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Metabolites, Volume 11, Issue 2 (February 2021) – 68 articles

Cover Story (view full-size image): The in utero environment during pregnancy has important implications for the developing health of the child. In mother–child pairs from the Vitamin D Antenatal Asthma Reduction Trial, we assessed the prospective relationship between maternal metabolites from 10–18-week and 32–38-week gestation, respectively, and the risk of child asthma or recurrent wheeze by age three. Coffee-related metabolites in the maternal metabolome appeared to be of particular interest (inverse associations observed). Additional observations also highlighted steroid and sphingolipid metabolites. Our results suggest that alterations in prenatal metabolites may play a role in the development of offspring asthma. View this paper
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Open AccessArticle
Behavioral and Metabolome Differences between C57BL/6 and DBA/2 Mouse Strains: Implications for Their Use as Models for Depression- and Anxiety-Like Phenotypes
Metabolites 2021, 11(2), 128; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020128 - 23 Feb 2021
Viewed by 566
Abstract
Mouse models are widely used to study behavioral phenotypes related to neuropsychiatric disorders. However, different mouse strains vary in their inherent behavioral and molecular characteristics, which needs to be taken into account depending on the nature of the study. Here, we performed a [...] Read more.
Mouse models are widely used to study behavioral phenotypes related to neuropsychiatric disorders. However, different mouse strains vary in their inherent behavioral and molecular characteristics, which needs to be taken into account depending on the nature of the study. Here, we performed a detailed behavioral and molecular comparison of C57BL/6 (B6) and DBA/2 (DBA) mice, two inbred strains commonly used in neuropsychiatric research. We analyzed anxiety-related and depression-like traits, quantified hippocampal and plasma metabolite profiles, and assessed total antioxidant capacity (ΤAC). B6 mice exhibit increased depression-like and decreased anxiety-related behavior compared to DBA mice. Metabolite level differences indicate alterations in amino acid, nucleotide and mitochondrial metabolism that are accompanied by a decreased TAC in B6 compared to DBA mice. Our data reveal multiple behavioral and molecular differences between B6 and DBA mouse strains, which should be considered in the experimental design for phenotype, pharmacological and mechanistic studies relevant for neuropsychiatric disorders. Full article
(This article belongs to the Special Issue Metabolomics and Its Application in Human Diseases Volume 2)
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Open AccessArticle
The Dysregulation of Eicosanoids and Bile Acids Correlates with Impaired Kidney Function and Renal Fibrosis in Chronic Renal Failure
Metabolites 2021, 11(2), 127; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020127 - 23 Feb 2021
Viewed by 381
Abstract
Chronic renal failure (CRF) is an irreversible deterioration of the renal functions that characterized by fluid electrolyte unbalance and metabolic-endocrine dysfunctions. Increasing evidence demonstrated that metabolic disturbances, especially dyslipidemia and profound changes in lipid and lipoprotein metabolism were involved in CRF. Identification of [...] Read more.
Chronic renal failure (CRF) is an irreversible deterioration of the renal functions that characterized by fluid electrolyte unbalance and metabolic-endocrine dysfunctions. Increasing evidence demonstrated that metabolic disturbances, especially dyslipidemia and profound changes in lipid and lipoprotein metabolism were involved in CRF. Identification of lipids associated with impaired kidney functions may play important roles in the understanding of biochemical mechanism and CRF treatment. Ultra-performance liquid chromatography coupled with high-definition mass spectrometry-based lipidomics was performed to identify important differential lipids in adenine-induced CRF rats and investigate the undergoing anti-fibrotic mechanism of Polyporus umbellatus (PPU) and ergone (ERG). Linear correlation analysis was performed between lipid species intensities and creatinine levels in serum. Adenine-induced rats exhibited declining kidney function and renal fibrosis. Compared with control rats, a panel of lipid species was identified in the serum of CRF rats. Our further study demonstrated that eight lipids, including leukotrienes and bile acids, presented a strong linear correlation with serum creatinine levels. In addition, receiver operating characteristics analysis showed that eight lipids exhibited excellent area under the curve for differentiating CRF from control rats, with high sensitivity and specificity. The aberrant changes of clinical biochemistry data and dysregulation of eight lipids could be significantly improved by the administration of PPU and ergone. In conclusion, CRF might be associated with the disturbance of leukotriene metabolism, bile acid metabolism and lysophospholipid metabolism. The levels of eicosanoids and bile acids could be used for indicating kidney function impairment in CRF. PPU could improve renal functions and either fully or partially reversed the levels of eicosanoids and bile acids. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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Open AccessArticle
Metabolomics of Cerebrospinal Fluid from Healthy Subjects Reveal Metabolites Associated with Ageing
Metabolites 2021, 11(2), 126; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020126 - 23 Feb 2021
Viewed by 384
Abstract
To increase our understanding of age-related diseases affecting the central nervous system (CNS) it is important to understand the molecular processes of biological ageing. Metabolomics of cerebrospinal fluid (CSF) is a promising methodology to increase our understanding of naturally occurring processes of ageing [...] Read more.
To increase our understanding of age-related diseases affecting the central nervous system (CNS) it is important to understand the molecular processes of biological ageing. Metabolomics of cerebrospinal fluid (CSF) is a promising methodology to increase our understanding of naturally occurring processes of ageing of the brain and CNS that could be reflected in CSF. In the present study the CSF metabolomes of healthy subjects aged 30–74 years (n = 23) were studied using liquid chromatography high-resolution mass spectrometry (LC-HRMS), and investigated in relation to age. Ten metabolites were identified with high confidence as significantly associated with ageing, eight with increasing levels with ageing: isoleucine, acetylcarnitine, pipecolate, methionine, glutarylcarnitine, 5-hydroxytryptophan, ketoleucine, and hippurate; and two decreasing with ageing: methylthioadenosine and 3-methyladenine. To our knowledge, this is the first time the CSF metabolomes of healthy subjects are assessed in relation to ageing. The present study contributes to the field of ageing metabolomics by presenting a number of metabolites present in CSF with potential relevance for ageing and the results motivate further studies. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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Open AccessReview
Worms, Fat, and Death: Caenorhabditis elegans Lipid Metabolites Regulate Cell Death
Metabolites 2021, 11(2), 125; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020125 - 23 Feb 2021
Viewed by 606
Abstract
Caenorhabditis elegans is well-known as the model organism used to elucidate the genetic pathways underlying the first described form of regulated cell death, apoptosis. Since then, C. elegans investigations have contributed to the further understanding of lipids in apoptosis, especially the roles of [...] Read more.
