabolites 2024, 14(5), 277; https://doi.org/10.3390/metabo14050277 - 10 May 2024

Cited by 2 | Viewed by 1872

Abstract

In recent years, salivary metabolome studies have provided new biological information and salivary biomarkers to diagnose different diseases at early stages. The saliva in the oral cavity is influenced by many factors that are reflected in the salivary metabolite profile. Oral microbes can [...] Read more.

In recent years, salivary metabolome studies have provided new biological information and salivary biomarkers to diagnose different diseases at early stages. The saliva in the oral cavity is influenced by many factors that are reflected in the salivary metabolite profile. Oral microbes can alter the salivary metabolite profile and may express oral inflammation or oral diseases. The released microbial metabolites in the saliva represent the altered biochemical pathways in the oral cavity. This review highlights the oral microbial profile and microbial metabolites released in saliva and its use as a diagnostic biofluid for different oral diseases. The importance of salivary metabolites produced by oral microbes as risk factors for oral diseases and their possible relationship in oral carcinogenesis is discussed. Full article

(This article belongs to the Special Issue Advances in Salivary Metabolomics for Oral and Systemic Diseases)

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16 pages, 249 KiB

Open AccessReview

Intake Biomarkers for Nutrition and Health: Review and Discussion of Methodology Issues

by Ross L. Prentice

Metabolites 2024, 14(5), 276; https://doi.org/10.3390/metabo14050276 - 10 May 2024

Cited by 1 | Viewed by 1319

Abstract

Metabolomics profiles from blood, urine, or other body fluids have the potential to assess intakes of foods and nutrients objectively, thereby strengthening nutritional epidemiology research. Metabolomics platforms may include targeted components that estimate the relative concentrations for individual metabolites in a predetermined set, [...] Read more.

Metabolomics profiles from blood, urine, or other body fluids have the potential to assess intakes of foods and nutrients objectively, thereby strengthening nutritional epidemiology research. Metabolomics platforms may include targeted components that estimate the relative concentrations for individual metabolites in a predetermined set, or global components, typically involving mass spectrometry, that estimate relative concentrations more broadly. While a specific metabolite concentration usually correlates with the intake of a single food or food group, multiple metabolites may be correlated with the intake of certain foods or with specific nutrient intakes, each of which may be expressed in absolute terms or relative to total energy intake. Here, I briefly review the progress over the past 20 years on the development and application intake biomarkers for foods/food groups, nutrients, and dietary patterns, primarily by drawing from several recent reviews. In doing so, I emphasize the criteria and study designs for candidate biomarker identification, biomarker validation, and intake biomarker application. The use of intake biomarkers for diet and chronic disease association studies is still infrequent in nutritional epidemiology research. My comments here will derive primarily from our research group’s recent contributions to the Women’s Health Initiative cohorts. I will complete the contribution by describing some opportunities to build on the collective 20 years of effort, including opportunities related to the metabolomics profiling of blood and urine specimens from human feeding studies that approximate habitual diets. Full article

(This article belongs to the Special Issue Metabolomics-Based Biomarkers for Nutrition and Health)

17 pages, 4141 KiB

Open AccessArticle

NMR Precision Metabolomics: Dynamic Peak Sum Thresholding and Navigators for Highly Standardized and Reproducible Metabolite Profiling of Clinical Urine Samples

by Alessia Trimigno, Nicole R. Holderman, Chen Dong, Kari D. Boardman, Jifang Zhao and Elizabeth M. O’Day

Metabolites 2024, 14(5), 275; https://doi.org/10.3390/metabo14050275 - 10 May 2024

Viewed by 1294

Abstract

Metabolomics, especially urine-based studies, offers incredible promise for the discovery and development of clinically impactful biomarkers. However, due to the unique challenges of urine, a highly precise and reproducible workflow for NMR-based urine metabolomics is lacking. Using 1D and 2D non-uniform sampled (NUS) [...] Read more.

