Metabolites

13 pages, 2106 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 3488

Abstract

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

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

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

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18 pages, 3450 KB

Open AccessEditor’s ChoiceArticle

Metabolomics Reveals Antioxidant Metabolites in Colored Rice Grains

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

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

Cited by 14 | Viewed by 2672

Abstract

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

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

(This article belongs to the Section Plant Metabolism)

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18 pages, 3547 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 2426

Abstract

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

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

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

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16 pages, 1418 KB

Open AccessEditor’s ChoiceTechnical Note

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

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

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

Cited by 4 | Viewed by 2684

Abstract

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

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

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

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21 pages, 3360 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 5 | Viewed by 2635

Abstract

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

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

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

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14 pages, 1158 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 2741

Abstract

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

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

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

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15 pages, 2534 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 8 | Viewed by 3574

Abstract

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

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

(This article belongs to the Section Food Metabolomics)

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16 pages, 2967 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 1997

Abstract

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

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

(This article belongs to the Section Plant Metabolism)

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12 pages, 816 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 2585

Abstract

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

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

(This article belongs to the Section Animal Metabolism)

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16 pages, 4181 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 4 | Viewed by 2288

Abstract

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

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

(This article belongs to the Section Plant Metabolism)

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16 pages, 3643 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Viewed by 1996

Abstract

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

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

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

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15 pages, 1939 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 4 | Viewed by 3215

Abstract

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

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

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

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14 pages, 2380 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 6 | Viewed by 2493

Abstract

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

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

(This article belongs to the Section Advances in Metabolomics)

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17 pages, 931 KB

Open AccessEditor’s ChoiceReview

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

by Bijay Gurung, Maranda Stricklin and Shaohua Wang

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

Cited by 17 | Viewed by 4788

Abstract

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

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

(This article belongs to the Section Advances in Metabolomics)

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11 pages, 2227 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 2732

Abstract

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

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

(This article belongs to the Section Advances in Metabolomics)

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17 pages, 3790 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 2848

Abstract

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

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

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

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13 pages, 4926 KB

Open AccessEditor’s ChoiceArticle

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

by Suzanne Paley and Peter D. Karp

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

Cited by 5 | Viewed by 4354

Abstract

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

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

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

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12 pages, 2356 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 2247

Abstract

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

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

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

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21 pages, 6619 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 2140

Abstract

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

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

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

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15 pages, 8154 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 2400

Abstract

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

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

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

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26 pages, 6562 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 5 | Viewed by 2561

Abstract

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

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

(This article belongs to the Section Animal Metabolism)

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17 pages, 4423 KB

Open AccessEditor’s ChoiceArticle

Metabolic Regulations of Smilax china L. against β-Amyloid Toxicity in Caenorhabditis elegans

by Lili Yan, Yuchan Deng, Yulan Du, Xutong Fang, Xin Fang and Qiang Zhang

Metabolites 2024, 14(1), 49; https://doi.org/10.3390/metabo14010049 - 13 Jan 2024

Cited by 1 | Viewed by 2592

Abstract

Smilax china L. (Chinaroot) is a natural herb that has multiple uses, such as being used to make tea and food. Both its roots and leaves have different uses due to their unique components. In this study, we analyzed the extract of S. [...] Read more.

Smilax china L. (Chinaroot) is a natural herb that has multiple uses, such as being used to make tea and food. Both its roots and leaves have different uses due to their unique components. In this study, we analyzed the extract of S. china. roots using LC-HRMS and evaluated the neuroprotective effects and metabolic regulation of S. china on Caenorhabditis elegans. Chinaroot extract prolonged the life span of healthy nematodes, delayed the paralysis time of transgenic CL4176, and reduced the level of β-amyloid deposition in transgenic CL2006. The comprehensive analysis of metabolomics and qRT-PCR revealed that Chinaroot extract exerted neuroprotective effects through the valine, leucine and isoleucine degradation and fatty acid degradation pathways. Moreover, we first discovered that the expressions of T09B4.8, ech-7, and agxt-1 were linked to the neuroprotective effects of Chinaroot. The material exerted neuroprotective effects by modulating metabolic abnormalities in AD model C. elegans. Our study provides a new foundation for the development of functional food properties and functions. Full article

(This article belongs to the Section Cell Metabolism)

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20 pages, 4215 KB

Open AccessEditor’s ChoiceArticle

Metabolomic Changes in Rat Serum after Chronic Exposure to Glyphosate-Based Herbicide

by Oluwatosin Daramola, Cristian D. Gutierrez Reyes, Jesús Chávez-Reyes, Bruno A. Marichal-Cancino, Judith Nwaiwu, Sherifdeen Onigbinde, Moyinoluwa Adeniyi, Joy Solomon, Md Mostofa Al Amin Bhuiyan and Yehia Mechref

Metabolites 2024, 14(1), 50; https://doi.org/10.3390/metabo14010050 - 13 Jan 2024

Cited by 9 | Viewed by 3393

Abstract

Glyphosate-based herbicides (GBHs) have gained extensive popularity in recent decades. For many years, glyphosate has been regarded as harmless or minimally toxic to mammals due to the absence of its primary target, the shikimic acid pathway in humans. Nonetheless, mounting evidence suggests that [...] Read more.

Glyphosate-based herbicides (GBHs) have gained extensive popularity in recent decades. For many years, glyphosate has been regarded as harmless or minimally toxic to mammals due to the absence of its primary target, the shikimic acid pathway in humans. Nonetheless, mounting evidence suggests that glyphosate may cause adverse health effects in humans via other mechanisms. In this study, we described the metabolomic changes in the serum of experimental rats exposed to chronic GBH using the highly sensitive LC-MS/MS technique. We investigated the possible relationship between chronic exposure to GBH and neurological disorders. Our findings suggest that chronic exposure to GBH can alter spatial learning memory and the expression of some important metabolites that are linked to neurophysiological disorders in young rats, with the female rats showing higher susceptibility compared to the males. This indicates that female rats are more likely to show early symptoms of the disorder on exposure to chronic GBH compared to male rats. We observed that four important metabolites (paraxanthine, epinephrine, L-(+)-arginine, and D-arginine) showed significant changes and involvement in neurological changes as suggested by ingenuity pathway analysis. In conclusion, our results indicate that chronic exposure to GBH can increase the risk of developing neurological disorders. Full article

(This article belongs to the Section Animal Metabolism)

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22 pages, 1737 KB

Open AccessEditor’s ChoiceReview

Revolutionizing Blood Collection: Innovations, Applications, and the Potential of Microsampling Technologies for Monitoring Metabolites and Lipids

by Eleonora Bossi, Elena Limo, Lisa Pagani, Nicole Monza, Simone Serrao, Vanna Denti, Giuseppe Astarita and Giuseppe Paglia

Metabolites 2024, 14(1), 46; https://doi.org/10.3390/metabo14010046 - 11 Jan 2024

Cited by 20 | Viewed by 5136

Abstract

Blood serves as the primary global biological matrix for health surveillance, disease diagnosis, and response to drug treatment, holding significant promise for personalized medicine. The diverse array of lipids and metabolites in the blood provides a snapshot of both physiological and pathological processes, [...] Read more.