Caenorhabditis elegans is well-known as the model organism used to elucidate the genetic pathways underlying the first described form of regulated cell death, apoptosis. Since then, C. elegans investigations have contributed to the further understanding of lipids in apoptosis, especially the roles of phosphatidylserines and phosphatidylinositols. More recently, studies in C. elegans have shown that dietary polyunsaturated fatty acids can induce the non-apoptotic, iron-dependent form of cell death, ferroptosis. In this review, we examine the roles of various lipids in specific aspects of regulated cell death, emphasizing recent work in C. elegans. Full article
(This article belongs to the Special Issue Caenorhabditis elegans Applied to Metabolism Research)
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Open AccessReview
Mitochondrial Lipid Signaling and Adaptive Thermogenesis
Metabolites 2021, 11(2), 124; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020124 - 22 Feb 2021
Viewed by 558
Abstract
Thermogenesis is an energy demanding process by which endotherms produce heat to maintain their body temperature in response to cold exposure. Mitochondria in the brown and beige adipocytes play a key role in thermogenesis, as the site for uncoupling protein 1 (UCP1), which [...] Read more.
Thermogenesis is an energy demanding process by which endotherms produce heat to maintain their body temperature in response to cold exposure. Mitochondria in the brown and beige adipocytes play a key role in thermogenesis, as the site for uncoupling protein 1 (UCP1), which allows for the diffusion of protons through the mitochondrial inner membrane to produce heat. To support this energy demanding process, the mitochondria in brown and beige adipocytes increase oxidation of glucose, amino acids, and lipids. This review article explores the various mitochondria-produced and processed lipids that regulate thermogenesis including cardiolipins, free fatty acids, and acylcarnitines. These lipids play a number of roles in thermogenic adipose tissue including structural support of UCP1, transcriptional regulation, fuel source, and activation of cell signaling cascades. Full article
(This article belongs to the Special Issue Mitochondrial Metabolism and Bioenergetics)
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Open AccessReview
Impact of Altered Gut Microbiota and Its Metabolites in Cystic Fibrosis
Metabolites 2021, 11(2), 123; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020123 - 22 Feb 2021
Viewed by 417
Abstract
Cystic fibrosis (CF) is the most common lethal, multisystemic genetic disorder in Caucasians. Mutations in the gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein are responsible for impairment of epithelial anionic transport, leading to impaired fluid regulation and pH imbalance across multiple [...] Read more.
Cystic fibrosis (CF) is the most common lethal, multisystemic genetic disorder in Caucasians. Mutations in the gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein are responsible for impairment of epithelial anionic transport, leading to impaired fluid regulation and pH imbalance across multiple organs. Gastrointestinal (GI) manifestations in CF may begin in utero and continue throughout the life, resulting in a chronic state of an altered intestinal milieu. Inherent dysfunction of CFTR leads to dysbiosis of the gut. This state of dysbiosis is further perpetuated by acquired factors such as use of antibiotics for recurrent pulmonary exacerbations. Since the gastrointestinal microbiome and their metabolites play a vital role in nutrition, metabolic, inflammatory, and immune functions, the gut dysbiosis will in turn impact various manifestations of CF—both GI and extra-GI. This review focuses on the consequences of gut dysbiosis and its metabolic implications on CF disease and possible ways to restore homeostasis. Full article
(This article belongs to the Special Issue Nutrition, Microbiota and Metabolism)
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Open AccessArticle
Host-Microbiome Interactions Mediated by Phenolic Metabolites in Chronically Critically Ill Patients
Metabolites 2021, 11(2), 122; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020122 - 20 Feb 2021
Viewed by 936
Abstract
The community structure and metabolic potential of gut microbiome is not well investigated, especially in chronically critically ill patients with prolonged dependence on support systems after severe brain disorders. Microbial phenolic metabolites can target the brain function by the direct and indirect modulation [...] Read more.
The community structure and metabolic potential of gut microbiome is not well investigated, especially in chronically critically ill patients with prolonged dependence on support systems after severe brain disorders. Microbial phenolic metabolites can target the brain function by the direct and indirect modulation of inflammation. The aim of this study was to investigate the features of the gut microbiota and profile of certain metabolites in the progression and reversibility of neurological disorders in chronically critically ill patients. Fecal samples were collected in dynamics from such patients (n = 44) and analyzed using 16S rRNA sequencing. Serum microbial and mitochondrial metabolites were measured by GC-MS and compared with the biomarkers and clinical neurological scores. The identified associations between specific bacterial taxa in fecal samples, neurological status and serum levels of metabolites suggest that impacts on specific members of the gut microbiota and their metabolism might be a promising tool for regulating brain function in future. Full article
(This article belongs to the Special Issue Microbiome and Metabolome)
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Open AccessArticle
NMR Metabolite Profiles in Male Meat-Eaters, Fish-Eaters, Vegetarians and Vegans, and Comparison with MS Metabolite Profiles
Metabolites 2021, 11(2), 121; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020121 - 20 Feb 2021
Viewed by 453
Abstract
Metabolomics may help to elucidate mechanisms underlying diet-disease relationships and identify novel risk factors for disease. To inform the design and interpretation of such research, evidence on diet-metabolite associations and cross-assay comparisons is needed. We aimed to compare nuclear magnetic resonance (NMR) metabolite [...] Read more.
Metabolomics may help to elucidate mechanisms underlying diet-disease relationships and identify novel risk factors for disease. To inform the design and interpretation of such research, evidence on diet-metabolite associations and cross-assay comparisons is needed. We aimed to compare nuclear magnetic resonance (NMR) metabolite profiles between meat-eaters, fish-eaters, vegetarians and vegans, and to compare NMR measurements to those from mass spectrometry (MS), clinical chemistry and capillary gas-liquid chromatography (GC). We quantified 207 serum NMR metabolite measures in 286 male participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford cohort. Using univariate and multivariate analyses, we found that metabolite profiles varied by diet group, especially for vegans; the main differences compared to meat-eaters were lower levels of docosahexaenoic acid, total n-3 and saturated fatty acids, cholesterol and triglycerides in very-low-density lipoproteins, various lipid factions in high-density lipoprotein, sphingomyelins, tyrosine and creatinine, and higher levels of linoleic acid, total n-6, polyunsaturated fatty acids and alanine. Levels in fish-eaters and vegetarians differed by metabolite measure. Concentrations of 13 metabolites measured using both NMR and MS, clinical chemistry or GC were mostly similar. In summary, vegans’ metabolite profiles were markedly different to those of men consuming animal products. The studied metabolomics platforms are complementary, with limited overlap between metabolite classes. Full article
(This article belongs to the Section Nutrition and Metabolism)
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Open AccessReview
The Impact of Microbiota on the Pathogenesis of Amyotrophic Lateral Sclerosis and the Possible Benefits of Polyphenols. An Overview
Metabolites 2021, 11(2), 120; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020120 - 20 Feb 2021
Viewed by 472
Abstract
The relationship between gut microbiota and neurodegenerative diseases is becoming clearer. Among said diseases amyotrophic lateral sclerosis (ALS) stands out due to its severity and, as with other chronic pathologies that cause neurodegeneration, gut microbiota could play a fundamental role in its pathogenesis. [...] Read more.
