Metabolites

14 pages, 2537 KiB

Open AccessArticle

Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino Acids

by Xiaoyu Guo, Kai Wang, Hongli Chen, Na Wang, Dongmei Qiu, Haiyun Huang, Jiyu Luo, Ao Xu, Lingyun Xu, Zejun Yu, Yuanyuan Li and Hongling Zhang

Metabolites 2024, 14(11), 645; https://doi.org/10.3390/metabo14110645 - 20 Nov 2024

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Abstract

Background/Objectives: Leflunomide, an isoxazole immunosuppressant, is widely used in the treatment of diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as lupus nephritis (LN). In recent years, clinical data have shown that some patients have obvious weight loss, liver [...] Read more.

Background/Objectives: Leflunomide, an isoxazole immunosuppressant, is widely used in the treatment of diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as lupus nephritis (LN). In recent years, clinical data have shown that some patients have obvious weight loss, liver injury, and other serious adverse reactions after taking leflunomide. However, the causes and mechanisms by which leflunomide reduces weight are unclear. Methods: Therefore, we used a mouse animal model to administer leflunomide, and we observed that the weight of mice in the leflunomide experimental group was significantly reduced (p < 0.01). In this animal experiment, a metabolomic method was used to analyze the livers of the mice in the experimental group and found that the main difference in terms of metabolic pathways was in the metabolism of aromatic amino acids, and it was confirmed that leflunomide can inhibit the limitations of phenylalanine, tyrosine, and tryptophan biosynthesis. Results: Our study revealed that leflunomide inhibited the activity of DAHPS in the gut microbiota, disrupting the metabolism of phenylalanine, tyrosine, and tryptophan, as well as the metabolism of carbohydrates and lipids. Leflunomide also increased endoplasmic reticulum stress by activating the PERK pathway, thereby promoting CHOP expression and increasing apoptosis-induced liver damage. Conclusions: These effects may be related to the observed weight loss induced by leflunomide. Full article

(This article belongs to the Special Issue The Interplay Between Inflammation and Metabolism in Disease)

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17 pages, 4027 KiB

Open AccessArticle

Type 1 Diabetes and Cataracts: Investigating Mediating Effects of Serum Metabolites Using Bidirectional Mendelian Randomization

by Yumeng Shi, Jingxi Qin, Yankai Li, Jin Yang and Yi Lu

Metabolites 2024, 14(11), 644; https://doi.org/10.3390/metabo14110644 - 20 Nov 2024

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Abstract

Purpose: To investigate the causal relationship between type 1 diabetes (T1D) and cataracts and to explore the mediating role of serum metabolites. Methods: This study employed bidirectional Mendelian randomization (MR) using genetic variants as instrumental variables to infer causality in both directions: from [...] Read more.

Purpose: To investigate the causal relationship between type 1 diabetes (T1D) and cataracts and to explore the mediating role of serum metabolites. Methods: This study employed bidirectional Mendelian randomization (MR) using genetic variants as instrumental variables to infer causality in both directions: from T1D to cataracts and cataracts to T1D. Genetic data for T1D, its complications, and cataracts were sourced from independent genome-wide association study (GWAS) datasets. A two-step multivariable MR combined with mediation analysis was conducted to evaluate the indirect effects of serum metabolites in the causal pathway from T1D to cataracts. Results: The MR analysis demonstrated a significant causal association between T1D and an increased risk of cataracts (OR = 1.01–1.05; p < 0.05). Further analysis showed that patients with T1D complications such as coma, ketoacidosis, nephropathy, and retinopathy exhibited a significantly higher risk of developing cataracts compared to those without complications. Sensitivity analyses upheld the robustness of these findings, with no evidence of heterogeneity or pleiotropy. Additionally, 102 serum metabolites were found to exhibit statistically significant mediation effects on cataract risk, with four (13-HODE + 9-HODE, 2-naphthol sulfate, docosadienoate (22:2n6), and X-12906) showing significant mediation effects. Specifically, 13-HODE + 9-HODE had a protective effect, while the other three metabolites were linked to an increased cataract risk. Conclusions: This study provides strong evidence of a causal link between T1D and cataracts, highlighting the mediating role of specific serum metabolites. These findings underscore the importance of early detection and management of cataracts in patients with T1D and suggest potential therapeutic targets for mitigating cataract risk. Further research should focus on replicating these findings in diverse populations and exploring the underlying metabolic pathways in greater detail. Full article

(This article belongs to the Special Issue Metabolomics of the Eye and Adnexa)

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13 pages, 1733 KiB

Open AccessArticle

Rapid Determination of Methamphetamine, Methylenedioxymethamphetamine, Methadone, Ketamine, Cocaine, and New Psychoactive Substances in Urine Samples Using Comprehensive Two-Dimensional Gas Chromatography

by Doreen N. B. Chandra Siri, Seng Yo Goh, Ngee Sing Chong, Philip J. Marriott and Yong Foo Wong

Metabolites 2024, 14(11), 643; https://doi.org/10.3390/metabo14110643 - 20 Nov 2024

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Abstract

Background/Objectives: This study evaluates the applicability of a comprehensive two-dimensional gas chromatography−flame ionisation detection (GC×GC−FID) approach for the simultaneous determination of 12 underivatised psychoactive drugs, including new psychoactive substances, that comprised of amphetamine, methamphetamine, mephedrone, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, α-pyrrolidinovalerophenone, n-ethylpentylone (ephylone), norketamine, ketamine, [...] Read more.

Background/Objectives: This study evaluates the applicability of a comprehensive two-dimensional gas chromatography−flame ionisation detection (GC×GC−FID) approach for the simultaneous determination of 12 underivatised psychoactive drugs, including new psychoactive substances, that comprised of amphetamine, methamphetamine, mephedrone, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, α-pyrrolidinovalerophenone, n-ethylpentylone (ephylone), norketamine, ketamine, 3,4-methylenedioxypyrovalerone, methadone, and cocaine. Methods: Separation was effected using a non-polar first dimension (¹D) and a polar second dimension (²D) column, demonstrating an improved separation of drug compounds compared to a polar/non-polar column configuration. Interference-free baseline separation of all psychoactive compounds in a urine matrix was achieved within 8 min. The GC×GC−FID method was validated according to the guidelines defined by Standard Practices for Method Validation in Forensic Toxicology. Results: The calibration curves for the 12 psychoactive drugs were well correlated (r² > 0.99) within the concentration ranges of 50–1500 ng mL⁻¹. Detection limits of 10–20 ng mL⁻¹ were obtained, and good repeatability and reproducibility (CV < 11.4%) were attained for retention times and peak areas. Method recoveries for the small-scale solvent extraction procedure ranged from 96.9 to 114.5%, and bias was between −3.1% and 14.5%. Conclusions: The validated approach was successfully applied for the determination of these illicit compounds in spiked urine samples of different concentrations, highlighting its potential for rapid forensic drug screening. Full article

(This article belongs to the Special Issue Meeting the Challenge of Metabolomics Analysis by Using Multidimensional Gas Chromatography with Mass Spectrometry)

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18 pages, 1511 KiB

Open AccessReview

Influence of Uric Acid on Vascular and Cognitive Functions: Evidence for an Ambivalent Relationship

by Francesco Baratta, Federica Moscucci, Evaristo Ettorre, Raffaella Bocale, Arrigo F. G. Cicero, Pietro Cirillo, Federica Fogacci, Ilaria Lospinuso, Carmine Savoia, Alessandro Mengozzi, Agostino Virdis, Claudio Borghi and Giovambattista Desideri

Metabolites 2024, 14(11), 642; https://doi.org/10.3390/metabo14110642 - 20 Nov 2024

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Abstract

The growing recognition of the public health impact of cognitive impairment and dementia has sparked a global initiative to identify risk factors and develop strategies to prevent or slow the progression of these cognitive disorders. Uric acid, the end product of the metabolism [...] Read more.