Blood serves as the primary global biological matrix for health surveillance, disease diagnosis, and response to drug treatment, holding significant promise for personalized medicine. The diverse array of lipids and metabolites in the blood provides a snapshot of both physiological and pathological processes, with many routinely monitored during conventional wellness checks. The conventional method involves intravenous blood collection, extracting a few milliliters via venipuncture, a technique limited to clinical settings due to its dependence on trained personnel. Microsampling methods have evolved to be less invasive (collecting ≤150 µL of capillary blood), user-friendly (enabling self-collection), and suitable for remote collection in longitudinal studies. Dried blood spot (DBS), a pioneering microsampling technique, dominates clinical and research domains. Recent advancements in device technology address critical limitations of classical DBS, specifically variations in hematocrit and volume. This review presents a comprehensive overview of state-of-the-art microsampling devices, emphasizing their applications and potential for monitoring metabolites and lipids in blood. The scope extends to diverse areas, encompassing population studies, nutritional investigations, drug discovery, sports medicine, and multi-omics research. Full article

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

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19 pages, 1280 KB

Open AccessEditor’s ChoiceArticle

The Urinary Metabolome of Newborns with Perinatal Complications

by Yamilé López-Hernández, Victoria Lima-Rogel, Rupasri Mandal, Jiamin Zheng, Lun Zhang, Eponine Oler, David Alejandro García-López, Claudia Torres-Calzada, Ana Ruth Mejía-Elizondo, Jenna Poelzer, Jesús Adrián López, Ashley Zubkowski and David S. Wishart

Metabolites 2024, 14(1), 41; https://doi.org/10.3390/metabo14010041 - 10 Jan 2024

Cited by 5 | Viewed by 4911

Abstract

Maternal pathological conditions such as infections and chronic diseases, along with unexpected events during labor, can lead to life-threatening perinatal outcomes. These outcomes can have irreversible consequences throughout an individual’s entire life. Urinary metabolomics can provide valuable insights into early physiological adaptations in [...] Read more.

Maternal pathological conditions such as infections and chronic diseases, along with unexpected events during labor, can lead to life-threatening perinatal outcomes. These outcomes can have irreversible consequences throughout an individual’s entire life. Urinary metabolomics can provide valuable insights into early physiological adaptations in healthy newborns, as well as metabolic disturbances in premature infants or infants with birth complications. In the present study, we measured 180 metabolites and metabolite ratios in the urine of 13 healthy (hospital-discharged) and 38 critically ill newborns (admitted to the neonatal intensive care unit (NICU)). We used an in-house-developed targeted tandem mass spectrometry (MS/MS)-based metabolomic assay (TMIC Mega) combining liquid chromatography (LC-MS/MS) and flow injection analysis (FIA-MS/MS) to quantitatively analyze up to 26 classes of compounds. Average urinary concentrations (and ranges) for 167 different metabolites from 38 critically ill NICU newborns during their first 24 h of life were determined. Similar sets of urinary values were determined for the 13 healthy newborns. These reference data have been uploaded to the Human Metabolome Database. Urinary concentrations and ranges of 37 metabolites are reported for the first time for newborns. Significant differences were found in the urinary levels of 44 metabolites between healthy newborns and those admitted at the NICU. Metabolites such as acylcarnitines, amino acids and derivatives, biogenic amines, sugars, and organic acids are dysregulated in newborns with bronchopulmonary dysplasia (BPD), asphyxia, or newborns exposed to SARS-CoV-2 during the intrauterine period. Urine can serve as a valuable source of information for understanding metabolic alterations associated with life-threatening perinatal outcomes. Full article

(This article belongs to the Special Issue Metabolomics in Pulmonary Diseases)

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23 pages, 2386 KB

Open AccessEditor’s ChoiceReview

Obesity, Dietary Fats, and Gastrointestinal Cancer Risk-Potential Mechanisms Relating to Lipid Metabolism and Inflammation

by Kathleen A. J. Mitchelson, Fiona O’Connell, Jacintha O’Sullivan and Helen M. Roche

Metabolites 2024, 14(1), 42; https://doi.org/10.3390/metabo14010042 - 10 Jan 2024

Cited by 18 | Viewed by 4925

Abstract

Obesity is a major driving factor in the incidence, progression, and poor treatment response in gastrointestinal cancers. Herein, we conducted a comprehensive analysis of the impact of obesity and its resulting metabolic perturbations across four gastrointestinal cancer types, namely, oesophageal, gastric, liver, and [...] Read more.

Obesity is a major driving factor in the incidence, progression, and poor treatment response in gastrointestinal cancers. Herein, we conducted a comprehensive analysis of the impact of obesity and its resulting metabolic perturbations across four gastrointestinal cancer types, namely, oesophageal, gastric, liver, and colorectal cancer. Importantly, not all obese phenotypes are equal. Obese adipose tissue heterogeneity depends on the location, structure, cellular profile (including resident immune cell populations), and dietary fatty acid intake. We discuss whether adipose heterogeneity impacts the tumorigenic environment. Dietary fat quality, in particular saturated fatty acids, promotes a hypertrophic, pro-inflammatory adipose profile, in contrast to monounsaturated fatty acids, resulting in a hyperplastic, less inflammatory adipose phenotype. The purpose of this review is to examine the impact of obesity, including dietary fat quality, on adipose tissue biology and oncogenesis, specifically focusing on lipid metabolism and inflammatory mechanisms. This is achieved with a particular focus on gastrointestinal cancers as exemplar models of obesity-associated cancers. Full article

(This article belongs to the Section Nutrition and Metabolism)

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25 pages, 1170 KB

Open AccessEditor’s ChoiceReview

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

by Amedeo Lonardo, Stefano Ballestri, Alessandro Mantovani, Giovanni Targher and Fernando Bril

Metabolites 2024, 14(1), 40; https://doi.org/10.3390/metabo14010040 - 8 Jan 2024

Cited by 19 | Viewed by 4858

Abstract

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments [...] Read more.

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular–kidney–metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone. Full article

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

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23 pages, 11632 KB

Open AccessEditor’s ChoiceArticle

Conditional Vitamin D Receptor Deletion Induces Fungal and Archaeal Dysbiosis and Altered Metabolites

by Duncan J. Claypool, Yong-Guo Zhang, Yinglin Xia and Jun Sun

Metabolites 2024, 14(1), 32; https://doi.org/10.3390/metabo14010032 - 1 Jan 2024

Viewed by 2791

Abstract

A vitamin D receptor (VDR) deficiency leads to the dysbiosis of intestinal bacteria and is associated with various diseases, including cancer, infections, and inflammatory bowel disease. However, the impact of a VDR deficiency on fungi and archaea is unknown. We conditionally deleted the [...] Read more.

A vitamin D receptor (VDR) deficiency leads to the dysbiosis of intestinal bacteria and is associated with various diseases, including cancer, infections, and inflammatory bowel disease. However, the impact of a VDR deficiency on fungi and archaea is unknown. We conditionally deleted the VDR in Paneth cells (VDR^ΔPC), intestinal epithelial cells (VDR^ΔIEC), or myeloid cells (VDR^ΔLyz) in mice and collected feces for shotgun metagenomic sequencing and untargeted metabolomics. We found that fungi were significantly altered in each knockout (KO) group compared to the VDR^Loxp control. The VDR^ΔLyz mice had the most altered fungi species (three depleted and seven enriched), followed by the VDR^ΔPC mice (six depleted and two enriched), and the VDR^ΔIEC mice (one depleted and one enriched). The methanogen Methanofollis liminatans was enriched in the VDR^ΔPC and VDR^ΔLyz mice and two further archaeal species (Thermococcus piezophilus and Sulfolobus acidocaldarius) were enriched in the VDR^ΔLyz mice compared to the Loxp group. Significant correlations existed among altered fungi, archaea, bacteria, and viruses in the KO mice. Functional metagenomics showed changes in several biologic functions, including decreased sulfate reduction and increased biosynthesis of cobalamin (vitamin B12) in VDR^ΔLyz mice relative to VDR^Loxp mice. Fecal metabolites were analyzed to examine the involvement of sulfate reduction and other pathways. In conclusion, a VDR deficiency caused the formation of altered fungi and archaea in a tissue- and sex-dependent manner. These results provide a foundation about the impact of a host factor (e.g., VDR deficiency) on fungi and archaea. It opens the door for further studies to determine how mycobiome and cross-kingdom interactions in the microbiome community and metabolites contribute to the risk of certain diseases. Full article

(This article belongs to the Special Issue Impact of Microbiome Community Changes on Host Health through Metabolic Dysregulation)

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16 pages, 3418 KB

Open AccessEditor’s ChoiceArticle

Induction of AHR Signaling in Response to the Indolimine Class of Microbial Stress Metabolites

by Dhwani Patel, Iain A. Murray, Fangcong Dong, Andrew J. Annalora, Krishne Gowda, Denise M. Coslo, Jacek Krzeminski, Imhoi Koo, Fuhua Hao, Shantu G. Amin, Craig B. Marcus, Andrew D. Patterson and Gary H. Perdew