The relationship between gut microbiota and neurodegenerative diseases is becoming clearer. Among said diseases amyotrophic lateral sclerosis (ALS) stands out due to its severity and, as with other chronic pathologies that cause neurodegeneration, gut microbiota could play a fundamental role in its pathogenesis. Therefore, polyphenols could be a therapeutic alternative due to their anti-inflammatory action and probiotic effect. Thus, the objective of our narrative review was to identify those bacteria that could have connection with the mentioned disease (ALS) and to analyze the benefits produced by administering polyphenols. Therefore, an extensive search was carried out selecting the most relevant articles published between 2005 and 2020 on the PubMed and EBSCO database on research carried out on cell, animal and human models of the disease. Thereby, after selecting, analyzing and debating the main articles on this topic, the bacteria related to the pathogenesis of ALS have been identified, among which we can positively highlight the presence mainly of Akkermansia muciniphila, but also Lactobacillus spp., Bifidobacterium spp. or Butyrivibrio fibrisolvens. Nevertheless, the presence of Escherichia coli or Ruminococcus torques stand out negatively for the disease. In addition, most of these bacteria are associated with molecular changes also linked to the pathogenesis of ALS. However, once the main polyphenols related to improvements in any of these three ALS models were assessed, many of them show positive results that could improve the prognosis of the disease. Nonetheless, epigallocatechin gallate (EGCG), curcumin and resveratrol are the polyphenols considered to show the most promising results as a therapeutic alternative for ALS through changes in microbiota. Full article
(This article belongs to the Special Issue Nutrition, Microbiota and Metabolism)
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Open AccessArticle
Untargeted Metabolomics Reveals Major Differences in the Plasma Metabolome between Colorectal Cancer and Colorectal Adenomas
Metabolites 2021, 11(2), 119; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020119 - 19 Feb 2021
Viewed by 482
Abstract
Sporadic colorectal cancer is characterized by a multistep progression from normal epithelium to precancerous low-risk and high-risk adenomas to invasive cancer. Yet, the underlying molecular mechanisms of colorectal carcinogenesis are not completely understood. Within the “Metabolomic profiles throughout the continuum of colorectal cancer” [...] Read more.
Sporadic colorectal cancer is characterized by a multistep progression from normal epithelium to precancerous low-risk and high-risk adenomas to invasive cancer. Yet, the underlying molecular mechanisms of colorectal carcinogenesis are not completely understood. Within the “Metabolomic profiles throughout the continuum of colorectal cancer” (MetaboCCC) consortium we analyzed data generated by untargeted, mass spectrometry-based metabolomics using plasma from 88 colorectal cancer patients, 200 patients with high-risk adenomas and 200 patients with low-risk adenomas recruited within the “Colorectal Cancer Study of Austria” (CORSA). Univariate logistic regression models comparing colorectal cancer to adenomas resulted in 442 statistically significant molecular features. Metabolites discriminating colorectal cancer patients from those with adenomas in our dataset included acylcarnitines, caffeine, amino acids, glycerophospholipids, fatty acids, bilirubin, bile acids and bacterial metabolites of tryptophan. The data obtained discovers metabolite profiles reflecting metabolic differences between colorectal cancer and colorectal adenomas and delineates a potentially underlying biological interpretation. Full article
(This article belongs to the Special Issue Metabolomics and Its Application in Human Diseases Volume 2)
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Open AccessArticle
The Efficacy of Pilates on Urinary Incontinence in Korean Women: A Metabolomics Approach
Metabolites 2021, 11(2), 118; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020118 - 19 Feb 2021
Viewed by 399
Abstract
Pilates has been known as exercise intervention that improves the function of pelvic floor muscle (PFM) associated with impacting urinary incontinence (UI). This study investigated the effect of Pilates on UI in Korean women by determining the change in functional movement of PFM [...] Read more.
Pilates has been known as exercise intervention that improves the function of pelvic floor muscle (PFM) associated with impacting urinary incontinence (UI). This study investigated the effect of Pilates on UI in Korean women by determining the change in functional movement of PFM (FMP) and metabolic profiles. UI group with Pilates (UIP, n = 13) participated in 8-weeks Oov Pilates program, and 8 subjects were assigned to Control and UI group with no Pilates (UINP), respectively. Before and after 8 weeks, plasma samples were collected from all participants, and ultrasonography was used to measure the functional change of PFM for calculating FMP ratio. Plasma samples were analyzed by mass spectrometry to identify the change of metabolic features. After 8-weeks intervention, FMP ratio was remarkably decreased in UIP (48.1% ↓, p < 0.001), but not in Control and UINP (p > 0.05). In metabolic features, L-Glutamine (m/z: 147.07 [M + H]+), L-Cystathionine (m/z: 240.09 [M + NH4]+), L-Arginine (m/z: 197.1 [M + Na]+), and L-1-Pyrroline-3-hydroxy-5-carboxylate (m/z: 147.07 [M + NH4]+) were significantly elevated solely in UIP (p < 0.001). Our study elucidated that Pilates can ameliorate the FMP and enhance the specific metabolic characteristics, which was potentially associated with invigorated PFM contractility to effectively control the bladder base and continence. Full article
(This article belongs to the Section Frontiers in Metabolomics)
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Open AccessArticle
Itaconate Alters Succinate and Coenzyme A Metabolism via Inhibition of Mitochondrial Complex II and Methylmalonyl-CoA Mutase
Metabolites 2021, 11(2), 117; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020117 - 18 Feb 2021
Viewed by 692
Abstract
Itaconate is a small molecule metabolite that is endogenously produced by cis-aconitate decarboxylase-1 (ACOD1) in mammalian cells and influences numerous cellular processes. The metabolic consequences of itaconate in cells are diverse and contribute to its regulatory function. Here, we have applied isotope tracing [...] Read more.