The growing recognition of the public health impact of cognitive impairment and dementia has sparked a global initiative to identify risk factors and develop strategies to prevent or slow the progression of these cognitive disorders. Uric acid, the end product of the metabolism of purine nucleotides, has been reported as a key factor of many conditions potentially involved in cognitive dysfunction/dementia. In addition, some studies support the hypothesis that elevated uric acid levels could reduce the risk of Alzheimer’s disease, slow down the decline of cognition, and delay the progression of Alzheimer’s disease, while other evidence achieves opposite positions. These discrepancies might reflect a biological ambivalence for uric acid depending on a very complex interplay of factors that include its concentrations achieved in biological fluids, the nature, and concentration of free radicals, the presence and concentration of other antioxidant molecules, potentially responsible for bi-directional effects of uric acid on brain health/functioning. In this narrative review, we attempt to elucidate the influential role of uric acid metabolism in cognitive functioning by discussing pathophysiological mechanisms putatively involved, being well aware that none of them can be considered one-sided due to the complexity of the human organism. Full article

(This article belongs to the Section Nutrition and Metabolism)

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21 pages, 6832 KiB

Open AccessArticle

Identification of Spatial Specific Lipid Metabolic Signatures in Long-Standing Diabetic Kidney Disease

by Yiran Zhang, Hai-Long Piao and Di Chen

Metabolites 2024, 14(11), 641; https://doi.org/10.3390/metabo14110641 - 20 Nov 2024

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Abstract

Background: Diabetic kidney disease (DKD) is a major complication of diabetes leading to kidney failure. Methods: This study investigates lipid metabolism profiles of long-standing DKD (LDKD, diabetes duration > 10 years) by integrative analysis of available single-cell RNA sequencing and spatial multi-omics data [...] Read more.

Background: Diabetic kidney disease (DKD) is a major complication of diabetes leading to kidney failure. Methods: This study investigates lipid metabolism profiles of long-standing DKD (LDKD, diabetes duration > 10 years) by integrative analysis of available single-cell RNA sequencing and spatial multi-omics data (focusing on spatial continuity samples) from the Kidney Precision Medicine Project. Results: Two injured cell types, an injured thick ascending limb (iTAL) and an injured proximal tubule (iPT), were identified and significantly elevated in LDKD samples. Both iTAL and iPT exhibit increased lipid metabolic and biosynthetic activities and decreased lipid and fatty acid oxidative processes compared to TAL/PT cells. Notably, compared to PT, iPT shows significant upregulation of specific injury and fibrosis-related genes, including FSHR and BMP7. Meanwhile, comparing iTAL to TAL, inflammatory-related genes such as ANXA3 and IGFBP2 are significantly upregulated. Furthermore, spatial metabolomics analysis reveals regionally distributed clusters in the kidney and notably differentially expressed lipid metabolites, such as triglycerides, glycerophospholipids, and sphingolipids, particularly pronounced in the inner medullary regions. Conclusions: These findings provide an integrative description of the lipid metabolism landscape in LDKD, highlighting injury-associated cellular processes and potential molecular mechanisms. Full article

(This article belongs to the Special Issue New Analytical Techniques and Applications of Metabolomics and Lipidomics)

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13 pages, 5229 KiB

Open AccessArticle

Liver Transcriptome Analysis Reveals the Mechanisms of Metabolic Adaptation of Xizang Sheep to Seasonal Changes

by Jianzhao Cui, Junru Pan, Fengbo Sun, Nan Zhang, Jiacuo Jinmei, Yang Zhen, Ciren Puchi, Luo Snag, Zengqiang Liu, Wangsheng Zhao and Yangzong Zhaxi

Metabolites 2024, 14(11), 640; https://doi.org/10.3390/metabo14110640 - 19 Nov 2024

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Abstract

Background/Objectives: The Xizang sheep is a unique breed of sheep in the highland regions of China that has gradually developed physiological characteristics adapted to the plate environment through long-term natural selection and artificial breeding. However, little is known about the molecular basis [...] Read more.

Background/Objectives: The Xizang sheep is a unique breed of sheep in the highland regions of China that has gradually developed physiological characteristics adapted to the plate environment through long-term natural selection and artificial breeding. However, little is known about the molecular basis of metabolic adaptation to seasons in Xizang sheep. Methods: In this study, liver tissues from Xizang sheep in summer (SL) and autumn (AL) were selected for transcriptome sequencing to explore the metabolic adaptability of Xizang sheep to seasons. Results: The results showed that a total of 12,046 differentially expressed genes (DEGs) were identified, with 1123 genes significantly upregulated and 951 genes significantly downregulated in autumn. The top five pathways enriched for DEGs were Metabolic pathways, Phagosome, Valine, leucine and isoleucine degradation, Propanoate metabolism, and Fatty acid metabolism, which are involved in immune regulation, fat oxidation, and synthesis. The reduction in lipid synthesis, fatty acid oxidation, and fat breakdown metabolism promotes gluconeogenesis by inhibiting the Peroxisome proliferator-activated receptors (PPAR) and Phosphoinositide 3-kinase- Protein kinase B (PI3K-Akt) signaling pathways. Conclusions: This process helps to maintain the whole-body energy homeostasis of Xizang sheep, facilitating their adaptation to the seasonal changes in the extreme high-altitude environment. These findings provide foundational data for studying the molecular mechanisms of metabolic adaptation to seasons in ruminants. Full article

(This article belongs to the Special Issue Metabolites in Ruminant Health)

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16 pages, 2628 KiB

Open AccessArticle

Possible Missing Sources of Atmospheric Glyoxal Part I: Phospholipid Oxidation from Marine Algae

by Renee T. Williams, Annika Caspers-Brown, Camille M. Sultana, Christopher Lee, Jessica L. Axson, Francesca Malfatti, Yanyan Zhou, Kathryn A. Moore, Natalie Stevens, Mitchell V. Santander, Farooq Azam, Kimberly A. Prather and Robert S. Pomeroy

Metabolites 2024, 14(11), 639; https://doi.org/10.3390/metabo14110639 - 19 Nov 2024

Viewed by 406

Abstract

Background: Glyoxal has been implicated as a significant contributor to the formation of secondary organic aerosols, which play a key role in our ability to estimate the impact of aerosols on climate. Elevated concentrations of glyoxal over remote ocean waters suggests that there [...] Read more.

Background: Glyoxal has been implicated as a significant contributor to the formation of secondary organic aerosols, which play a key role in our ability to estimate the impact of aerosols on climate. Elevated concentrations of glyoxal over remote ocean waters suggests that there is an additional source, distinct from urban and forest environments, which has yet to be identified. Herein, we demonstrate that the ocean can serve as an appreciable source of glyoxal in the atmosphere due to microbiological activity. Methods and Results: Based on mass spectrometric analyses of nascent sea spray aerosols and the sea surface microlayer (SSML) of naturally occurring algal blooms, we provide evidence that during the algae death phase phospholipids become enriched in the SSML and undergo autoxidation thereby generating glyoxal as a degradation product. Conclusions: We propose that the death phase of an algal bloom could serve as an important and currently missing source of glyoxal in the atmosphere. Full article

(This article belongs to the Special Issue Untargeted Profiling of Environmental Chemicals and Their Transformation Metabolites by Mass Spectrometry)

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15 pages, 4456 KiB

Open AccessArticle

Analysis of the Urine Volatilome of COVID-19 Patients and the Possible Metabolic Alterations Produced by the Disease

by Jennifer Narro-Serrano, Maruan Shalabi-Benavent, José María Álamo-Marzo, Álvaro Maximiliam Seijo-García and Frutos Carlos Marhuenda-Egea

Metabolites 2024, 14(11), 638; https://doi.org/10.3390/metabo14110638 - 19 Nov 2024

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Abstract

Alterations in metabolism caused by SARS-CoV-2 infection have been highlighted in various investigations and have been used to search for biomarkers in different biological matrices. However, the selected biomarkers vary greatly across studies. Our objective is to provide a robust selection of biomarkers, [...] Read more.