Metabolomics, especially urine-based studies, offers incredible promise for the discovery and development of clinically impactful biomarkers. However, due to the unique challenges of urine, a highly precise and reproducible workflow for NMR-based urine metabolomics is lacking. Using 1D and 2D non-uniform sampled (NUS) ¹H-¹³C NMR spectroscopy, we systematically explored how changes in hydration or specific gravity (SG) and pH can impact biomarker discovery. Further, we examined additional sources of error in metabolomics studies and identified Navigator molecules that could monitor for those biases. Adjustment of SG to 1.002–1.02 coupled with a dynamic sum-based peak thresholding eliminates false positives associated with urine hydration and reduces variation in chemical shift. We identified Navigator molecules that can effectively monitor for inconsistencies in sample processing, SG, protein contamination, and pH. The workflow described provides quality assurance and quality control tools to generate high-quality urine metabolomics data, which is the first step in biomarker discovery. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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13 pages, 13204 KiB

Open AccessArticle

Explorative Study on Volatile Organic Compounds of Cinnamon Based on GC-IMS

by Yu Pan, Liya Qiao, Shanshuo Liu, Ye He, Danna Huang, Wuwei Wu, Yingying Liu, Lu Chen and Dan Huang

Metabolites 2024, 14(5), 274; https://doi.org/10.3390/metabo14050274 - 9 May 2024

Cited by 1 | Viewed by 1428

Abstract

Cinnamon is one of the most popular spices worldwide, and volatile organic compounds (VOCs) are its main metabolic products. The misuse or mixing of cinnamon on the market is quite serious. This study used gas chromatography-ion migration spectroscopy (GC-IMS) technology to analyze the [...] Read more.

Cinnamon is one of the most popular spices worldwide, and volatile organic compounds (VOCs) are its main metabolic products. The misuse or mixing of cinnamon on the market is quite serious. This study used gas chromatography-ion migration spectroscopy (GC-IMS) technology to analyze the VOCs of cinnamon samples. The measurement results showed that 66 VOCs were detected in cinnamon, with terpenes being the main component accounting for 45.45%, followed by aldehydes accounting for 21.21%. The content of esters and aldehydes was higher in RG-01, RG-02, and RG-04; the content of alcohols was higher in RG-01; and the content of ketones was higher in RG-02. Principal component analysis, cluster analysis, and partial least squares regression analysis can be performed on the obtained data to clearly distinguish cinnamon. According to the VIP results of PLS-DA, 1-Hexanol, 2-heptanone, ethanol, and other substances are the main volatile substances that distinguish cinnamon. This study combined GC-IMS technology with chemometrics to accurately identify cinnamon samples, providing scientific guidance for the efficient utilization of cinnamon. At the same time, this study is of great significance for improving the relevant quality standards of spices and guiding the safe use of spices. Full article

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

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14 pages, 257 KiB

Open AccessReview

Environmental and Metabolic Risk Factors Linked to Gallbladder Dysplasia

by Andrei Bojan, Catalin Pricop, Manuela Ciocoiu, Maria Cristina Vladeanu, Iris Bararu Bojan, Oana Viola Badulescu, Minerva Codruta Badescu, Carmen Elena Plesoianu, Dan Iliescu Halitchi and Liliana Georgeta Foia

Metabolites 2024, 14(5), 273; https://doi.org/10.3390/metabo14050273 - 8 May 2024

Viewed by 1314

Abstract

Gallbladder disorders encompass a spectrum from congenital anomalies to inflammatory and neoplastic conditions, frequently requiring surgical intervention. Epithelial abnormalities like adenoma and metaplasia have the potential to progress to carcinoma, emphasizing the importance of histopathological assessment for early detection of malignancy. Gallbladder cancer [...] Read more.