Itaconate is a small molecule metabolite that is endogenously produced by cis-aconitate decarboxylase-1 (ACOD1) in mammalian cells and influences numerous cellular processes. The metabolic consequences of itaconate in cells are diverse and contribute to its regulatory function. Here, we have applied isotope tracing and mass spectrometry approaches to explore how itaconate impacts various metabolic pathways in cultured cells. Itaconate is a competitive and reversible inhibitor of Complex II/succinate dehydrogenase (SDH) that alters tricarboxylic acid (TCA) cycle metabolism leading to succinate accumulation. Upon activation with coenzyme A (CoA), itaconyl-CoA inhibits adenosylcobalamin-mediated methylmalonyl-CoA (MUT) activity and, thus, indirectly impacts branched-chain amino acid (BCAA) metabolism and fatty acid diversity. Itaconate, therefore, alters the balance of CoA species in mitochondria through its impacts on TCA, amino acid, vitamin B12, and CoA metabolism. Our results highlight the diverse metabolic pathways regulated by itaconate and provide a roadmap to link these metabolites to potential downstream biological functions. Full article
(This article belongs to the Special Issue Mitochondrial Metabolism and Bioenergetics)
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Open AccessReview
Vitamin D, Bone Metabolism, and Fracture Risk in Polycystic Ovary Syndrome
Metabolites 2021, 11(2), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020116 - 18 Feb 2021
Viewed by 608
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among premenopausal women. PCOS may have reproductive, metabolic, cardiovascular, and psychological implications. Vitamin D deficit is often encountered in PCOS women and may contribute to the pathophysiology of this disorder. As of the [...] Read more.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among premenopausal women. PCOS may have reproductive, metabolic, cardiovascular, and psychological implications. Vitamin D deficit is often encountered in PCOS women and may contribute to the pathophysiology of this disorder. As of the key role of vitamin D in bone and mineral metabolism, and because the vitamin D status appears to be closely linked with the PCOS manifestations including insulin resistance, obesity, ovulatory and menstrual irregularities, oxidative stress and PTH elevation, hypovitaminosis D may directly and indirectly via the different facets of PCOS impair bone health in these women. Although limited data are available on life-long fracture risk in women with PCOS, the importance of preserving bone health in youth and adults to prevent osteoporosis and related fractures is also recognized in PCOS women. Evidence of the association between vitamin D and the clinical hallmarks of PCOS are summarized and discussed. Vitamin D arises as a cornerstone in women with PCOS and contributes to the pathophysiological link between PCOS and bone metabolism. Full article
(This article belongs to the Special Issue Vitamin D and Bone Metabolism)
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Open AccessArticle
Untargeted and Targeted Metabolomic Profiling of Preterm Newborns with EarlyOnset Sepsis: A Case-Control Study
Metabolites 2021, 11(2), 115; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020115 - 18 Feb 2021
Viewed by 416
Abstract
Sepsis is a major concern in neonatology, but there are no reliable biomarkers for its early diagnosis. The aim of the study was to compare the metabolic profiles of plasma and urine samples collected at birth from preterm neonates with and without earlyonset [...] Read more.
Sepsis is a major concern in neonatology, but there are no reliable biomarkers for its early diagnosis. The aim of the study was to compare the metabolic profiles of plasma and urine samples collected at birth from preterm neonates with and without earlyonset sepsis (EOS) to identify metabolic perturbations that might orient the search for new early biomarkers. All preterm newborns admitted to the neonatal intensive care unit were eligible for this proof-of-concept, prospective case-control study. Infants were enrolled as “cases” if they developed EOS, and as “controls”if they did not. Plasma samples collected at birth and urine samples collected within 24 h of birth underwent untargeted and targeted metabolomic analysis using mass spectrometry coupled with ultra-performance liquid chromatography. Univariate and multivariate statistical analyses were applied. Of 123 eligible newborns, 15 developed EOS. These 15 newborns matched controls for gestational age and weight. Metabolomic analysis revealed evident clustering of the cases versus controls, with the glutathione and tryptophan metabolic pathways markedly disrupted in the former. In conclusion, neonates with EOS had a metabolic profile at birth that clearly distinguished them from those without sepsis, and metabolites of glutathione and tryptophan pathways are promising as new biomarkers of neonatal sepsis. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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Open AccessArticle
Novel Insights into Mice Multi-Organ Metabolism upon Exposure to a Potential Anticancer Pd(II)-Agent
Metabolites 2021, 11(2), 114; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020114 - 17 Feb 2021
Cited by 1 | Viewed by 496
Abstract
Pd(II)-compounds are presently regarded as promising anticancer drugs, as an alternative to Pt(II)-based drugs (e.g., cisplatin), which typically trigger severe side-effects and acquired resistance. Dinuclear Pd(II) complexes with biogenic polyamines such as spermine (Pd2Spm) have exhibited particularly beneficial cytotoxic properties, hence [...] Read more.
Pd(II)-compounds are presently regarded as promising anticancer drugs, as an alternative to Pt(II)-based drugs (e.g., cisplatin), which typically trigger severe side-effects and acquired resistance. Dinuclear Pd(II) complexes with biogenic polyamines such as spermine (Pd2Spm) have exhibited particularly beneficial cytotoxic properties, hence unveiling the importance of understanding their impact on organism metabolism. The present study reports the first nuclear magnetic resonance (NMR)-based metabolomics study to assess the in vivo impact of Pd2Spm on the metabolism of healthy mice, to identify metabolic markers with possible relation to biotoxicity/side-effects and their dynamics. The changes in the metabolic profiles of both aqueous and lipophilic extracts of mice kidney, liver, and breast tissues were evaluated, as a function of drug-exposure time, using cisplatin as a reference drug. A putative interpretation was advanced for the metabolic deviations specifically triggered by Pd2Spm, this compound generally inducing faster metabolic response and recovery to control levels for all organs tested, compared to cisplatin (except for kidney lipid metabolism). These results constitute encouraging preliminary metabolic data suggestive of potential lower negative effects of Pd2Spm administration. Full article
(This article belongs to the Special Issue Metabolomics in Drug Discovery and Development)
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Open AccessArticle
The Metano Modeling Toolbox MMTB: An Intuitive, Web-Based Toolbox Introduced by Two Use Cases
Metabolites 2021, 11(2), 113; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020113 - 17 Feb 2021
Viewed by 384
Abstract
Genome-scale metabolic models are of high interest in a number of different research fields. Flux balance analysis (FBA) and other mathematical methods allow the prediction of the steady-state behavior of metabolic networks under different environmental conditions. However, many existing applications for flux optimizations [...] Read more.