Metabolites 2023, 13(9), 985; https://doi.org/10.3390/metabo13090985 - 31 Aug 2023

Cited by 3 | Viewed by 3406

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that plays an important role in gastrointestinal barrier function, tumorigenesis, and is an emerging drug target. The resident microbiota is capable of metabolizing tryptophan to metabolites that are AHR ligands (e.g., indole-3-acetate). Recently, [...] Read more.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that plays an important role in gastrointestinal barrier function, tumorigenesis, and is an emerging drug target. The resident microbiota is capable of metabolizing tryptophan to metabolites that are AHR ligands (e.g., indole-3-acetate). Recently, a novel set of mutagenic tryptophan metabolites named indolimines have been identified that are produced by M. morganii in the gastrointestinal tract. Here, we determined that indolimine-200, -214, and -248 are direct AHR ligands that can induce Cyp1a1 transcription and subsequent CYP1A1 enzymatic activity capable of metabolizing the carcinogen benzo(a)pyrene in microsomal assays. In addition, indolimines enhance IL6 expression in a colonic tumor cell line in combination with cytokine treatment. The concentration of indolimine-248 that induces AHR transcriptional activity failed to increase DNA damage. These observations reveal an additional aspect of how indolimines may alter colonic tumorigenesis beyond mutagenic activity. Full article

(This article belongs to the Special Issue Impact of Microbiome Community Changes on Host Health through Metabolic Dysregulation)

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17 pages, 3331 KB

Open AccessEditor’s ChoiceArticle

The Integration of Metabolomics, Electronic Tongue, and Chromatic Difference Reveals the Correlations between the Critical Compounds and Flavor Characteristics of Two Grades of High-Quality Dianhong Congou Black Tea

by Shan Zhang, Xujiang Shan, Linchi Niu, Le Chen, Jinjin Wang, Qinghua Zhou, Haibo Yuan, Jia Li and Tian Wu

Metabolites 2023, 13(7), 864; https://doi.org/10.3390/metabo13070864 - 20 Jul 2023

Cited by 19 | Viewed by 2470

Abstract

Tea’s biochemical compounds and flavor quality vary depending on its grade ranking. Dianhong Congou black tea (DCT) is a unique tea category produced using the large-leaf tea varieties from Yunnan, China. To date, the flavor characteristics and critical components of two grades of [...] Read more.

Tea’s biochemical compounds and flavor quality vary depending on its grade ranking. Dianhong Congou black tea (DCT) is a unique tea category produced using the large-leaf tea varieties from Yunnan, China. To date, the flavor characteristics and critical components of two grades of high-quality DCT, single-bud-grade DCT (BDCT), and special-grade DCT (SDCT) manufactured mainly with single buds and buds with one leaf, respectively, are far from clear. Herein, comparisons of two grades were performed by the integration of human sensory evaluation, an electronic tongue, chromatic differences, the quantification of major components, and metabolomics. The BDCT possessed a brisk, umami taste and a brighter infusion color, while the SDCT presented a comprehensive taste and redder liquor color. Quantification analysis showed that the levels of total polyphenols, catechins, and theaflavins (TFs) were significantly higher in the BDCT. Fifty-six different key compounds were screened by metabolomics, including catechins, flavone/flavonol glycosides, amino acids, phenolic acids, etc. Correlation analysis revealed that the sensory features of the BDCT and SDCT were attributed to their higher contents of catechins, TFs, theogallin, digalloylglucose, and accumulations of thearubigins (TRs), flavone/flavonol glycosides, and soluble sugars, respectively. This report is the first to focus on the comprehensive evaluation of the biochemical compositions and sensory characteristics of two grades of high-quality DCT, advancing the understanding of DCT from a multi-dimensional perspective. Full article

(This article belongs to the Special Issue State-of-the-Art Metabolomics and Lipidomics in Life Sciences: Methods and Applications)

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17 pages, 1690 KB

Open AccessEditor’s ChoiceArticle

Bioavailable Microbial Metabolites of Flavanols Demonstrate Highly Individualized Bioactivity on In Vitro β-Cell Functions Critical for Metabolic Health

by Emily S. Krueger, Laura E. Griffin, Joseph L. Beales, Trevor S. Lloyd, Nathan J. Brown, Weston S. Elison, Colin D. Kay, Andrew P. Neilson and Jeffery S. Tessem

Metabolites 2023, 13(7), 801; https://doi.org/10.3390/metabo13070801 - 28 Jun 2023

Cited by 1 | Viewed by 2013

Abstract

Dietary flavanols are known for disease preventative properties but are often poorly absorbed. Gut microbiome flavanol metabolites are more bioavailable and may exert protective activities. Using metabolite mixtures extracted from the urine of rats supplemented with flavanols and treated with or without antibiotics, [...] Read more.

Dietary flavanols are known for disease preventative properties but are often poorly absorbed. Gut microbiome flavanol metabolites are more bioavailable and may exert protective activities. Using metabolite mixtures extracted from the urine of rats supplemented with flavanols and treated with or without antibiotics, we investigated their effects on INS-1 832/13 β-cell glucose stimulated insulin secretion (GSIS) capacity. We measured insulin secretion under non-stimulatory (low) and stimulatory (high) glucose levels, insulin secretion fold induction, and total insulin content. We conducted treatment-level comparisons, individual-level dose responses, and a responder vs. non-responder predictive analysis of metabolite composition. While the first two analyses did not elucidate treatment effects, metabolites from 9 of the 28 animals demonstrated significant dose responses, regardless of treatment. Differentiation of responders vs. non-responder revealed that levels of native flavanols and valerolactones approached significance for predicting enhanced GSIS, regardless of treatment. Although treatment-level patterns were not discernable, we conclude that the high inter-individual variability shows that metabolite bioactivity on GSIS capacity is less related to flavanol supplementation or antibiotic treatment and may be more associated with the unique microbiome or metabolome of each animal. These findings suggest flavanol metabolite activities are individualized and point to the need for personalized nutrition practices. Full article

(This article belongs to the Section Nutrition and Metabolism)

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17 pages, 14471 KB

Open AccessEditor’s ChoiceArticle

Maternal Magnolol Supplementation during Pregnancy and Lactation Promotes Antioxidant Capacity, Improves Gut Health, and Alters Gut Microbiota and Metabolites of Weanling Piglets

by Qiwen Fan, Encun Du, Fang Chen, Wenjing Tao, Na Zhao, Shaowen Huang, Wanzheng Guo, Jing Huang and Jintao Wei

Metabolites 2023, 13(7), 797; https://doi.org/10.3390/metabo13070797 - 27 Jun 2023

Cited by 4 | Viewed by 2040

Abstract

Maternal nutrition exerts a profound effect on the postnatal performance of offspring, especially during the weaning period. The multifunctional bioactive component magnolol (MAG) has shown promise as a dietary supplement. This study aimed to explore the effects of maternal MAG supplementation on the [...] Read more.