Alterations in metabolism caused by SARS-CoV-2 infection have been highlighted in various investigations and have been used to search for biomarkers in different biological matrices. However, the selected biomarkers vary greatly across studies. Our objective is to provide a robust selection of biomarkers, including results from different sample treatments in the analysis of volatile organic compounds (VOCs) present in urine samples from patients with COVID-19. Between September 2021 and May 2022, urine samples were collected from 35 hospitalized COVID-19 patients and 32 healthy controls. The samples were analyzed by headspace (HS) solid phase microextraction (SPME) coupled to gas chromatography–mass spectrometry (GC-MS). Analyses were conducted on untreated urine samples and on samples that underwent specific pretreatments: lyophilization and treatment with sulfuric acid. Partial Least Squares Linear Discriminant Analysis (PLS-LDA) and Subwindow Permutation Analysis (SPA) models were established to distinguish patterns between COVID-19 patients and healthy controls. The results identify compounds that are present in different proportions in urine samples from COVID-19 patients compared to those from healthy individuals. Analysis of urine samples using HS-SPME-GC-MS reveals differences between COVID-19 patients and healthy individuals. These differences are more pronounced when methods that enhance VOC formation are used. However, these pretreatments can cause reactions between sample components, creating additional products or removing compounds, so biomarker selection could be altered. Therefore, using a combination of methods may be more informative when evaluating metabolic alterations caused by viral infections and would allow for a better selection of biomarkers. Full article

(This article belongs to the Special Issue Advanced Metabolomics and Lipidomics Approaches in Studying Human Diseases)

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16 pages, 3187 KiB

Open AccessArticle

Non-Targeted Metabolomics of White Rhinoceros Colostrum and Its Changes During Early Lactation by ¹H Nuclear Magnetic Resonance Spectroscopy

by Gernot Osthoff and Petronella Nieuwoudt

Metabolites 2024, 14(11), 637; https://doi.org/10.3390/metabo14110637 - 18 Nov 2024

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Abstract

Background/Objectives: Dynamic changes in components from colostrum to mature milk occur in any mammal. However, the time it takes to reach the mature milk stage differs between taxa and species, as do the final concentrations of all the components. The white rhinoceros belongs [...] Read more.

Background/Objectives: Dynamic changes in components from colostrum to mature milk occur in any mammal. However, the time it takes to reach the mature milk stage differs between taxa and species, as do the final concentrations of all the components. The white rhinoceros belongs to the family Perissodactyla, of which the milk and milk metabolome of the domesticated Equidae have been studied to some detail. Metabolomic information on the colostrum and milk of the Rhinocerotidae is lacking. Methods: Colostrum and milk were obtained from seven white rhinoceroses. Of note is that it was their first parturition and all followed the same diet, two factors known to affect colostrum composition and its changes during early lactation in domesticated mammals. Milk serum was prepared by the ultrafiltration of the milk samples. Untargeted ¹N NMR spectra were processed with Topspin 3.2, calibration was carried out according to the alanine signal and the identification of signals was carried out with Chenomx and assignments in the literature. Statistical analysis of the data was carried out using MetaboAnalyst 6.0. Results: The changes in the metabolites were followed during the first 7 days of lactation as well as on day 20. The amounts of amino acids and their derivatives, organic acids and lipid metabolites decreased over lactation, while carbohydrates and their derivatives increased. The colostrum phase ended on day 2, while the transition to mature milk seemed to be complete by day 7. From day 3 to 7, galactose metabolism and tyrosine metabolism were uprated. Of interest is the presence of the oligosaccharide 3′-sialyllactose on days 3 and 4 of lactation. Conclusions: Mainly the content of carbohydrates increased over lactation, specifically lactose. The 3′-sialyllactose content peaked on days 3 and 4 of lactation. The colostrum phase ended on day 2. The mature milk stage was reached by day 7. The galactose metabolism and tyrosine metabolism were uprated after day 3 of lactation. Full article

(This article belongs to the Special Issue Animal Nutritional Metabolism and Toxicosis Disease)

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17 pages, 1839 KiB

Open AccessArticle

Strategy for Optimizing Vitamin B12 Production in Pseudomonas putida KT2440 Using Metabolic Modeling

by Thomaz Satuye Prieto-de Lima, Keilor Rojas-Jimenez and Christopher Vaglio

Metabolites 2024, 14(11), 636; https://doi.org/10.3390/metabo14110636 - 18 Nov 2024

Viewed by 564

Abstract

Background/Objectives: Vitamin B₁₂ is very important for human health, as it is a cofactor for enzymatic activities and plays various roles in human physiology. It is highly valued in the pharmaceutical, food, and additive production industries. Some of the bacteria currently [...] Read more.

Background/Objectives: Vitamin B₁₂ is very important for human health, as it is a cofactor for enzymatic activities and plays various roles in human physiology. It is highly valued in the pharmaceutical, food, and additive production industries. Some of the bacteria currently used for the vitamin production are difficult to modify with gene-editing tools and may have slow growth. We propose the use of the bacteria Pseudomonas putida KT2440 for the production of vitamin B₁₂ because it has a robust chassis for genetic modifications. The present wok evaluates P. putida KT2440 as a host for vitamin B₁₂ production and explore potential gene-editing optimization strategies. Methods: We curated and modified a genome-scale metabolic model of Pseudomonas putida KT2440 and evaluated different strategies to optimize vitamin B₁₂ production using the knockin and OptGene algorithms from the COBRA Toolbox. Furthermore, we examined the presence of riboswitches as cis-regulatory elements and calculated theoretical biomass growth yields and vitamin B₁₂ production using a flux balance analysis (FBA). Results: According to the flux balance analysis of P. putida KT2440 under culture conditions, the biomass production values could reach 1.802 gDW⁻¹·h¹·L⁻¹, and vitamin B₁₂ production could reach 0.359 µmol·gDW⁻¹·h⁻¹·L⁻¹. The theoretical vitamin B₁₂ synthesis rate calculated using P. putida KT2040 with two additional reactions was 14 times higher than that calculated using the control, Pseudomonas denitrificans, which has been used for the industrial production of this vitamin. Conclusions: We propose that, with the addition of aminopropanol linker genes and the modification of riboswitches, P. putida KT2440 may become a suitable host for the industrial production of vitamin B₁₂. Full article

(This article belongs to the Section Advances in Metabolomics)

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10 pages, 849 KiB

Open AccessSystematic Review

Associations Between Cardiorespiratory Fitness and Metabolic Syndrome in Adolescents: A Systematic Review and Meta-Analysis

by Jonathan Cesar do Prado, Dartagnan Pinto Guedes, Pedro Henrique Garcia Dias, Antonio Stabelini Neto and Raphael Gonçalves de Oliveira

Metabolites 2024, 14(11), 635; https://doi.org/10.3390/metabo14110635 - 18 Nov 2024

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Abstract

Introduction: Low levels of cardiorespiratory fitness (CRF) are associated with a greater risk of metabolic syndrome (MetS) in adolescence. In this sense, it is important to verify the strength of this association and the certainty that this evidence can be recommended. Objective: The [...] Read more.

Introduction: Low levels of cardiorespiratory fitness (CRF) are associated with a greater risk of metabolic syndrome (MetS) in adolescence. In this sense, it is important to verify the strength of this association and the certainty that this evidence can be recommended. Objective: The objective of this paper is to summarize, through a systematic review and meta-analysis, the evidence available to verify the association between CRF and MetS in adolescents. Methods: PubMed, Embase, CINAHL, SPORTDiscus, LILACS, and Web of Science were searched until 20 August 2024. The risk of bias in each study was assessed via the AXIS tool, and the certainty of the evidence was assessed via the GRADE system. For the meta-analysis, the odds ratio (OR) was calculated with a 95% confidence interval. Results: Nine studies (7077 participants), all with a low risk of bias, were included in the systematic review. There was a high certainty of evidence that adolescents with low CRF have significantly greater odds of developing MetS (OR = 3.63 [CI 95%, 2.54 to 5.20]). The odds increase for low vs. moderate (OR = 4.23 [CI 95%, 2.64 to 6.78]) and low vs. high (OR = 8.03 [CI 95%, 3.20 to 20.18]) CRF are considered separately. The effect does not change according to the type of test used to assess CRF (p = 0.51). Conclusions: There is high certainty of evidence that adolescents with low CRF levels have significantly greater odds of developing MetS; therefore, it is essential that intervention strategies be designed to increase CRF in this population. Full article

(This article belongs to the Special Issue Interactions of Diet, Exercise, and Metabolism)

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13 pages, 1635 KiB

Open AccessArticle

Modulation of Urea Transport Attenuates TLR2-Mediated Microglial Activation and Upregulates Microglial Metabolism In Vitro

by Najlaa A. Al-Thani, Dylan Zinck, Gavin S. Stewart and Derek A. Costello

Metabolites 2024, 14(11), 634; https://doi.org/10.3390/metabo14110634 - 17 Nov 2024

Viewed by 418

Abstract

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder traditionally characterised by the presence of amyloid beta (Aβ) plaques and neurofibrillary tau tangles in the brain. However, emerging research has highlighted additional metabolic hallmarks of AD pathology. These include the metabolic reprogramming of microglia [...] Read more.