Genome-scale metabolic models are of high interest in a number of different research fields. Flux balance analysis (FBA) and other mathematical methods allow the prediction of the steady-state behavior of metabolic networks under different environmental conditions. However, many existing applications for flux optimizations do not provide a metabolite-centric view on fluxes. Metano is a standalone, open-source toolbox for the analysis and refinement of metabolic models. While flux distributions in metabolic networks are predominantly analyzed from a reaction-centric point of view, the Metano methods of split-ratio analysis and metabolite flux minimization also allow a metabolite-centric view on flux distributions. In addition, we present MMTB (Metano Modeling Toolbox), a web-based toolbox for metabolic modeling including a user-friendly interface to Metano methods. MMTB assists during bottom-up construction of metabolic models by integrating reaction and enzymatic annotation data from different databases. Furthermore, MMTB is especially designed for non-experienced users by providing an intuitive interface to the most commonly used modeling methods and offering novel visualizations. Additionally, MMTB allows users to upload their models, which can in turn be explored and analyzed by the community. We introduce MMTB by two use cases, involving a published model of Corynebacterium glutamicum and a newly created model of Phaeobacter inhibens. Full article
(This article belongs to the Special Issue Computational Biology for Metabolic Modelling)
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Open AccessReview
Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism
Metabolites 2021, 11(2), 112; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020112 - 16 Feb 2021
Viewed by 894
Abstract
Mitochondria are central organelles that coordinate a vast array of metabolic and biologic functions important for cellular health. Amino acids are intricately linked to the bioenergetic, biosynthetic, and homeostatic function of the mitochondrion and require specific transporters to facilitate their import, export, and [...] Read more.
Mitochondria are central organelles that coordinate a vast array of metabolic and biologic functions important for cellular health. Amino acids are intricately linked to the bioenergetic, biosynthetic, and homeostatic function of the mitochondrion and require specific transporters to facilitate their import, export, and exchange across the inner mitochondrial membrane. Here we review key cellular metabolic outputs of eukaryotic mitochondrial amino acid metabolism and discuss both known and unknown transporters involved. Furthermore, we discuss how utilization of compartmentalized amino acid metabolism functions in disease and physiological contexts. We examine how improved methods to study mitochondrial metabolism, define organelle metabolite composition, and visualize cellular gradients allow for a more comprehensive understanding of how transporters facilitate compartmentalized metabolism. Full article
(This article belongs to the Special Issue Mitochondrial Metabolism and Bioenergetics)
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Open AccessArticle
The Acute Effects of Swimming Exercise on PGC-1α-FNDC5/Irisin-UCP1 Expression in Male C57BL/6J Mice
Metabolites 2021, 11(2), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020111 - 16 Feb 2021
Viewed by 392
Abstract
Irisin is a myokine primarily secreted by skeletal muscles and is known as an exercise-induced hormone. The purpose of this study was to determine whether the PGC-1α -FNDC5 /Irisin-UCP1 expression which is an irisin-related signaling pathway, is activated by an acute swimming exercise. [...] Read more.
Irisin is a myokine primarily secreted by skeletal muscles and is known as an exercise-induced hormone. The purpose of this study was to determine whether the PGC-1α -FNDC5 /Irisin-UCP1 expression which is an irisin-related signaling pathway, is activated by an acute swimming exercise. Fourteen to sixteen weeks old male C57BL/6J mice (n = 20) were divided into control (CON, n = 10) and swimming exercise groups (SEG, n = 10). The SEG mice performed 90 min of acute swimming exercise, while control (non-exercised) mice were exposed to shallow water (2 cm of depth) for 90 min. The mRNA and protein expression of PGC-1α, FNDC5 and browning markers including UCP1 were evaluated by quantitative real-time PCR and western blotting. Serum irisin concentration was measured by enzyme-linked immunosorbent assay. An acute swimming exercise did not lead to alterations in the mRNA and protein expression of PGC-1α in both soleus and gastrocnemius muscles, the mRNA and protein expression of UCP1 in brown adipose tissue, mRNA browning markers in visceral adipose tissue and circulating irisin when compared with the control group. On the other hand, an acute swimming exercise led to increases in the mRNA and protein expressions of FNDC5 in the soleus muscle, the protein expression of FNDC5 in the gastrocnemius muscles and the protein expression of UCP1 in subcutaneous adipose tissue. Full article
(This article belongs to the Special Issue Effect of Exercise on Energy Metabolism)
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Open AccessFeature PaperArticle
Metabolomics of Pigmented Rice Coproducts Applying Conventional or Deep Eutectic Extraction Solvents Reveal a Potential Antioxidant Source for Human Nutrition
Metabolites 2021, 11(2), 110; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020110 - 15 Feb 2021
Viewed by 455
Abstract
Rice bran (RB) corresponds to the outer layers of whole grain rice and contains several phenolic compounds (PCs) that make it an interesting functional food ingredient. PC richness is enhanced in pigmented RB varieties and requires effective ways of extraction of these compounds. [...] Read more.
Rice bran (RB) corresponds to the outer layers of whole grain rice and contains several phenolic compounds (PCs) that make it an interesting functional food ingredient. PC richness is enhanced in pigmented RB varieties and requires effective ways of extraction of these compounds. Therefore, we investigated conventional and deep eutectic solvents (DES) extraction methods to recover a wide array of PCs from red and black RB. The RB were extracted with ethanol/water (60:40, v/v) and two DES (choline chloride/1.2-propanediol/water, 1:1:1 and choline chloride/lactic acid, 1:10, mole ratios), based on Generally Recognized as Safe (GRAS) components. Besides the quantification of the most typical phenolic acids of cereals, nontargeted metabolomic approaches were applied to PCs profiling in the extracts. Globally, metabolomics revealed 89 PCs belonging to flavonoids (52%), phenolic acids (33%), other polyphenols (8%), lignans (6%) and stilbenes (1%) classes. All extracts, whatever the solvents, were highly concentrated in the main phenolic acids found in cereals (37–66 mg/100 g in black RB extracts vs. 6–20 mg/100 g in red RB extracts). However, the PC profile was highly dependent on the extraction solvent and specific PCs were extracted using the acidic DES. The PC-enriched DES extracts demonstrated interesting DPPH scavenging activity, which makes them candidates for novel antioxidant formulations. Full article
(This article belongs to the Special Issue Analysis and Metabolism of Bioactive Compounds)
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Open AccessArticle
Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma
Metabolites 2021, 11(2), 109; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020109 - 13 Feb 2021
Viewed by 471
Abstract
Approximately 80% of low-grade glioma (LGGs) harbor mutant isocitrate dehydrogenase 1/2 (IDH1/2) driver mutations leading to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Thus, inhibition of mutant IDH is considered a potential therapeutic target. Several mutant IDH inhibitors are currently in clinical trials, including [...] Read more.