Maternal nutrition exerts a profound effect on the postnatal performance of offspring, especially during the weaning period. The multifunctional bioactive component magnolol (MAG) has shown promise as a dietary supplement. This study aimed to explore the effects of maternal MAG supplementation on the antioxidant capacity, gut health, gut microbiome, and metabolome composition of weanling piglets. Fifty pregnant sows were randomly divided into two equally sized groups, the control group and the group supplemented with 100 g/t MAG during the gestation and lactation periods, and 7 days postweaning, the pups were euthanized. The microbiome and metabolome features of weanling piglet colons were compared. Our results revealed that maternal MAG supplementation modified the serum redox status of weanling piglets by decreasing malondialdehyde concentration and increasing superoxide dismutase activity and total antioxidant capacity. Moreover, the decreased indicators of diarrhea were accompanied by improved gut barrier function, in which serum diamine oxidase concentration was decreased, and expressions of zona occludens-1, claudin-1, and intestinal alkaline phosphatase were increased in the colon of weanling piglets from sows supplemented with MAG. Further analysis of the gut microbiota indicated that maternal MAG supplementation significantly increased the relative abundance of beneficial bacteria in the colon of weanling piglets, including Faecalibacterium prausnitzii and Oscillospira. Metabolome analysis identified 540 differential metabolites in the colon of piglets from MAG-fed dams, of which glycerophospholipid classes were highly correlated with progeny gut health and key beneficial bacteria. Our findings indicated that maternal MAG supplementation can improve the oxidative status and gut health of weanling piglets, possibly due to alterations in the gut microbiota and metabolites. Full article

(This article belongs to the Section Nutrition and Metabolism)

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27 pages, 3516 KB

Open AccessEditor’s ChoiceReview

Dietary Patterns, Gut Microbiota Remodeling, and Cardiometabolic Disease

by Letizia Guiducci, Giuseppina Nicolini and Francesca Forini

Metabolites 2023, 13(6), 760; https://doi.org/10.3390/metabo13060760 - 17 Jun 2023

Cited by 9 | Viewed by 4135

Abstract

The cardiovascular and metabolic disorders, collectively known as cardiometabolic disease (CMD), are high morbidity and mortality pathologies associated with lower quality of life and increasing health-care costs. The influence of the gut microbiota (GM) in dictating the interpersonal variability in CMD susceptibility, progression [...] Read more.

The cardiovascular and metabolic disorders, collectively known as cardiometabolic disease (CMD), are high morbidity and mortality pathologies associated with lower quality of life and increasing health-care costs. The influence of the gut microbiota (GM) in dictating the interpersonal variability in CMD susceptibility, progression and treatment response is beginning to be deciphered, as is the mutualistic relation established between the GM and diet. In particular, dietary factors emerge as pivotal determinants shaping the architecture and function of resident microorganisms in the human gut. In turn, intestinal microbes influence the absorption, metabolism, and storage of ingested nutrients, with potentially profound effects on host physiology. Herein, we present an updated overview on major effects of dietary components on the GM, highlighting the beneficial and detrimental consequences of diet–microbiota crosstalk in the setting of CMD. We also discuss the promises and challenges of integrating microbiome data in dietary planning aimed at restraining CMD onset and progression with a more personalized nutritional approach. Full article

(This article belongs to the Special Issue Dietary–Microbiome–Metabolic Interactions in Cardiovascular Disease)

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11 pages, 1302 KB

Open AccessEditor’s ChoiceReview

Metabolic Role of GABA in the Secretory Function of Pancreatic β-Cells: Its Hypothetical Implication in β-Cell Degradation in Type 2 Diabetes

by Jorge Tamarit-Rodriguez

Metabolites 2023, 13(6), 697; https://doi.org/10.3390/metabo13060697 - 27 May 2023

Cited by 8 | Viewed by 2766

Abstract

The stimulus-secretion coupling of a glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that [...] Read more.

The stimulus-secretion coupling of a glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that closes the ATP-dependent K⁺-channel at the plasma membrane. The resultant depolarization of the β-cells opens voltage-dependent Ca²⁺-channels at the plasma membrane that triggers the exocytosis of insulin secretory granules. The secretory response is biphasic with a first and transient peak followed by a sustained phase. The first phase is reproduced by a depolarization of the β-cells with high extracellular KCl maintaining the KATP-channels open with diazoxide (triggering phase); the sustained phase (amplifying phase) depends on the participation of metabolic signals that remain to be determined. Our group has been investigating for several years the participation of the β-cell GABA metabolism in the stimulation of insulin secretion by three different secretagogues (glucose, a mixture of L-leucine plus L-glutamine, and some branched chain alpha-ketoacids, BCKAs). They stimulate a biphasic secretion of insulin accompanied by a strong suppression of the intracellular islet content of gamma-aminobutyric acid (GABA). As the islet GABA release simultaneously decreased, it was concluded that this resulted from an increased GABA shunt metabolism. The entrance of GABA into the shunt is catalyzed by GABA transaminase (GABAT) that transfers an amino group between GABA and alpha-ketoglutarate, resulting in succinic acid semialdehyde (SSA) and L-glutamate. SSA is oxidized to succinic acid that is further oxidized in the citric acid cycle. Inhibitors of GABAT (gamma-vinyl GABA, gabaculine) or glutamic acid decarboxylating activity (GAD), allylglycine, partially suppress the secretory response as well as GABA metabolism and islet ATP content and the ATP/ADP ratio. It is concluded that the GABA shunt metabolism contributes together with the own metabolism of metabolic secretagogues to increase islet mitochondrial oxidative phosphorylation. These experimental findings emphasize that the GABA shunt metabolism is a previously unrecognized anaplerotic mitochondrial pathway feeding the citric acid cycle with a β-cell endogenous substrate. It is therefore a postulated alternative to the proposed mitochondrial cataplerotic pathway(s) responsible for the amplification phase of insulin secretion. It is concluded the new postulated alternative suggests a possible new mechanism of β-cell degradation in type 2 (perhaps also in type 1) diabetes. Full article

(This article belongs to the Special Issue Biosynthesis, Metabolism, and Physiological Functions of Gamma-Aminobutyric Acid)

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15 pages, 297 KB

Open AccessEditor’s ChoiceArticle

Associations between Plasma Lipid Mediators and Chronic Daily Headache Outcomes in Patients Randomized to a Low Linoleic Acid Diet with or without Added Omega-3 Fatty Acids

by Qing Shen, Jun Yang, Daisy Zamora, Mark Horowitz, Keturah R. Faurot, Beth A. MacIntosh, J. Douglas Mann, Bruce D. Hammock, Christopher E. Ramsden and Ameer Y. Taha

Metabolites 2023, 13(6), 690; https://doi.org/10.3390/metabo13060690 - 25 May 2023

Cited by 5 | Viewed by 2706

Abstract

A previous report showed that 12-week lowering of dietary omega-6 linoleic acid (LA) coupled with increased omega-3 polyunsaturated fatty acid (PUFA) intake (H3-L6 diet) reduced headache frequency and improved quality of life in patients with chronic daily headaches (CDHs) compared to dietary LA [...] Read more.

A previous report showed that 12-week lowering of dietary omega-6 linoleic acid (LA) coupled with increased omega-3 polyunsaturated fatty acid (PUFA) intake (H3-L6 diet) reduced headache frequency and improved quality of life in patients with chronic daily headaches (CDHs) compared to dietary LA reduction alone (L6 diet). The trial also showed that targeted dietary manipulation alters PUFA-derived lipid mediators and endocannabinoids. However, several additional classes of lipid mediators associated with pain in preclinical models were not measured. The current secondary analysis investigated whether the clinical benefits of the H3-L6 diet were related to changes in plasma unesterified PUFA-derived lipid mediators known to be involved in nociception, including prostanoids. Lipid mediators were measured by ultra-high-pressure liquid chromatography coupled with tandem mass-spectrometry. Compared to baseline, dietary LA lowering with or without added omega-3 fatty acids did not alter unesterified n-6 PUFA-derived lipid mediators, although several species derived from LA, di-homo-gamma-linolenic acid, and arachidonic acid were positively associated with headache frequency and intensity, as well as mental health burden. Alpha-linolenic acid (ALA)-derived metabolites were also associated with increased headache frequency and intensity, although they did not change from the baseline in either dietary group. Compared to baseline, docosahexaenoic acid (DHA)-derived epoxides were more elevated in the H3-L6 group compared to the L6 group. Diet-induced elevations in plasma DHA-epoxides were associated with reduced headache frequency, better physical and mental health, and improved quality of life (p < 0.05). Prostanoids were not detected, except for PGF2-alpha, which was not associated with any outcomes. This study demonstrates that diet-induced changes in DHA-epoxides were associated with pain reduction in patients with chronic headaches, whereas n-6 PUFA and ALA metabolites were associated with nociception. Lipid mediator associations with mental health and quality of life paralleled pain management outcomes in this population. The findings point to a network of multiple diet-modifiable lipid mediator targets for pain management in individuals with CDHs. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

16 pages, 987 KB

Open AccessEditor’s ChoiceReview

Instrumental Drift in Untargeted Metabolomics: Optimizing Data Quality with Intrastudy QC Samples

by Andre Märtens, Johannes Holle, Brit Mollenhauer, Andre Wegner, Jennifer Kirwan and Karsten Hiller

Metabolites 2023, 13(5), 665; https://doi.org/10.3390/metabo13050665 - 16 May 2023

Cited by 19 | Viewed by 5732

Abstract

Untargeted metabolomics is an important tool in studying health and disease and is employed in fields such as biomarker discovery and drug development, as well as precision medicine. Although significant technical advances were made in the field of mass-spectrometry driven metabolomics, instrumental drifts, [...] Read more.