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder traditionally characterised by the presence of amyloid beta (Aβ) plaques and neurofibrillary tau tangles in the brain. However, emerging research has highlighted additional metabolic hallmarks of AD pathology. These include the metabolic reprogramming of microglia in favour of glycolysis over oxidative phosphorylation. This shift is attributed to an ‘M1′-like pro-inflammatory phenotype, which exacerbates neuroinflammation and contributes to neuronal damage. The urea cycle also presents as an altered metabolic pathway in AD, due to elevated urea levels and altered expression of urea cycle enzymes, metabolites, and transporters in the brain. However, to date, these changes remain largely unexplored. Methods: This study focuses on understanding the effects of extracellular urea and urea transporter-B (UT-B) inhibition on inflammatory changes in lipoteichoic acid (LTA)-stimulated BV2 microglia and on the viability of SH-SY5Y neuronal cells under oxidative stress and neurotoxic conditions. Results: In BV2 microglia, UT-B inhibition demonstrated a notable anti-inflammatory effect by reducing the formation of nitric oxide (NO) and the expression of tumour necrosis factor α (TNFα) and CCL2 in response to stimulation with the toll-like receptor (TLR)2 agonist, lipoteichoic acid (LTA). This was accompanied by a reduction in extracellular urea and upregulation of UT-B expression. The application of exogenous urea was also shown to mediate the inflammatory profile of BV2 cells in a similar manner but had only a modest impact on UT-B expression. While exposure to LTA alone did not alter the microglial metabolic profile, inhibition of UT-B upregulated the expression of genes associated with both glycolysis and fatty acid oxidation. Conversely, neither increased extracellular urea nor UT-B inhibition had a significant impact on cell viability or cytotoxicity in SH-SY5Y neurones exposed to oxidative stressors tert-butyl hydroperoxide (t-BHP) and 6-hydroxydopamine (6-OHDA). Conclusions: This study further highlights the involvement of urea transport in regulating the neuroinflammation associated with AD. Moreover, we reveal a novel role for UT-B in maintaining microglial metabolic homeostasis. Taken together, these findings contribute supporting evidence to the regulation of UT-B as a therapeutic target for intervention into neuroinflammatory and neurodegenerative disease. Full article

(This article belongs to the Section Cell Metabolism)

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12 pages, 1190 KiB

Open AccessArticle

Detection of Sugar Syrups in Honey Using Untargeted Liquid Chromatography–Mass Spectrometry and Chemometrics

by Jule Hansen, Christof Kunert, Kurt-Peter Raezke and Stephan Seifert

Metabolites 2024, 14(11), 633; https://doi.org/10.3390/metabo14110633 - 16 Nov 2024

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Abstract

Background: Honey is one of the most adulterated foods worldwide, and several analytical methods have been developed over the last decade to detect syrup additions to honey. These include approaches based on stable isotopes and the specific detection of individual marker compounds [...] Read more.

Background: Honey is one of the most adulterated foods worldwide, and several analytical methods have been developed over the last decade to detect syrup additions to honey. These include approaches based on stable isotopes and the specific detection of individual marker compounds or foreign enzymes. Proton nuclear magnetic resonance (¹H-NMR) spectroscopy is applied as a rapid and comprehensive screening method, which also enables the detection of quality parameters and the analysis of the geographical and botanical origin. However, especially for the detection of foreign sugars, ¹H-NMR has insufficient sensitivity. Methods: Since untargeted liquid chromatography–mass spectrometry (LC-MS) is more sensitive, we used this approach for the detection of positive and negative ions in combination with a recently developed data processing workflow for routine laboratories based on bucketing and random forest for the detection of rice, beet and high-fructose corn syrup in honey. Results: We show that the distinction between pure and adulterated honey is possible for all three syrups, with classification accuracies ranging from 98 to 100%, while the accuracy of the syrup content estimation depends on the respective syrup. For rice and beet syrup, the deviations from the true proportion were in the single-digit percentage range, while for high-fructose corn syrup they were much higher, in some cases exceeding 20%. Conclusions: The approach presented here is very promising for the robust and sensitive detection of syrup in honey applied in routine laboratories. Full article

(This article belongs to the Special Issue Chemical Profiling of Metabolites from Honey Bee Products)

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11 pages, 1254 KiB

Open AccessReview

Introduction to the Proteomic Analysis of Placentas with Fetal Growth Restriction and Impaired Lipid Metabolism

by Malwina Sypiańska and Aleksandra Stupak

Metabolites 2024, 14(11), 632; https://doi.org/10.3390/metabo14110632 - 16 Nov 2024

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Abstract

Fetal growth restriction (FGR) is a disorder defined as the failure of a fetus to achieve its full biological development potential due to decreased placental function, which can be attributed to a range of reasons. FGR is linked to negative health outcomes during [...] Read more.

Fetal growth restriction (FGR) is a disorder defined as the failure of a fetus to achieve its full biological development potential due to decreased placental function, which can be attributed to a range of reasons. FGR is linked to negative health outcomes during the perinatal period, including increased morbidity and mortality. Long-term health problems, such as impaired neurological and cognitive development, as well as cardiovascular and endocrine diseases, have also been found in adulthood. Aspirin administered prophylactically to high-risk women can effectively prevent FGR. FGR pregnancy care comprises several steps, including the weekly assessment of several blood vessels using Doppler measurements, amniotic fluid index (AFI), estimated fetal weight (EFW), cardiotocography (CTG), as well as delivery by 37 weeks. Pregnancy is a complex condition characterized by metabolic adjustments that guarantee a consistent provision of vital metabolites allowing the fetus to grow and develop. The lipoprotein lipid physiology during pregnancy has significant consequences for both the fetus and baby, and for the mother. In the course of a typical pregnancy, cholesterol levels increase by roughly 50%, LDL-C (low-density lipoprotein cholesterol) levels by 30–40%, HDL-C by 25% (high-density lipoprotein cholesterol). Typically, there is also a 2- to 3-fold increase in triglycerides. Low maternal blood cholesterol levels during pregnancy are linked to a decrease in birth weight and an increased occurrence of microcephaly. FGR impacts the placenta during pregnancy, resulting in alterations in lipid metabolism. Research has been undertaken to distinguish variations in protein expression between normal placentas and those impacted by FGR. This can aid in comprehending the fundamental pathogenic mechanisms of FGR and perhaps pave the way for the creation of novel diagnostic and treatment methods. Commonly employed approaches for detecting and analyzing variations in placental proteomes include mass spectrometry, bioinformatic analysis, and various proteomic techniques. Full article

(This article belongs to the Special Issue Adipose Tissue, Reproduction and Metabolic Health in Women)

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14 pages, 2302 KiB

Open AccessArticle

Possible Missing Sources of Atmospheric Glyoxal Part II: Oxidation of Toluene Derived from the Primary Production of Marine Microorganisms

by Renee T. Williams, Annika Caspers-Brown, Jennifer Michaud, Natalie Stevens, Michael Meehan, Camille M. Sultana, Christopher Lee, Francesca Malfatti, Yanyan Zhou, Farooq Azam, Kimberly A. Prather, Pieter Dorrestein, Michael D. Burkart and Robert S. Pomeroy

Metabolites 2024, 14(11), 631; https://doi.org/10.3390/metabo14110631 - 16 Nov 2024

Viewed by 364

Abstract

Background: Glyoxal has been implicated as a significant contributor to the formation of secondary organic aerosols, which play a key role in our ability to estimate the impact of aerosols on climate. Elevated concentrations of glyoxal over open ocean waters suggest that there [...] Read more.