Gallbladder disorders encompass a spectrum from congenital anomalies to inflammatory and neoplastic conditions, frequently requiring surgical intervention. Epithelial abnormalities like adenoma and metaplasia have the potential to progress to carcinoma, emphasizing the importance of histopathological assessment for early detection of malignancy. Gallbladder cancer (GBC) may be incidentally discovered during cholecystectomy for presumed benign conditions, underscoring the need for a thorough examination. However, the lack of clarity regarding the molecular mechanisms of GBC has impeded diagnostic and therapeutic advancements. Timely detection is crucial due to GBC’s aggressive nature and poor prognosis. Chronic inflammation plays a central role in carcinogenesis, causing DNA damage and oncogenic alterations due to persistent insults. Inflammatory cytokines and microRNAs are among the various mediators contributing to this process. Gallbladder calcifications, particularly stippled ones, may signal malignancy and warrant preemptive removal. Molecular pathways involving mutations in oncogenes and tumor suppressor genes drive GBC pathogenesis, with proposed sequences such as gallstone-induced inflammation leading to carcinoma formation. Understanding these mechanisms, alongside evaluating mucin characteristics and gene mutations, can deepen comprehension of GBC’s pathophysiology. This, in turn, facilitates the identification of high-risk individuals and the development of improved treatment strategies, ultimately enhancing patient outcomes. Thus, in this review, our aim has been to underscore the primary mechanisms underlying the development of gallbladder dysplasia and neoplasia. Full article

(This article belongs to the Special Issue New Biomarkers for Diagnostics in Metabolic Diseases)

21 pages, 8955 KiB

Open AccessReview

A Review of Transcriptomics and Metabolomics in Plant Quality and Environmental Response: From Bibliometric Analysis to Science Mapping and Future Trends

by Qi Yan, Guoshuai Zhang, Xinke Zhang and Linfang Huang

Metabolites 2024, 14(5), 272; https://doi.org/10.3390/metabo14050272 - 8 May 2024

Cited by 1 | Viewed by 1809

Abstract

Transcriptomics and metabolomics offer distinct advantages in investigating the differentially expressed genes and cellular entities that have the greatest influence on end-phenotype, making them crucial techniques for studying plant quality and environmental responses. While numerous relevant articles have been published, a comprehensive summary [...] Read more.

Transcriptomics and metabolomics offer distinct advantages in investigating the differentially expressed genes and cellular entities that have the greatest influence on end-phenotype, making them crucial techniques for studying plant quality and environmental responses. While numerous relevant articles have been published, a comprehensive summary is currently lacking. This review aimed to understand the global and longitudinal research trends of transcriptomics and metabolomics in plant quality and environmental response (TMPQE). Utilizing bibliometric methods, we presented a comprehensive science mapping of the social structure, conceptual framework, and intellectual foundation of TMPQE. We uncovered that TMPQE research has been categorized into three distinct stages since 2020. A citation analysis of the 29 most cited articles, coupled with a content analysis of recent works (2020–2023), highlight five potential research streams in plant quality and environmental responses: (1) biosynthetic pathways, (2) abiotic stress, (3) biotic stress, (4) development and ripening, and (5) methodologies and tools. Current trends and future directions are shaped by technological advancements, species diversity, evolving research themes, and an environmental ecology focus. Overall, this review provides a novel and comprehensive perspective to understand the longitudinal trend on TMPQE. Full article

(This article belongs to the Special Issue Metabolomics: A Promising Tool for Environmental Sciences?)

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16 pages, 1028 KiB

Open AccessArticle

No Differences in Urine Bisphenol A Concentrations between Subjects Categorized with Normal Cognitive Function and Mild Cognitive Impairment Based on Montreal Cognitive Assessment Scores

by Małgorzata Jamka, Szymon Kurek, Aleksandra Makarewicz-Bukowska, Anna Miśkiewicz-Chotnicka, Maria Wasiewicz-Gajdzis and Jarosław Walkowiak

Metabolites 2024, 14(5), 271; https://doi.org/10.3390/metabo14050271 - 8 May 2024

Viewed by 1045

Abstract

A link between bisphenol A (BPA) exposure and cognitive disorders has been suggested. However, the differences in BPA concentrations between subjects with and without cognitive impairment have not been analysed. Therefore, this observational study aimed to compare urine BPA levels in subjects with [...] Read more.