Untargeted metabolomics is an important tool in studying health and disease and is employed in fields such as biomarker discovery and drug development, as well as precision medicine. Although significant technical advances were made in the field of mass-spectrometry driven metabolomics, instrumental drifts, such as fluctuations in retention time and signal intensity, remain a challenge, particularly in large untargeted metabolomics studies. Therefore, it is crucial to consider these variations during data processing to ensure high-quality data. Here, we will provide recommendations for an optimal data processing workflow using intrastudy quality control (QC) samples that identifies errors resulting from instrumental drifts, such as shifts in retention time and metabolite intensities. Furthermore, we provide an in-depth comparison of the performance of three popular batch-effect correction methods of different complexity. By using different evaluation metrics based on QC samples and a machine learning approach based on biological samples, the performance of the batch-effect correction methods were evaluated. Here, the method TIGER demonstrated the overall best performance by reducing the relative standard deviation of the QCs and dispersion-ratio the most, as well as demonstrating the highest area under the receiver operating characteristic with three different probabilistic classifiers (Logistic regression, Random Forest, and Support Vector Machine). In summary, our recommendations will help to generate high-quality data that are suitable for further downstream processing, leading to more accurate and meaningful insights into the underlying biological processes. Full article

(This article belongs to the Special Issue Application of Mass Spectrometry Analysis in Metabolomics)

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12 pages, 2720 KB

Open AccessEditor’s ChoiceArticle

Optimization of Carob Products Preparation for Targeted LC-MS/MS Metabolomics Analysis

by Olga Deda, Olga Begou, Helen Gika, Georgios Theodoridis and Agapios Agapiou

Metabolites 2023, 13(5), 645; https://doi.org/10.3390/metabo13050645 - 9 May 2023

Cited by 5 | Viewed by 2623

Abstract

Carob (Ceratonia siliqua) is an exceptional source of significant bioactive compounds with great economic importance in the Mediterranean region, where it is widely cultivated. Carob fruit is used for the production of a variety of products and commodities such as powder, [...] Read more.

Carob (Ceratonia siliqua) is an exceptional source of significant bioactive compounds with great economic importance in the Mediterranean region, where it is widely cultivated. Carob fruit is used for the production of a variety of products and commodities such as powder, syrup, coffee, flour, cakes, and beverages. There is growing evidence of the beneficial effects of carob and the products made from it on a range of health problems. Therefore, metabolomics could be used to explore the nutrient-rich compounds of carob. Sample preparation is a crucial step in metabolomics-based analysis and has a great impact on the quality of the data obtained. Herein, sample preparation of carob syrup and powder was optimized, to enable highly efficient metabolomics-based HILIC-MS/MS analysis. Pooled powder and syrup samples were extracted under different conditions by adjusting pH, solvent type, and sample weight to solvent volume ratio (Wc/Vs). The metabolomics profiles obtained were evaluated using the established criteria of total area and number of maxima. It was observed that the Wc/Vs ratio of 1:2 resulted in the highest number of metabolites, regardless of solvent type or pH. Aqueous acetonitrile with a Wc/Vs ratio of 1:2 satisfied all established criteria for both carob syrup and powder samples. However, when the pH was adjusted, basic aqueous propanol 1:2 Wc/Vs and acidic aqueous acetonitrile 1:2 Wc/Vs provided the best results for syrup and powder, respectively. We strongly believe that the current study could support the standardization of the metabolomics sample preparation process to enable more efficient LC-MS/MS carob analysis. Full article

(This article belongs to the Special Issue Analytical Developments in Mapping the Polar Metabolome)

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22 pages, 12196 KB

Open AccessEditor’s ChoiceReview

Benchtop NMR-Based Metabolomics: First Steps for Biomedical Application

by Pilar Alonso-Moreno, Ignacio Rodriguez and Jose Luis Izquierdo-Garcia

Metabolites 2023, 13(5), 614; https://doi.org/10.3390/metabo13050614 - 29 Apr 2023

Cited by 13 | Viewed by 4832

Abstract

Nuclear magnetic resonance (NMR)-based metabolomics is a valuable tool for identifying biomarkers and understanding the underlying metabolic changes associated with various diseases. However, the translation of metabolomics analysis to clinical practice has been limited by the high cost and large size of traditional [...] Read more.

Nuclear magnetic resonance (NMR)-based metabolomics is a valuable tool for identifying biomarkers and understanding the underlying metabolic changes associated with various diseases. However, the translation of metabolomics analysis to clinical practice has been limited by the high cost and large size of traditional high-resolution NMR spectrometers. Benchtop NMR, a compact and low-cost alternative, offers the potential to overcome these limitations and facilitate the wider use of NMR-based metabolomics in clinical settings. This review summarizes the current state of benchtop NMR for clinical applications where benchtop NMR has demonstrated the ability to reproducibly detect changes in metabolite levels associated with diseases such as type 2 diabetes and tuberculosis. Benchtop NMR has been used to identify metabolic biomarkers in a range of biofluids, including urine, blood plasma and saliva. However, further research is needed to optimize the use of benchtop NMR for clinical applications and to identify additional biomarkers that can be used to monitor and manage a range of diseases. Overall, benchtop NMR has the potential to revolutionize the way metabolomics is used in clinical practice, providing a more accessible and cost-effective way to study metabolism and identify biomarkers for disease diagnosis, prognosis, and treatment. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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11 pages, 1016 KB

Open AccessEditor’s ChoiceArticle

The Effect of Vitamin D Adequacy on Thyroid Hormones and Inflammatory Markers after Bariatric Surgery

by Roberta França, Adryana Cordeiro, Silvia Elaine Pereira, Carlos José Saboya and Andrea Ramalho

Metabolites 2023, 13(5), 603; https://doi.org/10.3390/metabo13050603 - 27 Apr 2023

Viewed by 2319

Abstract

Vitamin D status affects the clinical and corporal outcomes of postoperative patients who undergo a Roux-en-Y gastric bypass (RYGB). The aim of this study was to evaluate the effect of adequate vitamin D serum concentrations on thyroid hormones, body weight, blood cell count, [...] Read more.

Vitamin D status affects the clinical and corporal outcomes of postoperative patients who undergo a Roux-en-Y gastric bypass (RYGB). The aim of this study was to evaluate the effect of adequate vitamin D serum concentrations on thyroid hormones, body weight, blood cell count, and inflammation after an RYGB. A prospective observational study was conducted with eighty-eight patients from whom we collected blood samples before and 6 months after surgery to evaluate their levels of 25-hydroxyvitamin D 25(OH)D, thyroid hormones, and their blood cell count. Their body weight, body mass index (BMI), total weight loss, and excess weight loss were also evaluated 6 and 12 months after surgery. After 6 months, 58% of the patients achieved an adequate vitamin D nutritional status. Patients in the adequate group showed a decrease in the concentration of thyroid-stimulating hormone (TSH) (3.01 vs. 2.22 µUI/mL, p = 0.017) with lower concentrations than the inadequate group at 6 months (2.22 vs. 2.84 µUI/mL, p = 0.020). Six months after surgery, the group with vitamin D adequacy showed a significantly lower BMI compared with the inadequate group at 12 months (31.51 vs. 35.04 kg/m², p = 0.018). An adequate vitamin D nutritional status seems to favor a significant improvement in one’s thyroid hormone levels, immune inflammatory profile, and weight loss performance after an RYGB. Full article

(This article belongs to the Special Issue Metabolic and Functional Disorders of Essential Metals and Vitamin D)

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27 pages, 1696 KB

Open AccessEditor’s ChoiceReview

Multinuclear Magnetic Resonance Spectroscopy at Ultra-High-Field: Assessing Human Cerebral Metabolism in Healthy and Diseased States

by Pandichelvam Veeraiah and Jacobus F. A. Jansen

Metabolites 2023, 13(4), 577; https://doi.org/10.3390/metabo13040577 - 19 Apr 2023

Cited by 9 | Viewed by 5109

Abstract

The brain is a highly energetic organ. Although the brain can consume metabolic substrates, such as lactate, glycogen, and ketone bodies, the energy metabolism in a healthy adult brain mainly relies on glucose provided via blood. The cerebral metabolism of glucose produces energy [...] Read more.