Background: Glyoxal has been implicated as a significant contributor to the formation of secondary organic aerosols, which play a key role in our ability to estimate the impact of aerosols on climate. Elevated concentrations of glyoxal over open ocean waters suggest that there exists an additional source, different from urban and forest environments, which has yet to be identified. Methods: Based on mass spectrometric analyses of nascent sea spray aerosols (SSAs) and gas-phase molecules generated during the course of a controlled algal bloom, the work herein suggests that marine microorganisms are capable of excreting toluene in response to environmental stimuli. Additional culture flask experiments demonstrated that pathogenic attack could also serve as a trigger for toluene formation. Using solid-phase microextraction methods, the comparison of samples collected up-channel and over the breaking wave suggests it was transferred across the air–water interface primarily through SSA formation. Results: The presence and then absence of phenylacetic acid in the SSA days prior to the appearance of toluene support previous reports that proposed toluene is produced as a metabolite of phenylalanine through the Shikimate pathway. As a result, once in the atmosphere, toluene is susceptible to oxidation and subsequent degradation into glyoxal. Conclusions: This work adds to a minimal collection of literature that addresses the primary production of aromatic hydrocarbons from marine microorganisms and provides a potential missing source of glyoxal that should be considered when accounting for its origins in remote ocean regions. Full article

(This article belongs to the Special Issue Untargeted Profiling of Environmental Chemicals and Their Transformation Metabolites by Mass Spectrometry)

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20 pages, 1425 KiB

Open AccessReview

Antioxidant Therapy in Neonatal Hypoxic Ischemic Encephalopathy: Adjuvant or Future Alternative to Therapeutic Hypothermia?

by Veronica Notarbartolo, Bintu Ayla Badiane, Vita Maria Angileri, Ettore Piro and Mario Giuffrè

Metabolites 2024, 14(11), 630; https://doi.org/10.3390/metabo14110630 - 16 Nov 2024

Viewed by 445

Abstract

Background: Oxidative stress-related diseases in newborns arise from pro-oxidant/antioxidant imbalance in both term and preterm neonates. Pro-oxidant/antioxidant imbalance has shown to be present in different pathological conditions such as hypoxic ischemic encephalopathy (HIE), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), [...] Read more.

Background: Oxidative stress-related diseases in newborns arise from pro-oxidant/antioxidant imbalance in both term and preterm neonates. Pro-oxidant/antioxidant imbalance has shown to be present in different pathological conditions such as hypoxic ischemic encephalopathy (HIE), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and patent ductus arteriosus (PDA). Methods and Results: We performed a narrative review according to the most recent available literature (2012–2024), using Scopus and PubMed as electronic databases. Many observational and experimental studies in vitro and in vivo have evaluated the effectiveness of antioxidant therapies such as melatonin, erythropoietin (EPO), allopurinol, N-acetylcisteine (NAS), and nitric oxide synthase (NOS) inhibitors in these diseases. Perinatal asphyxia is one of the most important causes of mortality and morbidity in term and near-term newborns. Therapeutic hypothermia (TH) is the gold standard treatment for neonates with moderate-severe perinatal asphyxia, resulting in a reduction in the mortality and neurodevelopmental disability rates. Conclusions: According to the most recent literature and clinical trials, melatonin, allopurinol, NAS, NOS inhibitors, magnesium sulfate, and stem cells stand out as promising as both adjuvants and future probable alternatives to TH in the treatment of HIE. Full article

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

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14 pages, 724 KiB

Open AccessReview

The Action of Colchicine in Patients with Metabolic Syndrome and Obesity: Perspectives and Challenges

by Fábio Vieira de Bulhões, Gabriele Eliza Assis, Ana Beatriz Cazé, Jackson Pedro Barros-Pereira, Gabriela Garcia de Carvalho Laguna, Alex Cleber Improta-Caria and Roque Aras-Júnior

Metabolites 2024, 14(11), 629; https://doi.org/10.3390/metabo14110629 - 16 Nov 2024

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Abstract

Colchicine is an alkaloid traditionally used to treat inflammatory conditions such as gout and familial Mediterranean fever. Currently, there are proposals for the use of this drug in several other situations, such as cardiovascular and liver diseases and diabetes. In this study, the [...] Read more.

Colchicine is an alkaloid traditionally used to treat inflammatory conditions such as gout and familial Mediterranean fever. Currently, there are proposals for the use of this drug in several other situations, such as cardiovascular and liver diseases and diabetes. In this study, the current literature on the potential of colchicine in the treatment of obesity and metabolic syndrome (MS) was evaluated. The inhibitory action of the NLRP3 inflammasome and other processes, such as reductions in the migration and activation of immune system cells, are effects observed in both in vitro studies and animal models related to colchicine, as well as the promotion of mechanisms of the intensification of lipid metabolism, the reduction of tissue fibrosis, and the reduction of serum glucose and triglycerides. These factors are associated with changes in the prognoses of patients with MS, which, together with obesity, has a high association with inflammatory mechanisms for its maintenance and secondary impairments to homeostasis. In humans, clinical research has rarely addressed the use of colchicine in obesity and MS, with only one pilot randomized clinical trial having been conducted, which identified a beneficial anti-inflammatory effect on endothelial function and the process of insulin resistance in this population. However, it is not yet possible to extrapolate its findings and apply its results to a broader context. Given the potential of this “ancient drug” in various pathological contexts and its good tolerability, it is important that its properties continue to be investigated and that more clinical studies be conducted to expand the therapeutic applications of this low-cost substance in patients with obesity and MS. Full article

(This article belongs to the Special Issue Effects of Bioactive Compounds on Metabolic Syndrome)

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22 pages, 3268 KiB

Open AccessArticle

Comparison of Free Flavonoids and the Polyphenol Content in the Bran of a Newly Developed Sorghum Variety and Two Commercially Available Sorghum Varieties

by Mariely Cristine Dos Santos, Naoki Tanaka, Shigemitsu Kasuga, Kazuhiro Tanabe, Chihiro Hayashi, Masahiro Mizuno and Yoshihiko Amano

Metabolites 2024, 14(11), 628; https://doi.org/10.3390/metabo14110628 - 15 Nov 2024

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Abstract

Background/Objectives: Sorghum bicolor is a source of many bioactive components, such as polyphenols. Those components are present mainly in its bran, often removed in industrial processes through decortication. In that sense, this work aimed to analyze the polyphenol content, especially free flavonoids, [...] Read more.

Background/Objectives: Sorghum bicolor is a source of many bioactive components, such as polyphenols. Those components are present mainly in its bran, often removed in industrial processes through decortication. In that sense, this work aimed to analyze the polyphenol content, especially free flavonoids, from the bran of a newly developed variety compared to other commercially available varieties. Methods: The samples were white sorghum TDN^® Sorgho, red sorghum Mini Sorgho, and the newly developed red sorghum RILN-156. First, decortication was conducted to obtain the bran samples, which were triturated and then sieved. The use of colorimetric methods allowed the general quantification of the polyphenolic components. First, the polyphenol content was extracted using 70% methanol. Then, the samples’ total phenolic content, total flavonoid content, total tannin content, total anthocyanin content, and antioxidant potential were determined. To analyze the different components and identify the free flavonoids, an untargeted metabolomics analysis (with liquid chromatography coupled with mass spectrometer (LC/MS) and capillary electrophoresis coupled with a mass spectrometer (CE/MS)) was performed. Results: The results have shown that apart from anthocyanin and tannin, the newly developed variety, RILN-156, presented the highest concentration of polyphenolic content, including a higher antioxidant capacity. The exploratory analysis identified 19 flavonoids within the samples, with galangin and daidzein being the most abundant ones. Conclusions: These results show a promising finding for using this newly developed sorghum variety (RILN-156) industrially and further investigating its health benefits. They also elucidate the differences between colored sorghum within themselves and with white sorghum varieties. Full article

(This article belongs to the Section Plant Metabolism)

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2 pages, 132 KiB

Open AccessEditorial

Lipid Abundance and Metabolism Aberrations in Skin Diseases

by Julia Nowowiejska

Metabolites 2024, 14(11), 627; https://doi.org/10.3390/metabo14110627 - 15 Nov 2024

Viewed by 303

Abstract

This Special Issue of Metabolites, entitled “Lipid Abundance and Metabolism Aberrations in Skin Diseases” broadly discusses the issue of lipids that are engaged in pathogenesis, as well as in the clinical course and treatment of dermatoses [...] Full article

(This article belongs to the Special Issue Lipid Expression and Metabolism Aberrations in Skin Diseases)

25 pages, 1190 KiB

Open AccessReview

Understanding the Role of Alcohol in Metabolic Dysfunction and Male Infertility

by Valentina Annamaria Genchi, Angelo Cignarelli, Andrea Sansone, Dimitri Yannas, Leonardo Dalla Valentina, Daniele Renda Livraghi, Giorgia Spaggiari and Daniele Santi

Metabolites 2024, 14(11), 626; https://doi.org/10.3390/metabo14110626 - 15 Nov 2024

Viewed by 782

Abstract

Purpose: Over the past 40–50 years, demographic shifts and the obesity epidemic have coincided with significant changes in lifestyle habits, including a rise in excessive alcohol consumption. This increase in alcohol intake is a major public health concern due to its far-reaching effects [...] Read more.