A link between bisphenol A (BPA) exposure and cognitive disorders has been suggested. However, the differences in BPA concentrations between subjects with and without cognitive impairment have not been analysed. Therefore, this observational study aimed to compare urine BPA levels in subjects with normal cognitive function (NCF) and mild cognitive impairment (MCI). A total of 89 MCI subjects and 89 well-matched NCF individuals were included in this study. Cognitive functions were assessed using the Montreal Cognitive Assessment (MOCA) scale. Urine BPA concentrations were evaluated by gas chromatography–mass spectrometry and adjusted for creatinine levels. Moreover, anthropometric parameters, body composition, sociodemographic factors, and physical activity were also assessed. Creatinine-adjusted urine BPA levels did not differ between the NCF and MCI groups (1.8 (1.4–2.7) vs. 2.2 (1.4–3.6) µg/g creatinine, p = 0.1528). However, there were significant differences in MOCA results between groups when the study population was divided into tertiles according to BPA concentrations (p = 0.0325). Nevertheless, multivariate logistic regression demonstrated that only education levels were independently associated with MCI. In conclusion, urine BPA levels are not significantly different between subjects with MCI and NCF, but these findings need to be confirmed in further studies. Full article

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18 pages, 1373 KiB

Open AccessEditor’s ChoiceArticle

In Vivo and In Vitro Metabolic Fate and Urinary Detectability of Five Deschloroketamine Derivatives Studied by Means of Hyphenated Mass Spectrometry

by Fabian Frankenfeld, Lea Wagmann, Anush Abelian, Jason Wallach, Adeboye Adejare, Simon D. Brandt and Markus R. Meyer

Metabolites 2024, 14(5), 270; https://doi.org/10.3390/metabo14050270 - 8 May 2024

Viewed by 1127

Abstract

Ketamine derivatives such as deschloroketamine and deschloro-N-ethyl-ketamine show dissociative and psychoactive properties and their abuse as new psychoactive substances (NPSs) has been reported. Though some information is available on the biotransformation of dissociative NPSs, data on deschloro-N-cyclopropyl-ketamine deschloro-N [...] Read more.

Ketamine derivatives such as deschloroketamine and deschloro-N-ethyl-ketamine show dissociative and psychoactive properties and their abuse as new psychoactive substances (NPSs) has been reported. Though some information is available on the biotransformation of dissociative NPSs, data on deschloro-N-cyclopropyl-ketamine deschloro-N-isopropyl-ketamine and deschloro-N-propyl-ketamine concerning their biotransformation and, thus, urinary detectability are not available. The aims of the presented work were to study the in vivo phase I and II metabolism; in vitro phase I metabolism, using pooled human liver microsomes (pHLMs); and detectability, within a standard urine screening approach (SUSA), of five deschloroketamine derivatives. Metabolism studies were conducted by collecting urine samples from male Wistar rats over a period of 24 h after their administration at 2 mg/kg body weight. The samples were analyzed using liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS) and gas chromatography–mass spectrometry (GC-MS). The compounds were mainly metabolized by N-dealkylation, hydroxylation, multiple oxidations, and combinations of these metabolic reactions, as well as glucuronidation and N-acetylation. In total, 29 phase I and 10 phase II metabolites were detected. For the LC-HRMS/MS SUSA, compound-specific metabolites were identified, and suitable screening targets could be recommended and confirmed in pHLMs for all derivatives except for deschloro-N-cyclopropyl-ketamine. Using the GC-MS-based SUSA approach, only non-specific acetylated N-dealkylation metabolites could be detected. Full article

(This article belongs to the Section Pharmacology and Drug Metabolism)

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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 2309

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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13 pages, 2976 KiB