The brain is a highly energetic organ. Although the brain can consume metabolic substrates, such as lactate, glycogen, and ketone bodies, the energy metabolism in a healthy adult brain mainly relies on glucose provided via blood. The cerebral metabolism of glucose produces energy and a wide variety of intermediate metabolites. Since cerebral metabolic alterations have been repeatedly implicated in several brain disorders, understanding changes in metabolite levels and corresponding cell-specific neurotransmitter fluxes through different substrate utilization may highlight the underlying mechanisms that can be exploited to diagnose or treat various brain disorders. Magnetic resonance spectroscopy (MRS) is a noninvasive tool to measure tissue metabolism in vivo. ¹H-MRS is widely applied in research at clinical field strengths (≤3T) to measure mostly high abundant metabolites. In addition, X-nuclei MRS including, ¹³C, ²H, ¹⁷O, and ³¹P, are also very promising. Exploiting the higher sensitivity at ultra-high-field (>4T; UHF) strengths enables obtaining unique insights into different aspects of the substrate metabolism towards measuring cell-specific metabolic fluxes in vivo. This review provides an overview about the potential role of multinuclear MRS (¹H, ¹³C, ²H, ¹⁷O, and ³¹P) at UHF to assess the cerebral metabolism and the metabolic insights obtained by applying these techniques in both healthy and diseased states. Full article

(This article belongs to the Special Issue Brain Substrate Metabolism in Health and Disease)

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16 pages, 1156 KB

Open AccessEditor’s ChoiceArticle

A Machine-Learning Approach to Target Clinical and Biological Features Associated with Sarcopenia: Findings from Northern and Southern Italian Aging Populations

by Roberta Zupo, Alessia Moroni, Fabio Castellana, Clara Gasparri, Feliciana Catino, Luisa Lampignano, Simone Perna, Maria Lisa Clodoveo, Rodolfo Sardone and Mariangela Rondanelli

Metabolites 2023, 13(4), 565; https://doi.org/10.3390/metabo13040565 - 17 Apr 2023

Cited by 19 | Viewed by 3497

Abstract

Epidemiological and public health resonance of sarcopenia in late life requires further research to identify better clinical markers useful for seeking proper care strategies in preventive medicine settings. Using a machine-learning approach, a search for clinical and fluid markers most associated with sarcopenia [...] Read more.

Epidemiological and public health resonance of sarcopenia in late life requires further research to identify better clinical markers useful for seeking proper care strategies in preventive medicine settings. Using a machine-learning approach, a search for clinical and fluid markers most associated with sarcopenia was carried out across older populations from northern and southern Italy. A dataset of adults >65 years of age (n = 1971) made up of clinical records and fluid markers from either a clinical-based subset from northern Italy (Pavia) and a population-based subset from southern Italy (Apulia) was employed (n = 1312 and n = 659, respectively). Body composition data obtained by dual-energy X-ray absorptiometry (DXA) were used for the diagnosis of sarcopenia, given by the presence of either low muscle mass (i.e., an SMI < 7.0 kg/m² for males or <5.5 kg/m² for females) and of low muscle strength (i.e., an HGS < 27 kg for males or <16 kg for females) or low physical performance (i.e., an SPPB ≤ 8), according to the EWGSOP2 panel guidelines. A machine-learning feature-selection approach, the random forest (RF), was used to identify the most predictive features of sarcopenia in the whole dataset, considering every possible interaction among variables and taking into account nonlinear relationships that classical models could not evaluate. Then, a logistic regression was performed for comparative purposes. Leading variables of association to sarcopenia overlapped in the two population subsets and included SMI, HGS, FFM of legs and arms, and sex. Using parametric and nonparametric whole-sample analysis to investigate the clinical variables and biological markers most associated with sarcopenia, we found that albumin, CRP, folate, and age ranked high according to RF selection, while sex, folate, and vitamin D were the most relevant according to logistics. Albumin, CRP, vitamin D, and serum folate should not be neglected in screening for sarcopenia in the aging population. Better preventive medicine settings in geriatrics are urgently needed to lessen the impact of sarcopenia on the general health, quality of life, and medical care delivery of the aging population. Full article

(This article belongs to the Special Issue Epidemiology, Nutrition and Metabolism)

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15 pages, 2495 KB

Open AccessEditor’s ChoiceArticle

Amino Acid Profiles in Older Adults with Frailty: Secondary Analysis from MetaboFrail and BIOSPHERE Studies

by Riccardo Calvani, Anna Picca, Leocadio Rodriguez-Mañas, Matteo Tosato, Hélio José Coelho-Júnior, Alessandra Biancolillo, Olga Laosa, Jacopo Gervasoni, Aniello Primiano, Lavinia Santucci, Ottavia Giampaoli, Isabelle Bourdel-Marchasson, Sophie C. Regueme, Alan J. Sinclair, Andrea Urbani, Francesco Landi, Giovanni Gambassi, Federico Marini and Emanuele Marzetti

Metabolites 2023, 13(4), 542; https://doi.org/10.3390/metabo13040542 - 10 Apr 2023

Cited by 13 | Viewed by 3533

Abstract

An altered amino acid metabolism has been described in frail older adults which may contribute to muscle loss and functional decline associated with frailty. In the present investigation, we compared circulating amino acid profiles of older adults with physical frailty and sarcopenia (PF&S, [...] Read more.

An altered amino acid metabolism has been described in frail older adults which may contribute to muscle loss and functional decline associated with frailty. In the present investigation, we compared circulating amino acid profiles of older adults with physical frailty and sarcopenia (PF&S, n = 94), frail/pre-frail older adults with type 2 diabetes mellitus (F-T2DM, n = 66), and robust non-diabetic controls (n = 40). Partial least squares discriminant analysis (PLS–DA) models were built to define the amino acid signatures associated with the different frailty phenotypes. PLS–DA allowed correct classification of participants with 78.2 ± 1.9% accuracy. Older adults with F-T2DM showed an amino acid profile characterized by higher levels of 3-methylhistidine, alanine, arginine, ethanolamine, and glutamic acid. PF&S and control participants were discriminated based on serum concentrations of aminoadipic acid, aspartate, citrulline, cystine, taurine, and tryptophan. These findings suggest that different types of frailty may be characterized by distinct metabolic perturbations. Amino acid profiling may therefore serve as a valuable tool for frailty biomarker discovery. Full article

(This article belongs to the Special Issue Epidemiology, Nutrition and Metabolism)

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16 pages, 3518 KB

Open AccessEditor’s ChoiceArticle

Deciphering Gut Microbiome Responses upon Microplastic Exposure via Integrating Metagenomics and Activity-Based Metabolomics

by Pengcheng Tu, Jingchuan Xue, Huixia Niu, Qiong Tang, Zhe Mo, Xiaodong Zheng, Lizhi Wu, Zhijian Chen, Yanpeng Cai and Xiaofeng Wang

Metabolites 2023, 13(4), 530; https://doi.org/10.3390/metabo13040530 - 7 Apr 2023

Cited by 16 | Viewed by 4089

Abstract

Perturbations of the gut microbiome are often intertwined with the onset and development of diverse metabolic diseases. It has been suggested that gut microbiome perturbation could be a potential mechanism through which environmental chemical exposure induces or exacerbates human diseases. Microplastic pollution, an [...] Read more.