Approximately 80% of low-grade glioma (LGGs) harbor mutant isocitrate dehydrogenase 1/2 (IDH1/2) driver mutations leading to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Thus, inhibition of mutant IDH is considered a potential therapeutic target. Several mutant IDH inhibitors are currently in clinical trials, including AG-881 and BAY-1436032. However, to date, early detection of response remains a challenge. In this study we used high resolution 1H magnetic resonance spectroscopy (1H-MRS) to identify early noninvasive MR (Magnetic Resonance)-detectable metabolic biomarkers of response to mutant IDH inhibition. In vivo 1H-MRS was performed on mice orthotopically-implanted with either genetically engineered (U87IDHmut) or patient-derived (BT257 and SF10417) mutant IDH1 cells. Treatment with either AG-881 or BAY-1436032 induced a significant reduction in 2-HG. Moreover, both inhibitors led to a significant early and sustained increase in glutamate and the sum of glutamate and glutamine (GLX) in all three models. A transient early increase in N-acetylaspartate (NAA) was also observed. Importantly, all models demonstrated enhanced animal survival following both treatments and the metabolic alterations were observed prior to any detectable differences in tumor volume between control and treated tumors. Our study therefore identifies potential translatable early metabolic biomarkers of drug delivery, mutant IDH inhibition and glioma response to treatment with emerging clinically relevant therapies. Full article
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Open AccessFeature PaperArticle
Metabolic Fingerprinting of Feces from Calves, Subjected to Gram-Negative Bacterial Endotoxin
Metabolites 2021, 11(2), 108; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020108 - 13 Feb 2021
Viewed by 657
Abstract
Gram-negative bacteria have a well-known impact on the disease state of neonatal calves and their mortality. This study was the first to implement untargeted metabolomics on calves’ fecal samples to unravel the effect of Gram-negative bacterial endotoxin lipopolysaccharide (LPS). In this context, calves [...] Read more.
Gram-negative bacteria have a well-known impact on the disease state of neonatal calves and their mortality. This study was the first to implement untargeted metabolomics on calves’ fecal samples to unravel the effect of Gram-negative bacterial endotoxin lipopolysaccharide (LPS). In this context, calves were challenged with LPS and administered with fish oil, nanocurcumin, or dexamethasone to evaluate treatment effects. Ultra-high-performance liquid-chromatography high-resolution mass spectrometry (UHPLC-HRMS) was employed to map fecal metabolic fingerprints from the various groups before and after LPS challenge. Based on the generated fingerprints, including 9650 unique feature ions, significant separation according to LPS group was achieved through orthogonal partial least squares discriminant analysis (Q2 of 0.57 and p-value of 0.022), which allowed the selection of 37 metabolites as bacterial endotoxin markers. Tentative identification of these markers suggested that the majority belonged to the subclass of the carboxylic acid derivatives—amino acids, peptides, and analogs—and fatty amides, with these subclasses playing a role in the metabolism of steroids, histidine, glutamate, and folate. Biological interpretations supported the revealed markers’ potential to aid in disease diagnosis, whereas beneficial effects were observed following dexamethasone, fish oil, and nanocurcumin treatment. Full article
(This article belongs to the Special Issue Metabolomics in Dairy Research)
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Open AccessArticle
Chemical Elicitors Induce Rare Bioactive Secondary Metabolites in Deep-Sea Bacteria under Laboratory Conditions
Metabolites 2021, 11(2), 107; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020107 - 12 Feb 2021
Viewed by 543
Abstract
Bacterial genome sequencing has revealed a vast number of novel biosynthetic gene clusters (BGC) with potential to produce bioactive natural products. However, the biosynthesis of secondary metabolites by bacteria is often silenced under laboratory conditions, limiting the controlled expression of natural products. Here [...] Read more.
Bacterial genome sequencing has revealed a vast number of novel biosynthetic gene clusters (BGC) with potential to produce bioactive natural products. However, the biosynthesis of secondary metabolites by bacteria is often silenced under laboratory conditions, limiting the controlled expression of natural products. Here we describe an integrated methodology for the construction and screening of an elicited and pre-fractionated library of marine bacteria. In this pilot study, chemical elicitors were evaluated to mimic the natural environment and to induce the expression of cryptic BGCs in deep-sea bacteria. By integrating high-resolution untargeted metabolomics with cheminformatics analyses, it was possible to visualize, mine, identify and map the chemical and biological space of the elicited bacterial metabolites. The results show that elicited bacterial metabolites correspond to ~45% of the compounds produced under laboratory conditions. In addition, the elicited chemical space is novel (~70% of the elicited compounds) or concentrated in the chemical space of drugs. Fractionation of the crude extracts further evidenced minor compounds (~90% of the collection) and the detection of biological activity. This pilot work pinpoints strategies for constructing and evaluating chemically diverse bacterial natural product libraries towards the identification of novel bacterial metabolites in natural product-based drug discovery pipelines. Full article
(This article belongs to the Special Issue Microbiome and Metabolome)
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Open AccessArticle
Simultaneous Quantitation of Lipid Biomarkers for Inflammatory Bowel Disease Using LC–MS/MS
Metabolites 2021, 11(2), 106; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020106 - 12 Feb 2021
Viewed by 471
Abstract
Eicosanoids are key mediators and regulators of inflammation and oxidative stress that are often used as biomarkers for severity and therapeutic responses in various diseases. We here report a highly sensitive LC-MS/MS method for the simultaneous quantification of at least 66 key eicosanoids [...] Read more.