Purpose: Over the past 40–50 years, demographic shifts and the obesity epidemic have coincided with significant changes in lifestyle habits, including a rise in excessive alcohol consumption. This increase in alcohol intake is a major public health concern due to its far-reaching effects on human health, particularly on metabolic processes and male reproductive function. This narrative review focuses on the role of alcohol consumption in altering metabolism and impairing testicular function, emphasizing the potential damage associated with both acute and chronic alcohol intake. Conclusion: Chronic alcohol consumption has been shown to disrupt liver function, impair lipid metabolism, and dysregulate blood glucose levels, contributing to the development of obesity, metabolic syndrome, and related systemic diseases. In terms of male reproductive health, alcohol can significantly affect testicular function by lowering testosterone levels, reducing sperm quality, and impairing overall fertility. The extent of these effects varies, depending on the frequency, duration, and intensity of alcohol use, with chronic and abusive consumption posing greater risks. The complexity of alcohol’s impact is further compounded by individual variability and the interaction with other lifestyle factors such as diet, stress, and physical activity. Despite growing concern, research on alcohol’s effects remains inconclusive, with significant discrepancies across studies regarding the definition and reporting of alcohol consumption. These inconsistencies highlight the need for more rigorous, methodologically sound research to better understand how alcohol consumption influences metabolic and reproductive health. Ultimately, a clearer understanding is essential for developing targeted public health interventions, particularly in light of rising alcohol use, demographic changes, and the ongoing obesity crisis. Full article

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

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13 pages, 2091 KiB

Open AccessArticle

Hepatic Transcriptomics of Broilers with Low and High Feed Conversion in Response to Caloric Restriction

by Adewunmi O. Omotoso, Henry Reyer, Michael Oster, Siriluck Ponsuksili, Barbara Metzler-Zebeli and Klaus Wimmers

Metabolites 2024, 14(11), 625; https://doi.org/10.3390/metabo14110625 - 14 Nov 2024

Viewed by 440

Abstract

Background: In broiler chickens, the efficient utilization of macro- and micronutrients is influenced by various metabolic pathways that are closely linked to feed efficiency (FE), a critical metric in poultry industry, with residual feed intake (RFI) as the preferred proxy. Feed restriction is [...] Read more.

Background: In broiler chickens, the efficient utilization of macro- and micronutrients is influenced by various metabolic pathways that are closely linked to feed efficiency (FE), a critical metric in poultry industry, with residual feed intake (RFI) as the preferred proxy. Feed restriction is considered an approach to address the underlying molecular mechanisms of feed conversion. We hypothesized that broiler chickens with divergent RFI subjected to quantitative feed restriction differ in their pattern of molecular pathways for efficient nutrient utilization in liver as post-absorptive tissue. Methods: Cobb 500FF broiler chickens divergent for RFI (n = 112) were feed-restricted from day 9 until market weight at day 33–37 post-hatch. Based on a previous trial, feed restriction levels were set at 92% (low-RFI birds) and 80% (high-RFI birds) relative to the control groups. Transcriptomic analyses of the liver were conducted. Results: Due to the interaction of the RFI group and feeding regimen, a total of 140 to 507 differentially expressed genes were identified for the respective contrasts, with implications for hepatic metabolism and cellular stress response. Although the broilers did not realize their full growth potential under restrictive feeding (12.4% reduced body weight vs. controls, p = 0.094), the gene expression patterns indicate a lower susceptibility to blood coagulation (KNG1, FGG, and FGB), suggesting that controlled and mild feed restriction could lead to health benefits in less feed-efficient broilers. Moreover, FE traits are shown to be linked to cellular detoxification processes (MGST3 and CYP2AC2) and triacylglycerol syntheses (MOGAT1 and LPIN1). Conclusions: Divergent transcriptional profiles between broiler groups under varied caloric conditions indicate potential for optimizing nutritional management strategies. Full article

(This article belongs to the Special Issue Metabolic Research in Animal Nutrition and Production)

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31 pages, 1738 KiB

Open AccessArticle

Metabolic Fingerprinting of Blood and Urine of Dairy Cows Affected by Bovine Leukemia Virus: A Mass Spectrometry Approach

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

Metabolites 2024, 14(11), 624; https://doi.org/10.3390/metabo14110624 - 14 Nov 2024

Viewed by 431

Abstract

Objectives: This study investigated metabolic changes associated with bovine leukemia virus (BLV) infection in dairy cows, focusing on pre-parturition alterations. Methods: Metabolite identification in serum and urine samples was performed using a targeted metabolomics method, employing the TMIC Prime kit in combination with [...] Read more.

Objectives: This study investigated metabolic changes associated with bovine leukemia virus (BLV) infection in dairy cows, focusing on pre-parturition alterations. Methods: Metabolite identification in serum and urine samples was performed using a targeted metabolomics method, employing the TMIC Prime kit in combination with flow injection analysis and liquid chromatography–tandem mass spectrometry. Results: Of 145 cows examined, 42 (28.9%) were BLV-seropositive. Around 38% of infected cows showed high somatic cell counts indicative of subclinical mastitis, with 15 experiencing additional health issues such as ketosis, milk fever, and lameness. Despite these conditions, no significant differences in milk yield or composition were observed between the infected and control groups. Metabolomic analysis conducted at −8 and −4 weeks prepartum revealed significant metabolic differences between BLV-infected and healthy cows. At −8 weeks, 30 serum metabolites were altered, including sphingomyelins, lysophosphatidylcholines, amino acids, and acylcarnitines, suggesting disruptions in membrane integrity, energy metabolism, and immune function indicative of early neoplastic transformations. By −4 weeks, the number of altered metabolites decreased to 17, continuing to reflect metabolic disruptions in cows with leukemia. Multivariate analysis highlighted distinct metabolic profiles between infected and control cows, identifying key discriminating metabolites such as choline, aspartic acid, phenylalanine, and arginine. Urine metabolomics revealed significant prepartum shifts in metabolites related to glucose, asymmetric dimethylarginine, and pyruvic acid, among others. Conclusions: The research confirmed metabolomics’ efficacy in defining a BLV infection metabolic profile, elucidating leukosis-associated metabolic disruptions. This approach facilitates the identification of BLV-infected cows and enhances understanding of infection pathophysiology, providing a foundation for advanced management and intervention strategies in dairy herds. The study underscores the profound impact of leukosis on metabolic processes and highlights urine metabolomics’ utility in non-invasively detecting BLV infection, offering the potential for improved herd health management. Full article

(This article belongs to the Special Issue Metabolic Research in Animal Nutrition and Production)

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13 pages, 2892 KiB

Open AccessArticle

Analysis of In Vivo Plant Volatiles Using Active Sampling and TD-GC×GC-TOFMS

by Sheri A. Schmidt, Ewenet Yemane Mesfin, Chaminda De Silva Weeraddana, A. Paulina de la Mata, Alejandro C. Costamagna and James J. Harynuk

Metabolites 2024, 14(11), 623; https://doi.org/10.3390/metabo14110623 - 14 Nov 2024

Viewed by 525

Abstract

Background: Plants constantly produce primary and secondary metabolites, and a significant fraction of these are volatile organic compounds (VOCs). Factors including the life stage of the plant, temperature, environment, and stress influence the abundance and types of VOCs emitted. The analysis of VOCs [...] Read more.