Open AccessArticle

Comparison of Various Extraction Approaches for Optimized Preparation of Intracellular Metabolites from Human Mesenchymal Stem Cells and Fibroblasts for NMR-Based Study

by Slavomíra Nováková, Eva Baranovičová, Zuzana Hatoková, Gábor Beke, Janka Pálešová, Romana Záhumenská, Bibiána Baďurová, Mária Janíčková, Ján Strnádel, Erika Halašová and Henrieta Škovierová

Metabolites 2024, 14(5), 268; https://doi.org/10.3390/metabo14050268 - 7 May 2024

Viewed by 1730

Abstract

Metabolomics has proven to be a sensitive tool for monitoring biochemical processes in cell culture. It enables multi-analysis, clarifying the correlation between numerous metabolic pathways. Together with other analysis, it thus provides a global view of a cell’s physiological state. A comprehensive analysis [...] Read more.

Metabolomics has proven to be a sensitive tool for monitoring biochemical processes in cell culture. It enables multi-analysis, clarifying the correlation between numerous metabolic pathways. Together with other analysis, it thus provides a global view of a cell’s physiological state. A comprehensive analysis of molecular changes is also required in the case of mesenchymal stem cells (MSCs), which currently represent an essential portion of cells used in regenerative medicine. Reproducibility and correct measurement are closely connected to careful metabolite extraction, and sample preparation is always a critical point. Our study aimed to compare the efficiencies of four harvesting and six extraction methods. Several organic reagents (methanol, ethanol, acetonitrile, methanol–chloroform, MTBE) and harvesting approaches (trypsinization vs. scraping) were tested. We used untargeted nuclear magnetic resonance spectroscopy (NMR) to determine the most efficient method for the extraction of metabolites from human adherent cells, specifically human dermal fibroblasts adult (HDFa) and dental pulp stem cells (DPSCs). A comprehensive dataset of 29 identified and quantified metabolites were determined to possess statistically significant differences in the abundances of several metabolites when the cells were detached mechanically to organic solvent compared to when applying enzymes mainly in the classes of amino acids and peptides for both types of cells. Direct scraping to organic solvent is a method that yields higher abundances of determined metabolites. Extraction with the use of different polar reagents, 50% and 80% methanol, or acetonitrile, mostly showed the same quality. For both HDFa and DPSC cells, the MTBE method, methanol–chloroform, and 80% ethanol extractions showed higher extraction efficiency for the most identified and quantified metabolites Thus, preparation procedures provided a cell sample processing protocol that focuses on maximizing extraction yield. Our approach may be useful for large-scale comparative metabolomic studies of human mesenchymal stem cell samples. Full article

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

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13 pages, 3039 KiB

Open AccessArticle

Diabetes Causes Significant Alterations in Pulmonary Glucose Transporter Expression

by Allison Campolo, Zahra Maria and Véronique A. Lacombe

Metabolites 2024, 14(5), 267; https://doi.org/10.3390/metabo14050267 - 7 May 2024

Viewed by 1302

Abstract

Diabetes has been identified as a significant and independent risk factor for the development or increased severity of respiratory infections. However, the role of glucose transport in the healthy and diseased lung has received little attention. Specifically, the protein expression of the predominant [...] Read more.

Diabetes has been identified as a significant and independent risk factor for the development or increased severity of respiratory infections. However, the role of glucose transport in the healthy and diseased lung has received little attention. Specifically, the protein expression of the predominant glucose transporter (GLUT) isoforms in the adult lung remains largely to be characterized in both healthy and diabetic states. Type 1 diabetes was induced via streptozotocin and rescued via subcutaneous semi-osmotic insulin pump for 8 weeks. The gene and/or protein expression of the most predominant GLUT isoforms from Classes I and III, including the major insulin-sensitive isoform (i.e., GLUT4) and novel isoforms (i.e., GLUT-8 and GLUT-12), was quantified in the lung of healthy and diabetic mice via qRT-PCR and/or Western blotting. Pulmonary cell surface GLUT protein was measured using a biotinylated photolabeling assay, as a means to evaluate GLUT trafficking. Diabetic mice demonstrated significant alterations of total pulmonary GLUT protein expression, which were isoform- and location-dependent. Long-term insulin treatment rescued the majority of GLUT protein expression alterations in the lung during diabetes, as well as GLUT-4 and -8 trafficking to the pulmonary cell surface. These alterations in glucose homeostasis during diabetes may contribute to an increased severity of pulmonary infection during diabetes and may point to novel metabolic therapeutic strategies for diabetic patients with concurrent respiratory infections. Full article