Perturbations of the gut microbiome are often intertwined with the onset and development of diverse metabolic diseases. It has been suggested that gut microbiome perturbation could be a potential mechanism through which environmental chemical exposure induces or exacerbates human diseases. Microplastic pollution, an emerging environmental issue, has received ever increasing attention in recent years. However, interactions between microplastic exposure and the gut microbiota remain elusive. This study aimed to decipher the responses of the gut microbiome upon microplastic polystyrene (MP) exposure by integrating 16S rRNA high-throughput sequencing with metabolomic profiling techniques using a C57BL/6 mouse model. The results indicated that MP exposure significantly perturbed aspects of the gut microbiota, including its composition, diversity, and functional pathways that are involved in xenobiotic metabolism. A distinct metabolite profile was observed in mice with MP exposure, which probably resulted from changes in gut bacterial composition. Specifically, untargeted metabolomics revealed that levels of metabolites associated with cholesterol metabolism, primary and secondary bile acid biosynthesis, and taurine and hypotaurine metabolism were changed significantly. Targeted approaches indicated significant perturbation with respect to the levels of short-chain fatty acids derived from the gut microbiota. This study can provide evidence for the missing link in understanding the mechanisms behind the toxic effects of microplastics. Full article

(This article belongs to the Special Issue Effects of Environmental Exposure on Host and Microbial Metabolism)

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14 pages, 2838 KB

Open AccessEditor’s ChoiceArticle

Urinary Metabolomics for the Prediction of Radiation-Induced Cardiac Dysfunction

by Yaoxiang Li, Shivani Bansal, Vijayalakshmi Sridharan, Sunil Bansal, Meth M. Jayatilake, Jose A. Fernández, John H. Griffin, Marjan Boerma and Amrita K. Cheema

Metabolites 2023, 13(4), 525; https://doi.org/10.3390/metabo13040525 - 6 Apr 2023

Cited by 6 | Viewed by 2293

Abstract

Survivors of acute radiation exposure are likely to experience delayed effects that manifest as injury in late-responding organs such as the heart. Non-invasive indicators of radiation-induced cardiac dysfunction are important in the prediction and diagnosis of this disease. In this study, we aimed [...] Read more.

Survivors of acute radiation exposure are likely to experience delayed effects that manifest as injury in late-responding organs such as the heart. Non-invasive indicators of radiation-induced cardiac dysfunction are important in the prediction and diagnosis of this disease. In this study, we aimed to identify urinary metabolites indicative of radiation-induced cardiac damage by analyzing previously collected urine samples from a published study. The samples were collected from male and female wild-type (C57BL/6N) and transgenic mice constitutively expressing activated protein C (APCHi), a circulating protein with potential cardiac protective properties, who were exposed to 9.5 Gy of γ-rays. We utilized LC-MS-based metabolomics and lipidomics for the analysis of urine samples collected at 24 h, 1 week, 1 month, 3 months, and 6 months post-irradiation. Radiation caused perturbations in the TCA cycle, glycosphingolipid metabolism, fatty acid oxidation, purine catabolism, and amino acid metabolites, which were more prominent in the wild-type (WT) mice compared to the APCHi mice, suggesting a differential response between the two genotypes. After combining the genotypes and sexes, we identified a multi-analyte urinary panel at early post-irradiation time points that predicted heart dysfunction using a logistic regression model with a discovery validation study design. These studies demonstrate the utility of a molecular phenotyping approach to develop a urinary biomarker panel predictive of the delayed effects of ionizing radia-tion. It is important to note that no live mice were used or assessed in this study; instead, we focused solely on analyzing previously collected urine samples. Full article

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

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18 pages, 2206 KB

Open AccessEditor’s ChoiceArticle

Association of Maternal Metabolites and Metabolite Networks with Newborn Outcomes in a Multi-Ancestry Cohort

by Brooke Gleason, Alan Kuang, James R. Bain, Michael J. Muehlbauer, Olga R. Ilkayeva, Denise M. Scholtens and William L. Lowe, Jr.

Metabolites 2023, 13(4), 505; https://doi.org/10.3390/metabo13040505 - 31 Mar 2023

Cited by 6 | Viewed by 2942

Abstract

The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother–newborn [...] Read more.

The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother–newborn dyads. Targeted and untargeted metabolomic assays were performed on fasting and 1 h maternal serum samples collected during an oral glucose tolerance test performed at 24–32 week gestation in women participating in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Anthropometric measurements were obtained on newborns at birth. Following adjustment for maternal BMI and glucose, per-metabolite analyses demonstrated significant associations between maternal metabolite levels and birthweight, SSF, and cord C-peptide. In the fasting state, triglycerides were positively associated and several long-chain acylcarnitines were inversely associated with birthweight and SSF. At 1 h, additional metabolites including branched-chain amino acids, proline, and alanine were positively associated with newborn outcomes. Network analyses demonstrated distinct clusters of inter-connected metabolites significantly associated with newborn phenotypes. In conclusion, numerous maternal metabolites during pregnancy are significantly associated with newborn birthweight, SSF, and cord C-peptide independent of maternal BMI and glucose, suggesting that metabolites in addition to glucose contribute to newborn size at birth and adiposity. Full article

(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)

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14 pages, 2405 KB

Open AccessEditor’s ChoiceArticle

Effects of Different Storage Conditions on Lipid Stability in Mice Tissue Homogenates

by Erika Dorochow, Robert Gurke, Samuel Rischke, Gerd Geisslinger and Lisa Hahnefeld

Metabolites 2023, 13(4), 504; https://doi.org/10.3390/metabo13040504 - 31 Mar 2023

Cited by 7 | Viewed by 2983

Abstract

Lipids are biomolecules involved in numerous (patho-)physiological processes and their elucidation in tissue samples is of particular interest. However, tissue analysis goes hand in hand with many challenges and the influence of pre-analytical factors can intensively change lipid concentrations ex vivo, compromising the [...] Read more.

Lipids are biomolecules involved in numerous (patho-)physiological processes and their elucidation in tissue samples is of particular interest. However, tissue analysis goes hand in hand with many challenges and the influence of pre-analytical factors can intensively change lipid concentrations ex vivo, compromising the results of the whole research project. Here, we study the influence of pre-analytical factors on lipid profiles during the processing of homogenized tissues. Homogenates from four different mice tissues (liver, kidney, heart, spleen) were stored at room temperature as well as in ice water for up to 120 min and analyzed via ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS). Lipid class ratios were calculated since their suitability as indicators for sample stability has been previously illustrated. Only approx. 40% of lipid class ratios were unchanged after 35 min, which was further reduced to 25% after 120 min during storage at room temperature. In contrast, lipids in tissue homogenates were generally stable when samples were kept in ice water, as more than 90% of investigated lipid class ratios remained unchanged after 35 min. Ultimately, swift processing of tissue homogenates under cooled conditions represents a viable option for lipid analysis and pre-analytical factors require more attention to achieve reliable results. Full article

(This article belongs to the Special Issue Application of Mass Spectrometry Analysis in Metabolomics)

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14 pages, 821 KB

Open AccessEditor’s ChoiceArticle

Chronometabolism: The Timing of the Consumption of Meals Has a Greater Influence Than Glycemic Index (GI) on the Postprandial Metabolome

by Yi Ning Yong, Jiangwen Dong, Leroy Sivappiragasam Pakkiri, Christiani Jeyakumar Henry, Sumanto Haldar and Chester Lee Drum

Metabolites 2023, 13(4), 490; https://doi.org/10.3390/metabo13040490 - 29 Mar 2023

Cited by 3 | Viewed by 3234

Abstract

Eating late in the day is associated with circadian desynchrony, resulting in dysregulated metabolism and increased cardiometabolic disease risk. However, the underlying mechanisms remain unclear. Using targeted metabolomics of postprandial plasma samples from a secondary analysis of a randomised 2 × 2 crossover [...] Read more.