Background: Plants constantly produce primary and secondary metabolites, and a significant fraction of these are volatile organic compounds (VOCs). Factors including the life stage of the plant, temperature, environment, and stress influence the abundance and types of VOCs emitted. The analysis of VOCs released by plants during different stages or with different conditions provides insight into plant metabolism and stress responses. Collecting the VOC profiles of plants in vivo makes it possible to obtain a representative sample of the entire plant volatilome under controlled conditions with minimal invasiveness. In addition, in vivo sampling can also be used to compare the impacts of different environmental conditions or stressors on plants, i.e., the presence/absence of a pest or amount of nitrogen in soil. Methods: In this study, an in vivo plant sampling technique is introduced and validated using active sampling and thermal desorption (TD) tubes with comprehensive two-dimensional gas chromatography coupled to a time-of-flight mass spectrometer (TD-GC×GC-TOFMS). The purpose of this work is to highlight a novel technique to analyze headspace secondary plant metabolites with a minimal invasiveness. Results: It was concluded that in vivo active sampling onto TD tubes provides a wider global coverage of compounds and larger peak areas when compared to extraction by solid-phase microextraction (SPME). Additionally, the Horwitz ratio of active sampling onto TD tubes was 0.893, demonstrating this technique to be a reliable and reproducible method. Lastly, a variety of plants were sampled to assess the versatility of this technique across various plant species with different sizes and volatile profiles. Hundreds of compounds were measured with this analysis, including terpenes, aldehydes, ketones, terpenoids, and alcohols. Conclusions: This novel in vivo active sampling method provides an additional technique for extracting and analyzing volatile secondary plant metabolites. Full article

(This article belongs to the Special Issue Method Development in Metabolomics and Exposomics)

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17 pages, 2798 KiB

Open AccessArticle

A Comprehensive LC–MS Metabolomics Assay for Quantitative Analysis of Serum and Plasma

by Lun Zhang, Jiamin Zheng, Mathew Johnson, Rupasri Mandal, Meryl Cruz, Miriam Martínez-Huélamo, Cristina Andres-Lacueva and David S. Wishart

Metabolites 2024, 14(11), 622; https://doi.org/10.3390/metabo14110622 - 14 Nov 2024

Viewed by 603

Abstract

Background/Objectives: Targeted metabolomics is often criticized for the limited metabolite coverage that it offers. Indeed, most targeted assays developed or used by researchers measure fewer than 200 metabolites. In an effort to both expand the coverage and improve the accuracy of metabolite quantification [...] Read more.

Background/Objectives: Targeted metabolomics is often criticized for the limited metabolite coverage that it offers. Indeed, most targeted assays developed or used by researchers measure fewer than 200 metabolites. In an effort to both expand the coverage and improve the accuracy of metabolite quantification in targeted metabolomics, we decided to develop a comprehensive liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay that could quantitatively measure more than 700 metabolites in serum or plasma. Methods: The developed assay makes use of chemical derivatization followed by reverse phase LC–MS/MS and/or direct flow injection MS (DFI–MS) in both positive and negative ionization modes to separate metabolites. Multiple reaction monitoring (MRM), in combination with isotopic standards and multi-point calibration curves, is used to detect and absolutely quantify the targeted metabolites. The assay has been adapted to a 96-well plate format to enable automated, high-throughput sample analysis. Results: The assay (called MEGA) is able to detect and quantify 721 metabolites in serum/plasma, covering 20 metabolite classes and many commonly used clinical biomarkers. The limits of detection were determined to range from 1.4 nM to 10 mM, recovery rates were from 80% to 120%, and quantitative precision was within 20%. LC–MS/MS metabolite concentrations of the NIST^® SRM^®1950 plasma standard were found to be within 15% of NMR quantified levels. The MEGA assay was further validated in a large dietary intervention study. Conclusions: The MEGA assay should make comprehensive quantitative metabolomics much more affordable, accessible, automatable, and applicable to large-scale clinical studies. Full article

(This article belongs to the Special Issue Method Development in Metabolomics and Exposomics)

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5 pages, 200 KiB

Open AccessEditorial

Editorial: Roles of the Circadian Rhythms in Metabolic Disease and Health

by Letizia Galasso, Lucia Castelli and Eleonora Bruno

Metabolites 2024, 14(11), 621; https://doi.org/10.3390/metabo14110621 - 14 Nov 2024

Viewed by 449

Abstract

Chronobiology is the field of study focused on understanding the temporal patterns of biological functions, specifically examining the regular cycles or oscillations in these processes [...] Full article

(This article belongs to the Special Issue Roles of the Circadian Rhythms in Metabolic Disease and Health)

14 pages, 1004 KiB

Open AccessArticle

The Roles of Vitamin D Levels, Gla-Rich Protein (GRP) and Matrix Gla Protein (MGP), and Inflammatory Markers in Predicting Mortality in Intensive Care Patients: A New Biomarker Link?

by Fatih Seğmen, Semih Aydemir, Onur Küçük and Recep Dokuyucu

Metabolites 2024, 14(11), 620; https://doi.org/10.3390/metabo14110620 - 13 Nov 2024

Viewed by 492

Abstract

Objectives: Identifying reliable biomarkers to predict mortality in critically ill patients is crucial for optimizing management in intensive care units (ICUs). Inflammatory and metabolic markers are increasingly recognized for their prognostic value. This study aims to evaluate the association of various inflammatory and [...] Read more.

Objectives: Identifying reliable biomarkers to predict mortality in critically ill patients is crucial for optimizing management in intensive care units (ICUs). Inflammatory and metabolic markers are increasingly recognized for their prognostic value. This study aims to evaluate the association of various inflammatory and metabolic markers with ICU mortality. Methods: This prospective observational study was conducted from January 2023 to January 2024 in the City Hospital’s ICU. A total of 160 critically ill patients were enrolled. Laboratory parameters, including white blood cell (WBC) count, red cell distribution width (RDW), platelet count, neutrophil count, mean platelet volume (MPV), monocyte count, lymphocyte count, procalcitonin (PCT), C-reactive protein (CRP), calcium (Ca⁺⁺), and vitamin D levels, were analyzed. Additionally, ratios such as the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), systemic inflammatory index (SII), and pan-immune-inflammation value (PIV) were calculated. Plasma levels of Gla-rich protein (GRP) and dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) were measured using ELISA. Results: The mean age of the patients included in the study was 60.5 ± 15.8 years. Cardiovascular disease was present in 72 patients (45%), respiratory system disease in 58 (36%), and chronic kidney disease (CKD) in 38 (24%). Additionally, 61 patients (38%) had diabetes, and 68 (42%) had hypertension. Inflammatory markers, including PLR, NLR, and PIV, were all significantly higher in non-survivors, while calcium and vitamin D levels were lower (p < 0.05). Higher WBC, RDW, neutrophil count, PLR, NLR, PIV, CRP, procalcitonin, GRP, and dp-ucMGP levels were positively correlated with longer hospital stays and increased mortality. In contrast, platelet and lymphocyte counts were negatively correlated with both outcomes (p < 0.05). Vitamin D levels showed an inverse relationship with both hospital stay and mortality, indicating that lower levels were associated with worse outcomes (p < 0.05). In multiple logistic regression analysis, elevated WBC count (OR = 1.20, p = 0.02), RDW (OR = 1.35, p = 0.01), neutrophil count (OR = 1.25, p = 0.01), MPV (OR = 1.20, p = 0.02), PLR (OR = 1.30, p = 0.01), NLR (OR = 1.40, p = 0.001), PIV (OR = 1.50, p = 0.001), CRP (OR = 1.32, p = 0.01), procalcitonin (OR = 1.45, p = 0.001), GRP (OR = 1.40, p = 0.001), and dp-ucMGP (OR = 1.30, p = 0.001) levels were significantly associated with increased mortality. Conclusions: Inflammatory and metabolic markers, particularly NLR, PLR, PIV, GRP, and dp-ucMGP, are strong predictors of mortality in ICU patients. These markers provide valuable insights for risk stratification and early identification of high-risk patients, potentially guiding more targeted interventions to improve outcomes. Full article

(This article belongs to the Special Issue The Interplay Between Inflammation and Metabolism in Disease)

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10 pages, 2845 KiB

Open AccessArticle

Improving the Characteristics of Fruiting Bodies in Lentinus edodes: The Impact of Rolipram-Induced cAMP Modulation

by Hongman Li, Fei Chen, Chong Xu, Yanhua Wang, Chunhai Deng, Qingguo Meng and Weiwei Zhu

Metabolites 2024, 14(11), 619; https://doi.org/10.3390/metabo14110619 - 12 Nov 2024

Viewed by 527

Abstract

Background: Strains XG04 and XGT2 of Lentinus edodes (Berk.) Singer demonstrate a high degree of genomic similarity, with XGT2 representing a systematic selection of XG04 and exhibiting enhanced phenotypic traits. Methods: An investigation into the differences between these strains was conducted using untargeted [...] Read more.