Eicosanoids are key mediators and regulators of inflammation and oxidative stress that are often used as biomarkers for severity and therapeutic responses in various diseases. We here report a highly sensitive LC-MS/MS method for the simultaneous quantification of at least 66 key eicosanoids in a widely used murine model of colitis. Chromatographic separation was achieved with Shim-Pack XR-ODSIII, 150 × 2.00 mm, 2.2 µm. The mobile phase was operated in gradient conditions and consisted of acetonitrile and 0.1% acetic acid in water with a total flow of 0.37 mL/min. This method is sensitive, with a limit of quantification ranging from 0.01 to 1 ng/mL for the various analytes, has a large dynamic range (200 ng/mL), and a total run time of 25 min. The inter- and intraday accuracy (85–115%), precision (≥85%), and recovery (40–90%) met the acceptance criteria per the US Food and Drug Administration guidelines. This method was successfully applied to evaluate eicosanoid metabolites in mice subjected to colitis versus untreated, healthy control mice. In summary, we developed a highly sensitive and fast LC−MS/MS method that can be used to identify biomarkers for inflammation and potentially help in prognosis of the disease in inflammatory bowel disease (IBD) patients, including the response to therapy. Full article
(This article belongs to the Special Issue MS-Based Drug Metabolism in Cancer Research)
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Open AccessArticle
Elevated Trehalose Levels in C. elegans daf-2 Mutants Increase Stress Resistance, Not Lifespan
Metabolites 2021, 11(2), 105; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020105 - 12 Feb 2021
Viewed by 1314
Abstract
The C. elegans insulin/IGF-1 (insulin-like growth factor 1) signaling mutant daf-2 recapitulates the dauer metabolic signature—a shift towards lipid and carbohydrate accumulation—which may be linked to its longevity and stress resistance phenotypes. Trehalose, a disaccharide of glucose, is highly upregulated in daf‑2 mutants [...] Read more.
The C. elegans insulin/IGF-1 (insulin-like growth factor 1) signaling mutant daf-2 recapitulates the dauer metabolic signature—a shift towards lipid and carbohydrate accumulation—which may be linked to its longevity and stress resistance phenotypes. Trehalose, a disaccharide of glucose, is highly upregulated in daf‑2 mutants and it has been linked to proteome stabilization and protection against heat, cold, desiccation, and hypoxia. Earlier studies suggested that elevated trehalose levels can explain up to 43% of the lifespan extension observed in daf-2 mutants. Here we demonstrate that trehalose accumulation is responsible for increased osmotolerance, and to some degree thermotolerance, rather than longevity in daf-2 mutants. This indicates that particular stress resistance phenotypes can be uncoupled from longevity. Full article
(This article belongs to the Special Issue Caenorhabditis elegans Applied to Metabolism Research)
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Open AccessArticle
Variability of Lipids in Human Milk
Metabolites 2021, 11(2), 104; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020104 - 11 Feb 2021
Viewed by 421
Abstract
Lipids in breastmilk play a critical role in infant growth and development. However, few studies have investigated sources of variability of both high- and low-abundant milk lipids. The objective of our study was to investigate individual and morning–evening differences in the human milk [...] Read more.
Lipids in breastmilk play a critical role in infant growth and development. However, few studies have investigated sources of variability of both high- and low-abundant milk lipids. The objective of our study was to investigate individual and morning–evening differences in the human milk lipidome. In this study, a modified two-phase method (MTBE: Methanol 7:2) was validated for the extraction of lipids from human breastmilk. This method was then applied to samples from a group of 20 healthy women to measure inter- and intra-individual (morning versus evening) variability of the breastmilk lipidome. We report here the levels of 237 lipid species from 13 sub-classes using reversed-phase liquid chromatography mass spectrometry (RP-LCMS) and direct-infusion mass spectrometry (DI-MS). About 85% of lipid species showed stable inter-individual differences across time points. Half of lipid species showed higher concentrations in the evening compared with the morning, with phosphatidylethanolamines (PEs) and triacylglycerols (TAGs) exhibiting the largest changes. In morning and evening samples, the biological variation was greater for diacylglycerols (DAGs) and TAGs compared with phospholipids and sphingolipids, and the variation in DAGs and TAGs was greater in evening samples compared with morning samples. These results demonstrate that variation in the milk lipidome is strongly influenced by individual differences and time of day. Full article
(This article belongs to the Special Issue Metabolomics in Dairy Research)
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Open AccessArticle
Ranking Metabolite Sets by Their Activity Levels
Metabolites 2021, 11(2), 103; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020103 - 11 Feb 2021
Viewed by 767
Abstract
Related metabolites can be grouped into sets in many ways, e.g., by their participation in series of chemical reactions (forming metabolic pathways), or based on fragmentation spectral similarities or shared chemical substructures. Understanding how such metabolite sets change in relation to experimental factors [...] Read more.
Related metabolites can be grouped into sets in many ways, e.g., by their participation in series of chemical reactions (forming metabolic pathways), or based on fragmentation spectral similarities or shared chemical substructures. Understanding how such metabolite sets change in relation to experimental factors can be incredibly useful in the interpretation and understanding of complex metabolomics data sets. However, many of the available tools that are used to perform this analysis are not entirely suitable for the analysis of untargeted metabolomics measurements. Here, we present PALS (Pathway Activity Level Scoring), a Python library, command line tool, and Web application that performs the ranking of significantly changing metabolite sets over different experimental conditions. The main algorithm in PALS is based on the pathway level analysis of gene expression (PLAGE) factorisation method and is denoted as mPLAGE (PLAGE for metabolomics). As an example of an application, PALS is used to analyse metabolites grouped as metabolic pathways and by shared tandem mass spectrometry fragmentation patterns. A comparison of mPLAGE with two other commonly used methods (overrepresentation analysis (ORA) and gene set enrichment analysis (GSEA)) is also given and reveals that mPLAGE is more robust to missing features and noisy data than the alternatives. As further examples, PALS is also applied to human African trypanosomiasis, Rhamnaceae, and American Gut Project data. In addition, normalisation can have a significant impact on pathway analysis results, and PALS offers a framework to further investigate this. PALS is freely available from our project Web site. Full article
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Open AccessArticle
Comprehensive Characterization of Bile Acids in Human Biological Samples and Effect of 4-Week Strawberry Intake on Bile Acid Composition in Human Plasma
Metabolites 2021, 11(2), 99; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020099 - 10 Feb 2021
Viewed by 475
Abstract
Primary bile acids (BAs) and their gut microbial metabolites have a role in regulating human health. Comprehensive characterization of BAs species in human biological samples will aid in understanding the interaction between diet, gut microbiota, and bile acid metabolism. Therefore, we developed a [...] Read more.