Eating late in the day is associated with circadian desynchrony, resulting in dysregulated metabolism and increased cardiometabolic disease risk. However, the underlying mechanisms remain unclear. Using targeted metabolomics of postprandial plasma samples from a secondary analysis of a randomised 2 × 2 crossover study in 36 healthy older Chinese adults, we have compared postprandial metabolic responses between high (HI) glycemic index (GI) or low-GI (LO) meals, consumed either at breakfast (BR) or at dinner (DI). 29 out of 234 plasma metabolites exhibited significant differences (p < 0.05) in postprandial AUC between BR and DI sessions, whereas only five metabolites were significantly different between HI and LO sessions. There were no significant interactions between intake timing and meal GI. Lower glutamine: glutamate ratio, lower lysine and higher trimethyllysine (TML) levels were found during DI compared with BR, along with greater postprandial reductions (δAUC) in creatine and ornithine levels during DI, indicating a worse metabolic state during the evening DI period. Greater reductions (δAUC) in postprandial creatine and ornithine were also observed during HI compared with LO (both p < 0.05). These metabolomic changes may indicate potential molecular signatures and/or pathways linking metabolic responses with cardiometabolic disease risk between different meal intake timings and/or meals with variable GI. Full article

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

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11 pages, 927 KB

Open AccessEditor’s ChoiceArticle

Enhanced Carotid Plaque Echolucency Is Associated with Reduced Cognitive Performance in Elderly Patients with Atherosclerotic Disease Independently on Metabolic Profile

by Daniela Mastroiacovo, Alessandro Mengozzi, Francesco Dentali, Fulvio Pomero, Agostino Virdis, Antonio Camerota, Mario Muselli, Stefano Necozione, Raffaella Bocale, Claudio Ferri and Giovambattista Desideri

Metabolites 2023, 13(4), 478; https://doi.org/10.3390/metabo13040478 - 27 Mar 2023

Cited by 9 | Viewed by 2186

Abstract

Vulnerable carotid atherosclerotic plaques are related to an increased risk of cognitive impairment and dementia in advanced age. In this study, we investigated the relationship between the echogenicity of carotid plaques and cognitive performance in patients with asymptomatic carotid atherosclerotic plaques. We enrolled [...] Read more.

Vulnerable carotid atherosclerotic plaques are related to an increased risk of cognitive impairment and dementia in advanced age. In this study, we investigated the relationship between the echogenicity of carotid plaques and cognitive performance in patients with asymptomatic carotid atherosclerotic plaques. We enrolled 113 patients aged 65 years or more (72.4 ± 5.9 years) who underwent carotid duplex ultrasound to evaluate plaque echogenicity by grey-scale median (GSM) and neuropsychological tests to assess cognitive function. The GSM values at baseline were inversely correlated with the number of seconds required to complete Trail Makin Test (TMT) A (rho: −0.442; p < 0.0001), TMT B (rho: −0.460; p < 0.0001) and TMT B-A (rho: −0.333; p < 0.0001) and directly correlated with Mini Mental State Examination (MMSE) and Verbal Fluency Test (VFT) score (rho: 0.217; p = 0.021 and rho: 0.375; p < 0.0001, respectively) and the composite cognitive z-score (rho: 0.464; p < 0.0001). After a mean period of 3.5 ± 0.5 years, 55 patients were reevaluated according to the same baseline study protocol. Patients with baseline GSM value higher than the median value of 29 did not show any significant variation in the z-score. Instead, those with GSM ≤ 29 showed a significant worsening of z-score (−1.2; p = 0.0258). In conclusion, this study demonstrates the existence of an inverse relationship between the echolucency of carotid plaques and cognitive function in elderly patients with atherosclerotic carotid disease. These data suggest that the assessment of plaque echogenicity if used appropriately, might aid in identifying subjects at increased risk for cognitive dysfunction. Full article

(This article belongs to the Special Issue Lipid Metabolism Regulation and Obesity Treatment)

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27 pages, 1713 KB

Open AccessEditor’s ChoiceReview

Exosomes in Cardiovascular Disease: From Mechanism to Therapeutic Target

by Allison B. Reiss, Saba Ahmed, Maryann Johnson, Usman Saeedullah and Joshua De Leon

Metabolites 2023, 13(4), 479; https://doi.org/10.3390/metabo13040479 - 27 Mar 2023

Cited by 27 | Viewed by 6451

Abstract

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent decades, clinical research has made significant advances, resulting in improved survival and recovery rates for patients with CVD. Despite this progress, there is substantial residual CVD risk and an [...] Read more.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent decades, clinical research has made significant advances, resulting in improved survival and recovery rates for patients with CVD. Despite this progress, there is substantial residual CVD risk and an unmet need for better treatment. The complex and multifaceted pathophysiological mechanisms underlying the development of CVD pose a challenge for researchers seeking effective therapeutic interventions. Consequently, exosomes have emerged as a new focus for CVD research because their role as intercellular communicators gives them the potential to act as noninvasive diagnostic biomarkers and therapeutic nanocarriers. In the heart and vasculature, cell types such as cardiomyocytes, endothelial cells, vascular smooth muscle, cardiac fibroblasts, inflammatory cells, and resident stem cells are involved in cardiac homeostasis via the release of exosomes. Exosomes encapsulate cell-type specific miRNAs, and this miRNA content fluctuates in response to the pathophysiological setting of the heart, indicating that the pathways affected by these differentially expressed miRNAs may be targets for new treatments. This review discusses a number of miRNAs and the evidence that supports their clinical relevance in CVD. The latest technologies in applying exosomal vesicles as cargo delivery vehicles for gene therapy, tissue regeneration, and cell repair are described. Full article

(This article belongs to the Special Issue Advances in Cholesterol and Lipid Metabolism II)

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14 pages, 2245 KB

Open AccessEditor’s ChoiceArticle

The Effect of 75 Grams of Glucose during OGTT on Plasma Markers of Lipid and Lipoprotein Peroxidation, Oxidized LDL and Thiobarbituric Acid Reactive Substances, in People with Increased Body Mass

by Lena Bielawska, Ewa Wysocka, Aleksandra Baszczuk, Anna Dżumak, Aleksandra Ludziejewska, Maciej Cymerys and Alicja Płóciniczak

Metabolites 2023, 13(4), 483; https://doi.org/10.3390/metabo13040483 - 27 Mar 2023

Cited by 3 | Viewed by 1786

Abstract

Obesity, currently defined as a disease, is associated with a number of metabolic disorders, and oxidative stress is discussed as the link between them. The aim of this study was to analyze the plasma markers reflecting oxidative modification of lipids and lipoproteins, oxidized [...] Read more.

Obesity, currently defined as a disease, is associated with a number of metabolic disorders, and oxidative stress is discussed as the link between them. The aim of this study was to analyze the plasma markers reflecting oxidative modification of lipids and lipoproteins, oxidized LDL (oxLDL) and thiobarbituric acid reactive substances (TBARS), under the influence of the 75 g of oral glucose during oral glucose tolerance test (OGTT), in patients with increased body mass. One hundred twenty individuals of both genders (46 women and 74 men) aged 26 to 75 years with increased body mass (BMI > 25 kg/m²) were recruited for the study. OGTT was performed in each of the qualified persons, and glycemia, insulinemia, and concentrations of oxLDL and TBARS were measured fasting and at 120 min of OGTT. The homeostasis model assessment of insulin resistance (HOMA-IR) was used to assess the degree of insulin resistance (IR). In order to assess the changes of the investigated parameters under the influence of 75 g glucose, the index R_OGTT = [120’]/[0’] was calculated to obtain oxLDL-R_OGTT and TBARS-R_OGTT. The statistical analysis was performed in the entire study population and subsequent groups from H1 to H4, defined by HOMA-IR quartiles. In the entire study population and the subgroups, oxidative stress markers changed during OGTT. From H1 to H4 group, increasing oxLDL and TBARS were observed both in the fasting state and at 120 min of OGTT, and the oxLDL-R_OGTT index decreased from the H2 to the H4 group. The intensification of IR in people with increased body mass may predispose them to enhanced oxidative modification of lipoproteins. Individual reduction in the concentration of oxLDL during OGTT, in reference to fasting value (decreased oxLDL-R_OGTT), suggests increased uptake of modified lipoproteins by scavenger receptor-presenting cells or increased migration to the vascular wall. Full article

(This article belongs to the Special Issue Prooxidant–Antioxidant and Inflammation Markers in Metabolic Syndrome and Its Complications)

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