(This article belongs to the Section Cell Metabolism)

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21 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 2 | Viewed by 1224

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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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 1411

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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20 pages, 1068 KiB

Open AccessReview

Ketoacidosis and SGLT2 Inhibitors: A Narrative Review

by Carmela Morace, Giuseppe Lorello, Federica Bellone, Cristina Quartarone, Domenica Ruggeri, Annalisa Giandalia, Giuseppe Mandraffino, Letteria Minutoli, Giovanni Squadrito, Giuseppina T. Russo and Herbert Ryan Marini

Metabolites 2024, 14(5), 264; https://doi.org/10.3390/metabo14050264 - 6 May 2024

Cited by 3 | Viewed by 2066

Abstract

An acute metabolic complication of diabetes mellitus, especially type 1, is diabetic ketoacidosis (DKA), which is due to an increase in blood ketone concentrations. Sodium/glucose co-transporter-2 inhibitor (SGLT2-i) drugs have been associated with the occurrence of a particular type of DKA defined as [...] Read more.

An acute metabolic complication of diabetes mellitus, especially type 1, is diabetic ketoacidosis (DKA), which is due to an increase in blood ketone concentrations. Sodium/glucose co-transporter-2 inhibitor (SGLT2-i) drugs have been associated with the occurrence of a particular type of DKA defined as euglycemic (euDKA), characterized by glycemic levels below 300 mg/dL. A fair number of euDKA cases in SGLT2-i-treated patients have been described, especially in the last few years when there has been a significant increased use of these drugs. This form of euDKA is particularly insidious because of its latent onset, associated with unspecific symptomatology, until it evolves (progressing) to severe systemic forms. In addition, its atypical presentation can delay diagnosis and treatment. However, the risk of euDKA associated with SGLT2-i drugs remains relatively low, but it is essential to promptly diagnose and manage it to prevent its serious life-threatening complications. In this narrative review, we intended to gather current research evidence on SGLT2i-associated euDKA from randomized controlled trials and real-world evidence studies, its diagnostic criteria and precipitating factors. Full article

(This article belongs to the Special Issue Lipid Metabolism in Obesity and Diabetes, 2nd Edition)

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9 pages, 775 KiB

Open AccessArticle

Effect of Fluid Intake on Acute Changes in Plasma Volume: A Randomized Controlled Crossover Pilot Trial

by Janis Schierbauer, Sabrina Sanfilippo, Auguste Grothoff, Ulrich Fehr, Nadine Wachsmuth, Thomas Voit, Paul Zimmermann and Othmar Moser

Metabolites 2024, 14(5), 263; https://doi.org/10.3390/metabo14050263 - 6 May 2024

Viewed by 1176

Abstract

Plasma volume (PV) undergoes constant and dynamic changes, leading to a large intra-day variability in healthy individuals. Hydration is known to induce PV changes; however, the response to the intake of osmotically different fluids is still not fully understood. In a randomized controlled [...] Read more.