Background: Strains XG04 and XGT2 of Lentinus edodes (Berk.) Singer demonstrate a high degree of genomic similarity, with XGT2 representing a systematic selection of XG04 and exhibiting enhanced phenotypic traits. Methods: An investigation into the differences between these strains was conducted using untargeted metabolomics to identify potential causal factors. Five exogenous inducers were assessed for their relationship with the observed phenotypes, and their impacts on fruiting body characteristics were analyzed. Results: Notably, the exogenous inducer rolipram, at a concentration of 0.4%, was found to increase cAMP expression levels in L. edodes primordia, which subsequently affected gill development, leading to the formation of gill-free fruiting bodies. Morphological differences between the two strains were evident; XG04 exhibited a spherical morphology with absent gills, rendering it commercially unviable, whereas XGT2 displayed a thicker cap and a more robust stipe, maintaining its characteristic umbrella shape. Conclusions: As the concentration of rolipram increased, both cap retraction and gill reduction in XGT2 occurred in a dose-dependent manner. The endogenous cAMP levels in the fruiting bodies were measured before and after rolipram treatment, revealing that the cap retraction and gill reduction in XGT2 progressed in a dose-dependent manner alongside increasing cAMP expression levels. Furthermore, a positive correlation was observed between cAMP levels and rolipram concentration. This study provides a foundation for improving the quality and productivity of mushroom cultivation by manipulating fruiting body characteristics through external stimuli. Full article

(This article belongs to the Section Plant Metabolism)

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12 pages, 908 KiB

Open AccessArticle

Unraveling the Association of Liver Steatosis and Fibrosis with Vitamin B12: A Cross-Sectional Study

by Silvia Espina, Diego Casas-Deza, Vanesa Bernal-Monterde, Ana Royo-Esteban, Maria Pilar García-Sobreviela, Pilar Calmarza, Ana B. Martinez-Martinez, Jesús Osada and Jose M. Arbones-Mainar

Metabolites 2024, 14(11), 618; https://doi.org/10.3390/metabo14110618 - 12 Nov 2024

Viewed by 421

Abstract

Background: There are conflicting studies reporting both an increase and a decrease in vitamin B12 (VB12) levels in non-alcoholic fatty liver disease (NAFLD). In this study, we aimed to dissect the effects of steatosis and fibrosis on VB12. Methods: This is a cross-sectional [...] Read more.

Background: There are conflicting studies reporting both an increase and a decrease in vitamin B12 (VB12) levels in non-alcoholic fatty liver disease (NAFLD). In this study, we aimed to dissect the effects of steatosis and fibrosis on VB12. Methods: This is a cross-sectional study including all patients with a vibration-controlled transient elastography (VCTE) performed at the Hospital Miguel Servet (Zaragoza, Spain) between 2019 and 2022 for a chronic liver disease and having a recent blood test for VB12 levels. Liver fibrosis was assessed by VCTE and hepatic steatosis by ultrasonography and/or through controlled attenuation parameter (CAP). Results: 1195 patients (NAFLD n = 441, other chronic liver disease n = 754) were included. Median age was 57 years, 53% female. Patients with NAFLD had lower levels of VB12 compared to the rest of chronic liver diseases (289 vs. 313 pg/mL, p < 0.001). A significant negative correlation was observed between VB12 levels and hepatic steatosis measured by CAP (r = −0.13, p < 0.001). A significant positive correlation was observed between VB12 levels and liver stiffness in patients with NAFLD in both sexes (men r = 0.31, p < 0.001 and women r = 0.15, p = 0.016). A significant association between VB12 levels and liver fibrosis in cirrhosis stage was observed in patients with NAFLD (OR 1.06, 95% CI, 1.025–1.098, p = 0.001). Conclusion: VB12 levels were lower with greater hepatic steatosis. In NAFLD, VB12 levels were lower compared to other chronic liver diseases but their levels increased with higher liver stiffness and in cirrhosis stage. Full article

(This article belongs to the Special Issue Clinical Nutrition and Metabolic Diseases)

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13 pages, 1269 KiB

Open AccessReview

Metabolomic Insights into COVID-19 Severity: A Scoping Review

by Eric Pimentel, Mohammad Mehdi Banoei, Jasnoor Kaur, Chel Hee Lee and Brent W. Winston

Metabolites 2024, 14(11), 617; https://doi.org/10.3390/metabo14110617 - 12 Nov 2024

Viewed by 448

Abstract

Background: In 2019, SARS-CoV-2, the novel coronavirus, entered the world scene, presenting a global health crisis with a broad spectrum of clinical manifestations. Recognizing the significance of metabolomics as the omics closest to symptomatology, it has become a useful tool for predicting clinical [...] Read more.

Background: In 2019, SARS-CoV-2, the novel coronavirus, entered the world scene, presenting a global health crisis with a broad spectrum of clinical manifestations. Recognizing the significance of metabolomics as the omics closest to symptomatology, it has become a useful tool for predicting clinical outcomes. Several metabolomic studies have indicated variations in the metabolome corresponding to different disease severities, highlighting the potential of metabolomics to unravel crucial insights into the pathophysiology of SARS-CoV-2 infection. Methods: The PRISMA guidelines were followed for this scoping review. Three major scientific databases were searched: PubMed, the Directory of Open Access Journals (DOAJ), and BioMed Central, from 2020 to 2024. Initially, 2938 articles were identified and vetted with specific inclusion and exclusion criteria. Of these, 42 articles were retrieved for analysis and summary. Results: Metabolites were identified that were repeatedly noted to change with COVID-19 and its severity. Phenylalanine, glucose, and glutamic acid increased with severity, while tryptophan, proline, and glutamine decreased, highlighting their association with COVID-19 severity. Additionally, pathway analysis revealed that phenylalanine, tyrosine and tryptophan biosynthesis, and arginine biosynthesis were the most significantly impacted pathways in COVID-19 severity. Conclusions: COVID-19 severity is intricately linked to significant metabolic alterations that span amino acid metabolism, energy production, immune response modulation, and redox balance. Full article

(This article belongs to the Section Cell Metabolism)

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18 pages, 10039 KiB

Open AccessArticle

Transcriptomics and Metabolomics Explain the Crisping Mechanisms of Broad Bean-Based Crisping Diets on Nile Tilapia (Orechromis niloticus)

by Xiaogang He, Haoming Shu, Tian Xu, Minhui Yu, Honglin Li, Yanru Hu, Jiajun Mo and Chunxiang Ai

Metabolites 2024, 14(11), 616; https://doi.org/10.3390/metabo14110616 - 12 Nov 2024

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Abstract

Background/Objectives: To investigate the crisping mechanism of broad bean-based crisping diets on Nile Tilapia. Methods: Four crisping diets were designed to feed 360 fish for 90 days, and multiomics analyses were employed. Results: Our results indicated that the designed crisping diets for Nile [...] Read more.

Background/Objectives: To investigate the crisping mechanism of broad bean-based crisping diets on Nile Tilapia. Methods: Four crisping diets were designed to feed 360 fish for 90 days, and multiomics analyses were employed. Results: Our results indicated that the designed crisping diets for Nile tilapia can effectively make tilapia muscle crispy. The ingestion of broad bean-based diets induced metabolic reprogramming dominated by glycolytic metabolism inhibition in fish, and metabolic reprogramming is the initiator of muscle structural remodeling. Among these, glucose is the main DAMP to be recognized by cellular PRRs, activating further immune response and oxidative stress and finally resulting in muscle change. Conclusions: Based on our results of multiomics, pck2, and ldh played main roles in crisping molecular mechanisms in driving the initial metabolic reprogram. Moreover, the addition of the crisping package further activated the ErbB signaling pathway and downstream MAPK signaling pathway to strengthen immune response, promoting muscle fiber development and growth. Our study delved into the effects of crisping formula diet on the liver of Nile tilapia at the molecular level, providing theoretical guidance for the nutritional regulation of crispy Nile tilapia. Full article

(This article belongs to the Section Animal Metabolism)

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Metabolites, Volume 14, Issue 11 (November 2024) – 77 articles

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