Primary bile acids (BAs) and their gut microbial metabolites have a role in regulating human health. Comprehensive characterization of BAs species in human biological samples will aid in understanding the interaction between diet, gut microbiota, and bile acid metabolism. Therefore, we developed a qualitative method using ultra-high performance liquid chromatography (UHPLC) coupled with a quadrupole time-of-flight (Q-TOF) to identify BAs in human plasma, feces, and urine samples. A quantitative method was developed using UHPLC coupled with triple quadrupole (QQQ) and applied to a previous clinical trial conducted by our group to understand the bile acid metabolism in overweight/obese middle-aged adults (n = 34) after four weeks strawberry vs. control intervention. The qualitative study tentatively identified a total of 81 BAs in human biological samples. Several BA glucuronide-conjugates were characterized for the first time in human plasma and/or urine samples. The four-week strawberry intervention significantly reduced plasma concentrations of individual secondary BAs, deoxycholic acid, lithocholic acid and their glycine conjugates, as well as glycoursodeoxycholic acid compared to control (p < 0.05); total glucuronide-, total oxidized-, total dehydroxyl-, total secondary, and total plasma BAs were also lowered compared to control (p < 0.05). The reduced secondary BAs concentrations suggest that regular strawberry intake modulates the microbial metabolism of BAs. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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Open AccessArticle
Characteristics of Black Ginseng (Panax ginseng C.A. Mayer) Production Using Ginseng Stored at Low Temperature after Harvest
Metabolites 2021, 11(2), 98; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020098 - 10 Feb 2021
Viewed by 500
Abstract
Ginseng processing often involves multiple drying and heat treatments. Ginseng is typically processed within one week of harvesting or is stored at low temperatures to prevent spoilage. Black ginseng (BG) is manufactured by repeating the heat treatment and drying process of ginseng several [...] Read more.
Ginseng processing often involves multiple drying and heat treatments. Ginseng is typically processed within one week of harvesting or is stored at low temperatures to prevent spoilage. Black ginseng (BG) is manufactured by repeating the heat treatment and drying process of ginseng several times. We compared the suitability of low-temperature stored ginseng (SG) and harvested ginseng (HG) as the components for black ginseng production. SG and HG were processed into black ginseng and the appearance change, free sugar content, and benzo[a]pyrene (BAP) content were observed. Appearance observations showed the SG to be suitable in terms of quality when heat-treated at a temperature of 95 ℃ or higher. The BAP content of the SG increased significantly as the steaming process was repeated. A maximum BAP concentration of 5.31 ± 1.12 μg/kg was measured in SG steamed from 2 to 5 times, making it unsuitable for processing into BG. SG and HG showed similar trends in the content of sucrose, fructose, and glucose during steaming. This study aimed to facilitate the proper choice of base material to improve the safety of black ginseng by limiting BAP production during processing. Full article
(This article belongs to the Section Frontiers in Metabolomics)
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Open AccessArticle
Untargeted Metabolic Profiling of 4-Fluoro-Furanylfentanyl and Isobutyrylfentanyl in Mouse Hepatocytes and Urine by Means of LC-HRMS
Metabolites 2021, 11(2), 97; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020097 - 10 Feb 2021
Viewed by 418
Abstract
The diffusion of new psychoactive substances (NPS) is highly dynamic and the available substances change over time, resulting in forensic laboratories becoming highly engaged in NPS control. In order to manage NPS diffusion, efficient and innovative legal responses have been provided by several [...] Read more.
The diffusion of new psychoactive substances (NPS) is highly dynamic and the available substances change over time, resulting in forensic laboratories becoming highly engaged in NPS control. In order to manage NPS diffusion, efficient and innovative legal responses have been provided by several nations. Metabolic profiling is also part of the analytical fight against NPS, since it allows to identify the biomarkers of drug intake which are needed for the development of suitable analytical methods in biological samples. We have recently reported the characterization of two new analogs of fentanyl, i.e., 4-fluoro-furanylfentanyl (4F-FUF) and isobutyrylfentanyl (iBF), which were found for the first time in Italy in 2019; 4F-FUF was identified for the first time in Europe and was notified to the European Early Warning System. The goal of this study was the characterization of the main metabolites of both drugs by in vitro and in vivo experiments. To this end, incubation with mouse hepatocytes and intraperitoneal administration to mice were carried out. Samples were analyzed by means of liquid chromatography-high resolution mass spectrometry (LC–HRMS), followed by untargeted data evaluation using Compound Discoverer software with a specific workflow, designed for the identification of the whole metabolic pattern, including unexpected metabolites. Twenty metabolites were putatively annotated for 4F-FUF, with the dihydrodiol derivative appearing as the most abundant, whereas 22 metabolites were found for iBF, which was mainly excreted as nor-isobutyrylfentanyl. N-dealkylation of 4F-FUF dihydrodiol and oxidation to carbonyl metabolites for iBF were also major biotransformations. Despite some differences, in general there was a good agreement between in vitro and in vivo samples. Full article
(This article belongs to the Special Issue New Psychoactive Substances - Metabolism and Metabolomics)
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Open AccessArticle
Use of Clopidogrel and Proton Pump Inhibitors Alone or in Combinations in Persons with Diabetes in Denmark; Potential for CYP2C19 Genotype-Guided Drug Therapy
Metabolites 2021, 11(2), 96; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11020096 - 10 Feb 2021
Viewed by 552
Abstract
Background: Clopidogrel and proton pump inhibitors (PPIs) are among the most used drugs in Denmark for which there exists pharmacogenomics (PGx)-based dosing guidelines and FDA annotations. In this study, we further scrutinized the use of clopidogrel and PPIs when prescriptions were redeemed from [...] Read more.
Background: Clopidogrel and proton pump inhibitors (PPIs) are among the most used drugs in Denmark for which there exists pharmacogenomics (PGx)-based dosing guidelines and FDA annotations. In this study, we further scrutinized the use of clopidogrel and PPIs when prescriptions were redeemed from Danish Pharmacies alone or in combination in the Danish population and among persons with diabetes in Denmark. The focus deals with the potential of applying PGx-guided antiplatelet therapy taking both drug–drug interactions (DDI) and drug–gene interactions (DGI) into account. Methods: The Danish Register of Medicinal Product Statistics was the source to retrieve consumption data. Results: The consumption of PPIs and clopidogrel in terms of prevalence (users/1000 inhabitants) increased over a five-year period by 6.3% to 103.1 (PPIs) and by 41.7% to 22.1 (clopidogrel), respectively. The prevalence of the use of clopidogrel and PPIs in persons with diabetes are 3.8 and 2.1–2.8 times higher compared to the general population. When redeemed in combination, the prevalence increased to 4.7. The most used combination was clopidogrel and pantoprazole. Conclusions: The use of clopidogrel and PPIs either alone or in combination is quite widespread, in particular among the elderly and persons with diabetes. This further supports the emerging need of accessing and accounting for not only DDI but also for applying PGx-guided drug therapy in clinical decision making for antiplatelet therapy with clopidogrel having a particular focus on persons with diabetes and the elderly. Full article
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