Plasma volume (PV) undergoes constant and dynamic changes, leading to a large intra-day variability in healthy individuals. Hydration is known to induce PV changes; however, the response to the intake of osmotically different fluids is still not fully understood. In a randomized controlled crossover trial, 18 healthy individuals (10 females) orally received an individual amount of an isotonic sodium-chloride (ISO), Ringer (RIN), or glucose (GLU) solution. Hemoglobin mass (Hbmass) was determined with the optimized carbon monoxide re-breathing method. Fluid-induced changes in PV were subsequently calculated based on capillary hemoglobin concentration ([Hb]) and hematocrit (Hct) before and then every 10 minutes until 120 min (t_0–120) after the fluid intake and compared to a control trial arm (CON), where no fluid was administered. Within GLU and CON trial arms, no statistically significant differences from baseline until t₁₂₀ were found (p > 0.05). In the ISO trial arm, PV was significantly increased at t₇₀ (+138 mL, p = 0.01), t₈₀ (+191 mL, p < 0.01), and t₁₁₀ (+182 mL, p = 0.01) when compared to t₀. Moreover, PV in the ISO trial arm was significantly higher at t₇₀ (p = 0.02), t₁₁₀ (p = 0.04), and t₁₂₀ (p = 0.01) when compared to the same time points in the CON trial arm. Within the RIN trial arm, PV was significantly higher between t₇₀ and t₉₀ (+183 mL, p = 0.01) and between t₁₁₀ (+194 mL, p = 0.03) and t₁₂₀ (+186 mL, p < 0.01) when compared to t₀. These results demonstrated that fluids with a higher content of osmotically active particles lead to acute hemodilution, which is associated with a decrease in [Hb] and Hct. These findings underpin the importance of the hydration state on PV and especially on PV constituent levels in healthy individuals. Full article

(This article belongs to the Special Issue Sports: Nutrition and Metabolism in Relation to Athletes’ Health and Performance)

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14 pages, 2945 KiB

Open AccessArticle

Metabolome in Tibialis and Soleus Muscles in Wild-Type and Pin1 Knockout Mice through High-Resolution Magic Angle Spinning ¹H Nuclear Magnetic Resonance Spectroscopy

by Valeria Righi, Martina Grosso, Renata Battini, Takafumi Uchida, Anna Gambini, Susanna Molinari and Adele Mucci

Metabolites 2024, 14(5), 262; https://doi.org/10.3390/metabo14050262 - 6 May 2024

Viewed by 1048

Abstract

Skeletal muscles are heterogenous tissues composed of different myofiber types that can be classified as slow oxidative, fast oxidative, and fast glycolytic which are distinguished on the basis of their contractile and metabolic properties. Improving oxidative metabolism in skeletal muscles can prevent metabolic [...] Read more.

Skeletal muscles are heterogenous tissues composed of different myofiber types that can be classified as slow oxidative, fast oxidative, and fast glycolytic which are distinguished on the basis of their contractile and metabolic properties. Improving oxidative metabolism in skeletal muscles can prevent metabolic diseases and plays a protective role against muscle wasting in a number of neuromuscular diseases. Therefore, achieving a detailed understanding of the factors that regulate myofiber metabolic properties might provide new therapeutic opportunities for these diseases. Here, we investigated whether peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is involved in the control of myofiber metabolic behaviors. Indeed, PIN1 controls glucose and lipid metabolism in a number of tissues, and it is also abundant in adult skeletal muscles; however, its role in the control of energy homeostasis in this tissue is still to be defined. To start clarifying this topic, we compared the metabolome of the tibialis anterior muscle (mainly glycolytic) and soleus muscle (oxidative) in wild-type and Pin1 knockout mice with High-Resolution Magic Angle Spinning (HR-MAS) NMR on intact tissues. Our analysis reveals a clear demarcation between the metabolomes in the two types of muscles and allows us to decode a signature able to discriminate the glycolytic versus oxidative muscle phenotype. We also detected some changes in Pin1-depleted muscles that suggest a role for PIN1 in regulating the metabolic phenotype of skeletal muscles. Full article

(This article belongs to the Special Issue Determination and Analysis of Known and Unknown Metabolites in NMR-Based Metabolomics)

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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

Viewed by 1693

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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